JP2011251944A - Analgesic preparation for embedding - Google Patents
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本発明は、体内に埋植するための鎮痛製剤、および当該埋植用鎮痛製剤を構成要素の一つとする鎮痛用キットに関するものである。 The present invention relates to an analgesic preparation for implantation in the body and an analgesic kit comprising the analgesic preparation for implantation as one of the components.
手術の後では、通常、切開部位を中心として痛みが感じられる。これは切開が原因となる急性痛であり、術後１２〜１６時間程度をピークとし、切開部位の治癒と共に次第に緩和される。それに加えて、術後２４〜４８時間程度から、急性痛とは異なり、痛む部位が特定され難く慢性的な疼痛が生じる場合がある。手術を受ける患者にとり、手術自体のみならずこれら手術後疼痛への恐れは大きく、手術に対する大きな不安要素の一つである。 After surgery, usually pain is felt around the incision site. This is an acute pain caused by an incision, which peaks at about 12 to 16 hours after the operation, and is gradually relieved with the healing of the incision site. In addition, from about 24 to 48 hours after the operation, unlike acute pain, it is difficult to identify a painful site and chronic pain may occur. For patients undergoing surgery, there is a great fear of not only the surgery itself but also post-surgery pain, which is one of the major anxiety factors for the surgery.
また、手術後疼痛は、それ自体が患者にとり苦痛であるばかりでなく、生体に様々な反射やストレスを引き起こす。例えば、痛みがある部分では血管の収縮が見られ、神経への酸素や栄養の送達が阻害されることにより神経がダメージを受け、さらに痛みが増強されるという悪循環に陥る。 In addition, post-operative pain is not only painful for the patient, but also causes various reflexes and stress on the living body. For example, blood vessel contraction is seen in the painful part, and the nerve is damaged by the delivery of oxygen and nutrients to the nerve, resulting in a vicious circle in which the pain is further enhanced.
最近、手術侵襲を軽減するために内視鏡手術が導入され、普及し始めている。内視鏡手術であれば、切開部位を極めて小さくできるため、手術後疼痛の問題は比較的起こり難いといえる。しかし、同手術を適用できない場合も多く、手術後疼痛は依然として問題である。 Recently, endoscopic surgery has been introduced to reduce surgical invasion and has begun to spread. In endoscopic surgery, the incision site can be made extremely small, so that the problem of pain after surgery is relatively unlikely. However, the surgery is often not applicable and postoperative pain remains a problem.
手術後疼痛に対しては、一般的には非ステロイド性消炎鎮痛薬が主に用いられている。また、脊髄を被覆する髄膜のうち一番外側の硬膜の外側にある空間へ局所麻酔薬などの鎮痛薬を注入して神経を麻痺させることにより痛みを緩和する硬膜外ブロックが用いられることもある。硬膜外ブロックは、硬膜外腔に管を留置して鎮痛薬を継続的に供給することも可能なので、持続的な手術後疼痛にも有効である。さらに、オピオイドの経静脈投与も行われている。また、最近では、患者間における痛みの違いや鎮痛薬の必要量などの相違から、患者自らが鎮痛薬の投与量を調節する患者自己調節鎮痛法も一般化しつつある。 In general, non-steroidal anti-inflammatory analgesics are mainly used for post-operative pain. In addition, an epidural block that relieves pain by injecting analgesics such as local anesthetics into the space outside the outermost dura mater that covers the spinal cord and paralyzing the nerve is used Sometimes. The epidural block is also effective for continuous postoperative pain because it is possible to continuously supply an analgesic by placing a tube in the epidural space. In addition, intravenous administration of opioids is also performed. Recently, patient self-adjusting analgesic methods in which the patient himself / herself adjusts the dose of the analgesic is becoming common due to differences in pain among patients and the required amount of analgesic.
しかし、非ステロイド性消炎鎮痛薬は血圧降下作用などを示すため、自己調節鎮痛法には使用できない。また、硬膜外ブロックは体動時の痛みに対する効果が十分ではなく、オピオイドには習慣性や呼吸障害などの重篤な副作用があり、患者自己調節鎮痛法では過鎮痛の問題がある。 However, non-steroidal anti-inflammatory analgesics cannot be used for self-regulating analgesia because of their blood pressure lowering effects. In addition, epidural block is not effective for pain during body movement, opioids have serious side effects such as habituality and respiratory disorder, and patient self-regulation analgesia has the problem of over analgesia.
そこで、安全性が高く、簡便で効果の高い手術後疼痛の抑制手段が切望されている。 Therefore, there is an urgent need for a means for suppressing postoperative pain that is highly safe, simple and effective.
ところで、薬剤を経口投与や血中投与した後では、薬剤の血中濃度が急激に上昇した後に低下する。薬剤の副作用の問題はその血中濃度が過剰に高まった際に顕著なものとなる一方で、血中濃度が十分でなければ効果が得られない。そこで、副作用の問題を解決しつつ薬剤の効果を持続的に得るために、薬剤を徐放できる製剤が検討されている。 By the way, after a drug is administered orally or in blood, the blood concentration of the drug rapidly increases and then decreases. The problem of side effects of drugs becomes prominent when the blood concentration is excessively increased, but the effect cannot be obtained unless the blood concentration is sufficient. Therefore, in order to continuously obtain the effect of the drug while solving the problem of side effects, a preparation capable of sustained release of the drug has been studied.
例えば特許文献１には、架橋したゼラチンからなる医療用ハイドロゲルが開示されている。薬剤を含む当該ハイドロゲルを体内に埋植すれば薬剤を徐放でき、また、ゼラチンからなることから、やがて体内に分解吸収される。 For example, Patent Document 1 discloses a medical hydrogel made of crosslinked gelatin. If the hydrogel containing the drug is implanted in the body, the drug can be released slowly, and since it is made of gelatin, it is eventually decomposed and absorbed in the body.
かかるハイドロゲルは製品化されているが、そのカタログに記載の実用例で用いられている薬剤は上皮増殖因子（ＥＧＦ）やベクターなど、ペプチドや高分子のみである。 Such hydrogels have been commercialized, but the only drugs used in practical examples described in the catalog are peptides and polymers such as epidermal growth factor (EGF) and vectors.
本発明は、安全性が高く、簡便で薬剤徐放性に優れ、効果の高い手術後疼痛の抑制手段として用いられる埋植用鎮痛製剤、および当該埋植用鎮痛製剤を構成要素の一つとする鎮痛用キットを提供することを目的とする。 The present invention is one of the components of an analgesic preparation for implantation used as a highly safe, simple, excellent drug sustained release and highly effective postoperative pain suppression means, and the analgesic preparation for implantation. An object is to provide an analgesic kit.
本発明者らは、上記課題を解決するために鋭意研究を重ねた。その結果、架橋ゼラチンと鎮痛薬を含む製剤であれば、上記の効果が発揮され、手術後疼痛を持続的かつ有効に抑制できることを見出して、本発明を完成した。 The inventors of the present invention have made extensive studies to solve the above problems. As a result, the present invention was completed by finding that a preparation containing crosslinked gelatin and an analgesic can exert the above-described effects and can suppress postoperative pain continuously and effectively.
本発明に係る埋植用鎮痛製剤は、架橋ゼラチンおよび鎮痛薬を含むことを特徴とする。 The analgesic preparation for implantation according to the present invention is characterized by containing a crosslinked gelatin and an analgesic.
上記埋植用鎮痛製剤としては、架橋ゼラチンに対する質量比（鎮痛薬／架橋ゼラチン）で鎮痛薬を１×１０-4以上、１以下含むものが好適である。当該比が１×１０-4未満であると、架橋ゼラチンに対する鎮痛薬の量が少な過ぎ、鎮痛効果が十分に発揮されないおそれがあり得る。一方、当該比が１を超えると、鎮痛薬が架橋ゼラチンから過剰に漏れ出すおそれがあり得る。 As the analgesic preparation for implantation, those containing 1 × 10 −4 or more and 1 or less of an analgesic at a mass ratio (analgesic / crosslinked gelatin) to crosslinked gelatin are suitable. If the ratio is less than 1 × 10 −4 , the amount of the analgesic with respect to the crosslinked gelatin is too small, and the analgesic effect may not be sufficiently exhibited. On the other hand, if the ratio exceeds 1, the analgesic may leak excessively from the crosslinked gelatin.
上記埋植用鎮痛製剤に配合される鎮痛薬としては、非ステロイド性消炎鎮痛薬および局所麻酔薬が好適である。 Non-steroidal anti-inflammatory analgesics and local anesthetics are suitable as the analgesics to be blended in the analgesic preparation for implantation.
本発明に係る鎮痛用キットは、上記埋植用鎮痛製剤、および鎮痛薬を含む先制鎮痛用製剤から構成されていることを特徴とする。 The analgesic kit according to the present invention comprises the above-mentioned analgesic preparation for implantation and a preemptive analgesic preparation containing an analgesic.
本発明に係る埋植用鎮痛製剤は、手術部位に埋植されると、生体内のコラゲナーゼなどの分解酵素により架橋ゼラチンが徐々に分解されて可溶化され、それと共に、捕捉されていた鎮痛薬が徐放される。よって、鎮痛薬の濃度が投与部位で急激に上がることはなく、安全である。また、鎮痛薬が手術部位で徐放されるため、鎮痛効果が持続的に発揮され、手術後の疼痛が効果的に抑制される。また、本発明に係る鎮痛用キットは、当該埋植用鎮痛製剤よりもさらに効果が高い。従って本発明は、手術後における患者の苦痛を効果的に抑制できるものとして、非常に有用である。 When the analgesic preparation for implantation according to the present invention is implanted at a surgical site, the crosslinked gelatin is gradually decomposed and solubilized by a degrading enzyme such as collagenase in the living body, and the analgesic that has been captured. Is released slowly. Therefore, the concentration of the analgesic does not increase rapidly at the administration site, and it is safe. In addition, since the analgesic is gradually released at the surgical site, the analgesic effect is continuously exerted, and pain after surgery is effectively suppressed. In addition, the analgesic kit according to the present invention is more effective than the analgesic preparation for implantation. Therefore, this invention is very useful as what can suppress the patient's pain after an operation effectively.
本発明に係る埋植用鎮痛製剤は、架橋ゼラチンおよび鎮痛薬を含む。 The analgesic preparation for implantation according to the present invention contains crosslinked gelatin and an analgesic.
ゼラチンは、コラーゲンが変性してその三重らせん構造が崩壊したものをいう。コラーゲンは高等動物の結合組織を構成する主要タンパク質であるので、ゼラチンは、ブタやウシなどの哺乳類や、サメなどの魚類などに含まれるコラーゲンを変性させることにより得られる。また、天然由来のゼラチンを一部加水分解したものや、その側鎖にコハク酸、エチレンジアミン、ポリ乳酸、ポリエチレングリコールなどを結合させたもの、疎水性残基を導入したものなど、ゼラチン誘導体を用いてもよい。 Gelatin refers to a product in which collagen is denatured and its triple helix structure is destroyed. Since collagen is a major protein constituting connective tissue of higher animals, gelatin can be obtained by denaturing collagen contained in mammals such as pigs and cows, fish such as sharks, and the like. In addition, gelatin derivatives such as those obtained by partially hydrolyzing naturally-derived gelatin, those in which succinic acid, ethylenediamine, polylactic acid, polyethylene glycol, etc. are bonded to the side chain, or those having a hydrophobic residue introduced are used. May be.
ゼラチンは一般的なプロテアーゼには分解され難く、コラゲナーゼなど主にコラーゲンに特異的な分解酵素により分解される。また、本発明で用いるゼラチンは架橋されたものであり、水溶性が高い未処理ゼラチンと異なり、体内で体液と接触しても溶解しない。よって、本発明製剤は、他のタンパク質や未処理ゼラチンを用いた製剤に比べて分解され難く、薬剤徐放性により一層優れる。 Gelatin is difficult to be decomposed by general proteases and is decomposed mainly by collagenases such as collagenase. Further, gelatin used in the present invention is cross-linked, and unlike untreated gelatin having high water solubility, it does not dissolve even when it comes into contact with body fluids in the body. Therefore, the preparation of the present invention is less decomposed than preparations using other proteins and untreated gelatin, and is more excellent in drug sustained release.
ゼラチンはペプチドであることから、多くの反応性官能基を側鎖として有する。よって、これら反応性官能基に対して反応性を有する官能基を複数有する架橋剤や、反応性官能基同士の結合を促進する架橋剤により、容易に架橋することができる。かかる架橋剤としては、例えば、グルタルアルデヒドなどの多価アルデヒド化合物；１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩などのカルボジイミド化合物；ジアミン化合物；ジエポキシ化合物；エピクロロヒドリンなどのハロゲン化エポキシ化合物；カルシウムイオンやマグネシウムイオンなどの多価金属イオンなどを挙げることができる。 Since gelatin is a peptide, it has many reactive functional groups as side chains. Therefore, it can bridge | crosslink easily by the crosslinking agent which has multiple functional groups which have reactivity with respect to these reactive functional groups, and the crosslinking agent which accelerates | stimulates the coupling | bonding of reactive functional groups. Examples of such cross-linking agents include polyvalent aldehyde compounds such as glutaraldehyde; carbodiimide compounds such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride; diamine compounds; diepoxy compounds; epichlorohydrin and the like. Halogenated epoxy compounds; polyvalent metal ions such as calcium ions and magnesium ions.
架橋ゼラチンは、常法により製造することができる。即ち、ゼラチンの溶液に架橋剤を加えて反応させた後、架橋ゼラチンを単離すればよい。架橋度は、ゼラチンに対する架橋剤の量や反応時間などにより容易に調整することができる。 Cross-linked gelatin can be produced by a conventional method. That is, the cross-linked gelatin may be isolated after the cross-linking agent is added to the gelatin solution and reacted. The degree of cross-linking can be easily adjusted by the amount of cross-linking agent relative to gelatin, reaction time, and the like.
架橋ゼラチンの架橋度は、適宜調整することができる。即ち、架橋度が低過ぎると架橋ゼラチンが体内中で過剰に溶解し易くなったり分解され易くなり、鎮痛薬の持続性を十分に確保し難くなるおそれがあり得る。一方、架橋度が高過ぎると、鎮痛薬が放出されなくなり、鎮痛効果が十分に得られなくなる可能性があり得る。そこで、鎮痛薬の鎮痛効果を持続させたい期間に応じて、架橋度を調節することが好ましい。具体的な架橋度は予備実験などで決定すればよいが、通常、１分子当たり０．０１個以上、５０個以下の架橋点を有するよう調整すればよい。なお、１分子当たりの架橋点の数は、レオメーターなどを用いて測定した動的粘弾性や、引張試験機などを用いて測定した初期弾性率の値から、Ｆｌｏｒｙ−Ｈｕｇｇｉｎｓの式を用いて求めることができる。 The degree of crosslinking of the crosslinked gelatin can be adjusted as appropriate. That is, if the degree of cross-linking is too low, the cross-linked gelatin is likely to be excessively dissolved or decomposed in the body, and it may be difficult to sufficiently secure the analgesic. On the other hand, if the degree of crosslinking is too high, the analgesic agent will not be released, and the analgesic effect may not be sufficiently obtained. Therefore, it is preferable to adjust the degree of crosslinking in accordance with the period for which the analgesic effect of the analgesic is desired to be sustained. The specific degree of cross-linking may be determined by preliminary experiments or the like, but usually it may be adjusted to have 0.01 or more and 50 or less cross-linking points per molecule. The number of cross-linking points per molecule is calculated using the Flory-Huggins equation based on the dynamic viscoelasticity measured using a rheometer and the initial elastic modulus measured using a tensile tester. Can be sought.
なお、架橋ゼラチンは、市販品がある場合には、例えば、目的とする鎮痛効果の持続期間などに応じて適切なものを選択して使用してもよい。 In addition, when there exists a commercial item, you may select and use a suitable crosslinked gelatin according to the duration of the target analgesic effect etc., for example.
鎮痛薬としては、小分子の化学物質のものを用い、患者の症状などに応じて適宜選択すればよい。例えば、リドカイン、ブピバカイン、プロカイン、メピバカインなどの局所麻酔薬；サリチル酸、アスピリン、エテンザミド、アセトアミノフェン、フェナセチン、アンチピリン、スルピリン、フェニルブタゾン、メフェナム酸、ケトプロフェン、イブプロフェン、ジクロフェナクナトリウム、インドメタシン、ロキソプロフェン、エピリゾール、ブフェキサマク、ザルトプロフェンなどの非ステロイド性消炎鎮痛薬などを挙げることができる。好適には、リドカイン、ブピバカイン、プロカイン、メピバカイン、ケトプロフェン、ロキソプロフェン、ザルトプロフェンなどの水溶性鎮痛薬を用いる。 As the analgesic, a small molecule chemical substance may be used and appropriately selected according to the patient's symptoms. For example, local anesthetics such as lidocaine, bupivacaine, procaine, mepivacaine; salicylic acid, aspirin, etenzamide, acetaminophen, phenacetin, antipyrine, sulpyrine, phenylbutazone, mefenamic acid, ketoprofen, ibuprofen, diclofenac sodium, indomethacin, loxoprofen, epirizole Non-steroidal anti-inflammatory analgesics such as bufexamac and zaltoprofen. Preferably, water-soluble analgesics such as lidocaine, bupivacaine, procaine, mepivacaine, ketoprofen, loxoprofen, zaltoprofen and the like are used.
本発明に係る埋植用鎮痛製剤における架橋ゼラチンと鎮痛薬の割合は特に制限されず、適宜調整すればよい。好ましくは、架橋ゼラチンに対する鎮痛薬の質量比を１×１０-4以上、１以下とする。当該比が１×１０-4未満であると、架橋ゼラチンに対する鎮痛薬の量が少な過ぎ、鎮痛効果が十分に発揮されないおそれがあり得る。一方、当該比が１を超えると、鎮痛薬が架橋ゼラチンから過剰に漏れ出すおそれがあり得る。 The ratio of the crosslinked gelatin and the analgesic in the analgesic preparation for implantation according to the present invention is not particularly limited, and may be adjusted as appropriate. Preferably, the mass ratio of the analgesic to the cross-linked gelatin is 1 × 10 −4 or more and 1 or less. If the ratio is less than 1 × 10 −4 , the amount of the analgesic with respect to the crosslinked gelatin is too small, and the analgesic effect may not be sufficiently exhibited. On the other hand, if the ratio exceeds 1, the analgesic may leak excessively from the crosslinked gelatin.
本発明に係る埋植用鎮痛製剤は、非常に簡便に製造することができる。例えば、乾燥させた架橋ゼラチンへ鎮痛薬の溶液を添加した後、静置すればよい。 The analgesic preparation for implantation according to the present invention can be produced very simply. For example, the analgesic solution may be added to the dried crosslinked gelatin and then allowed to stand.
具体的な製造条件は、適宜調整すればよい。例えば、静置時間は、鎮痛薬が架橋ゼラチン中へ分散するに十分な時間とすればよいが、通常、室温で静置する場合には１０分間以上、２時間以下程度とすることができる。１℃以上、１０℃以下程度に冷却する場合には、１０時間以上、２４時間以下程度とすることもできる。 Specific manufacturing conditions may be adjusted as appropriate. For example, the standing time may be a time sufficient for the analgesic to disperse in the cross-linked gelatin. However, when standing at room temperature, the standing time can usually be about 10 minutes to 2 hours. In the case of cooling to about 1 ° C. or more and about 10 ° C. or less, the cooling time may be about 10 hours or more and 24 hours or less.
本発明に係る埋植用鎮痛製剤の大きさは、製造後における乾燥の程度にもよるが、使用する架橋ゼラチンとほぼ同じとすることができる。即ち、乾燥された架橋ゼラチンに鎮痛薬溶液を添加すると、使用する架橋ゼラチンの状態により膨潤したり逆に収縮したりすることがあるものの、その前後の大きさはほぼ同じとしてよい。よって、本発明に係る埋植用鎮痛製剤の大きさは、使用する架橋ゼラチンの大きさにより調節することができる。 The size of the analgesic preparation for implantation according to the present invention can be almost the same as that of the crosslinked gelatin to be used, although it depends on the degree of drying after production. That is, when an analgesic solution is added to the dried crosslinked gelatin, it may swell or conversely shrink depending on the state of the crosslinked gelatin used, but the sizes before and after may be substantially the same. Therefore, the size of the analgesic preparation for implantation according to the present invention can be adjusted by the size of the crosslinked gelatin used.
本発明に係る埋植用鎮痛製剤は、手術の切開部位に埋植して用いることができる。その結果、架橋ゼラチンがコラゲナーゼなどにより徐々に分解して体液に対して可溶するにつれて、内部に包含された鎮痛薬が徐放される。よって、鎮痛薬の副作用が生じ難い上に、手術後における疼痛を効果的かつ持続的に抑制できる。なお、切開部分に本発明に係る埋植用鎮痛製剤を埋植した後は、通常とおり切開部分を縫合すればよい。 The analgesic preparation for implantation according to the present invention can be used by being implanted in the surgical incision site. As a result, as the cross-linked gelatin is gradually decomposed by collagenase or the like and becomes soluble in the body fluid, the analgesic drug contained therein is gradually released. Therefore, side effects of analgesics are unlikely to occur, and pain after surgery can be effectively and continuously suppressed. In addition, what is necessary is just to sew an incision part as usual, after implanting the analgesic formulation for implantation which concerns on this invention in an incision part.
埋植用鎮痛製剤の大きさは、疾患の重篤度、患者の症状、切開部位の大きさなどに応じて適宜調整すればよい。また、埋植用鎮痛製剤における鎮痛薬の量も、切開部位の大きさなどの他、使用する鎮痛薬の適切な使用量を考慮して決定すべきである。 The size of the analgesic preparation for implantation may be appropriately adjusted according to the severity of the disease, the symptoms of the patient, the size of the incision site, and the like. In addition, the amount of analgesic in the analgesic preparation for implantation should be determined in consideration of the appropriate amount of analgesic used, in addition to the size of the incision site.
本発明に係る鎮痛用キットは、上記埋植用鎮痛製剤、および鎮痛薬を含む先制鎮痛用製剤から構成されていることを特徴とする。手術後疼痛は、手術前の先制鎮痛用製剤の投与と、手術後における上記埋植用鎮痛製剤の投与により、より一層顕著に抑制される。 The analgesic kit according to the present invention comprises the above-mentioned analgesic preparation for implantation and a preemptive analgesic preparation containing an analgesic. Postoperative pain is more significantly suppressed by administration of the preemptive analgesic preparation before surgery and administration of the analgesic preparation for implantation after surgery.
先制鎮痛用製剤は、手術に先立って患者に投与するものである。当該鎮痛用製剤に含まれる鎮痛薬としては、上記埋植用鎮痛製剤に添加される鎮痛薬と同様のものを挙げることができる。また、先制鎮痛用製剤の投与量や投与方法は、先制鎮痛用製剤に応じた通常の投与量や投与方法とすればよい。 Preemptive analgesic preparations are administered to patients prior to surgery. Examples of the analgesic contained in the analgesic preparation include those similar to the analgesic added to the implantable analgesic. Further, the dosage and administration method of the preemptive analgesic preparation may be the normal dosage and administration method corresponding to the preemptive analgesic preparation.
先制鎮痛用製剤の投与時期は、手術執刀開始時に十分な鎮痛効果が得られている限り特に制限されないが、通常、手術の２時間から３０分間前に投与することができる。 The timing of administration of the preemptive analgesic preparation is not particularly limited as long as a sufficient analgesic effect is obtained at the start of the surgical operation, but can usually be administered 2 to 30 minutes before the operation.
手術の後は、上述したとおり、本発明に係る埋植用鎮痛製剤を投与すればよい。先制鎮痛用製剤と上記埋植用鎮痛製剤との両方の効果により、手術後疼痛をより一層有効かつ持続的に抑制することが可能になる。 After the surgery, as described above, the analgesic preparation for implantation according to the present invention may be administered. Due to the effects of both the preemptive analgesic preparation and the implant analgesic preparation, it becomes possible to more effectively and continuously suppress postoperative pain.
以下、実施例を挙げて本発明をより具体的に説明するが、本発明はもとより下記実施例によって制限を受けるものではなく、前・後記の趣旨に適合し得る範囲で適当に変更を加えて実施することも勿論可能であり、それらはいずれも本発明の技術的範囲に包含される。 EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited by the following examples, but may be appropriately modified within a range that can meet the purpose described above and below. Of course, it is possible to implement them, and they are all included in the technical scope of the present invention.
実施例１ 本発明製剤の製造
２ｗ／ｖ％塩酸リドカイン溶液（１０μＬ，アストラゼネカ社製「静注用キシロカイン（登録商標）２％」）を、架橋ゼラチンシート（メドジェルＰ１５，メドジェル社製，１ｍｇ）に含浸させた後、４℃で一晩静置した。
Example 1 Production of the Formulation of the Invention 2 w / v% Lidocaine Hydrochloride Solution (10 μL, “Intravenous Xylocaine (registered trademark) 2%” manufactured by AstraZeneca) and a crosslinked gelatin sheet (Medgel P15, manufactured by Medgel, 1 mg) After impregnating, the solution was allowed to stand at 4 ° C. overnight.
実施例２ 本発明製剤の製造
架橋ゼラチンシート（メドジェルＰ１９，メドジェル社製，０．８ｍｇ）に、ケトプロフェン溶液（８μＬ，日新製薬社製「メジェイド（登録商標）筋注５０ｍｇ」）を含浸させた後、４℃で一晩静置した。
Example 2 Production of the Formulation of the Present Invention A crosslinked gelatin sheet (Medgel P19, manufactured by Medgel, 0.8 mg) was impregnated with a ketoprofen solution (8 μL, “Mejade (registered trademark) intramuscular injection 50 mg” manufactured by Nissin Pharmaceutical Co., Ltd.). Then, it was left overnight at 4 ° C.
実施例３ 動物実験
１０週齢の雄性ウィスター・ラット（体重：２８０ｇ前後）１８匹を、６匹ずつ任意に擬似手術群、対照群、製剤投与群に分けた。各ラットへ、ペントバルビタールナトリウム注射液（ネンブタール注射液，大日本住友製薬社製）を体重１００ｇ当たり０．１ｍＬ腹腔内投与して麻酔した後、左足底の踵より５ｍｍの位置から縦に１０ｍｍ切開した。切開部から足底筋をすくい出し、縦に切開した。バイポーラ型電気メスで皮下を十分に止血した後、対照群にはリン酸緩衝液を含浸させた架橋ゼラチンシート（０．８ｍｇ）を足底筋直下に埋め込み、製剤投与群には上記実施例１の本発明製剤を埋め込んだ。次いで、切開部を５−０Ｍａｘｏｎ糸により２針縫合した。
Example 3 Animal Experiment Sixteen 10-week-old male Wistar rats (body weight: around 280 g) were arbitrarily divided into 6 groups each in a sham operation group, a control group, and a preparation administration group. Each rat was anesthetized by intraperitoneally administering 0.1 mL of pentobarbital sodium injection solution (Nembutal injection solution, manufactured by Dainippon Sumitomo Pharma Co., Ltd.) per 100 g of body weight, and then incised 10 mm vertically from the position of 5 mm from the left footpad did. The plantar muscle was scooped out from the incision, and a longitudinal incision was made. After the hemostasis was sufficiently stopped with a bipolar electrosurgical unit, a cross-linked gelatin sheet (0.8 mg) impregnated with a phosphate buffer was embedded in the control group directly under the plantar muscle, and the above-mentioned Example 1 was applied to the preparation administration group. Of the formulation of the present invention. The incision was then sutured with 2 needles using 5-0 Maxon thread.
施術前、手術から６時間後、さらに５日後まで１日ごと、並びに７，９日後に、ｖｏｎ Ｆｒｅｙ ｆｉｌａｍｅｎｔ ｔｅｓｔを行った。具体的には、曲がるまでに所定の応力を要するｖｏｎ Ｆｒｅｙ Ｈａｉｒセットを用い、上記ラットを入れたゲージの下から手術部に押し当て、ラットが驚愕して足を上げた際の応力を求めた。結果を図１に示す。 The von Frey filament test was performed before the treatment, 6 hours after the operation, and every day until the 5th day, and after 7 and 9 days. Specifically, using a von Frey Hair set that requires a predetermined stress to bend, it was pressed against the surgical site from under the gauge containing the rat, and the stress when the rat was surprised and raised the foot was determined. . The results are shown in FIG.
図１のとおり、本発明に係る製剤を用いた群では、擬似手術群と対照群に比して、ｖｏｎ Ｆｒｅｙ ｆｉｌａｍｅｎｔ閾値が明らかに高い。手術から時間が経つにつれ、本発明製剤投与群と擬似手術群との差が小さくなっていくのは、切開部の治癒によるものであると考えられる。しかし、手術後６時間から４日目には本発明製剤投与群と擬似手術群との間で有意差が見られることは、手術後疼痛が優位に抑制されていることを意味し、特筆すべきである。 As shown in FIG. 1, the von Frey filament threshold is clearly higher in the group using the preparation according to the present invention than in the sham operation group and the control group. It is considered that the difference between the preparation-administered group of the present invention and the sham operation group becomes smaller as time passes from the operation due to the healing of the incision. However, a significant difference between the group administered with the preparation of the present invention and the sham-operated group from 6 hours to 4 days after the operation means that post-operative pain is preferentially suppressed. Should.
実施例４ 動物実験
上記実施例３において、上記実施例１の本発明製剤の代わりに上記実施例２の本発明製剤を用いた以外は同様にして、動物実験を行った。結果を図２に示す。
Example 4 Animal Experiment An animal experiment was conducted in the same manner as in Example 3, except that the preparation of the present invention of Example 2 was used instead of the preparation of the present invention of Example 1. The results are shown in FIG.
図２のとおり、本発明製剤投与群では、手術から一貫して、擬似手術群と対照群に比べてｖｏｎ Ｆｒｅｙ ｆｉｌａｍｅｎｔ閾値が有意に高い。かかる結果から、本発明製剤は、極めて優れた手術後疼痛の抑制効果を示すことが実証された。 As shown in FIG. 2, the von Frey filament threshold is significantly higher in the preparation-administered group of the present invention than in the sham-operated group and the control group. From these results, it was demonstrated that the preparation of the present invention exhibits a very excellent postoperative pain suppression effect.
実施例５ 動物実験
１５週齢の雄性ウィスター・ラット（体重：４００ｇ前後）１８匹を、６匹ずつ任意に擬似手術群、埋植用鎮痛製剤投与群、先制鎮痛用製剤＋埋植用鎮痛製剤投与群に分けた。各ラットへ、ペントバルビタールナトリウム注射液（ネンブタール注射液，大日本住友製薬社製）を体重１００ｇ当たり０．１ｍＬ腹腔内投与して麻酔した後、胃管を胃内に挿入し、先制鎮痛用製剤＋埋植用鎮痛製剤投与群には、ザルトプロフェン（４ｍｇ）を０．５％カルボキシメチルセルロース水溶液（０．５ｍＬ）に溶解した溶液を、擬似手術群と埋植用鎮痛製剤投与群には０．５％カルボキシメチルセルロース水溶液（０．５ｍＬ）を胃管から投与した。３０分後、左足底の踵より５ｍｍの位置から縦に１０ｍｍ切開した。切開部から足底筋をすくい出し、縦に切開した。バイポーラ型電気メスで皮下を十分に止血した後、埋植用鎮痛製剤投与群と先制鎮痛用製剤＋埋植用鎮痛製剤投与群には上記実施例２の埋植用鎮痛製剤を埋め込んだ。次いで、切開部を５−０Ｍａｘｏｎ糸により２針縫合した。
Example 5 Animal Experiment Sixteen 15-week-old male Wistar rats (body weight: around 400 g), each of which was arbitrarily sham-operated, implanted analgesic preparation group, preemptive analgesic preparation + implanted analgesic preparation Divided into administration groups. Each rat was anesthetized by intraperitoneally administering 0.1 mL of pentobarbital sodium injection solution (Nembutal injection solution, manufactured by Dainippon Sumitomo Pharma Co., Ltd.) per 100 g of body weight, and then inserting a gastric tube into the stomach to prepare a preemptive analgesic. + For the analgesic preparation group for implantation, a solution obtained by dissolving zaltoprofen (4 mg) in 0.5% carboxymethylcellulose aqueous solution (0.5 mL) is used for the sham operation group and the analgesic preparation group for implantation. % Carboxymethylcellulose aqueous solution (0.5 mL) was administered through the gastric tube. Thirty minutes later, a 10 mm incision was made from a position of 5 mm from the heel of the left sole. The plantar muscle was scooped out from the incision, and a longitudinal incision was made. After the hemostasis was sufficiently stopped with a bipolar electric scalpel, the analgesic preparation for implantation of Example 2 was embedded in the group for the analgesic preparation for implantation and the group for preemptive analgesic preparation + the group for analgesic preparation for implantation. The incision was then sutured with 2 needles using 5-0 Maxon thread.
施術前、手術から６時間後、さらに５日後まで１日ごと、並びに７，９，１３日後に、上記実施例３と同様にｖｏｎ Ｆｒｅｙ ｆｉｌａｍｅｎｔ ｔｅｓｔを行った。結果を図３に示す。 The von Frey filament test was performed in the same manner as in Example 3 before the treatment, 6 hours after the operation, and every day until 5 days later, and after 7, 9, and 13 days. The results are shown in FIG.
図３のとおり、擬似手術群に比べ、埋植用鎮痛製剤投与群と先制鎮痛用製剤＋埋植用鎮痛製剤投与群では、手術後６時間から５日目まで、有意に閾値の上昇が見られた。さらに、先制鎮痛用製剤＋埋植用鎮痛製剤投与群では、擬似手術群と埋植用鎮痛製剤投与群に比べ、手術後１日目から５日目まで、有意に閾値の上昇が見られた。このように、先制鎮痛用製剤と上記埋植用鎮痛製剤を組合わせることにより、手術後疼痛をより一層有効かつ持続的に抑制できることが明らかとなった。 As shown in FIG. 3, compared with the sham-operated group, the threshold value significantly increased in the implanted analgesic preparation group and the preemptive analgesic preparation + implanted analgesic preparation administered group from 6 hours to 5 days after the operation. It was. Furthermore, in the preemptive analgesic preparation + implant analgesic preparation administration group, the threshold value was significantly increased from the first to fifth day after the operation, compared with the sham operation group and the implantation analgesic preparation administration group. . As described above, it has been clarified that postoperative pain can be more effectively and continuously suppressed by combining the preemptive analgesic preparation and the above-mentioned analgesic preparation for implantation.
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