JP6653931B2 - Levetiracetam-containing gel oral pharmaceutical composition - Google Patents
Levetiracetam-containing gel oral pharmaceutical composition Download PDFInfo
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- JP6653931B2 JP6653931B2 JP2019525283A JP2019525283A JP6653931B2 JP 6653931 B2 JP6653931 B2 JP 6653931B2 JP 2019525283 A JP2019525283 A JP 2019525283A JP 2019525283 A JP2019525283 A JP 2019525283A JP 6653931 B2 JP6653931 B2 JP 6653931B2
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- 239000008203 oral pharmaceutical composition Substances 0.000 title claims description 18
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- 230000004054 inflammatory process Effects 0.000 description 1
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- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
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- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- HELXLJCILKEWJH-NCGAPWICSA-N rebaudioside A Chemical compound O([C@H]1[C@H](O)[C@@H](CO)O[C@H]([C@@H]1O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)O[C@]12C(=C)C[C@@]3(C1)CC[C@@H]1[C@@](C)(CCC[C@]1([C@@H]3CC2)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O HELXLJCILKEWJH-NCGAPWICSA-N 0.000 description 1
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- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
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- 230000001954 sterilising effect Effects 0.000 description 1
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- 239000000126 substance Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 1
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
- 239000000892 thaumatin Substances 0.000 description 1
- 235000010436 thaumatin Nutrition 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 229940038773 trisodium citrate Drugs 0.000 description 1
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- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
-
- 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
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Neurology (AREA)
- Pain & Pain Management (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Neurosurgery (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は、レベチラセタム（ｌｅｖｅｔｉｒａｃｅｔａｍ）を有効成分として含有するゲル経口投与用医薬組成物に関する。 The present invention relates to a pharmaceutical composition for oral administration of a gel, which contains levetiracetam as an active ingredient.
一回服用量が多い有効成分を製剤化すると、錠剤やカプセル剤では容量が大きくなり、ドライシロップ、散剤又は細粒剤等においても服用量が多くなり服薬し難いという問題が生じる。錠剤の硬度は一般的に５ｋｇｆ以上もあるので非常に硬く、服用時に咽頭上部で反射的な拒否反応が起こる。大多数の患者は、錠剤やカプセル剤の服用に慣れてこれらを飲み込むことができるが、小児や嚥下力が低下した患者にとっては大変飲み込み難い。また、カプセル剤は剤皮が硬く異物感もあり、大きいものは錠剤と同様に飲み込み難い。カプセル剤の問題として、唾液の少ないお年寄りが喉に詰まらせたり、食道に付着したりして薬物による炎症を起こすことも報告されている。散剤等においても用量の増加と共に、口腔内に残留するなど服薬し難くなり、腎障害などにより水分摂取を制限されている患者には服用し難い製剤である。ドライシロップにおいては、用時調製が必要となり煩雑である。 When an active ingredient with a large dose is formulated, a large volume is required for tablets and capsules, and there is a problem that the dose is also large for dry syrups, powders, fine granules and the like, making it difficult to take the drug. Tablets generally have a hardness of 5 kgf or more, so they are very hard, and a reflexive rejection reaction occurs in the upper pharynx during ingestion. Most patients are accustomed to taking tablets and capsules and can swallow them, but it is very difficult for children and patients with reduced swallowing power to swallow. In addition, capsules have a hard coat and a foreign-body sensation, and large capsules are difficult to swallow like tablets. As a problem of capsules, it has also been reported that elderly people with little saliva can cause clogging in the throat or adhere to the esophagus, causing inflammation due to drugs. Even with powders and the like, it is difficult to take the drug, such as remaining in the oral cavity as the dose increases, and it is difficult to take it for patients whose water intake is restricted due to renal disorder or the like. In dry syrup, it is necessary to prepare it before use, which is complicated.
元来、医薬品は食べ物とは異なり、異物感のある医薬品を我慢して服用してきた時代があったが、服用しやすい医薬品の開発が進められてきた。 Originally, medicine was different from food, and there was an era when patients had to endure taking medicine with a foreign-body sensation, but the development of medicines that are easy to take has been promoted.
近年、錠剤の服用しづらさの改良として、口腔内崩壊錠の開発が盛んに行われている。この錠剤は口中で１０〜２０秒で崩壊させて飲み込むものである。しかし、口中で崩壊させると薬物が溶解して、薬物の苦味が出ると飲み難い。そのため苦味のマスクを物理的に行う原薬コーティングや、造粒コーティングで苦味を抑える技術も発展した。しかし、口中でのザラツキや広がりを嫌う患者も居る。 BACKGROUND ART In recent years, development of orally disintegrating tablets has been actively carried out to improve the difficulty of taking tablets. This tablet is disintegrated in the mouth in 10 to 20 seconds and swallowed. However, when disintegrated in the mouth, the drug dissolves, and if the drug becomes bitter, it is difficult to drink. For this reason, a drug substance coating that physically masks bitterness and a technology to suppress bitterness by granulation coating have been developed. However, some patients dislike roughness and spread in the mouth.
一方、医師の指示通りに服薬しない患者の実態が報告されており、残薬が社会問題にもなっている。その調査では処方される薬の種類が多いことから服薬回数を間違えたり、副作用を避けたい患者は服薬量を自らの判断で減らしたり、容量が大きく飲み難い製剤の服薬回数を間引いていることも報告されている。 On the other hand, it has been reported that patients do not take medicines as instructed by doctors, and residual medicine has become a social problem. According to the survey, because there are many types of prescribed drugs, patients may take the wrong number of doses, patients who want to avoid side effects may reduce their doses at their own discretion, and may reduce the number of doses of large-capacity drugs that are difficult to drink. It has been reported.
このような問題は、服薬し難い製剤を提供してきた製薬企業の問題でもある。大多数の患者が服用できれば「それで良し」とすることより、どのような患者でも服用しやすい剤形を提供することが求められる時代になった。 Such problems are also problems of pharmaceutical companies that have provided difficult-to-dose formulations. The era has come to be demanded to provide a dosage form that is easy for any patient to take, rather than saying “that's good” if most patients can take it.
一方、抗てんかん薬の有効成分として、レベチラセタムが知られている（非特許文献１）。レベチラセタムを含有する製剤として様々な剤形が知られているが（特許文献１〜４）、必ずしも満足すべきものでなかった。また、レベチラセタムを含有するゲル状の製剤はこれまでに知られていなかった。 On the other hand, levetiracetam is known as an active ingredient of an antiepileptic drug (Non-Patent Document 1). Various dosage forms are known as preparations containing levetiracetam (Patent Documents 1 to 4), but they have not always been satisfactory. Further, a gel-form preparation containing levetiracetam has not been known so far.
本発明の課題は、（１）一回の服用量が多いレベチラセタムの苦味が低減され、（２）服用感が良く、及び／又は（３）溶出性が良好な、経口医薬組成物を提供することである。
本発明者らは、下記課題解決手段が本発明の課題を解決しうることを見出し、さらに鋭意検討を重ねて本発明を完成するに至った。An object of the present invention is to provide an oral pharmaceutical composition which (1) reduces the bitterness of levetiracetam taken in a single dose, (2) has a good feeling upon taking, and / or (3) has good dissolution. That is.
The present inventors have found that the following means for solving the problems can solve the problems of the present invention, and have further diligently studied to complete the present invention.
本発明は、以下の[１]〜[１５]に関する。 The present invention relates to the following [1] to [15].
[１]有効成分であるレベチラセタム、並びにゲル化剤、甘味剤及びｐＨ調整剤を含有し、ｐＨが約６〜７程度であるゲル経口医薬組成物。
[２]ゲル化剤としてカラギーナン及びカロブビーンガムを含み、ゼリー状であることを特徴とする、前記[１]に記載の組成物。
[３]ゲル化剤としてキサンタンガムを含み、粘稠状であることを特徴とする、前記[１]に記載の組成物。
[４]ゲル化剤としてグリセリン及びプロピレングリコールを含む、前記[１]〜[３]のいずれかに記載の組成物。
[５]ゲル破断強度が１０００〜３００００Ｎ／ｍ２である、前記[１]、[２]又は[４]に記載の組成物。
[６]カラギーナンが、組成物全体に対して０．１〜１質量％である、前記[２]、[４]又は[５]に記載の組成物。
[７]カロブビーンガムが、組成物全体に対して０．１〜０．５質量％である、前記[２]、[４]、[５]又は[６]に記載の組成物。
[８]ずり速度Ｄ１５０のときの粘度が１０〜１００ｍＰａ・Ｓである、前記[１]、[３]又は[４]に記載の組成物。
[９]キサンタンガムが、組成物全体に対して０．０１〜１質量％である、前記[３]、[４]又は[８]に記載の組成物。
[１０]グリセリンが、組成物全体に対して５〜３０質量％である、前記[４]〜[９]のいずれかに記載の組成物。
[１１]プロピレングリコールが、組成物全体に対して５〜３０質量％である、前記[４]〜[１０]のいずれかに記載の組成物。
[１２]甘味剤が、スクラロース又はアセスルファムカリウムである、前記[１]〜[１１]のいずれかに記載の組成物。
[１３]スクラロースが、組成物全体に対して０．０１〜２質量％である、前記[１２]に記載の組成物。
[１４]アセスルファムカリウムが、組成物全体に対して０．１〜１質量％である、前記[１２]又は[１３]に記載の組成物。
[１５]ｐＨ調整剤がリン酸水素二ナトリウム及び／又はクエン酸である、前記[１]〜[１４]のいずれかに記載の組成物。[1] A gel oral pharmaceutical composition containing an active ingredient, levetiracetam, and a gelling agent, a sweetening agent and a pH adjuster, and having a pH of about 6 to 7.
[2] The composition according to the above [1], wherein the composition comprises carrageenan and carob bean gum as gelling agents and is in a jelly state.
[3] The composition according to [1], wherein the composition comprises xanthan gum as a gelling agent, and is in a viscous state.
[4] The composition according to any of [1] to [3] above, comprising glycerin and propylene glycol as the gelling agent.
[5] The composition according to the above [1], [2] or [4], which has a gel breaking strength of 1000 to 30000 N / m 2 .
[6] The composition according to the above [2], [4] or [5], wherein carrageenan is 0.1 to 1% by mass based on the whole composition.
[7] The composition according to [2], [4], [5] or [6], wherein the carob bean gum is 0.1 to 0.5% by mass based on the whole composition.
[8] The composition according to [1], [3] or [4], wherein the viscosity at a shear rate D150 is 10 to 100 mPa · S.
[9] The composition according to the above [3], [4] or [8], wherein the amount of xanthan gum is 0.01 to 1% by mass based on the whole composition.
[10] The composition according to any of the above [4] to [9], wherein glycerin is 5 to 30% by mass based on the whole composition.
[11] The composition according to any of [4] to [10], wherein propylene glycol is 5 to 30% by mass based on the whole composition.
[12] The composition according to any of [1] to [11], wherein the sweetener is sucralose or acesulfame potassium.
[13] The composition according to the above [12], wherein sucralose is 0.01 to 2% by mass based on the whole composition.
[14] The composition according to the above [12] or [13], wherein acesulfame potassium is 0.1 to 1% by mass relative to the whole composition.
[15] The composition according to any of the above [1] to [14], wherein the pH adjuster is disodium hydrogen phosphate and / or citric acid.
本発明によれば、（１）一回の服用量が多いにもかかわらずレベチラセタムの苦味が低減され、（２）口当たりが良く、飲み込みやすい柔らかさや粘性で、食べ物のような感覚で服用でき、（３）コクがあり、飲み応えがあり、飲み物のような感覚で服用でき、及び／又は（４）溶出性が良好な、経口医薬組成物を提供することができ、理想的である。
てんかん発作を抑えるレベチラセタムは特有の苦みがある上に服用量が多いことから、服用し難い製剤を我慢して服用している患者も居る。このような患者に、味や食感が良く、服用しやすい剤形（ゼリー状又は粘稠状）のゲル製剤を提供すれば、患者は風味、旨味、コク、歯ごたえ、又は舌ざわりを感じながら、安心して楽にレベチラセタムを服用できる。食べ物や飲み物のような感覚で服用できる薬学的製剤の提供は、患者の服薬遵守率やＱＯＬの向上にも繋がる。特に、病気と長期間（場合によっては生涯）服用の二重の苦しみ、又は、更に服用し難いという三重の苦しみを格段に低減することができる。本発明の経口医薬組成物は、食べ物のような感覚で服用できる製剤であるので、子供、老人又は嚥下困難者もレベチラセタム含有製剤を飲み込みやすい。適度な弾力を有する本発明の経口医薬組成物は歯ごたえを有し、食感が良く、他の製剤との差別化や服薬のアクセントになるので、薬の嫌いな小児はもとより、錠剤やカプセルが服用できる成人でも、飲み忘れを防ぐ効果がある。
また、その結果、患者に対する服薬アドヒアランスの向上だけでなく、拒薬や残薬を減らす製剤的な工夫が、残薬が年間約１０００億円とも試算されている大変な無駄を少しでも減らし、残薬の社会問題に対しても解決の一助となる。According to the present invention, (1) the bitterness of levetiracetam is reduced in spite of a large dose, (2) it is soft, sticky, and easy to swallow, and can be taken with a food-like sensation, (3) It is ideal because it can provide an oral pharmaceutical composition that is rich, responsive to drinking, can be taken with a drink-like sensation, and / or (4) has good dissolution.
Levetiracetam, which suppresses epileptic seizures, has its own specific bitterness and high dose, so some patients take patience with difficult-to-take formulations. If such a patient is provided with a gel preparation in a dosage form (jelly-like or viscous) that has a good taste and texture and is easy to take, the patient can feel flavor, umami, full body, chewy, or tongue, You can easily take Levetiracetam with ease. Providing a pharmaceutical preparation that can be taken with the sensation of food and drink will also lead to an improvement in patient compliance and QOL. In particular, it is possible to remarkably reduce the double suffering of illness and long-term (or in some cases, life-long) taking, or the triple suffering of being more difficult to take. Since the oral pharmaceutical composition of the present invention is a preparation that can be taken with a food-like sensation, children, the elderly, or those who have difficulty swallowing can easily swallow the preparation containing levetiracetam. The oral pharmaceutical composition of the present invention having a moderate elasticity has a chewy texture, has a good texture, and can be differentiated from other preparations and accentuated in taking medicine, so that not only children who dislike the medicine, but also tablets and capsules can be used. Even adults who can take it are effective in preventing forgetting to drink.
In addition, as a result, not only the improvement of adherence to patients, but also the formulation of pharmaceuticals to reduce rejection and residual drugs has reduced the amount of waste that is estimated to be about 100 billion yen per year. It also helps to solve social problems of medicine.
〔レベチラセタム含有ゲル経口医薬組成物〕
本発明は、有効成分であるレベチラセタム、並びにゲル化剤、甘味剤及びｐＨ調整剤を含有し、ｐＨが約６〜７程度であるゲル経口医薬組成物（以下、本発明の組成物ともいう。）を提供することができる。(Levetiracetam-containing gel oral pharmaceutical composition)
The present invention contains an active ingredient, levetiracetam, and a gel oral pharmaceutical composition containing a gelling agent, a sweetener and a pH adjuster and having a pH of about 6 to 7 (hereinafter also referred to as the composition of the present invention). ) Can be provided.
（有効成分レベチラセタム）
有効成分であるレベチラセタムの構造式を以下に示す。
The structural formula of the active ingredient levetiracetam is shown below.
レベチラセタムは、通常、化学式：（２Ｓ）−２−（２−Ｏｘｏｐｙｒｒｏｌｉｄｉｎｅ−１−ｙｌ）ｂｕｔｙｒａｍｉｄｅ、分子式：Ｃ８Ｈ１４Ｎ２Ｏ２、分子量：１７０．２１で、融点：１１５〜１１９℃の白色〜淡灰白色の結晶性の粉末である。Levetiracetam is usually white with a chemical formula: (2S) -2- (2-Oxopyrrolidine-1-yl) butyramide, a molecular formula: C 8 H 14 N 2 O 2 , a molecular weight: 170.21, and a melting point of 115 to 119 ° C. ~ Light grayish white crystalline powder.
レベチラセタムは、例えばてんかん患者の部分発作（二次性全般化発作を含む）、他の抗てんかん薬で十分な効果が認められないてんかん患者の強直間代発作に対する抗てんかん薬との併用療法に用いられてもよい。 Levetiracetam is used in combination therapy with antiepileptic drugs for partial seizures (including secondary generalized seizures) in epileptic patients and tonic-clonic seizures in epileptic patients who have not been sufficiently effective with other antiepileptic drugs You may be.
本発明の組成物におけるレベチラセタムの含有量（濃度）は、特に限定されるものではないが、例えば、組成物全体に対して０．１〜５０．０質量％、０．１〜３５．０質量％、又は０．３〜２０．０質量％であってもよい。レベチラセタムは、例えば、遊離塩基、結晶多形体（例えば、無水物結晶、無水物Ｂ形結晶等）、水和物、薬理学的に許容される塩（例えば、酸付加塩等）等のいずれの形態であってもよい。公知の方法によって、レベチラセタムを製造することができ、また、例えばイーケプラ（登録商標）等の市販品を購入することでレベチラセタムを入手することができる。 Although the content (concentration) of levetiracetam in the composition of the present invention is not particularly limited, for example, 0.1 to 50.0% by mass, 0.1 to 35.0% by mass based on the whole composition. %, Or 0.3 to 20.0% by mass. Levetiracetam is, for example, any of free base, crystalline polymorphs (eg, anhydrous crystals, anhydrous Form B crystals, etc.), hydrates, pharmacologically acceptable salts (eg, acid addition salts, etc.), etc. It may be in a form. Levetiracetam can be produced by a known method, and levetiracetam can be obtained by purchasing a commercial product such as Ekepra (registered trademark).
成人に対して、通常１日１０００ｍｇのレベチラセタムを１日２回に分けて経口投与する。なお、症状により１日３０００ｍｇを超えない範囲で適宜増減してもよいが、増量は２週間以上の間隔をあけて１日用量として１０００ｍｇ以下ずつ行うことが好ましい。また、４歳以上の小児に対しては、通常１日２０ｍｇ／ｋｇを１日２回に分けて服用してもよい。なお、症状により１日６０ｍｇ／ｋｇを超えない範囲で適宜増減してもよいが、増量は２週間以上の間隔をあけて１日用量として２０ｍｇ/ｋｇ以下ずつ行うことが好ましい。ただし、体重５０ｋｇ以上の小児では、成人と同じ用法用量を用いてよい。 For adults, 1000 mg of levetiracetam is usually orally administered twice a day to an adult. The dose may be appropriately increased or decreased within a range not exceeding 3000 mg per day depending on symptoms, but it is preferable to increase the dose at intervals of 2 weeks or more by 1000 mg or less as a daily dose. For children 4 years and older, the usual dosage of 20 mg / kg per day may be divided and taken twice a day. The dose may be appropriately increased or decreased within a range not exceeding 60 mg / kg per day depending on symptoms, but it is preferable to increase the dose at intervals of 2 weeks or more by 20 mg / kg or less as a daily dose. However, for children weighing 50 kg or more, the same dosage as for adults may be used.
（ゲル化剤）
本発明の組成物におけるゲル化剤として、カラギーナン（ιカラギーナン、κカラギーナン等）、カロブビーンガム、キサンタンガム、グリセリン、若しくはプロピレングリコール、又はこれらの２種以上の混合物が挙げられる。中でも、（１）カラギーナン（ιカラギーナン、κカラギーナン等）及びカロブビーンガム、（２）キサンタンガム、（３）カラギーナン（ιカラギーナン、κカラギーナン等）、カロブビーンガム、グリセリン及びプロピレングリコール、（４）キサンタンガム、グリセリン及びプロピレングリコール等の組み合わせが好ましい。
追加のゲル化剤として、さらに、例えば、アラビアゴム、アラビアゴム末、アルギン酸、アルギン酸ナトリウム、アルギン酸プロピレングリコールエステル、カラヤガム末、カルメロースナトリウム、結晶セルロース・カルメロースナトリウム、カードラン、カンテン、カンテン末、グァーガム、サイリウムシードガム、ジェランガム、精製ゼラチン、ゼラチン、タマリンド種子ガム、タラガム、トラガント、トラガント末、ファーセルラン、プルラン、ペクチン等を使用してもよい。
本発明の組成物におけるゲル化剤の配合割合は、本発明の効果を妨げない限り特に限定されないが、例えば組成物全体に対して０．０１〜３０質量％、０．１〜１質量％、０．１〜０．５質量％、又は５〜３０質量％であってもよい。当該配合割合の設定によって、特に優れた本発明の効果（中でも、溶出性が良好であるという効果）が得られる。
本発明の組成物におけるグリセリンの配合割合は、組成物全体に対して５〜３０質量％であることが好ましく、１５〜３０質量％であることがさらに好ましい。当該配合割合の設定によって、特に優れた本発明の効果（中でも、溶出性が良好であるという効果）が得られる。
本発明の組成物におけるプロピレングリコールの配合割合は、組成物全体に対して５〜３０質量％であることが好ましく、１０〜２５質量％であることがさらに好ましい。当該配合割合の設定によって、特に優れた本発明の効果（中でも、溶出性が良好であるという効果）が得られる。
本発明の組成物が、グリセリン及びプロピレングリコールを含有する場合、それらの質量比（グリセリン：プロピレングリコール）は、１：（０．１〜１）であることが好ましく、１：（０．３〜１）であることがさらに好ましく、１：（０．５〜１）であることがより好ましい。当該比率に設定することで、特に優れた本発明の効果が得られる。(Gelling agent)
Examples of the gelling agent in the composition of the present invention include carrageenan (ι-carrageenan, κ-carrageenan, etc.), carob bean gum, xanthan gum, glycerin, or propylene glycol, or a mixture of two or more thereof. Among them, (1) carrageenan (ι carrageenan, κ carrageenan, etc.) and carob bean gum, (2) xanthan gum, (3) carrageenan (ι carrageenan, κ carrageenan, etc.), carob bean gum, glycerin and propylene glycol, (4) xanthan gum, glycerin and propylene A combination such as glycol is preferred.
Additional gelling agents include, for example, gum arabic, gum arabic, alginic acid, sodium alginate, propylene glycol alginate, karaya gum powder, carmellose sodium, crystalline cellulose carmellose sodium, curdlan, agar, agar powder, Guar gum, psyllium seed gum, gellan gum, purified gelatin, gelatin, tamarind seed gum, cod gum, tragacanth, tragacanth powder, furcellane, pullulan, pectin, and the like may be used.
The mixing ratio of the gelling agent in the composition of the present invention is not particularly limited as long as the effect of the present invention is not impaired. For example, 0.01 to 30% by mass, 0.1 to 1% by mass, It may be 0.1 to 0.5% by mass, or 5 to 30% by mass. By setting the blending ratio, a particularly excellent effect of the present invention (among others, an effect of good dissolution) can be obtained.
The blending ratio of glycerin in the composition of the present invention is preferably 5 to 30% by mass, and more preferably 15 to 30% by mass, based on the whole composition. By setting the blending ratio, a particularly excellent effect of the present invention (among others, an effect of good dissolution) can be obtained.
The blending ratio of propylene glycol in the composition of the present invention is preferably 5 to 30% by mass, and more preferably 10 to 25% by mass, based on the whole composition. By setting the blending ratio, a particularly excellent effect of the present invention (among others, an effect of good dissolution) can be obtained.
When the composition of the present invention contains glycerin and propylene glycol, the mass ratio (glycerin: propylene glycol) thereof is preferably 1: (0.1 to 1), and 1: (0.3 to 1). 1) is more preferable, and the ratio is more preferably 1: (0.5 to 1). By setting the ratio, the excellent effect of the present invention can be obtained.
（ゼリー状）
本発明の組成物の一態様において、本発明の組成物はゲル化剤としてカラギーナン及びカロブビーンガムを含み、ゼリー状であることが好ましい。このような本発明の組成物を、以下、本発明のゼリー状ゲル経口医薬組成物ともいう。本発明のゼリー状ゲル経口医薬組成物は、口当たりが良く、飲み込みやすい柔らかさや粘性で、食べ物のような感覚で服用することが可能である。
本発明のゼリー状ゲル経口医薬組成物におけるカラギーナン（ιカラギーナン、κカラギーナン等）の配合割合は、組成物全体に対して０．１〜１質量％であることが好ましい。当該配合割合の設定によって、特に優れた本発明の効果（中でも、飲み込みやすい柔らかさや粘性であるという効果）が得られる。また、カラギーナンとしては、ιカラギーナン及びκカラギーナンの組み合わせが好ましい。カラギーナンの配合割合は、本発明の効果を妨げない限り特に限定されないが、ιカラギーナンについては、例えば組成物全体に対して０．０１〜１質量％、０．１〜０．７質量％、０．１〜０．６質量％であってもよく、κカラギーナンについては、例えば組成物全体に対して０．０１〜１質量％、０．１〜１質量％、０．１〜０．５質量％であってもよい。このような組み合わせ又は当該配合割合の設定によって、特に優れた本発明の効果（中でも、飲み込みやすい柔らかさや粘性であるという効果）が得られる。
本発明の組成物が、ιカラギーナン及びκカラギーナンを含有する場合、それらの質量比（ιカラギーナン：κカラギーナン）は、１：（０．１〜１）であることが好ましく、１：（０．３〜１）であることが好ましい。当該比率に設定することで、特に優れた本発明の効果が得られる。
本発明のゼリー状ゲル経口医薬組成物におけるカロブビーンガムの配合割合は、組成物全体に対して０．１〜０．５質量％であることが好ましく、０．１〜０．２質量％がさらに好ましい。当該配合割合の設定によって、特に優れた本発明の効果（中でも、飲み込みやすい柔らかさや粘性であるという効果）が得られる。(Jelly-like)
In one embodiment of the composition of the present invention, the composition of the present invention contains carrageenan and carob bean gum as gelling agents, and is preferably in a jelly state. Hereinafter, such a composition of the present invention is also referred to as a jelly gel oral pharmaceutical composition of the present invention. The oral jelly gel pharmaceutical composition of the present invention has a good mouthfeel, is soft and easy to swallow, and can be taken with a food-like sensation.
The compounding ratio of carrageenan (ι-carrageenan, κ-carrageenan, etc.) in the jelly gel oral pharmaceutical composition of the present invention is preferably 0.1 to 1% by mass based on the whole composition. By setting the mixing ratio, particularly excellent effects of the present invention (among others, effects of softness and viscosity that are easy to swallow) can be obtained. As the carrageenan, a combination of l-carrageenan and κ-carrageenan is preferable. The mixing ratio of carrageenan is not particularly limited as long as the effects of the present invention are not hindered. However, for carrageenan, for example, 0.01 to 1% by mass, 0.1 to 0.7% by mass, Κ carrageenan, for example, 0.01 to 1% by mass, 0.1 to 1% by mass, 0.1 to 0.5% by mass based on the whole composition. %. By setting such a combination or the mixing ratio, particularly excellent effects of the present invention (among others, effects of softness and viscosity that are easy to swallow) can be obtained.
When the composition of the present invention contains ι-carrageenan and κ-carrageenan, their mass ratio (ι-carrageenan: κ-carrageenan) is preferably 1: (0.1 to 1), and 1: (0.1 to 0.1). 3-1) is preferable. By setting the ratio, the excellent effect of the present invention can be obtained.
The mixing ratio of carob bean gum in the jelly gel oral pharmaceutical composition of the present invention is preferably 0.1 to 0.5% by mass, more preferably 0.1 to 0.2% by mass, based on the whole composition. . By setting the mixing ratio, particularly excellent effects of the present invention (among others, effects of softness and viscosity that are easy to swallow) can be obtained.
本発明のゼリー状ゲル経口医薬組成物は、そのゲル破断強度又はその最大値が１０００〜３００００Ｎ／ｍ２であることが好ましい。ゲル破断強度の測定は、ゲル破断強度測定機器を用いて、直径５ｍｍステンレス製のプランジャ速度６０ｍｍ／ｍｉｎの条件下で、行ってもよい。ゲル破断強度測定機器として、例えば島津製作所社製ＥＺＴｅｓｔを用いてもよい。The oral pharmaceutical composition for jelly gel of the present invention preferably has a gel breaking strength or a maximum value of 1,000 to 30,000 N / m 2 . The measurement of the gel breaking strength may be performed using a gel breaking strength measuring instrument under the condition of a stainless steel plunger having a diameter of 5 mm and a plunger speed of 60 mm / min. As the gel breaking strength measuring instrument, for example, EZTest manufactured by Shimadzu Corporation may be used.
（粘稠状）
本発明の組成物の一態様において、本発明の組成物はゲル化剤としてキサンタンガムを含み、粘稠状であることが好ましい。このような本発明の組成物を、以下、本発明の粘稠状ゲル経口医薬組成物ともいう。
本発明の粘稠状ゲル経口医薬組成物におけるキサンタンガムの配合割合は、組成物全体に対して０．０１〜１質量％であることが好ましい。当該配合割合の設定によって、特に優れた本発明の効果（中でも、とろみがあるという効果）が得られる。
本発明の粘稠状ゲル経口医薬組成物は、例えばとろみがあり、コクがあり、飲み応えがあり、飲み物のような感覚で服用することが可能である。(Viscous)
In one embodiment of the composition of the present invention, the composition of the present invention contains xanthan gum as a gelling agent and is preferably viscous. Hereinafter, such a composition of the present invention is also referred to as a viscous gel oral pharmaceutical composition of the present invention.
It is preferable that the mixing ratio of xanthan gum in the viscous gel oral pharmaceutical composition of the present invention is 0.01 to 1% by mass based on the whole composition. By setting the mixing ratio, particularly excellent effects of the present invention (among others, an effect of thickening) can be obtained.
The viscous gel oral pharmaceutical composition of the present invention is, for example, thick, rich, responsive, and can be taken with a drink-like sensation.
本発明の粘稠状ゲル経口医薬組成物は、非ニュートン流体であることが好ましく、例えば、Ｅ形（コーン・プレートタイプ）粘度計を用いて、測定温度２０℃条件下で、ずり速度Ｄ１５０のとき１０〜１００ｍＰａ・Ｓであることが好ましい。Ｅ形（コーン・プレートタイプ）粘度計として、例えばＴｏｋｉｍｅｃ社製ＴＶ２０を用いてもよい。 The oral viscous gel pharmaceutical composition of the present invention is preferably a non-Newtonian fluid. For example, using an E-type (cone-plate type) viscometer at a measurement temperature of 20 ° C., a shear rate of D150 is obtained. In this case, the pressure is preferably 10 to 100 mPa · S. As the E-type (cone / plate type) viscometer, for example, TV20 manufactured by Tokimec may be used.
（甘味剤）
本発明の組成物における甘味剤としては、例えば、スクラロース、アセスルファムカリウム、アスパルテーム、果糖ブドウ糖液糖、還元麦芽糖水アメ、粉末還元麦芽糖水アメ、サッカリン、サッカリンナトリウム、ステビア、ソーマチン、エリスリトール、ソルビトール、ソルビトール液、乳糖、ハチミツ、キシリトール、グリセリン、濃グリセリン、マルチトール、若しくはマルチトール液等又はこれらの２種以上の混合物が挙げられ、好ましくは、スクラロース、アセスルファムカリウム、若しくは還元麦芽糖水アメ又はこれらの２種以上の混合物が挙げられる。
本発明の組成物における甘味剤の配合割合は、本発明の効果を妨げない限り特に限定されないが、例えば組成物全体に対して０．０１〜３０質量％、０．１〜１質量％、又は０．１〜０．５質量％であってもよい。当該配合割合の設定によって、特に優れた本発明の効果（中でも、苦味が低減されるという効果）が得られる。
本発明の組成物におけるスクラロースの配合割合は、組成物全体に対して０．０１〜２質量％であることが好ましい。当該配合割合の設定によって、特に優れた本発明の効果（中でも、苦味が低減されるという効果）が得られる。
本発明の組成物におけるアセスルファムカリウムの配合割合は、組成物全体に対して０．１〜１質量％であることが好ましい。当該配合割合の設定によって、特に優れた本発明の効果（中でも、苦味が低減されるという効果）が得られる。(Sweetener)
As the sweetener in the composition of the present invention, for example, sucralose, acesulfame potassium, aspartame, fructose dextrose liquid sugar, reduced maltose water candy, powdered reduced maltose water candy, saccharin, saccharin sodium, stevia, thaumatin, erythritol, sorbitol, sorbitol solution , Lactose, honey, xylitol, glycerin, concentrated glycerin, maltitol, maltitol solution or a mixture of two or more thereof, preferably sucralose, acesulfame potassium, or reduced maltose aqueous candy or two of these A mixture of the above is mentioned.
The blending ratio of the sweetener in the composition of the present invention is not particularly limited as long as the effect of the present invention is not impaired. For example, 0.01 to 30% by mass, 0.1 to 1% by mass, or It may be 0.1 to 0.5% by mass. By setting the mixing ratio, particularly excellent effects of the present invention (among others, an effect of reducing bitterness) can be obtained.
The blending ratio of sucralose in the composition of the present invention is preferably 0.01 to 2% by mass based on the whole composition. By setting the mixing ratio, particularly excellent effects of the present invention (among others, an effect of reducing bitterness) can be obtained.
The compounding ratio of acesulfame potassium in the composition of the present invention is preferably 0.1 to 1% by mass based on the whole composition. By setting the mixing ratio, particularly excellent effects of the present invention (among others, an effect of reducing bitterness) can be obtained.
（ｐＨ）
本発明の組成物は、ｐＨ約６〜７程度であることが好ましい。ｐＨ約６〜７程度とは、四捨五入してｐＨ６〜７となるｐＨ値、すなわちｐＨ値５．５以上７．５未満、切り上げてｐＨ６〜７となるｐＨ値、すなわちｐＨ値５．０超７.０以下、及び切り捨ててｐＨ６〜７となるｐＨ値、すなわちｐＨ値６．０以上８．０未満のいずれかのことをいう。すなわち、本発明の組成物は、ｐＨ５.０超８．０未満であることが好ましい。中でもｐＨ約６〜７程度とは、四捨五入してｐＨ６〜７となるｐＨ値、すなわちｐＨ５．５以上７．５未満であることが好ましい。当該範囲から著しく離れたｐＨ値である場合には、本発明の課題が解決できない。(PH)
The composition of the present invention preferably has a pH of about 6 to 7. A pH value of about 6 to 7 means a pH value at which the value is rounded to pH 6 to 7, that is, a pH value of 5.5 or more and less than 7.5, and a pH value at which the value is rounded up to pH 6 to 7, that is, a pH value of more than 5.0 0.0 or less, and any pH value that is rounded down to pH 6 to 7, that is, any one of a pH value of 6.0 or more and less than 8.0. That is, the composition of the present invention preferably has a pH of more than 5.0 and less than 8.0. Above all, the pH value of about 6 to 7 is preferably a pH value at which pH is rounded to 6 to 7, that is, a pH value of 5.5 or more and less than 7.5. If the pH value is significantly different from the above range, the problem of the present invention cannot be solved.
本発明の組成物は、ｐＨ調整剤を含有することにより、そのｐＨを調整することができる。ｐＨ調整剤として、クエン酸塩若しくはその水和物、リンゴ酸塩若しくはその水和物、リン酸塩若しくはその水和物及びエデト酸塩若しくはその水和物、乳酸塩若しくはその水和物等の塩基性緩衝剤、並びに／又は有機酸（例えば、酢酸、トリフルオロ酢酸、ギ酸、プロピオン酸、フマル酸、マレイン酸、コハク酸、酒石酸、Ｄ−酒石酸、クエン酸、ＤＬ−リンゴ酸、乳酸、シュウ酸、安息香酸、ベシル酸、アスコルビン酸、メタンスルホン酸、エタンスルホン酸、ベンゼンスルホン酸、トルエンスルホン酸、エデト酸等）、無機酸（例えば、塩酸、リン酸、臭化水素酸、沃化水素酸、硝酸、硫酸等）等の酸類若しくはその塩が挙げられる。 The composition of the present invention can adjust its pH by containing a pH adjuster. pH adjusters such as citrate or hydrate thereof, malate or hydrate thereof, phosphate or hydrate thereof and edetate or hydrate thereof, lactate or hydrate thereof, etc. Basic buffers and / or organic acids such as acetic acid, trifluoroacetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, D-tartaric acid, citric acid, DL-malic acid, lactic acid, oxalate Acid, benzoic acid, besylic acid, ascorbic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, edetic acid, etc.), inorganic acids (for example, hydrochloric acid, phosphoric acid, hydrobromic acid, hydrogen iodide) Acids, nitric acid, sulfuric acid, etc.) and salts thereof.
前記塩は、薬理学的に許容される塩であれば、特に限定されず、例えば、薬理学的に許容される金属塩、アンモニウム塩、有機アミン付加塩、アミノ酸付加塩等が挙げられる。前記薬理学的に許容される金属塩としては、特に限定されず、例えば、ナトリウム塩、カリウム塩等のアルカリ金属塩；例えばカルシウム塩、マグネシウム塩等のアルカリ土類金属塩；アルミニウム塩、亜鉛塩等が挙げられる。薬理学的に許容される有機アミン付加塩としては、特に限定されず、例えば、モルホリン、ピペリジン等の付加塩が挙げられる。薬理学的に許容されるアミノ酸付加塩としては、特に限定されず、例えば、リジン、グリシン、フェニルアラニン等の付加塩等が挙げられる。これらの塩は、無水物又は水和物のいずれであってもよい。 The salt is not particularly limited as long as it is a pharmacologically acceptable salt, and includes, for example, pharmacologically acceptable metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like. The pharmacologically acceptable metal salt is not particularly limited and includes, for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; aluminum salt and zinc salt And the like. The pharmacologically acceptable organic amine addition salt is not particularly limited, and examples thereof include addition salts such as morpholine and piperidine. The pharmacologically acceptable amino acid addition salt is not particularly limited, and includes, for example, addition salts of lysine, glycine, phenylalanine and the like. These salts may be either anhydrous or hydrated.
前記クエン酸塩又はその水和物としては、特に限定されず、例えば、クエン酸ナトリウム、クエン酸二ナトリウム等が挙げられる。前記リンゴ酸塩又はその水和物としては、特に限定されず、例えば、ＤＬ−リンゴ酸ナトリウム等が挙げられる。リン酸塩又はその水和物としては、特に限定されず、例えば、リン酸三ナトリウム、リン酸水素二ナトリウム、リン酸水素二カリウム等が挙げられる。エデト酸塩又はその水和物としては、特に限定されず、例えば、エデト酸四ナトリウム等が挙げられる。乳酸塩又はその水和物としては、特に限定されず、例えば、乳酸ナトリウム等が挙げられる。特に好適には、リン酸水素二ナトリウムが挙げられる。これらの塩基性緩衝剤は、１種単独で用いてもよく、２種以上を混合して用いてもよい。 The citrate or a hydrate thereof is not particularly limited, and examples thereof include sodium citrate and disodium citrate. The malate or a hydrate thereof is not particularly limited, and examples include DL-sodium malate. The phosphate or a hydrate thereof is not particularly limited, and examples thereof include trisodium phosphate, disodium hydrogen phosphate, and dipotassium hydrogen phosphate. The edetate or its hydrate is not particularly limited, and includes, for example, tetrasodium edetate and the like. Lactate or a hydrate thereof is not particularly limited, and examples thereof include sodium lactate. Particularly preferred is disodium hydrogen phosphate. These basic buffers may be used alone or in a combination of two or more.
前記した酸類のうち、塩酸、クエン酸、ＤＬ−リンゴ酸、リン酸、エデト酸、リン酸二水素カリウム、リン酸二水素ナトリウム及びエデト酸二ナトリウムが好適に挙げられ、特に好適にはクエン酸が挙げられる。これらの酸類は、１種単独で用いてもよく、２種以上を混合して用いてもよい。 Among the above-mentioned acids, hydrochloric acid, citric acid, DL-malic acid, phosphoric acid, edetic acid, potassium dihydrogen phosphate, sodium dihydrogen phosphate and disodium edetate are preferred, and citric acid is particularly preferred. Is mentioned. These acids may be used alone or as a mixture of two or more.
前記塩基性緩衝剤と酸類とを組み合わせて用いる場合、クエン酸ナトリウム、クエン酸二ナトリウム、クエン酸三ナトリウム、ＤＬ−リンゴ酸ナトリウム、リン酸三ナトリウム、リン酸水素二ナトリウム、リン酸水素二カリウム及びエデト酸四ナトリウムからなる群より選ばれる１以上の塩基性緩衝剤と、塩酸、クエン酸、ＤＬ−リンゴ酸、リン酸、エデト酸、リン酸二水素カリウム、リン酸二水素ナトリウム及びエデト酸二ナトリウムからなる群より選ばれる１以上の酸類との組み合わせが好ましく、リン酸水素二ナトリウムとクエン酸との組み合わせがより好ましい。 When the basic buffer and an acid are used in combination, sodium citrate, disodium citrate, trisodium citrate, DL-sodium malate, trisodium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate And one or more basic buffers selected from the group consisting of and sodium edetate, hydrochloric acid, citric acid, DL-malic acid, phosphoric acid, edetic acid, potassium dihydrogen phosphate, sodium dihydrogen phosphate and edetate A combination with one or more acids selected from the group consisting of disodium is preferred, and a combination of disodium hydrogen phosphate and citric acid is more preferred.
本発明の組成物における塩基性緩衝剤のモル濃度は、溶出性良好の点から、約０．０００１Ｍ〜０．０３Ｍ程度が好ましい。本発明の組成物における酸類のモル濃度は、塩基性緩衝剤を１Ｍと仮定した場合、約０．００１〜０．９５Ｍ程度の比率が好ましい。 The molar concentration of the basic buffer in the composition of the present invention is preferably about 0.0001M to 0.03M from the viewpoint of good elution. The molar concentration of the acids in the composition of the present invention is preferably about 0.001 to 0.95M, assuming that the basic buffer is 1M.
（比率）
本発明における、レベチラセタム、ゲル化剤、甘味剤及びｐＨ調整剤の比率（レベチラセタム：ゲル化剤：甘味剤：ｐＨ調整剤）は、１：（０．０１〜５）：（０．０１〜５）：（０．０１〜０．０３）であってもよく、１：（０．０３〜４．５）：（０．０５〜２．５）：（０．０１〜０．０３）であってもよい。
上記比率の設定によって、特に優れた本発明の効果が得られる。(ratio)
In the present invention, the ratio of levetiracetam, gelling agent, sweetener and pH adjuster (levetiracetam: gelling agent: sweetener: pH adjuster) is 1: (0.01 to 5): (0.01 to 5). ): (0.01 to 0.03), and 1: (0.03 to 4.5): (0.05 to 2.5): (0.01 to 0.03). You may.
By setting the above ratio, particularly excellent effects of the present invention can be obtained.
（糖度）
製剤としての糖度（Ｂｒｉｘ）は、約１〜５０％程度が好ましく、より好ましくは約１０〜４５％程度である。前記範囲であれば良好な溶出性を維持し、患者は風味（中でも甘味）を感じることができる。(sugar content)
The sugar content (Brix) of the preparation is preferably about 1 to 50%, more preferably about 10 to 45%. Within the above range, good dissolution is maintained, and the patient can feel the flavor (especially, sweetness).
（香料）
本発明の組成物は、香料を加えなくても苦みを感じないが、必要に応じて、例えば小児が好む香料を風味付けとして行ってもよい。このような香料としては、例えば、オレンジフレーバー、バナナフレーバー、イチゴフレーバー、バニラフレーバーや各エッセンス類を加えてもよい。これらは、１種単独で使用してもよく、２種以上を混合して用いてもよい。本発明の組成物における香料の配合量は、本発明の効果を妨げない限り特に限定されない。(Fragrance)
Although the composition of the present invention does not cause bitterness even without adding a flavor, it may be flavored with a flavor, for example, which is preferred by children, if necessary. As such a fragrance, for example, an orange flavor, a banana flavor, a strawberry flavor, a vanilla flavor, or each essence may be added. These may be used alone or as a mixture of two or more. The blending amount of the fragrance in the composition of the present invention is not particularly limited as long as the effects of the present invention are not hindered.
（防腐剤）
本発明の組成物には、必要に応じて、防腐剤を配合してもよい。前記防腐剤としては、通常医薬用として用いられるものであれば制限するものではないが、例えば、パラオキシ安息香酸メチル（メチルパラベン）、パラオキシ安息香酸エチル（エチルパラベン）、パラオキシ安息香酸プロピル（プロピルパラベン）、パラオキシ安息香酸イソプロピル（イソプロピルパラベン）、パラオキシ安息香酸ブチル（ブチルパラベン）、パラオキシ安息香酸イソブチル（イソブチルパラベン）、パラオキシ安息香酸ベンジル（ベンジルパラベン）、安息香酸ナトリウム、安息香酸、安息香酸ベンジル、塩化ベンザルコニウム、塩化セチルピリジニウム、塩化ベンゼトニウム、アミノエチルスルホン酸、ソルビン酸、ソルビン酸塩、デヒドロ酢酸、デヒドロ酢酸塩等が挙げられる。これらは、１種単独で使用してもよく、２種以上を混合して用いてもよい。防腐剤を配合して保存性を高めておけば、長期間の製品劣化（微生物汚染）を防ぐことができる。本発明の組成物における防腐剤の配合量は、本発明の効果を妨げない限り特に限定されない。(Preservative)
The composition of the present invention may optionally contain a preservative. The preservative is not limited as long as it is generally used as a medicament. For example, methyl paraoxybenzoate (methyl paraben), ethyl paraoxybenzoate (ethyl paraben), propyl paraoxybenzoate (propyl paraben) Isopropyl paraoxybenzoate (isopropylparaben), butyl paraoxybenzoate (butylparaben), isobutyl paraoxybenzoate (isobutylparaben), benzyl paraoxybenzoate (benzylparaben), sodium benzoate, benzoic acid, benzyl benzoate, benzal chloride Examples thereof include ruconium, cetylpyridinium chloride, benzethonium chloride, aminoethylsulfonic acid, sorbic acid, sorbate, dehydroacetic acid, and dehydroacetate. These may be used alone or as a mixture of two or more. If a preservative is added to enhance the preservability, long-term product deterioration (microbial contamination) can be prevented. The amount of the preservative in the composition of the present invention is not particularly limited as long as the effect of the present invention is not hindered.
（その他の添加剤）
本発明を実施する上で、本発明の組成物中に医薬品添加物辞典「２０１６」に記載されている医薬品添加物のうち経口投与が可能なものを添加して、さらに柔らかさや粘性、風味や食感を整えることも可能である。
具体的には経口投与可能な添加剤であれば制限するものではなく、増粘剤、粘稠化剤、溶剤、安定剤、安定化剤、等張剤、等張化剤、可塑剤、可溶化剤、その他の添加剤を加えて、製品性を整え向上させることができる。例えば、本発明の組成物に、食塩を添加することが好ましい。本発明の組成物における食塩の配合割合は、組成物全体に対して０．１〜０．２質量％であってもよい。食塩の配合、又は当該食塩の配合割合の設定によって、特に優れた本発明の効果（中でも、苦味が低減されるという効果）が得られ、より好ましくは味に深みが増し、又はコクが増大する。(Other additives)
In practicing the present invention, among the excipients described in the excipient excipient dictionary "2016" in the composition of the present invention, those that can be administered orally can be added, and further softness and viscosity, flavor and It is also possible to adjust the texture.
Specifically, there is no limitation as long as it is an orally administrable additive. Thickeners, thickeners, solvents, stabilizers, stabilizers, isotonic agents, isotonic agents, plasticizers, By adding a solubilizer and other additives, the product properties can be adjusted and improved. For example, it is preferable to add salt to the composition of the present invention. The compounding ratio of salt in the composition of the present invention may be 0.1 to 0.2% by mass based on the whole composition. Particularly excellent effects of the present invention (among others, an effect of reducing bitterness) are obtained by setting the mixing ratio of the salt or the mixing ratio of the salt, and more preferably the taste is deepened or the body is increased. .
（製造方法）
本発明の組成物は、各成分を所望の分量を秤取り、撹拌しながら加温溶解し、その後、所望の容器に加温溶解した各成分の混合物を充填して、放冷固化させることにより製造することができる。溶解温度は例えば７５〜９０℃であってもよい。また撹拌時間は殺菌工程を含めて例えば１〜２時間であってもよい。その後の充填温度は、６０〜９０℃であってもよい。(Production method)
The composition of the present invention is obtained by weighing a desired amount of each component, heating and dissolving while stirring, and then filling a desired container with a mixture of the heated and dissolved components and allowing the mixture to cool and solidify. Can be manufactured. The dissolution temperature may be, for example, 75-90 ° C. The stirring time may be, for example, 1 to 2 hours including the sterilization step. The subsequent filling temperature may be between 60 and 90C.
（溶出性）
本発明の組成物は、例えば、パドル法（５０ｒｐｍ、３７±０．５℃、９００ｍＬ（水）、測定波長λ２５０ｎｍ）で、１５分後の溶出率（％）が７５％以上、８０％以上、８５％以上、９０％以上、又は９５％以上であってもよく、または３０分後の溶出率（％）が９０％以上、９５％以上、９８％以上、又は９９％以上であってもよい。溶出率の測定には、溶出試験器として、富山産業社製ＮＴＲ−６２００ＡＣ２２を用いてもよく、また、ＵＶ測定器として、島津製作所社製ＵＶ１８００を用いてもよい。(Leachability)
For example, the composition of the present invention has a dissolution rate (%) of 75% or more, 80% or more after 15 minutes by a paddle method (50 rpm, 37 ± 0.5 ° C., 900 mL (water), measurement wavelength λ250 nm), It may be 85% or more, 90% or more, or 95% or more, or the dissolution rate (%) after 30 minutes may be 90% or more, 95% or more, 98% or more, or 99% or more. . For measurement of the dissolution rate, NTR-6200AC22 manufactured by Toyama Sangyo Co., Ltd. may be used as a dissolution tester, and UV1800 manufactured by Shimadzu Corporation may be used as a UV measurement device.
本発明は、本発明の効果を奏する限り、本発明の技術的範囲内において、上記の構成を種々組み合わせた態様を含む。 The present invention includes embodiments in which the above-described configurations are variously combined within the technical scope of the present invention as long as the effects of the present invention are exerted.
次に、実施例を挙げて本発明をさらに具体的に説明するが、本発明はこれらの実施例により何ら限定されるものではなく、多くの変形が本発明の技術的思想内で当分野において通常の知識を有する者により可能である。なお、実施例の濃度において「％」は、特に限定がない場合「質量％」を示す。 Next, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to these examples at all, and many modifications may be made within the technical concept of the present invention. It is possible by a person having ordinary knowledge. In the examples, “%” indicates “% by mass” unless otherwise specified.
表１〜３に示す実施例の各分量を秤取り、攪拌しながら８０〜８５℃で１時間、加温溶解する。その後、容器（スティック容器又はポーション容器）に加温溶解した各実施例３ｇ、５ｇ又は１０ｇを秤取り充填して放冷固化させて、ゲル製剤を得た。
（ｐＨ測定）
製剤のｐＨは、ＨＯＲＩＢＡ ｐＨメーター Ｂ−２１２で測定した。The respective amounts of the examples shown in Tables 1 to 3 are weighed and heated and dissolved at 80 to 85 ° C. for 1 hour with stirring. Thereafter, 3 g, 5 g or 10 g of each of the examples, which had been heated and dissolved in a container (stick container or portion container), was weighed, filled and allowed to cool and solidify to obtain a gel preparation.
(PH measurement)
The pH of the formulation was measured with a HORIBA pH meter B-212.
〔試験例〕
１．溶出試験
実施例１〜１０について、溶出試験を以下の条件で行った。試験開始後１５分又は３０分の各実施例の３ベッセルの溶出率平均値を求め、試験時間と溶出率との関係を、表４及び５並びに図１に示した。なお、単位はレベチラセタムの表示量に対する溶出率（％）で示した。
溶出試験器：富山産業社製ＮＴＲ−６２００ＡＣ
溶出試験条件：パドル法、５０ｒｐｍ
試験温度：３７±０．５℃
溶出試験液量：９００ｍＬ（水）
ＵＶ測定器：島津製作所社製ＵＶ１８００
測定波長：λ２５０ｎｍ(Test example)
1. Dissolution test About Examples 1 to 10, a dissolution test was performed under the following conditions. The average value of the dissolution rate of 3 vessels in each Example 15 minutes or 30 minutes after the start of the test was determined, and the relationship between the test time and the dissolution rate was shown in Tables 4 and 5 and FIG. The unit was indicated by the dissolution rate (%) relative to the indicated amount of levetiracetam.
Dissolution tester: NTR-6200AC manufactured by Toyama Sangyo Co., Ltd.
Dissolution test conditions: paddle method, 50 rpm
Test temperature: 37 ± 0.5 ° C
Dissolution test liquid volume: 900 mL (water)
UV measuring device: UV1800 manufactured by Shimadzu Corporation
Measurement wavelength: λ250nm
表４及び５並びに図１から明らかなように、実施例の溶出試験は、後発医薬品の生物学的同等性試験ガイドライン（「後発医薬品の生物学的同等性試験ガイドライン等の一部改正について」（平成２４年２月２９日薬食審査発０２２９第１０号））に「１５分値で８５％以上、及び／又は３０分値で８５％以上」として示される規格に適合する良好な溶出性が示された。 As is clear from Tables 4 and 5 and FIG. 1, the dissolution test in the Examples is based on the guidelines for bioequivalence testing of generic drugs (“Partial revision of bioequivalence testing guidelines for generic drugs, etc.” Good dissolution properties conforming to the standards indicated as “85% or more for 15-minute value and / or 85% or more for 30-minute value” in February 29, 2012 Pharmaceutical and Food Review No. 0229 No. 10) Indicated.
２．ゲル破断強度試験
実施例１〜１０について、ゲル破断強度試験を以下の条件で行った。各実施例のゼリー破断の最大強度を表６及び７に示した。なお、ゲル強度の単位はプランジャ直径５ｍｍの面積より、Ｎ／ｍ２の面積単位に換算して示した。
測定機器：島津製作所社製ＥＺＴｅｓｔ
プランジャ：直径５ｍｍステンレス製
プランジャ速度：６０ｍｍ／ｍｉｎ 2. Gel Break Strength Test For Examples 1 to 10, a gel break strength test was performed under the following conditions. Tables 6 and 7 show the maximum strength of jelly break of each example. The unit of the gel strength was shown by converting the area of the plunger diameter of 5 mm into the area unit of N / m 2 .
Measuring equipment: EZTest manufactured by Shimadzu Corporation
Plunger: 5mm diameter stainless steel Plunger speed: 60mm / min
表６及び７から明らかなように、ゲル破断の最大ピークの強度は１０００〜３００００Ｎ／ｍ２で、強度が異なるゼリー剤を作製することができた。すなわち、破断強度が高く歯応えがあるゲルから、舌触りが柔らかい食感のゲルまで所望に応じて柔らかさを設定できることが確認できた。As is clear from Tables 6 and 7, the maximum peak intensity of gel break was 1000 to 30000 N / m 2 , and jelly agents having different intensities could be produced. That is, it was confirmed that the softness can be set as desired from a gel having a high breaking strength and a chewy texture to a gel having a soft texture.
３．粘度試験
粘稠性のゲルである実施例１１及び比較例１について、粘度試験を以下の条件で行い、ずり速度Ｄに対する粘度の関係を表８及び図２に示した。なお、単位は非ニュートン流体であるために、ずり速度Ｄに対する見かけの粘度ηをｍＰa・ｓで示した。
粘度計：Ｔｏｋｉｍｅｃ社製ＴＶ２０
ロータ：０．８°×Ｒ２４
試験温度：２０℃
ロータ回転数：２．５、５、１０、２０、５０、１００ｒｐｍ 3. Viscosity Test A viscosity test was performed on Example 11 and Comparative Example 1 which are viscous gels under the following conditions, and the relationship between the shear rate D and the viscosity is shown in Table 8 and FIG. Since the unit is a non-Newtonian fluid, the apparent viscosity η with respect to the shear rate D is represented by mPa · s.
Viscometer: TV20 manufactured by Tokimec
Rotor: 0.8 ° × R24
Test temperature: 20 ° C
Rotor speed: 2.5, 5, 10, 20, 50, 100 rpm
実施例１１は比較例１に比べて粘性が高い非ニュートン流体の良好な物性を示した。すなわち、コクがあり、飲み応えがある組成物の物性であることを確認できた。 Example 11 showed good physical properties of the non-Newtonian fluid having higher viscosity than Comparative Example 1. That is, it was confirmed that the composition had a richness and was responsive to drinking.
これらの実施例及び試験例で得られた一回の服用量が多いレベチラセタムの経口投与用製剤のゼリー状製剤は口当たりが良く、飲み込みやすい柔らかさ乃至粘性で食べ応えがあり、粘稠状製剤はコクがあり、飲み応えがある。何れも食べ物や飲み物のような感覚で服用できるゲル状製剤の経口医薬組成物である。これらの製剤は高齢者や小児、あるいは嚥下機能が低下した患者、唾液が少なく飲み込み難い患者でも、口中や喉に残り難く、服用後の違和感もない製剤である。 The jelly-like preparation of oral administration of levetiracetam obtained in these Examples and Test Examples, which has a large single dose, has a good mouthfeel, is easy to swallow, is soft to viscous, has a good taste, and the viscous preparation is There is richness, there is a response to drinking. All are oral pharmaceutical compositions in the form of gels that can be taken with the sensation of food or drink. These preparations are hard to remain in the mouth and throat even in elderly people, children, patients with reduced swallowing function, and patients who have difficulty in swallowing due to low saliva, and do not feel uncomfortable after taking.
本発明のゲル経口医薬組成物は、レベチラセタム含有医薬の製造に有用である。 The oral pharmaceutical composition for gel of the present invention is useful for producing a drug containing levetiracetam.
Claims (14)
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| JP2017118545 | 2017-06-16 | ||
| JP2017118545 | 2017-06-16 | ||
| PCT/JP2018/020563 WO2018230329A1 (en) | 2017-06-16 | 2018-05-29 | Levetiracetam-containing gel oral pharmaceutical composition |
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| JP4309481B2 (en) * | 1996-01-12 | 2009-08-05 | テイコクメディックス株式会社 | Jelly oral pharmaceutical composition |
| JP5739080B2 (en) * | 2005-01-27 | 2015-06-24 | アレムビック・リミテッドＡｌｅｍｂｉｃ Ｌｉｍｉｔｅｄ | Sustained release formulation of levetiracetam |
| US20080014271A1 (en) * | 2006-07-13 | 2008-01-17 | Ucb, S.A. | Novel pharmaceutical compositions comprising levetiracetam |
| JP4941977B2 (en) * | 2007-04-11 | 2012-05-30 | 大蔵製薬株式会社 | Oral jelly-like pharmaceutical composition of benzisoxazole derivative |
| JP2010024156A (en) * | 2008-07-16 | 2010-02-04 | Ucb Pharma Sa | Pharmaceutical composition comprising levetiracetam |
| WO2010150400A1 (en) * | 2009-06-26 | 2010-12-29 | 日医工株式会社 | Jelly preparation containing isosorbide |
| JP6170234B2 (en) * | 2013-03-15 | 2017-07-26 | アプレシア・ファーマスーティカルズ・カンパニー | A rapidly dispersing dosage form containing levetiracetam |
| WO2016021215A1 (en) * | 2014-08-08 | 2016-02-11 | 日医工株式会社 | Jelly-like medicinal composition of potassium iodide |
| CN104922057A (en) * | 2015-05-31 | 2015-09-23 | 黑龙江佰彤儿童药物研究有限公司 | Child-type oral anti-epileptic pharmaceutical gel unit and preparation method thereof |
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