JP2019019113A - Orally disintegrating tablet containing memantine hydrochloride - Google Patents
Orally disintegrating tablet containing memantine hydrochloride Download PDFInfo
- Publication number
- JP2019019113A JP2019019113A JP2017147187A JP2017147187A JP2019019113A JP 2019019113 A JP2019019113 A JP 2019019113A JP 2017147187 A JP2017147187 A JP 2017147187A JP 2017147187 A JP2017147187 A JP 2017147187A JP 2019019113 A JP2019019113 A JP 2019019113A
- Authority
- JP
- Japan
- Prior art keywords
- memantine hydrochloride
- orally disintegrating
- tablet
- disintegrating tablet
- hardness
- Prior art date
- Legal status (The legal status 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 status listed.)
- Granted
Links
- LDDHMLJTFXJGPI-UHFFFAOYSA-N memantine hydrochloride Chemical compound Cl.C1C(C2)CC3(C)CC1(C)CC2(N)C3 LDDHMLJTFXJGPI-UHFFFAOYSA-N 0.000 title claims abstract description 88
- 229960000967 memantine hydrochloride Drugs 0.000 title claims abstract description 86
- 239000006191 orally-disintegrating tablet Substances 0.000 title claims abstract description 66
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- 239000003826 tablet Substances 0.000 claims description 52
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- 229960002622 triacetin Drugs 0.000 description 1
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Abstract
Description
本発明は、少量の水又は水なしで服用しても口腔内で速やかに崩壊するメマンチン塩酸塩含有口腔内崩壊錠及びその製造方法に関する。特に、加湿条件下に保存しても錠剤の硬度低下が少なく、かつ良好な口腔内崩壊性を維持するメマンチン塩酸塩含有口腔内崩壊錠及びその製造方法に関する。 The present invention relates to a memantine hydrochloride-containing orally disintegrating tablet that rapidly disintegrates in the oral cavity even if it is taken with a small amount of water or without water, and a method for producing the same. In particular, the present invention relates to a memantine hydrochloride-containing orally disintegrating tablet that maintains little orally disintegrating property even when stored under humidified conditions, and a method for producing the same.
メマンチン（１‐アミノ‐３，５‐ジメチルアダマンタン）は強い電位依存性及び速い遮断／非遮断動力性を有し、中等度及び高度アルツハイマー型認知症症状の進行を抑制する非競合ＮＭＤＡ受容体遮断薬である。 Memantine (1-amino-3,5-dimethyladamantane) has strong voltage dependence and fast blocking / non-blocking kinetics, non-competitive NMDA receptor blockade that suppresses the progression of moderate and severe Alzheimer's dementia symptoms It is a medicine.
中等度及び高度アルツハイマー型認知症状の進行を抑制する治療薬であるメマンチン塩酸塩は、現在、フィルムコーティング錠及び口腔内崩壊錠として市販されている（非特許文献１）。 Memantine hydrochloride, a therapeutic agent that suppresses the progression of moderate and severe Alzheimer-type cognitive symptoms, is currently marketed as a film-coated tablet and an orally disintegrating tablet (Non-patent Document 1).
中等度及び高度アルツハイマー型認知症は高齢者の患者が大半であり、嚥下力が低下している場合があるため、口腔内で速やかに崩壊し、口腔内の唾液や少量の水で服用可能な口腔内崩壊錠を剤型とするメマンチン塩酸塩製剤が提案されている。例えば、特許文献１には、微晶質セルロースが２０重量％から９５重量％の範囲で存在する即効型経口固形投与形が記載されている。 Moderate and severe Alzheimer's dementia is mostly elderly and may have reduced swallowing power, so it can quickly disintegrate in the oral cavity and be taken with oral saliva or small amounts of water A memantine hydrochloride formulation having an orally disintegrating tablet as a dosage form has been proposed. For example, Patent Document 1 describes an immediate-acting oral solid dosage form in which microcrystalline cellulose is present in the range of 20% to 95% by weight.
また、特許文献２には、かさ密度が０．２３ｇ／ｃｍ３以下の結晶セルロース、糖アルコール及びアルファー化デンプンを含有する口腔内崩壊錠が記載されている。Patent Document 2 describes an orally disintegrating tablet containing crystalline cellulose having a bulk density of 0.23 g / cm 3 or less, a sugar alcohol, and pregelatinized starch.
口腔内崩壊錠は、水なしで服用しても口腔内で速やかに崩壊する錠剤であり、嚥下機能が低下した高齢者にも服用しやすい製剤である。近年、病院や調剤薬局では患者が複数の薬を服用する場合には、患者が薬を飲み忘れたり、飲み違えたりするのを防ぐために、服用する時間帯ごとに複数の薬を一つの簡易の小袋に納める一包化による服薬コンプライアンス改善の取り組みが盛んとなっている。この一包化の際に、調剤ミスの防止や調剤業務の効率化を目的に自動錠剤分包機が用いられる。このため、薬局での一包化の作業時から患者が薬を服用するまでの間に、防湿等の効果を有する本来のパッケージやＰＴＰシートから薬剤が取り出され、加湿条件下に曝露される。特に、口腔内崩壊錠は、一般的に口腔内で容易に崩壊するように設計されているため、通常の錠剤よりも硬度が低く、加湿条件下に曝露されると、経時的に錠剤の硬度が低下し、服用前に錠剤が破損したり、口腔内崩壊時間が変動したりする恐れがある。また、錠剤硬度が低下すると、錠剤自動分包機による一包化の際の衝撃で、錠剤が破損する危険性もある。このため、医療現場では、加湿条件下で保存しても錠剤の硬度低下が小さく、崩壊性が維持され、更には自動分包による一包化にも破損が生じない口腔内崩壊錠の開発が望まれている。 Orally disintegrating tablets are tablets that disintegrate rapidly in the oral cavity even when taken without water, and are easy to take even for elderly people with reduced swallowing function. In recent years, when patients take multiple drugs at hospitals and dispensing pharmacies, to prevent patients from forgetting to take drugs or taking them wrongly, multiple simple drugs are taken for each time period. Efforts to improve medication compliance by packaging into small bags are thriving. An automatic tablet packaging machine is used for the purpose of preventing the dispensing mistake and improving the efficiency of the dispensing operation. For this reason, the medicine is taken out from the original package or PTP sheet having an effect of moisture prevention or the like and exposed to the humidified condition from the time of encapsulating in the pharmacy until the patient takes the medicine. In particular, orally disintegrating tablets are generally designed to disintegrate easily in the oral cavity, and therefore have a lower hardness than ordinary tablets, and when exposed to humid conditions, the hardness of the tablets over time There is a risk that the tablet will be damaged before taking or the disintegration time in the oral cavity may fluctuate. Moreover, when tablet hardness falls, there exists a danger that a tablet may be damaged by the impact at the time of the packaging by the tablet automatic packaging machine. For this reason, the development of orally disintegrating tablets has been developed in the medical field, where the decrease in tablet hardness is small even when stored under humidified conditions, the disintegration property is maintained, and further, there is no breakage even in packaging by automatic packaging. It is desired.
特許文献１は、薬物放出性と生体内吸収性に優れる即効型経口固形投与形態を提供することを目的としているものであり、良好な口腔内崩壊性であること、さらに加湿条件下での保存後でも良好な硬度や良好な口腔内崩壊性を兼ね備えているという課題及び解決手段を示唆しているものではない。 Patent Document 1 is intended to provide an immediate-acting oral solid dosage form that is excellent in drug release and in vivo absorption, has good oral disintegration, and is stored under humidified conditions. There is no suggestion of a problem and a solution that both have good hardness and good disintegration properties in the oral cavity.
特許文献２には、良好な口腔内崩壊性および十分な硬度を有した口腔内崩壊錠が記載されている。しかしながら、加湿条件下での保存後でも良好な硬度や良好な口腔内崩壊性を有しているという課題及び解決手段を示唆しているものではない。 Patent Document 2 describes an orally disintegrating tablet having good orally disintegrating property and sufficient hardness. However, it does not suggest the problem and solution means that it has good hardness and good oral disintegration even after storage under humidified conditions.
非特許文献１には、メマンチン塩酸塩を含む市販の口腔内崩壊錠について、錠剤自動分包機による一包化が可能であるものの、湿気を避けて保存する必要があることや吸湿により錠剤表面がざらつく等の注意が記載されている。 Non-Patent Document 1 discloses that a commercially available orally disintegrating tablet containing memantine hydrochloride can be packaged by a tablet automatic packaging machine, but it must be stored away from moisture, and the tablet surface may be absorbed by moisture absorption. Precautions such as roughness are described.
従って、本発明は、適度な硬度と口腔内での速やかな崩壊性を兼ね備え、かつ加湿保存による経時的な硬度低下が小さく、加湿保存後も良好な硬度と良好な口腔内崩壊性が維持される、ユーザービリティに優れたメマンチン塩酸塩含有口腔内崩壊錠およびその製造方法を提供することを課題とする。 Therefore, the present invention has an appropriate hardness and rapid disintegration in the oral cavity, and the decrease in hardness over time due to humid storage is small, and good hardness and good oral disintegration are maintained even after humid storage. Another object of the present invention is to provide a memantine hydrochloride-containing orally disintegrating tablet excellent in usability and a method for producing the same.
本発明者らは、上記課題を解決すべく鋭意検討した結果、メマンチン塩酸塩の粉末またはメマンチン塩酸塩を含有する顆粒に、低置換度ヒドロキシプロピルセルロースを添加し圧縮成型することで、適度な硬度と口腔内での速やかな崩壊性を兼ね備え、従来より知られていた市販の口腔内崩壊錠等に比して、加湿保存による経時的な硬度低下が小さく、加湿保存後も良好な硬度と良好な口腔内崩壊性を維持するメマンチン塩酸塩含有口腔内崩壊錠を見出し、本発明を完成させた。 As a result of intensive studies to solve the above problems, the present inventors have added low-substituted hydroxypropylcellulose to a granule containing memantine hydrochloride or memantine hydrochloride and compression-molded to obtain an appropriate hardness. In addition, it has a rapid disintegration property in the oral cavity, and compared with the conventionally known commercially available orally disintegrating tablets, the decrease in hardness over time due to humid storage is small, and good hardness and good after humid storage The present invention was completed by finding a memantine hydrochloride-containing orally disintegrating tablet that maintains a good orally disintegrating property.
すなわち本発明は、メマンチン塩酸塩の粉末またはメマンチン塩酸塩を含有する顆粒に低置換度ヒドロキシプロピルセルロースを混合し圧縮成型することを特徴とする口腔内崩壊錠及びその製造方法を提供するものである。 That is, the present invention provides an orally disintegrating tablet characterized in that low-substituted hydroxypropylcellulose is mixed with a powder of memantine hydrochloride or memantine hydrochloride-containing granules and compression-molded, and a method for producing the same. .
すなわち本発明は、以下の発明を含む。
（１）メマンチン塩酸塩の粉末又はメマンチン塩酸塩を含有する顆粒、及び低置換度ヒドロキシプロピルセルロースを含有する、メマンチン塩酸塩含有口腔内崩壊錠。
（２）メマンチン塩酸塩の粉末又はメマンチン塩酸塩を含有する顆粒が、糖アルコールで被覆されている、（１）に記載のメマンチン塩酸塩含有口腔内崩壊錠。
（３）錠剤の全重量に対して、メマンチン塩酸塩の含量が２．０重量％以上１０．０重量％以下である、（１）または（２）に記載のメマンチン塩酸塩含有口腔内崩壊錠。
（４）錠剤の全重量に対して、低置換度ヒドロキシプロピルセルロースの含量が０．５重量％以上１５．０重量％以下である、（１）から（３）のいずれか１つに記載のメマンチン塩酸塩含有口腔内崩壊錠。
（５）糖アルコールがマンニトールである、（２）から（４）のいずれか１つに記載のメマンチン塩酸塩含有口腔内崩壊錠。
（６）２５℃、相対湿度７５％に３日間保存後の錠剤硬度が２．０Ｋｇｆ以上である、（１）から（５）のいずれか１つに記載のメマンチン塩酸塩含有口腔内崩壊錠。
（７）流動層造粒法によって製造することを特徴とする、（１）から（６）のいずれか１つに記載のメマンチン塩酸塩含有口腔内崩壊錠の製造方法。That is, the present invention includes the following inventions.
(1) A memantine hydrochloride-containing orally disintegrating tablet containing memantine hydrochloride powder or granules containing memantine hydrochloride and low-substituted hydroxypropylcellulose.
(2) The memantine hydrochloride-containing orally disintegrating tablet according to (1), wherein memantine hydrochloride powder or memantine hydrochloride-containing granules are coated with a sugar alcohol.
(3) The memantine hydrochloride-containing orally disintegrating tablet according to (1) or (2), wherein the content of memantine hydrochloride is 2.0% by weight to 10.0% by weight with respect to the total weight of the tablet .
(4) The content of low-substituted hydroxypropylcellulose is 0.5% by weight or more and 15.0% by weight or less with respect to the total weight of the tablet, according to any one of (1) to (3) Memantine hydrochloride-containing orally disintegrating tablets.
(5) The memantine hydrochloride-containing orally disintegrating tablet according to any one of (2) to (4), wherein the sugar alcohol is mannitol.
(6) The memantine hydrochloride-containing orally disintegrating tablet according to any one of (1) to (5), wherein the tablet hardness after storage for 3 days at 25 ° C. and 75% relative humidity is 2.0 kgf or more.
(7) The method for producing a memantine hydrochloride-containing orally disintegrating tablet according to any one of (1) to (6), which is produced by a fluidized bed granulation method.
本発明によると、適度な硬度と口腔内での速やかな崩壊性を兼ね備え、かつ加湿条件下保存における経時的な硬度低下が小さく、加湿条件下保存後も良好な硬度と良好な口腔内崩壊性が維持されるメマンチン塩酸塩含有口腔内崩壊錠が提供される。また、特殊な生産設備を設けることなく、一般的な製造設備にて製造可能な製造方法が提供される。
このため、医療現場や流通過程において加湿条件下に錠剤が曝露された場合でも、良好な硬度と良好な口腔内崩壊性を具備するメマンチン塩酸塩含有口腔内崩壊錠を提供することができる。According to the present invention, it has moderate hardness and quick disintegration in the oral cavity, and has a small decrease in hardness over time when stored under humidified conditions. Good hardness and good oral disintegration even after storage under humidified conditions. An orally disintegrating tablet containing memantine hydrochloride is provided. Moreover, the manufacturing method which can be manufactured with a general manufacturing facility without providing special production facilities is provided.
Therefore, a memantine hydrochloride-containing orally disintegrating tablet having good hardness and good orally disintegrating property can be provided even when the tablet is exposed under humidified conditions in the medical field or distribution process.
以下、本発明に係るメマンチン塩酸塩含有口腔内崩壊錠について説明する。ただし、本発明のメマンチン塩酸塩含有口腔内崩壊錠は、以下に示す実施の形態及び実施例の記載内容に限定して解釈されるものではない。 Hereinafter, the memantine hydrochloride-containing orally disintegrating tablet according to the present invention will be described. However, the memantine hydrochloride-containing orally disintegrating tablet of the present invention is not construed as being limited to the description of the embodiments and examples shown below.
本発明において、加湿条件下で保存した後の「良好な口腔内崩壊性」とは、温度２５℃、湿度７５％に３日間、開封状態で保存した口腔内崩壊錠が口腔内の唾液のみ又は少量の水で約２０秒前後、もしくはそれ以下の時間で速やかに崩壊することをいう。 In the present invention, “good oral disintegration” after storage under humidified conditions means that the orally disintegrating tablet stored in an opened state at a temperature of 25 ° C. and a humidity of 75% for 3 days is only the saliva in the oral cavity or It means that it quickly disintegrates with a small amount of water in about 20 seconds or less.
本発明において、加湿条件下で保存した後の「良好な硬度」とは、温度２５℃、湿度７５％に３日間、開封状態で保存した口腔内崩壊錠の硬度が２．０ｋｇｆ以上となることを意味する（非特許文献２）。 In the present invention, “good hardness” after storage under humidified conditions means that the hardness of an orally disintegrating tablet stored in an opened state at 25 ° C. and 75% humidity for 3 days is 2.0 kgf or more. (Non-Patent Document 2).
本発明者らは、良好な口腔内崩壊性を有し、さらに加湿条件下で保存した後でも良好な硬度と良好な口腔内崩壊性を兼ね備えるメマンチン塩酸塩含有口腔内崩壊錠について検討を行ったところ、メマンチン塩酸塩の粉末又はメマンチン塩酸塩を含む顆粒に低置換度ヒドロキシプロピルセルロースを混合し圧縮成型することで、上記の目的を満たす錠剤が得られることを新たに見出した。 The present inventors examined memantine hydrochloride-containing orally disintegrating tablets that have good orally disintegrating properties and also have good hardness and good orally disintegrating properties even after storage under humidified conditions. However, it has been newly found that tablets satisfying the above-mentioned purpose can be obtained by mixing low-substituted hydroxypropylcellulose with a powder of memantine hydrochloride or granules containing memantine hydrochloride and compression molding.
本発明に係るメマンチン塩酸塩含有口腔内崩壊錠は、メマンチン塩酸塩と低置換度ヒドロキシプロピルセルロースを含有する。本発明において、メマンチン塩酸塩含有口腔内崩壊錠中のメマンチン塩酸塩の含有量は、例えば、５ｍｇ／錠、１０ｍｇ／錠又は２０ｍｇ／錠である。 The memantine hydrochloride-containing orally disintegrating tablet according to the present invention contains memantine hydrochloride and low-substituted hydroxypropylcellulose. In the present invention, the content of memantine hydrochloride in the memantine hydrochloride-containing orally disintegrating tablet is, for example, 5 mg / tablet, 10 mg / tablet, or 20 mg / tablet.
メマンチン塩酸塩は粉末状のメマンチン塩酸塩として含有されてもよく、また、任意に他の添加剤を含む、顆粒状のメマンチン塩酸塩として含有されてもよい。 Memantine hydrochloride may be contained as powdered memantine hydrochloride or may be contained as granular memantine hydrochloride, optionally containing other additives.
メマンチン塩酸塩は、所望により、粉末状のメマンチン塩酸塩の表面（例えば、メマンチン塩酸塩結晶の表面）または造粒されたメマンチン塩酸塩の顆粒表面をコーティングして用いてもよい。コーティングは薬物由来の不快な味、においや刺激をマスクし服用しやすくなる、光・水・酸素などから薬物を保護し、また、配合変化を起こしやすい成分同士を分離して安定性を向上させる、腸溶化や徐放化により薬物の有効性・安全性を向上させる、などの目的で施され、目的に応じてコーティング方法やコーティング剤が選択される。コーティングは、製剤技術分野において慣用の方法を用いることができ、例えば、流動層造粒・コーティング機、転動流動層造粒・コーティング機、遠心流動型造粒・コーティング機、ワースター型流動層造粒・コーティング機などを用いて行われる。本発明に係るメマンチン塩酸塩の粉末またはメマンチン塩酸塩を含有する顆粒にコーティングする場合、流動層造粒・コーティング機が好ましい。 Memantine hydrochloride may be used by coating the surface of powdered memantine hydrochloride (for example, the surface of memantine hydrochloride crystals) or the granule surface of granulated memantine hydrochloride, if desired. The coating masks the unpleasant taste, smell and irritation caused by the drug, makes it easier to take, protects the drug from light, water, oxygen, etc., and improves stability by separating components that tend to change the formulation. It is applied for the purpose of improving the effectiveness and safety of the drug by enterolysis or sustained release, and a coating method or coating agent is selected according to the purpose. For the coating, a method commonly used in the field of pharmaceutical technology can be used. For example, fluidized bed granulation / coating machine, rolling fluidized bed granulation / coating machine, centrifugal fluidized granulation / coating machine, Wurster type fluidized bed granulator. This is done using a grain / coating machine. When coating on memantine hydrochloride powder or memantine hydrochloride-containing granules according to the present invention, a fluidized bed granulator / coating machine is preferred.
本発明に係る低置換度ヒドロキシプロピルセルロースは、水不溶性添加剤であるため、服用感を考慮して、その配合量はメマンチン塩酸塩含有口腔内崩壊錠に対して０．５重量％以上１５．０重量％以下が好ましく、１．０重量％以上５．０重量％以下が特に好ましい。 Since the low-substituted hydroxypropylcellulose according to the present invention is a water-insoluble additive, the blending amount thereof is 0.5% by weight or more and 15.5% or more based on the memantine hydrochloride-containing orally disintegrating tablet in consideration of the ingestion feeling. 0 wt% or less is preferable, and 1.0 wt% or more and 5.0 wt% or less is particularly preferable.
本発明に係る低置換度ヒドロキシプロピルセルロースの９０％積算粒子径は、２００μｍ以下、好ましくは１５０μｍ以下、より好ましくは７０μｍ以上１３０μｍ以下である。９０％積算粒子径が２００μｍを超えると服用感が悪化するため好ましくない。 The 90% cumulative particle size of the low-substituted hydroxypropylcellulose according to the present invention is 200 μm or less, preferably 150 μm or less, more preferably 70 μm or more and 130 μm or less. If the 90% cumulative particle size exceeds 200 μm, the feeling of dosing deteriorates, which is not preferable.
本発明に係るメマンチン塩酸塩含有口腔内崩壊錠は、低置換度ヒドロキシプロピルセルロース以外にも、種々の添加剤を含有しても良い。添加剤としては、例えば、賦形剤、崩壊剤、結合剤、マスキング剤、被覆剤、着色剤、甘味剤、滑沢剤などが挙げられる。 The memantine hydrochloride-containing orally disintegrating tablet according to the present invention may contain various additives in addition to the low-substituted hydroxypropylcellulose. Examples of the additive include an excipient, a disintegrant, a binder, a masking agent, a coating agent, a coloring agent, a sweetening agent, and a lubricant.
（賦形剤）
本発明に係るメマンチン塩酸塩含有口腔内崩壊錠において、賦形剤は口当たりなどを考慮すると水溶性もしくは水親和性のものが好ましい。例えば、マンニトール、エリスリトール、ソルビトールおよびキシリトールなどの糖アルコール、トレハロース、シクロデキストリン、トウモロコシデンプン、ショ糖、結晶セルロース、無水リン酸水素カルシウム、炭酸カルシウムなどを単体又は適宜組み合わせて使用することができる。本発明においては糖アルコールが好ましく、マンニトールが特に好ましい。(Excipient)
In the memantine hydrochloride-containing orally disintegrating tablet according to the present invention, the excipient is preferably water-soluble or water-affinity considering the mouthfeel and the like. For example, sugar alcohols such as mannitol, erythritol, sorbitol and xylitol, trehalose, cyclodextrin, corn starch, sucrose, crystalline cellulose, anhydrous calcium hydrogen phosphate, calcium carbonate and the like can be used alone or in appropriate combination. In the present invention, sugar alcohol is preferred, and mannitol is particularly preferred.
（崩壊剤）
本発明に係るメマンチン塩酸塩含有口腔内崩壊錠において、崩壊剤は、例えば、低置換度ヒドロキシプロピルセルロース、クロスポビドン、カルメロースカルシウム、カルメロースナトリウム、クロスカルメロースナトリウム、カルメロース、各種デンプン類等から選択することができる。これらの崩壊剤は、単独又は二種以上組み合わせて使用できる。本発明においては、低置換度ヒドロキシプロピルセルロース、クロスポビドンおよびカルメロースカルシウムが好ましい。低置換度ヒドロキシプロピルセルロースは、良好な口腔内崩壊性、さらに高湿度環境下での保存後も良好な硬度を付与する崩壊剤として最も好適である。(Disintegrant)
In the memantine hydrochloride-containing orally disintegrating tablet according to the present invention, the disintegrant is, for example, from low-substituted hydroxypropylcellulose, crospovidone, carmellose calcium, carmellose sodium, croscarmellose sodium, carmellose, various starches, etc. You can choose. These disintegrants can be used alone or in combination of two or more. In the present invention, low-substituted hydroxypropylcellulose, crospovidone and carmellose calcium are preferred. Low-substituted hydroxypropylcellulose is most suitable as a disintegrating agent that imparts good disintegration property in the oral cavity and further provides good hardness even after storage in a high humidity environment.
（結合剤）
本発明に係るメマンチン塩酸塩含有口腔内崩壊錠において、結合剤は、例えば、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン、ポリビニルアルコール、マクロゴール及び上記に賦形剤として示した化合物等から選択することができる。これらの結合剤は、単体または適宜組み合わせて使用することができる。本発明においてはヒドロキシプロピルセルロースが好ましい。(Binder)
In the memantine hydrochloride-containing orally disintegrating tablet according to the present invention, the binder is selected from, for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, macrogol, and the compounds shown above as excipients. be able to. These binders can be used alone or in appropriate combination. In the present invention, hydroxypropylcellulose is preferred.
（マスキング剤）
本発明に係るメマンチン塩酸塩含有口腔内崩壊錠において、メマンチン塩酸塩の粉末またはメマンチン塩酸塩を含有する顆粒に、苦味を軽減するマスキング剤として、例えば、ｐＨ非依存型水不溶性ポリマー及び／またはｐＨ依存型水不溶性ポリマーを用いて造粒又は被覆することができる。ｐＨ非依存型水不溶性ポリマーの例としては、エチルセルロース、アミノアルキルメタクリレートコポリマーＲＳが挙げられ、ｐＨ依存型水不溶性ポリマーの例としては、メタクリル酸コポリマー（Ｌ、ＬＤ、Ｓ）、アミノアルキルメタクリレートコポリマーＥ、ポリビニルアセタールジエチルアミノアセテートが挙げられる。これらのマスキング剤は、単体または適宜組み合わせて使用することができるが、これらに限定されるものではない。本発明においてはメタクリル酸コポリマーＬＤが好ましい。また、マスキング剤に可塑剤を配合して用いることが好ましい。(Masking agent)
In the memantine hydrochloride-containing orally disintegrating tablet according to the present invention, a memantine hydrochloride powder or a granule containing memantine hydrochloride is used as a masking agent for reducing bitterness, for example, a pH-independent water-insoluble polymer and / or pH. Dependent water-insoluble polymers can be used to granulate or coat. Examples of the pH-independent water-insoluble polymer include ethyl cellulose and aminoalkyl methacrylate copolymer RS. Examples of the pH-dependent water-insoluble polymer include methacrylic acid copolymer (L, LD, S), aminoalkyl methacrylate copolymer E. And polyvinyl acetal diethylaminoacetate. These masking agents can be used alone or in appropriate combination, but are not limited thereto. In the present invention, methacrylic acid copolymer LD is preferred. Moreover, it is preferable to mix and use a plasticizer for a masking agent.
（可塑剤）
本発明に係るメマンチン塩酸塩含有口腔内崩壊錠において、メマンチン塩酸塩の粉末またはメマンチン塩酸塩を含有する顆粒に、苦味を軽減するマスキング剤に配合する可塑剤は、例えば、クエン酸トリエチル、マクロゴール、ポリソルベート８０、トリアセチン、モノステアリン酸グリセリン等から選択することができる。これらの可塑剤は単体または適宜組み合わせて使用することができる。本発明においてはクエン酸トリエチルが好ましい。(Plasticizer)
In the orally disintegrating tablet containing memantine hydrochloride according to the present invention, the plasticizer blended in the masking agent for reducing bitterness in the granule containing memantine hydrochloride powder or memantine hydrochloride includes, for example, triethyl citrate, macrogol , Polysorbate 80, triacetin, glyceryl monostearate and the like. These plasticizers can be used alone or in appropriate combination. In the present invention, triethyl citrate is preferred.
（被覆剤）
本発明に係るメマンチン塩酸塩の粉末又はメマンチン塩酸塩を含有する顆粒は、成型性と崩壊性を高めるため、糖アルコールで被覆することもできる。糖アルコールとしては、例えばマンニトール、エリスリトール、ソルビトール、キシリトールなどを単体又は適宜組み合わせて使用することができるが、特にマンニトールが好ましい。(Coating agent)
The memantine hydrochloride powder or granule containing memantine hydrochloride according to the present invention can be coated with a sugar alcohol in order to improve moldability and disintegration. As the sugar alcohol, for example, mannitol, erythritol, sorbitol, xylitol and the like can be used alone or in appropriate combination, and mannitol is particularly preferable.
（着色剤）
本発明に係るメマンチン塩酸塩含有口腔内崩壊錠において、着色剤は、例えば、黄色三二酸化鉄、三二酸化鉄、黒酸化鉄、食用黄色５号、食用黄色５号アルミニウムレーキ、リボフラビン等から選択することができる。これらの着色剤は、単体または適宜組み合わせて使用することができる。(Coloring agent)
In the memantine hydrochloride-containing orally disintegrating tablet according to the present invention, the colorant is selected from, for example, yellow ferric oxide, ferric oxide, black iron oxide, edible yellow No. 5, edible yellow No. 5 aluminum lake, riboflavin and the like. be able to. These colorants can be used alone or in appropriate combination.
（甘味剤）
本発明に係るメマンチン酸塩酸含有口腔内崩壊錠において、甘味剤を用いることも可能であり、例えば、スクラロース、サッカリン、サッカリンナトリウム、アスパルテーム、ステビオシド、還元麦芽糖水飴などを挙げることができる。本発明においてはアスパルテームが好ましい。(Sweetener)
In the memantic acid-containing orally disintegrating tablet according to the present invention, a sweetening agent can be used, and examples thereof include sucralose, saccharin, sodium saccharin, aspartame, stevioside, and reduced maltose starch syrup. In the present invention, aspartame is preferred.
（滑沢剤）
本発明に係るメマンチン塩酸塩含有口腔内崩壊錠において、滑沢剤は、例えば、ステアリン酸マグネシウム、ステアリン酸、ステアリン酸カルシウム、軽質無水ケイ酸、フマル酸ステアリルナトリウム、タルク、水素添加植物油、マイクロクリスタリンワックス、ショ糖脂肪酸エステル、ポリエチレングリコール等から選択することができる。これらの滑沢剤は、単体または適宜組み合わせて使用することができる。本発明においてはステアリン酸マグネシウムおよびタルクが好ましい。(lubricant)
In the memantine hydrochloride-containing orally disintegrating tablet according to the present invention, the lubricant includes, for example, magnesium stearate, stearic acid, calcium stearate, light anhydrous silicic acid, sodium stearyl fumarate, talc, hydrogenated vegetable oil, microcrystalline wax. , Sucrose fatty acid ester, polyethylene glycol and the like. These lubricants can be used alone or in appropriate combination. In the present invention, magnesium stearate and talc are preferred.
本発明において、さらに、その他の添加剤として、例えば、甘味剤以外の矯味剤、香料、流動化剤、帯電防止剤、界面活性剤、湿潤剤、充填剤、増量剤、吸着剤、防湿剤、抗酸化剤、保存剤（例えば防腐剤）、緩衝剤などを用いることもできる。 In the present invention, as other additives, for example, flavoring agents other than sweeteners, fragrances, fluidizing agents, antistatic agents, surfactants, wetting agents, fillers, extenders, adsorbents, moisture-proofing agents, Antioxidants, preservatives (for example, preservatives), buffers and the like can also be used.
以上説明したように、本発明に係るメマンチン塩酸塩含有口腔内崩壊錠は、メマンチン塩酸塩の粉末又はメマンチン塩酸塩を含む顆粒に、任意で糖アルコールを被覆した後に、低置換度ヒドロキシプロピルセルロースを添加し圧縮成型することにより得られる。このようにして得られたメマンチン塩酸塩含有口腔内崩壊錠は、適度な硬度と口腔内での良好な崩壊性、さらに加湿条件下での保存後も良好な硬度と良好な口腔内崩壊性を兼ね備える。また、本発明によると、特殊な生産設備を設けることなく、一般的な製造設備にて製造可能な製造方法を提供することができる。 As described above, the memantine hydrochloride-containing orally disintegrating tablet according to the present invention comprises a memantine hydrochloride powder or a granule containing memantine hydrochloride, optionally coated with a sugar alcohol, and then a low-substituted hydroxypropylcellulose. It is obtained by adding and compression molding. The memantine hydrochloride-containing orally disintegrating tablet thus obtained has moderate hardness and good disintegration property in the oral cavity, and also has good hardness and good oral disintegration property after storage under humidified conditions. Have both. Moreover, according to this invention, the manufacturing method which can be manufactured with a general manufacturing facility can be provided, without providing a special production facility.
次に実施例を挙げて、本発明を詳しく説明するが、本発明はこれに限られるものではない。 EXAMPLES Next, although an Example is given and this invention is demonstrated in detail, this invention is not limited to this.
実施例１
（メマンチン塩酸塩１０ｍｇ含有口腔内崩壊錠）
メマンチン塩酸塩８００．０ｇ、Ｄ−マンニトール（ロケット製）１８４０．０ｇ、カルメロースカルシウム（五徳薬品製）１７６．０ｇを流動層造粒機（フロイント製、ＦＬＯ‐５Ｍ）に投入し、ヒドロキシプロピルセルロース（日本曹達製）８８．０ｇを精製水２８４５．３ｇに溶解した液を噴霧後、乾燥することで造粒物を得た。得られた造粒物２９０４．０ｇを流動層造粒機（フロイント製、ＦＬＯ‐５Ｍ）に投入しコーティング液１０５６２．７ｇ（メタクリル酸コポリマーＬＤ（エボニック製、オイドラギットＬ３０Ｄ−５５）３８６６．７ｇ、クエン酸トリエチル（森村商事製）１２０．０ｇ、タルク（勝光山鉱業所製）５７６．０ｇ、精製水６０００．０ｇ）を噴霧し、乾燥することで薬物含有コーティング顆粒を得た。薬物含有コーティング顆粒４７６０．０ｇを流動層造粒機に投入し、Ｄ−マンニトール７２０．０ｇを精製水６４８０．０ｇに溶解した液を噴霧後、乾燥することで薬物含有粒子被覆顆粒を得た。薬物含有粒子被覆顆粒１３７．０ｇ、Ｄ−マンニトール（フロイント製、グラニュトールＳ）１１３．８ｇ、クロスポビドン（ＢＡＳＦ製、コリドンＣＬ−Ｆ）８．４ｇ、低置換度ヒドロキシプロピルセルロース（信越化学工業製、ＮＢＤ−０２２）８．４ｇ、アスパルテーム（味の素製）９．６ｇ、香料（高砂香料工業製）０．２ｇを３分間混合した。得られた混合物にステアリン酸マグネシウム（太平化学産業製）２．８ｇを加え１分間混合後、ロータリー打錠機にて口腔内崩壊錠（打錠条件：錠剤径７．５φ、錠厚３．５ｍｍ、１錠あたりの質量１４０ｍｇ）を作製した。 Example 1
(Memantine hydrochloride 10mg containing orally disintegrating tablets)
Memantine hydrochloride 800.0 g, D-mannitol (Rocket) 1840.0 g, Carmellose calcium (Gotoku Pharmaceutical) 176.0 g were charged into a fluidized bed granulator (Freund, FLO-5M), and hydroxypropylcellulose. A granulated product was obtained by spraying a solution obtained by dissolving 88.0 g (manufactured by Nippon Soda) in 2845.3 g of purified water and then drying. 2904.0 g of the obtained granulated product was put into a fluidized bed granulator (Freund, FLO-5M), and coating liquid 10562.7 g (methacrylic acid copolymer LD (Evonik, Eudragit L30D-55) 3866.7 g, 120.0 g of triethyl acid (manufactured by Morimura Shoji Co., Ltd.), 576.0 g of talc (manufactured by Katsumiyama Mining), 6000.0 g of purified water) were sprayed and dried to obtain drug-containing coated granules. 4760.0 g of drug-containing coated granules were charged into a fluidized bed granulator, and a solution obtained by dissolving 720.0 g of D-mannitol in 6480.0 g of purified water was sprayed and dried to obtain drug-containing particle-coated granules. Drug-containing particle-coated granules 137.0 g, D-mannitol (Freund, Granitol S) 113.8 g, crospovidone (BASF, Kollidon CL-F) 8.4 g, low-substituted hydroxypropylcellulose (Shin-Etsu Chemical) , NBD-022) 8.4 g, Aspartame (Ajinomoto Co., Ltd.) 9.6 g, and Fragrance (Takasago Fragrance Co., Ltd.) 0.2 g were mixed for 3 minutes. 2.8 g of magnesium stearate (manufactured by Taihei Chemical Sangyo) was added to the resulting mixture and mixed for 1 minute, followed by orally disintegrating tablets (tablet conditions: tablet diameter 7.5φ, tablet thickness 3.5 mm) using a rotary tableting machine. A mass of 140 mg per tablet) was prepared.
実施例２
（メマンチン塩酸塩２０ｍｇ含有口腔内崩壊錠）
メマンチン塩酸塩１００．０ｇ、Ｄ−マンニトール（ロケット製）２３０．０ｇ、カルメロースカルシウム（五徳薬品製）２２．０ｇを流動層造粒機（パウレック製、ＭＰ−０１）に投入し、ヒドロキシプロピルセルロース（日本曹達製）１１．０ｇを精製水３５６．０ｇに溶解した液を噴霧後、乾燥することで造粒物を得た。得られた造粒物３６３．０ｇを流動層造粒機（パウレック製、ＭＰ−０１）に投入しコーティング液１３２０．３ｇ（メタクリル酸コポリマーＬＤ（エボニック製、オイドラギットＬ３０Ｄ−５５）４８３．３ｇ、クエン酸トリエチル（森村商事製）１５．０ｇ、タルク（勝光山鉱業所製）７２．０ｇ、精製水７５０．０ｇ）を噴霧し、乾燥することで薬物含有コーティング顆粒を得た。薬物含有コーティング顆粒５９５．０ｇを流動層造粒機に投入し、Ｄ−マンニトール１１９．０ｇを精製水１０７１．０ｇに溶解した液を噴霧後、乾燥することで薬物含有粒子被覆顆粒を得た。薬物含有粒子被覆顆粒１４２．８ｇ、Ｄ−マンニトール（フロイント製、グラニュトールＳ）１１１．２ｇ、クロスポビドン（ＢＡＳＦ製、コリドンＣＬ−Ｆ）８．２ｇ、低置換度ヒドロキシプロピルセルロース（信越化学工業製、ＮＢＤ−０２２）５．４ｇ、アスパルテーム（味の素製）９．６ｇ、香料（高砂香料工業製）０．２ｇを３分間混合した。得られた混合物にステアリン酸マグネシウム（太平化学産業製）２．８ｇを加え１分間混合後、ロータリー打錠機にて口腔内崩壊錠（打錠条件：錠剤径９．０φ、錠厚４．８ｍｍ、１錠あたりの質量２８０ｍｇ）を作製した。 Example 2
(Memantine hydrochloride 20 mg containing orally disintegrating tablets)
100.0 g of memantine hydrochloride, 230.0 g of D-mannitol (manufactured by Rocket) and 22.0 g of carmellose calcium (manufactured by Gotoku Pharmaceutical) were charged into a fluidized bed granulator (manufactured by Paulek, MP-01), and hydroxypropylcellulose A granulated product was obtained by spraying a solution obtained by dissolving 11.0 g (manufactured by Nippon Soda) in 356.0 g of purified water and then drying. 363.0 g of the obtained granulated product was charged into a fluidized bed granulator (manufactured by Paul Wrec, MP-01), and coating solution 1320.3 g (methacrylic acid copolymer LD (Evonik, Eudragit L30D-55) 483.3 g, 35.0 g of triethyl acid (manufactured by Morimura Shoji), 72.0 g of talc (manufactured by Katsumiyama Mining), 750.0 g of purified water) were sprayed and dried to obtain drug-containing coated granules. 595.0 g of the drug-containing coated granule was put into a fluidized bed granulator, and a solution obtained by dissolving 119.0 g of D-mannitol in 1071.0 g of purified water was sprayed and dried to obtain a drug-containing particle-coated granule. 142.8 g of drug-containing particle-coated granules, 111.2 g of D-mannitol (Freund, Granitol S), 8.2 g of crospovidone (BASF, Kollidon CL-F), low-substituted hydroxypropyl cellulose (manufactured by Shin-Etsu Chemical) , NBD-022) 5.4 g, Aspartame (Ajinomoto Co., Ltd.) 9.6 g, and Fragrance (Takasago Fragrance Co., Ltd.) 0.2 g were mixed for 3 minutes. 2.8 g of magnesium stearate (manufactured by Taihei Chemical Sangyo) was added to the resulting mixture and mixed for 1 minute, followed by orally disintegrating tablet (tablet conditions: tablet diameter 9.0φ, tablet thickness 4.8 mm) using a rotary tableting machine. A mass per tablet (280 mg) was prepared.
実施例３
（メマンチン塩酸塩１０ｍｇ含有口腔内崩壊錠）
実施例１に記載の薬物含有粒子被覆顆粒１３７．０ｇ、低置換度ヒドロキシプロピルセルロースを含有する乾式直打用賦形剤（信越化学工業製、ＳｍａｒｔＥｘ（登録商標） ＱＤ−５０）１２２．２ｇ、クロスポビドン（ＢＡＳＦ製、コリドンＣＬ−Ｆ）８．４ｇ、アスパルテーム（味の素製）９．６ｇ、香料（高砂香料工業製）０．２ｇを３分間混合した。得られた混合物にステアリン酸マグネシウム（太平化学産業製）２．８ｇを加え１分間混合後、得られた打錠用顆粒からロータリー打錠機にて口腔内崩壊錠（打錠条件：錠剤径７．５φ、錠厚３．５ｍｍ、１錠あたりの質量１４０ｍｇ）を作製した。 Example 3
(Memantine hydrochloride 10mg containing orally disintegrating tablets)
137.0 g of drug-containing particle-coated granules described in Example 1 and 122.2 g of dry direct-implanting excipient (Shin-Etsu Chemical Co., Ltd., SmartEx (registered trademark) QD-50) containing low-substituted hydroxypropylcellulose. 8.4 g of crospovidone (BASF, Kollidon CL-F), 9.6 g of aspartame (manufactured by Ajinomoto), and 0.2 g of fragrance (manufactured by Takasago Kagaku Kogyo) were mixed for 3 minutes. 2.8 g of magnesium stearate (manufactured by Taihei Chemical Industry) was added to the resulting mixture and mixed for 1 minute, and then the tableting granules obtained were orally disintegrated with a rotary tableting machine (tablet conditions: tablet diameter 7). .5φ, tablet thickness 3.5 mm, mass per tablet 140 mg).
実施例４
（メマンチン塩酸塩２０ｍｇ含有口腔内崩壊錠）
実施例３で作製した打錠用顆粒を用いて、ロータリー打錠機にて口腔内崩壊錠（打錠条件：錠剤径９．０φ、錠厚４．８ｍｍ、１錠あたりの質量２８０ｍｇ）を作製した。 Example 4
(Memantine hydrochloride 20 mg containing orally disintegrating tablets)
Orally disintegrating tablets (tablet conditions: tablet diameter 9.0φ, tablet thickness 4.8 mm, mass per tablet 280 mg) using a tableting granule prepared in Example 3 using a rotary tableting machine did.
比較例１
（メマンチン塩酸塩１０ｍｇ含有口腔内崩壊錠）
実施例１に記載の薬物含有粒子被覆顆粒１３７．０ｇ、Ｄ−マンニトール（フロイント製、グラニュトールＳ）１２１．４ｇ、クロスポビドン（ＢＡＳＦ製、コリドンＣＬ−Ｆ）８．４ｇ、アスパルテーム（味の素製）９．６ｇ、香料（高砂香料工業製）０．２ｇを３分間混合した。得られた混合物にステアリン酸マグネシウム（太平化学産業製）３．６ｇを加え１分間混合後、ロータリー打錠機にて口腔内崩壊錠（打錠条件：錠剤径７．５φ、錠厚３．５ｍｍ、１錠あたりの質量１４０ｍｇ）を作製した。 Comparative Example 1
(Memantine hydrochloride 10mg containing orally disintegrating tablets)
137.0 g of drug-containing particle-coated granules described in Example 1, D-mannitol (Freund, Granitol S) 121.4 g, crospovidone (BASF, Kollidon CL-F) 8.4 g, aspartame (Ajinomoto) 9.6 g and fragrance | flavor (product made from Takasago fragrance industry) 0.2g were mixed for 3 minutes. To the obtained mixture, 3.6 g of magnesium stearate (manufactured by Taihei Chemical Industry) was added and mixed for 1 minute, and then orally disintegrating tablet (tablet conditions: tablet diameter 7.5φ, tablet thickness 3.5 mm) using a rotary tableting machine. A mass of 140 mg per tablet) was prepared.
比較例２
（メマンチン塩酸塩１０ｍｇ含有口腔内崩壊錠）
実施例１に記載の薬物含有粒子被覆顆粒１３７．０ｇ、Ｄ−マンニトール（フロイント製、グラニュトールＳ）１１７．８ｇ、結晶セルロース（旭化成製、セオラスＰＨ−３０２）８．４ｇ、クロスポビドン（ＢＡＳＦ製、コリドンＣＬ−Ｆ）８．４ｇ、アスパルテーム（味の素製）４．８ｇ、香料（高砂香料工業製）０．２ｇを３分間混合した。得られた混合物にステアリン酸マグネシウム（太平化学産業製）３．６ｇを加え１分間混合後、ロータリー打錠機にて口腔内崩壊錠（打錠条件：錠剤径７．５φ、錠厚３．５ｍｍ、１錠あたりの質量１４０ｍｇ）を作製した。 Comparative Example 2
(Memantine hydrochloride 10mg containing orally disintegrating tablets)
137.0 g of drug-containing particle-coated granules described in Example 1, D-mannitol (Freund, Granitol S) 117.8 g, crystalline cellulose (Asahi Kasei, Theolas PH-302) 8.4 g, crospovidone (BASF) , Kollidon CL-F) 8.4 g, aspartame (Ajinomoto Co., Ltd.) 4.8 g, and fragrance (Takasago Fragrance Co., Ltd.) 0.2 g were mixed for 3 minutes. To the obtained mixture, 3.6 g of magnesium stearate (manufactured by Taihei Chemical Industry) was added and mixed for 1 minute, and then orally disintegrating tablet (tablet conditions: tablet diameter 7.5φ, tablet thickness 3.5 mm) using a rotary tableting machine. A mass of 140 mg per tablet) was prepared.
実施例１から実施例４、比較例１と比較例２及び市販製剤（比較例３、メマリー（登録商標）ＯＤ錠１０ｍｇ）の錠剤について、加湿前、及び２５℃相対湿度７５％の条件下で３日間加湿後に、錠剤硬度（平均硬度）及び崩壊時間を測定した。得られた結果を表１に示す。 About Example 1 to Example 4, Comparative Example 1 and Comparative Example 2, and a tablet of a commercially available formulation (Comparative Example 3, Memary (registered trademark) OD tablet 10 mg) under humidification conditions and under conditions of 25% relative humidity 75% After humidification for 3 days, tablet hardness (average hardness) and disintegration time were measured. The obtained results are shown in Table 1.
メマンチン塩酸塩を含有する顆粒に、低置換ヒドロキシプロピルセルロースを添加し圧縮成型した実施例１から４の錠剤は、良好な硬度（加湿前硬度；４．４〜８．７Ｋｇｆ）ならびに良好な口腔内崩壊性（加湿前崩壊時間；１２〜２０秒）を示した。さらに、加湿保存後にも良好な硬度（加湿後硬度；２．３〜５．６Ｋｇｆ）及び良好な口腔内崩壊性（加湿後崩壊時間；９〜１８秒）を保持していた。低置換度ヒドロキシプロピルセルロースを含有しない比較例１〜３の口腔内崩壊錠では加湿保存後の硬度が大きく低下したことと比較して、本発明が奏する効果は顕著に優れたものである。 The tablets of Examples 1 to 4, which were compression-molded by adding low-substituted hydroxypropylcellulose to granules containing memantine hydrochloride, had good hardness (hardness before humidification; 4.4 to 8.7 kgf) and good oral cavity. Disintegration property (disintegration time before humidification; 12 to 20 seconds) was exhibited. Furthermore, after humidification preservation | save, favorable hardness (hardness after humidification; 2.3-5.6Kgf) and favorable oral disintegration (disintegration time after humidification; 9-18 seconds) were maintained. In the orally disintegrating tablets of Comparative Examples 1 to 3 that do not contain low-substituted hydroxypropylcellulose, the effect of the present invention is remarkably excellent as compared with the fact that the hardness after humid storage is greatly reduced.
本発明により、加湿前のみならず加湿保存後であっても良好な硬度と良好な口腔内崩壊性を併せ持った、ユーザービリティに優れるメマンチン塩酸塩含有口腔内崩壊錠が提供される。また、本発明によれば、特殊な生産設備を設けることなく、一般的な製造設備にて製造可能であり、容易に大量生産しうるメマンチン塩酸塩含有口腔内崩壊錠が提供される。 According to the present invention, there is provided a memantine hydrochloride-containing orally disintegrating tablet excellent in usability, having both good hardness and good oral disintegration property not only before humidification but also after humidification storage. Moreover, according to this invention, the memantine hydrochloride containing orally disintegrating tablet which can be manufactured with a general manufacturing facility and can be mass-produced easily without providing a special production facility is provided.
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| US11690849B2 (en) | 2019-04-12 | 2023-07-04 | LA PharmaTech Inc. | Method of treating dementia |
| US11744833B2 (en) | 2019-04-12 | 2023-09-05 | LA PharmaTech Inc. | Pharmaceutical compositions and methods for treatment of insomnia |
| US11938139B2 (en) | 2019-04-12 | 2024-03-26 | LA PharmaTech Inc. | Pharmaceutical compositions and methods for anxiety, depression and other psychiatric disorders |
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