JP7411983B2 - Anti-inflammatory agents, prefilled syringes, and kits - Google Patents
Anti-inflammatory agents, prefilled syringes, and kits Download PDFInfo
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- JP7411983B2 JP7411983B2 JP2019154679A JP2019154679A JP7411983B2 JP 7411983 B2 JP7411983 B2 JP 7411983B2 JP 2019154679 A JP2019154679 A JP 2019154679A JP 2019154679 A JP2019154679 A JP 2019154679A JP 7411983 B2 JP7411983 B2 JP 7411983B2
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- inflammatory agent
- polyethyleneimine
- inflammatory
- agent according
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Description
本発明は、抗炎症剤、プレフィルドシリンジ、及び、キットに関する。 The present invention relates to an anti-inflammatory agent, a prefilled syringe, and a kit.
超高齢社会に突入した我が国において、急性、及び、慢性炎症疾患に対する治療法の開発がより一層望まれる。炎症反応は、感染等の外的因子に対する生体防御システムである一方で、関節炎、動脈硬化、褥瘡、及び、がん等の疾患との関連性が知られている。 In Japan, which has entered a super-aging society, the development of treatments for acute and chronic inflammatory diseases is even more desired. While the inflammatory response is a biological defense system against external factors such as infection, it is known to be associated with diseases such as arthritis, arteriosclerosis, pressure ulcers, and cancer.
炎症を抑制する薬剤として、ステロイド、及び、非ステロイド系の薬剤、並びに、抗体医薬等が使用されるが、副腎不全、感染症、骨粗しょう症、及び、自己免疫疾患等の副作用が問題であり、また、薬剤の安定性、並びに、開発コスト、及び、製造コストに課題があった。 Steroids, nonsteroidal drugs, and antibody drugs are used as drugs to suppress inflammation, but side effects such as adrenal insufficiency, infection, osteoporosis, and autoimmune diseases are a problem. In addition, there were problems with drug stability, development costs, and manufacturing costs.
そのため、より安全性が高く、かつ、抗炎症性を有する薬剤の研究が進められている。例えば、ステロイドを内包したハイドロゲル(非特許文献1)、抗炎症性を示す多糖類(非特許文献2)、及び、抗炎症効果を示す高分子量ヒアルロン酸(非特許文献3)等が提案されている。 Therefore, research is underway into drugs that are safer and have anti-inflammatory properties. For example, hydrogels containing steroids (Non-Patent Document 1), polysaccharides that exhibit anti-inflammatory properties (Non-Patent Document 2), and high molecular weight hyaluronic acid that exhibits anti-inflammatory effects (Non-Patent Document 3) have been proposed. ing.
非特許文献1に記載されたステロイドを内包したハイドロゲルは、ステロイドの徐放速度を制御することが難しく、ステロイドに由来する副作用が問題である。
非特許文献2に記載されたような天然物より単離した多糖類は抗炎症性を示すものもあるが、その効果は弱く、また、大量生産することは困難である。
非特許文献3に記載された高分子量体のヒアルロン酸は低分子量体と比較して抗炎症性を示すが、その効果は微弱で、不十分である。
In the steroid-encapsulating hydrogel described in Non-Patent Document 1, it is difficult to control the sustained release rate of the steroid, and side effects originating from the steroid are a problem.
Although some polysaccharides isolated from natural products such as those described in Non-Patent Document 2 exhibit anti-inflammatory properties, their effects are weak and it is difficult to mass produce them.
Although the high molecular weight hyaluronic acid described in Non-Patent Document 3 exhibits anti-inflammatory properties compared to low molecular weight hyaluronic acid, its effect is weak and insufficient.
そこで、本発明は、ステロイド化合物を含有しなくとも十分な抗炎症作用を奏する、言い換えれば、優れた安全性、及び、優れた抗炎症性を有する抗炎症剤を提供することを課題とする。また、本発明は、プレフィルドシリンジ、及び、キットを提供することも課題とする。 Therefore, an object of the present invention is to provide an anti-inflammatory agent that exhibits a sufficient anti-inflammatory effect without containing a steroid compound, in other words, has excellent safety and anti-inflammatory properties. Another object of the present invention is to provide a prefilled syringe and a kit.
本発明者らは、上記課題を達成すべく鋭意検討した結果、以下の構成により上記課題を達成することができることを見出した。 As a result of intensive studies to achieve the above-mentioned problems, the present inventors have found that the above-mentioned problems can be achieved by the following configuration.
[1] エチレンジアミン、及び、分子量が100~2000であるポリエチレンイミンからなる群より選択される少なくとも1種の化合物を有効成分として含有する、抗炎症剤。
[2] 上記ポリエチレンイミンの分子量が100~1200である[1]に記載の抗炎症剤。
[3] 上記ポリエチレンイミンの分子量が200~1000である[1]に記載の抗炎症剤。
[4] 分子量が200~1000であるポリエチレンイミンを含有する[1]に記載の抗炎症剤。
[5] 上記ポリエチレンイミンが分岐鎖状である、[1]~[4]のいずれかに記載の抗炎症剤。
[6] 更にゲル化剤を含有する[1]~[5]のいずれかに記載の抗炎症剤。
[7] 上記ゲル化剤が、ヒアルロン酸又はその誘導体である、[6]に記載の抗炎症剤。
[8] 更に架橋剤を含有する[7]に記載の抗炎症剤。
[9] 上記架橋剤が、スルホン化セルロースである、[8]に記載の抗炎症剤。
[10] 更に水を含有する[1]~[9]のいずれかに記載の抗炎症剤。
[11] マクロファージに作用して炎症性サイトカインの産生を抑制する、[1]~[10]のいずれかに記載の抗炎症剤。
[12] [1]~[10]のいずれかに記載の抗炎症剤と、上記抗炎症剤が収容されたシリンジと、を有するプレフィルドシリンジ。
[13] エチレンジアミン、及び、分子量が100~2000であるポリエチレンイミンからなる群より選択される少なくとも1種の化合物と、ゲル化剤とを備え、使用時に混合して上記化合物を含有するゲルを調製するためのキット。
[14] 更に水を備える[13]に記載のキット。
[1] An anti-inflammatory agent containing as an active ingredient at least one compound selected from the group consisting of ethylenediamine and polyethyleneimine having a molecular weight of 100 to 2000.
[2] The anti-inflammatory agent according to [1], wherein the polyethyleneimine has a molecular weight of 100 to 1200.
[3] The anti-inflammatory agent according to [1], wherein the polyethyleneimine has a molecular weight of 200 to 1,000.
[4] The anti-inflammatory agent according to [1], which contains polyethyleneimine having a molecular weight of 200 to 1000.
[5] The anti-inflammatory agent according to any one of [1] to [4], wherein the polyethyleneimine is branched.
[6] The anti-inflammatory agent according to any one of [1] to [5], further containing a gelling agent.
[7] The anti-inflammatory agent according to [6], wherein the gelling agent is hyaluronic acid or a derivative thereof.
[8] The anti-inflammatory agent according to [7], further containing a crosslinking agent.
[9] The anti-inflammatory agent according to [8], wherein the crosslinking agent is sulfonated cellulose.
[10] The anti-inflammatory agent according to any one of [1] to [9], further containing water.
[11] The anti-inflammatory agent according to any one of [1] to [10], which acts on macrophages to suppress the production of inflammatory cytokines.
[12] A prefilled syringe comprising the anti-inflammatory agent according to any one of [1] to [10] and a syringe containing the anti-inflammatory agent.
[13] At least one compound selected from the group consisting of ethylenediamine and polyethyleneimine having a molecular weight of 100 to 2000, and a gelling agent, and mixed at the time of use to prepare a gel containing the above compound. kit for.
[14] The kit according to [13], further comprising water.
本発明によれば、優れた安全性、及び、優れた抗炎症性を有する抗炎症剤を提供できる。また、本発明によれば、プレフィルドシリンジ、及び、キットも提供できる。 According to the present invention, an anti-inflammatory agent having excellent safety and anti-inflammatory properties can be provided. Further, according to the present invention, a prefilled syringe and a kit can also be provided.
以下、本発明について詳細に説明する。
以下に記載する構成要件の説明は、本発明の代表的な実施形態に基づいてなされることがあるが、本発明はそのような実施形態に制限されるものではない。
なお、本明細書において、「~」を用いて表される数値範囲は、「~」の前後に記載される数値を下限値及び上限値として含む範囲を意味する。
The present invention will be explained in detail below.
Although the description of the constituent elements described below may be made based on typical embodiments of the present invention, the present invention is not limited to such embodiments.
In this specification, a numerical range expressed using "~" means a range that includes the numerical values written before and after "~" as the lower limit and upper limit.
[抗炎症剤]
本発明の実施形態に係る抗炎症剤は、エチレンジアミン、及び、分子量が100~2000であるポリエチレンイミン(以下、「特定ポリエチレンイミン」ともいう。)からなる群より選択される少なくとも1種の化合物を有効成分として含有する、抗炎症剤である。
[Anti-inflammatory agent]
The anti-inflammatory agent according to the embodiment of the present invention contains at least one compound selected from the group consisting of ethylenediamine and polyethyleneimine having a molecular weight of 100 to 2000 (hereinafter also referred to as "specific polyethyleneimine"). It is an anti-inflammatory agent that contains it as an active ingredient.
抗炎症剤における上記化合物の含有量としては、用法、用量に応じて適宜定めればよく、効果の得られる範囲であれば特に制限されないが、一般に抗炎症剤の全質量に対して、0.001~99.999質量%が好ましい。なお、抗炎症剤は、上記化合物の1種を単独で含有してもよく、2種以上を含有していてもよい。抗炎症剤が、2種以上の上記化合物を含有する場合には、その合計含有量が上記数値範囲内であることが好ましい。 The content of the above-mentioned compound in the anti-inflammatory agent may be determined as appropriate depending on the usage and dosage, and is not particularly limited as long as the effect can be obtained, but it is generally 0.00000% based on the total mass of the anti-inflammatory agent. 001 to 99.999% by mass is preferred. Note that the anti-inflammatory agent may contain one kind of the above-mentioned compounds alone, or two or more kinds thereof. When the anti-inflammatory agent contains two or more of the above compounds, the total content is preferably within the above numerical range.
本明細書においてポリエチレンイミンとは、アミンと上記アミンに結合した-CH2CH2-からなる繰り返し単位を有する化合物を意味し、上記繰り返し単位は、下記式1で表される。
式1中、X1は水素原子、又は、A1で表される基を表す。式A1中、X2及びX3はそれぞれ独立に水素原子、又は、A1で表される基を表し、*は結合位置を表す。
ポリエチレンイミンは、直鎖状、すなわち、-CH2CH2-NH-で表される繰り返し単位のみから構成されていてもよいし、分岐鎖状であってもよいが、より優れた本発明の効果を有する抗炎症剤が得られる点で、分岐鎖状であることが好ましい。
In Formula 1, X 1 represents a hydrogen atom or a group represented by A1. In formula A1, X 2 and X 3 each independently represent a hydrogen atom or a group represented by A1, and * represents a bonding position.
Polyethyleneimine may be linear, that is, composed only of repeating units represented by -CH 2 CH 2 -NH-, or may be branched, but the more excellent polyethyleneimine of the present invention A branched chain is preferred in that an effective anti-inflammatory agent can be obtained.
ポリエチレンイミンとしては特に制限されないが、例えば、以下の式で表される化合物が挙げられる。
上記ポリエチレンイミンは公知の合成方法により合成可能である。具体的には、例えば、エチレンジアミン、及び/又は、ジエチレントリアミン等に、塩酸、硫酸、又は、パラトルエンスルホン酸等の酸触媒下でエチレンイミンを反応させればよい。
また、ポリエチレンイミンとしては市販品を使用することもできる。市販品としては、エポミン(登録商標)SPシリーズ(日本触媒製)、Lupasolシリーズ(BASF社製)、及び、LUGALVAN-G15000(BASF社製)等が挙げられる。
The above polyethyleneimine can be synthesized by a known synthesis method. Specifically, for example, ethylenediamine and/or diethylenetriamine may be reacted with ethyleneimine under an acid catalyst such as hydrochloric acid, sulfuric acid, or para-toluenesulfonic acid.
Moreover, commercially available products can also be used as polyethyleneimine. Commercially available products include Epomin (registered trademark) SP series (manufactured by Nippon Shokubai), Lupasol series (manufactured by BASF), and LUGALVAN-G15000 (manufactured by BASF).
ポリエチレンイミンは、分子中に、少なくとも1級アミノ基、及び、2級アミノ基を有する。ポリエチレンイミンが更に3級アミノ基を有する場合、分岐鎖状となる。なお、本明細書において分岐鎖状のポリエチレンイミンには、1級アミノ基と3級アミノ基とからなるデンドリマー形態のポリエチレンイミンも含まれる。 Polyethyleneimine has at least a primary amino group and a secondary amino group in its molecule. When polyethyleneimine further has a tertiary amino group, it becomes branched. Note that in this specification, branched polyethyleneimine also includes polyethyleneimine in the form of a dendrimer consisting of a primary amino group and a tertiary amino group.
ポリエチレンイミン中における1級アミノ基の含有量としては特に制限されないが、1級アミノ基、2級アミノ基、及び、3級アミノ基の全体に対して1~99モル%であるのが好ましい。
なお、ポリエチレンイミン中における、1級アミノ基、2級アミノ基、及び、3級アミノ基の比率は、例えば、13C-NMR(Nuclear Magnetic Resonance)法、又は、赤外分光法で測定して求められる。
また、このような分岐鎖状のポリエチレンイミンは、公知の方法によりエチレンイミンを開環重合して得られる。
The content of primary amino groups in polyethyleneimine is not particularly limited, but it is preferably 1 to 99 mol% based on the total of primary amino groups, secondary amino groups, and tertiary amino groups.
Note that the ratio of primary amino groups, secondary amino groups, and tertiary amino groups in polyethyleneimine is measured by, for example, 13 C-NMR (Nuclear Magnetic Resonance) method or infrared spectroscopy. Desired.
Further, such branched polyethyleneimine can be obtained by ring-opening polymerization of ethyleneimine using a known method.
特定ポリエチレンイミンは、分子量が100~2000であり、100~1200が好ましく、200~1000が好ましい。なお、本明細書において、ポリエチレンイミンの分子量は、平均分子量を意味し、沸点上昇法、又は、粘度法により測定される分子量を意味する。ポリエチレンイミンの分子量が2000以上だと、所望の抗炎症性が得られず、1200以下だと、より優れた抗炎症効果が得られ、1000以下だと更に優れた抗炎症効果が得られる。また、ポリエチレンイミンの分子量が200以上だと、より優れた抗炎症効果が得られる。 The specific polyethyleneimine has a molecular weight of 100 to 2,000, preferably 100 to 1,200, and preferably 200 to 1,000. In addition, in this specification, the molecular weight of polyethyleneimine means an average molecular weight, and means the molecular weight measured by the boiling point elevation method or the viscosity method. If the molecular weight of polyethyleneimine is 2000 or more, the desired anti-inflammatory properties cannot be obtained, if it is 1200 or less, a better anti-inflammatory effect can be obtained, and if it is 1000 or less, an even better anti-inflammatory effect can be obtained. Further, when the molecular weight of polyethyleneimine is 200 or more, a more excellent anti-inflammatory effect can be obtained.
特定ポリエチレンイミンの分子量分散度としては特に制限されないが、一般に、1.1~1.5が好ましい。 The molecular weight dispersity of the specific polyethyleneimine is not particularly limited, but is generally preferably from 1.1 to 1.5.
本発明の実施形態に係る抗炎症剤は、エチレンジアミン、及び、特定ポリエチレンイミンからなる群より選択される少なくとも1種の化合物を含有していればよく、より優れた効果を有する抗炎症剤が得られる点で、分子量が200~1000であるポリエチレンイミンを含有することがより好ましく、分子量が200~1000である分岐鎖状のポリエチレンイミンを含有することが更に好ましい。 The anti-inflammatory agent according to the embodiment of the present invention only needs to contain at least one compound selected from the group consisting of ethylenediamine and specific polyethyleneimine, and an anti-inflammatory agent with better effects can be obtained. In this respect, it is more preferable to contain polyethyleneimine having a molecular weight of 200 to 1000, and even more preferable to contain branched polyethyleneimine having a molecular weight of 200 to 1000.
本発明の実施形態に係る抗炎症剤は、後述する実施例で示したとおり、マクロファージに作用して炎症性サイトカインの産生を抑制する作用を有する。 The anti-inflammatory agent according to the embodiment of the present invention has the effect of acting on macrophages and suppressing the production of inflammatory cytokines, as shown in the Examples described below.
本発明の実施形態に係る抗炎症剤は、皮膚外用剤として使用されることができ、上記用途において許容可能な媒質又は基材を含有して剤形化されてもよい。これは、局所適用に適した全ての剤形として、例えば、溶液、ゲル、固体、練りこねた無水生成物、水相に油相を分散させて得られたエマルジョン、懸濁液、マイクロエマルジョン、マイクロカプセル、及び、微細顆粒球等の形態で、クリーム、スキン、ローション、パウダー、軟膏、スプレー、及び、コンシーラースティック等として提供されてもよい。 The anti-inflammatory agent according to the embodiment of the present invention can be used as an external preparation for the skin, and may be formulated into a dosage form containing a medium or base material acceptable for the above uses. It includes all dosage forms suitable for topical application, such as solutions, gels, solids, kneaded anhydrous products, emulsions obtained by dispersing an oil phase in an aqueous phase, suspensions, microemulsions, It may be provided in the form of microcapsules, fine granulocytes, etc., as creams, skins, lotions, powders, ointments, sprays, concealer sticks, etc.
本発明の実施形態に係る抗炎症剤は、溶媒、溶解剤、濃縮剤、ゲル化剤、軟化剤、抗酸化剤、懸濁化剤、安定化剤、発泡剤、芳香剤、界面活性剤、乳化剤、充填剤、金属イオン封鎖剤、キレート化剤、保存剤、ビタミン、遮断剤、湿潤化剤、必須オイル、染料、顔料、及び、親水性又は親油性活性剤を含有してもよい。 The anti-inflammatory agent according to the embodiment of the present invention includes a solvent, a solubilizing agent, a concentrating agent, a gelling agent, a softening agent, an antioxidant, a suspending agent, a stabilizer, a foaming agent, a fragrance, a surfactant, It may also contain emulsifiers, fillers, sequestrants, chelating agents, preservatives, vitamins, blocking agents, wetting agents, essential oils, dyes, pigments, and hydrophilic or lipophilic active agents.
また、本発明の実施形態に係る抗炎症剤は、薬学組成物として経口又は非経口投与剤に剤形化してもよい。非経口投与剤としては、直腸、局所、経皮、静脈内、筋肉内、腹腔内、及び、皮下等に投与されてよい。 Furthermore, the anti-inflammatory agent according to the embodiment of the present invention may be formulated into a pharmaceutical composition for oral or parenteral administration. Parenteral administration may include rectal, topical, transdermal, intravenous, intramuscular, intraperitoneal, and subcutaneous administration.
上記非経口投与のための剤形としては、注射製剤、フィラー、点滴剤、軟膏、ローション、スプレー、懸濁化剤、油剤、及び、坐剤等が挙げられる。本発明の実施形態に係る抗炎症剤は、ゲル化剤、架橋剤、界面活性剤、賦形剤、着色料、香辛料、保存料、安定化剤、緩衝剤、懸濁化剤、及び、その他の補助剤を含有してもよい。 Dosage forms for parenteral administration include injection preparations, fillers, drops, ointments, lotions, sprays, suspensions, oils, suppositories, and the like. The anti-inflammatory agent according to the embodiment of the present invention includes a gelling agent, a crosslinking agent, a surfactant, an excipient, a coloring agent, a spice, a preservative, a stabilizer, a buffering agent, a suspending agent, and others. It may also contain adjuvants.
本発明の実施形態に係る抗炎症剤は、ゲル化剤を含有していてもよい。ゲル化剤を含有すると、注射製剤とした際の取り扱い性が向上する。ゲル化剤としては特に制限されないが、例えば、グアーガム、ローカストビーンガム、クィーンスシード、カラギーナン、ガラクタン、アラビアガム、タラガム、タマリンド、ファーセレラン、カラヤガム、トロロアオイ、キャラガム、トラガントガム、ペクチン、ペクチン酸及びナトリウム塩等の塩、アルギン酸及びナトリウム塩等の塩、マンナン;コメ、トウモロコシ、バレイショ、コムギ等のデンプン;キサンタンガム、デキストラン、サクシノグルカン、カードラン、ヒアルロン酸及びその誘導体並びにその塩、ザンサンガム、プルラン、ジェランガム、キチン、キトサン、寒天、カッソウエキス、コンドロイチン硫酸塩、カゼイン、コラーゲン、ゼラチン、アルブミン;メチルセルロース、エチルセルロース、ヒドロキシエチルセルロース、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、カルボキシメチルセルロース及びそのナトリウム等の塩、メチルヒドロキシプロピルセルロース、セルロース硫酸ナトリウム、ジアルキルジメチルアンモニウム硫酸セルロース、結晶セルロース、セルロース末等のセルロース及びその誘導体;可溶性デンプン、カルボキシメチルデンプン、メチルヒドロキシプロピルデンプン、メチルデンプン等のデンプン系高分子、塩化ヒドロキシプロピルトリモニウムデンプン、オクテニルコハク酸トウモロコシデンプンアルミニウム等のデンプン誘導体;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等アルギン酸誘導体;ポリビニルピロリドン(PVP)、ポリビニルアルコール(PVA)、ビニルピロリドン・ビニルアルコール共重合体、ポリビニルメチルエーテル;ポリエチレングリコール、ポリプロピレングリコール、ポリオキシエチレン・ポリオキシプロピレン共重合体;(メタクリロイルオキシエチルカルボキシベタイン/メタクリル酸アルキル)コポリマー、(アクリレーツ/アクリル酸ステアリル/メタクリル酸エチルアミンオキシド)コポリマー等の両性メタクリル酸エステル共重合体;(ジメチコン/ビニルジメチコン)クロスポリマー、(アクリル酸アルキル/ジアセトンアクリルアミド)コポリマー、(アクリル酸アルキル/ジアセトンアクリルアミド)コポリマーAMP;ポリ酢酸ビニル部分けん化物、マレイン酸共重合体;ビニルピロリドン・メタクリル酸ジアルキルアミノアルキル共重合体;アクリル樹脂アルカノールアミン;ポリエステル、水分散性ポリエステル;ポリアクリルアミド;ポリアクリル酸エチル等のポリアクリル酸エステル共重合体、カルボキシビニルポリマー、ポリアクリル酸及びそのナトリウム塩等の塩、アクリル酸・メタアクリル酸エステル共重合体;アクリル酸・メタアクリル酸アルキル共重合体;ポリクオタニウム-10等のカチオン化セルロース、ポリクオタニウム-7等のジアリルジメチルアンモニウムクロリド・アクリルアミド共重合体、ポリクオタニウム-22等のアクリル酸・ジアリルジメチルアンモニウムクロリド共重合体、ポリクオタニウム-39等のアクリル酸・ジアリルジメチルアンモニウムクロリド・アクリルアミド共重合体、アクリル酸・カチオン化メタアクリル酸エステル共重合体、アクリル酸・カチオン化メタアクリル酸アミド共重合体、ポリクオタニウム-47等のアクリル酸・アクリル酸メチル・塩化メタクリルアミドプロピルトリメチルアンモニウム共重合体、塩化メタクリル酸コリンエステル重合体;カチオン化オリゴ糖、カチオン化デキストラン、グアーヒドロキシプロピルトリモニウムクロリド等のカチオン化多糖類;ポリエチレンイミン;カチオンポリマー;ポリクオタニウム-51等の2-メタクリロイルオキシエチルホスホリルコリンの重合体及びメタクリル酸ブチル共重合体等との共重合体;アクリル樹脂エマルション、ポリアクリル酸エチルエマルション、ポリアクリルアルキルエステルエマルション、ポリ酢酸ビニル樹脂エマルション、天然ゴムラテックス、合成ラテックス等の高分子エマルション;ニトロセルロース;ポリウレタン類及び各種共重合体;各種シリコーン類;アクリル-シリコーングラフト共重合体等のシリコーン系各種共重合体;各種フッ素系高分子;12-ヒドロキシステアリン酸及びその塩;パルミチン酸デキストリン、ミリスチン酸デキストリン等のデキストリン脂肪酸エステル;無水ケイ酸、煙霧状シリカ(超微粒子無水ケイ酸)、ケイ酸アルミニウムマグネシウム、ケイ酸ナトリウムマグネシウム、金属石鹸、ジアルキルリン酸金属塩、ベントナイト、ヘクトライト、有機変性粘土鉱物、ショ糖脂肪酸エステル、フラクトオリゴ糖脂肪酸エステル等が挙げられる。 The anti-inflammatory agent according to the embodiment of the present invention may contain a gelling agent. Containing a gelling agent improves the ease of handling when used as an injection preparation. Gelling agents are not particularly limited, but include, for example, guar gum, locust bean gum, queen seed, carrageenan, galactan, gum arabic, tara gum, tamarind, farcellan, gum karaya, tragacanth, carra gum, gum tragacanth, pectin, pectic acid, and sodium salt. salts such as alginic acid and sodium salts, mannan; starches such as rice, corn, potato, wheat, etc.; xanthan gum, dextran, succinoglucan, curdlan, hyaluronic acid and its derivatives and salts thereof, xanthan gum, pullulan, gellan gum , chitin, chitosan, agar, cassow extract, chondroitin sulfate, casein, collagen, gelatin, albumin; methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose and its salts such as sodium, methylhydroxypropylcellulose, Cellulose and its derivatives such as sodium cellulose sulfate, dialkyldimethylammonium cellulose sulfate, crystalline cellulose, and cellulose powder; starch-based polymers such as soluble starch, carboxymethyl starch, methylhydroxypropyl starch, and methyl starch; hydroxypropyltrimonium chloride starch; Starch derivatives such as corn starch aluminum octenyl succinate; alginic acid derivatives such as sodium alginate and propylene glycol alginate; polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), vinylpyrrolidone/vinyl alcohol copolymer, polyvinyl methyl ether; polyethylene glycol, polypropylene Glycol, polyoxyethylene/polyoxypropylene copolymer; Amphoteric methacrylate ester copolymer such as (methacryloyloxyethyl carboxybetaine/alkyl methacrylate) copolymer, (acrylates/stearyl acrylate/ethylamine oxide methacrylate) copolymer; ( dimethicone/vinyl dimethicone) crosspolymer, (alkyl acrylate/diacetone acrylamide) copolymer, (alkyl acrylate/diacetone acrylamide) copolymer AMP; partially saponified polyvinyl acetate, maleic acid copolymer; vinylpyrrolidone/dialkyl methacrylate Aminoalkyl copolymers; acrylic resin alkanolamines; polyesters, water-dispersible polyesters; polyacrylamides; polyacrylic acid ester copolymers such as polyethyl acrylate, carboxyvinyl polymers, polyacrylic acids and their salts such as sodium salts; Acrylic acid/methacrylic acid ester copolymer; acrylic acid/alkyl methacrylate copolymer; cationized cellulose such as polyquaternium-10, diallyldimethylammonium chloride/acrylamide copolymer such as polyquaternium-7, polyquaternium-22, etc. acrylic acid/diallyldimethylammonium chloride copolymer such as polyquaternium-39, acrylic acid/diallyldimethylammonium chloride/acrylamide copolymer such as polyquaternium-39, acrylic acid/cationized methacrylate ester copolymer, acrylic acid/cationized methacrylic Acid amide copolymer, acrylic acid/methyl acrylate/methacrylamidopropyltrimethylammonium chloride copolymer such as polyquaternium-47, chlorinated methacrylic acid choline ester polymer; cationized oligosaccharide, cationized dextran, guar hydroxypropyltrimonium Cationized polysaccharides such as chloride; polyethyleneimine; cationic polymers; copolymers of 2-methacryloyloxyethylphosphorylcholine such as polyquaternium-51 and butyl methacrylate copolymers; acrylic resin emulsions, polyethyl acrylates Polymer emulsions such as emulsions, polyacrylalkyl ester emulsions, polyvinyl acetate resin emulsions, natural rubber latex, synthetic latex; nitrocellulose; polyurethanes and various copolymers; various silicones; acrylic-silicone graft copolymers, etc. Various silicone copolymers; Various fluorinated polymers; 12-hydroxystearic acid and its salts; Dextrin fatty acid esters such as dextrin palmitate and dextrin myristate; silicic anhydride, fumed silica (ultrafine silicic anhydride), Examples include aluminum magnesium silicate, sodium magnesium silicate, metal soap, dialkyl phosphate metal salt, bentonite, hectorite, organically modified clay mineral, sucrose fatty acid ester, fructooligosaccharide fatty acid ester, and the like.
なかでも、後述する実施例に示すとおり、得られる抗炎症剤の細胞に対する毒性がより低くなる、又は、より優れた抗炎症作用を有する観点で、ゲル化剤としては、ヒアルロン酸又はその誘導体が好ましい。 Among them, as shown in the examples below, hyaluronic acid or its derivatives are preferred as gelling agents, from the viewpoint that the resulting anti-inflammatory agent has lower toxicity to cells or has a better anti-inflammatory effect. preferable.
また、本発明の実施形態に抗炎症剤がゲル化剤を含有する場合、更に、架橋剤を含有していてもよい。架橋剤は得られるゲルの力学強度を向上させることができる。 Furthermore, when the anti-inflammatory agent in the embodiment of the present invention contains a gelling agent, it may further contain a crosslinking agent. A crosslinking agent can improve the mechanical strength of the resulting gel.
架橋剤としては特に制限されないが、例えば、以下の式で表されるスルホン化セルロースを用いてもよい。
上記式中、k、m、及び、nは、各繰り返し単位のモル%を表し、特に制限されないが、kは25~95モル%が好ましく、40~90モル%がより好ましい。mは4~70モル%が好ましく、7~60モル%がより好ましい。nは1~70モル%が好ましく、10~30モル%がより好ましい。 In the above formula, k, m, and n represent mol% of each repeating unit, and are not particularly limited, but k is preferably 25 to 95 mol%, more preferably 40 to 90 mol%. m is preferably 4 to 70 mol%, more preferably 7 to 60 mol%. n is preferably 1 to 70 mol%, more preferably 10 to 30 mol%.
上記スルホン化セルロースは、下記式に示すグルコース単位の3位と4位の間が開環されて、スルホン化された構造を含むセルロースである。 The above-mentioned sulfonated cellulose is a cellulose containing a sulfonated structure in which a ring is opened between the 3rd and 4th positions of a glucose unit shown in the following formula.
上式は、水中等においてスルホン基(-SO3H)が解離された状態を示し、対カチオンはNa+に限定されずプロトン、K+等であってよい。 The above formula shows a state in which the sulfone group (-SO 3 H) is dissociated in water or the like, and the counter cation is not limited to Na + but may be a proton, K + or the like.
スルホン化セルロースは、例えばHenrikki Liimatainenら,Cellulose(2013)20:741-749に記載された下記式に示す経路で合成することができる。
先ず、原料セルロースを水に分散させ、分散液を得る。上記分散液に、セルロース中のグルコース単位の量(k)を100モル%としたときに50~200モル%の過ヨウ素酸ナトリウム(NaIO4)を添加し、遮光しながら、40~60℃で2~6時間撹拌することによって、アルデヒド化セルロースを生成する。
Sulfonated cellulose can be synthesized, for example, by the route shown in the following formula described in Henrikki Liimatainen et al., Cellulose (2013) 20:741-749.
First, raw cellulose is dispersed in water to obtain a dispersion. To the above dispersion, 50 to 200 mol% of sodium periodate (NaIO 4 ) was added when the amount (k) of glucose units in cellulose was 100 mol%, and the mixture was heated at 40 to 60°C while shielding from light. By stirring for 2 to 6 hours, aldehyde cellulose is produced.
次に減圧濾過によって未反応物を含む水溶液を除去し、超純水で洗浄する操作を数回繰り返した後に凍結乾燥することで、アルデヒド化セルロースの乾燥粉末を得る。上記式において、kの初期値を100モル%としたときに、mは1~80モル%、好ましくは10~50モル%である。 Next, the aqueous solution containing unreacted substances is removed by vacuum filtration, and the procedure of washing with ultrapure water is repeated several times, followed by freeze-drying to obtain a dry powder of aldehyde cellulose. In the above formula, when the initial value of k is 100 mol%, m is 1 to 80 mol%, preferably 10 to 50 mol%.
アルデヒド基の量は、水酸化ナトリウム水溶液を用いた導電率測定による中和滴定により求めることができ、0.5~8ミリモル/g、好ましくは1~7ミリモル/g、より好ましくは1~5ミリモル/gである。 The amount of aldehyde groups can be determined by neutralization titration using conductivity measurement using an aqueous sodium hydroxide solution, and is 0.5 to 8 mmol/g, preferably 1 to 7 mmol/g, more preferably 1 to 5 mmol/g. mmol/g.
原料セルロースとしては、例えば、針葉樹系パルプ、広葉樹系パルプ、綿系パルプ等の植物、動物等から得られたセルロース、これらを用いた紙、古紙等を用いることができる。 As the raw material cellulose, for example, cellulose obtained from plants, animals, etc. such as softwood pulp, hardwood pulp, and cotton pulp, paper using these, waste paper, etc. can be used.
次いで、アルデヒド化セルロースを超純水に分散させ、ピロ亜硫酸ナトリウム(Na2S2O5)を、アルデヒド基量を100モル%として20~200モル%、好ましくは50~150モル%で添加して、室温で12~24時間、攪拌しながら反応させる。生成物を遠心分離により回収し、超純水等で洗浄して未反応物を除去して精製した後、超音波ホモジナイザーによって10~30分間程度ホモジナイズすることによって、スルホン化セルロースのナノファイバー(「sCNF」と略す場合がある)を得ることができる。収率は、約80~90%である。 Next, the aldehyde cellulose is dispersed in ultrapure water, and sodium pyrosulfite (Na 2 S 2 O 5 ) is added in an amount of 20 to 200 mol%, preferably 50 to 150 mol%, with the aldehyde group amount being 100 mol%. and react at room temperature for 12 to 24 hours with stirring. The product is collected by centrifugation, purified by washing with ultrapure water etc. to remove unreacted substances, and then homogenized for about 10 to 30 minutes using an ultrasonic homogenizer to obtain sulfonated cellulose nanofibers ( (sometimes abbreviated as "sCNF") can be obtained. Yield is approximately 80-90%.
sCNFは生分解性である。本発明において「生分解性」は37℃のp7.4のリン酸緩衝生理食塩水(PBS)中で、1日で1質量%以上分解したことにより確認した。この生分解性は、原料セルロースのグルコース単位の量(k)の初期値を100モル%としたとき、m+n、即ち開環された単位が、少なくとも1モル%、好ましくは10~50モル%であることによるものと考えられる。また、sCNFは開環単位を有することによって、X線回折測定による結晶化度が20~70%であり、90%程度の結晶化度を有する原料セルロースに比べて低い。 sCNF is biodegradable. In the present invention, "biodegradability" was confirmed by decomposition of 1% by mass or more in 1 day in phosphate buffered saline (PBS) of p7.4 at 37°C. This biodegradability is determined when m+n, that is, ring-opened units, is at least 1 mol%, preferably 10 to 50 mol%, when the initial value of the amount (k) of glucose units in the raw material cellulose is 100 mol%. This is thought to be due to certain reasons. Furthermore, since sCNF has a ring-opening unit, the degree of crystallinity measured by X-ray diffraction is 20 to 70%, which is lower than the raw material cellulose, which has a degree of crystallinity of about 90%.
また、本発明の実施形態に係る抗炎症剤は、溶媒を含有してもよい。溶媒としては特に制限されないが、水、水と任意の割合で混和する有機溶媒、及び、これらの混合溶媒が好ましく、水がより好ましい。上記有機溶媒としては例えば、アルコール類(多価アルコールを含む)等が挙げられる。 Moreover, the anti-inflammatory agent according to the embodiment of the present invention may contain a solvent. The solvent is not particularly limited, but water, organic solvents that are miscible with water in any proportion, and mixed solvents thereof are preferred, and water is more preferred. Examples of the organic solvent include alcohols (including polyhydric alcohols).
また、本発明の実施形態に係る抗炎症剤がゲル化剤を含有する場合、更に、その他の成分を含有していてもよく、デリバリーしたい各種薬剤、及び、タンパク質等を配合し、これらの局所デリバリー担体、又は、徐放性デリバリー担体として使用してもよい。
薬剤としては、例えば抗炎症薬、抗血栓薬、抗生物質、線維芽細胞増殖因子、血管内皮細胞増殖因子、及び、肝細胞増殖因子等の成長因子が挙げられる。
また、ワクチンとして、ウイルスや癌の抗原タンパク質を担持することで、ワクチンキャリアとして使用してもよい。
In addition, when the anti-inflammatory agent according to the embodiment of the present invention contains a gelling agent, it may further contain other ingredients, and various drugs to be delivered, proteins, etc. are blended, and these local It may be used as a delivery carrier or a sustained release delivery carrier.
Examples of the drug include anti-inflammatory drugs, antithrombotic drugs, antibiotics, growth factors such as fibroblast growth factor, vascular endothelial cell growth factor, and hepatocyte growth factor.
Furthermore, it may be used as a vaccine carrier by supporting a virus or cancer antigen protein.
本発明の実施形態に係る抗炎症剤の製造方法としては特に制限されず、すでに説明した各成分を混合すればよい。混合方法としては特に制限されないが、溶媒中に他の固体成分を分散、溶解させてもよく、固体同士を混合してもよい。固体同士を混合する場合、混合前に各成分の固体を粉砕してもよい。粉砕する方法としては特に制限されないが、例えば、湿式粉砕法が挙げられる。湿式粉砕法としては、ボールミリング、及び、ホモジナイザー粉砕等が挙げられる。 The method for producing the anti-inflammatory agent according to the embodiment of the present invention is not particularly limited, and the components described above may be mixed. The mixing method is not particularly limited, but other solid components may be dispersed or dissolved in the solvent, or solids may be mixed together. When mixing solids, the solids of each component may be pulverized before mixing. The method of pulverization is not particularly limited, but includes, for example, a wet pulverization method. Examples of the wet pulverization method include ball milling and homogenizer pulverization.
また、本発明の実施形態に係る抗炎症剤をシリンジに充填して静置することにより、抗炎症剤がプレフィルドされたプレフィルドシリンジを製造することができる。 Further, by filling a syringe with the anti-inflammatory agent according to the embodiment of the present invention and leaving it to stand, a pre-filled syringe pre-filled with the anti-inflammatory agent can be manufactured.
このようにして得られるプレフィルドシリンジは、中に含まれる注射製剤(抗炎症剤)を、シリンジのプランジャーロッドを押し込み注射針から排出させるだけで、流動性を示すため、そのままスムーズに注射針から排出させることが可能であるうえ、抗炎症剤の保存安定性にも優れる。なお、本発明は、当該プレフィルドシリンジを備えたキットも包含する。 The prefilled syringe obtained in this way exhibits fluidity by simply pushing the plunger rod of the syringe and expelling the injection preparation (anti-inflammatory agent) contained therein from the needle. Not only can it be excreted, but the anti-inflammatory agent also has excellent storage stability. Note that the present invention also includes a kit including the prefilled syringe.
本発明の実施形態に係る抗炎症剤の有効成分(すでに説明した化合物)の投与容量は、投与される対象の年齢、性別、体重、病履状態及びその重症度、投与経路又は処方者の判断によって異なる。このような因子に基づいて適当な容量の決定は、当業者の水準内にあり、その1日の投与容量は、例えば、0.1mg/kg/日~100mg/kg/日、より具体的には5mg/kg/日~50mg/kg/日になり得るが、これらに限定されるものではない。 The dosage of the active ingredient (already explained compound) of the anti-inflammatory agent according to the embodiment of the present invention is determined by the age, sex, weight, disease status and severity of the subject to be administered, the route of administration, or the judgment of the prescriber. It depends. Determination of appropriate doses based on such factors is within the level of those skilled in the art, and the daily dose may be, for example, from 0.1 mg/kg/day to 100 mg/kg/day, more specifically. can be, but is not limited to, 5 mg/kg/day to 50 mg/kg/day.
以下に実施例に基づいて本発明を更に詳細に説明する。以下の実施例に示す材料、使用量、割合、処理内容、処理手順等は、本発明の趣旨を逸脱しない限り適宜変更することができる。したがって、本発明の範囲は以下に示す実施例により限定的に解釈されるべきものではない。 The present invention will be explained in more detail below based on Examples. The materials, usage amounts, proportions, processing details, processing procedures, etc. shown in the following examples can be changed as appropriate without departing from the spirit of the present invention. Therefore, the scope of the present invention should not be construed as being limited by the Examples shown below.
(TNF-αの産生抑制)
3×104個のマウス骨髄由来マクロファージ(BMDM)を96ウェルプレートに播種し、24時間予備培養した。培地で100μg/mLに調製したポリエチレンイミンに、LPS(リポ多糖)を添加し100ng/mLとした。この溶液を各ウェルに100μLずつ添加し、24時間培養した。なお、試料としては、エチレンジアミン(図中、「PEI60」と記載した。)、分子量が150の「PEI150」(トリス(2-アミノエチル)アミンの純度90%以上)、分子量が300の「PEI300」、分子量が600の「PEI600」、分子量が1200の「PEI1200」、及び、分子量が10000の「PEI10000」を用いた。
また、コントロールとして、培地のみを加えたサンプル(コントロール)とLPSとを100ng/mLで添加したサンプルを用いた。
(Suppression of TNF-α production)
3 × 10 4 mouse bone marrow-derived macrophages (BMDM) were seeded in a 96-well plate and precultured for 24 hours. LPS (lipopolysaccharide) was added to polyethyleneimine, which was adjusted to 100 μg/mL in a medium, to 100 ng/mL. 100 μL of this solution was added to each well and cultured for 24 hours. The samples include ethylenediamine (indicated as "PEI60" in the figure), "PEI150" with a molecular weight of 150 (tris(2-aminoethyl)amine purity of 90% or more), and "PEI300" with a molecular weight of 300. , "PEI600" with a molecular weight of 600, "PEI1200" with a molecular weight of 1200, and "PEI10000" with a molecular weight of 10,000 were used.
Furthermore, as controls, a sample to which only the medium was added (control) and a sample to which LPS was added at 100 ng/mL were used.
培養後、上清を回収し、酵素結合免疫吸着法(ELISA)によって、上清中に含まれている炎症性サイトカインの一種である腫瘍壊死因子(TNF-α)の濃度を定量した。その結果、LPSのみを添加した場合はTNF-αが346pg/mL産生されるのに対して、PEI300を同時に添加することによって、2倍以上TNF-αの産生を抑制することができた。PEI1200も同様に高い抗炎症効果を示した。一方で、PEI10000はTNF-αが検出限界以下であった。 After culturing, the supernatant was collected, and the concentration of tumor necrosis factor (TNF-α), a type of inflammatory cytokine, contained in the supernatant was determined by enzyme-linked immunosorbent assay (ELISA). As a result, when only LPS was added, 346 pg/mL of TNF-α was produced, whereas by adding PEI300 at the same time, the production of TNF-α could be suppressed more than twice. PEI1200 also showed high anti-inflammatory effects. On the other hand, TNF-α was below the detection limit in PEI10000.
この原因として、PEI10000の有する細胞毒性が考えられたため、細胞生存率をWST-8アッセイによって評価した。その結果、PEI10000は高い細胞毒性を有することがわかった。結果を図1にまとめて示した。 Since the cytotoxicity of PEI10,000 was thought to be the cause of this, cell viability was evaluated by WST-8 assay. As a result, PEI10000 was found to have high cytotoxicity. The results are summarized in Figure 1.
図1の結果から、分子量が100~2000であるPEI600は、PEI10000と比較してより優れた抗炎症作用を有し、分子量が200~1200であるPEI600は、PEI150と比較して更に優れた抗炎症効果を有し、分子量が200~1000であるPEI600は、PEI1200と比較して特に優れた抗炎症効果を有することがわかった。 From the results in Figure 1, PEI600 with a molecular weight of 100 to 2000 has a better anti-inflammatory effect compared to PEI10000, and PEI600 with a molecular weight of 200 to 1200 has an even better anti-inflammatory effect compared to PEI150. PEI600, which has an inflammatory effect and has a molecular weight of 200-1000, was found to have a particularly good anti-inflammatory effect compared to PEI1200.
なお、図1中、A表は、TNF-αの産生量(単位:pg/mL)を表しており、B表はWST-8アッセイによる細胞生存率を表しており、C表はA表及びB表の結果から計算された1×104個の細胞当たりのTNF-αの産生量(単位:pg/1×104cells)を表している。なお、図1中「-」は検出限界以下だった(抗炎症効果が得られなかった)ことを示している。 In Figure 1, Table A represents the production amount of TNF-α (unit: pg/mL), Table B represents the cell survival rate by WST-8 assay, and Table C represents the amount of TNF-α produced (unit: pg/mL). It represents the amount of TNF-α produced per 1×10 4 cells (unit: pg/1×10 4 cells) calculated from the results in Table B. In addition, "-" in FIG. 1 indicates that it was below the detection limit (no anti-inflammatory effect was obtained).
(IL-6の産生抑制)
3×104個のマウス骨髄由来マクロファージ(BMDM)を96ウェルプレートに播種し、24時間予備培養した。培地で100μg/mLに調製したポリエチレンイミン(分子量300の「PEI300」)に、LPSを添加し100ng/mLとした。この溶液を各ウェルに100μLずつ添加し、24時間培養した。コントロールとして、培地のみを加えたサンプル(コントロール)とLPSとを100ng/mLで添加したサンプルを用いた。
培養後、上清を回収し、ELISAによって、上清中に含まれている炎症性サイトカインであるインターロイキン-6(IL-6)の濃度を定量した。その結果、コントロールと比較して、ポリエチレンイミンを用いた場合IL-6の産生量が半分以下に低下し、優れた抗炎症効果が確認された。
(Suppression of IL-6 production)
3 × 10 4 mouse bone marrow-derived macrophages (BMDM) were seeded in a 96-well plate and precultured for 24 hours. LPS was added to polyethyleneimine ("PEI300" with a molecular weight of 300) adjusted to 100 ng/mL in a medium to 100 ng/mL. 100 μL of this solution was added to each well and cultured for 24 hours. As controls, a sample to which only the medium was added (control) and a sample to which LPS was added at 100 ng/mL were used.
After culturing, the supernatant was collected, and the concentration of interleukin-6 (IL-6), an inflammatory cytokine, contained in the supernatant was determined by ELISA. As a result, compared to the control, when polyethyleneimine was used, the amount of IL-6 produced was reduced by more than half, confirming an excellent anti-inflammatory effect.
Claims (14)
分子量が300~2000であり、3級アミノ基を有するポリエチレンイミンを有効成分として含有する、抗炎症剤。 It is an anti-inflammatory agent,
An anti-inflammatory agent having a molecular weight of 300 to 2000 and containing polyethyleneimine having a tertiary amino group as an active ingredient.
分子量が300~2000であり、3級アミノ基を有するポリエチレンイミンと、
ゲル化剤とを備え、
使用時に混合して前記ポリエチレンイミンを含有するゲルを調製するためのキット。 It is a kit,
polyethyleneimine having a molecular weight of 300 to 2000 and having a tertiary amino group;
and a gelling agent,
A kit for preparing a gel containing the polyethyleneimine by mixing at the time of use.
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