WO2013133413A1 - 粘膜隆起剤 - Google Patents
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- WO2013133413A1 WO2013133413A1 PCT/JP2013/056472 JP2013056472W WO2013133413A1 WO 2013133413 A1 WO2013133413 A1 WO 2013133413A1 JP 2013056472 W JP2013056472 W JP 2013056472W WO 2013133413 A1 WO2013133413 A1 WO 2013133413A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- A61K9/00—Medicinal preparations characterised by special physical form
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- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/54—Biologically active materials, e.g. therapeutic substances
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/58—Materials at least partially resorbable by the body
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/34—Materials or treatment for tissue regeneration for soft tissue reconstruction
Definitions
- the present invention relates to a mucosa-elevating agent characterized by containing a self-assembling peptide hydrogel.
- EMR Endoscopic mucosal resection
- ESD endoscopic submucosal dissection
- Endoscopic surgery is a method to remove the lesion without laparotomy, injecting a hypertonic saline solution or a polymer solution into the submucosa, including the lesion, Resect and remove with high frequency therapy equipment.
- ESD which has been widely used for surgery, exfoliates the submucosa more extensively than EMR. Therefore, there is a high possibility of perforation by incision of the proper fascia. It is necessary to maintain the bulge / fist of the lower layer.
- a high-frequency therapeutic device such as an electric knife is used for excision and detachment of a lesion, but it is necessary to avoid that the mucosal bulging agent adversely affects its electrical effect and operability.
- An example of an existing mucosal protuberance agent is sodium hyaluronate.
- Sodium hyaluronate is often used clinically as an effective mucosal protuberance, but these drawbacks are 1) risk of infection because it is a biological product, 2) not filled into a syringe, A point is mentioned.
- the self-assembling peptide has the property of forming a self-aggregate in which a large number of peptide molecules are regularly arranged depending on the amino acid sequence. In recent years, it has attracted attention as a new material because of its physical, chemical and biological properties. Self-assembling peptides have a structure in which charged hydrophilic amino acids and electrically neutral hydrophobic amino acids are alternately arranged, and positive and negative charges are alternately distributed, at physiological pH and salt concentration. Takes a ⁇ structure.
- hydrophilic amino acid an acidic amino acid selected from aspartic acid and glutamic acid, and a basic amino acid selected from arginine, lysine, histidine and ornithine can be used.
- hydrophobic amino acid alanine, valine, leucine, isoleucine, methionine, phenylalanine, tyrosine, tryptophan, serine, threonine, and glycine can be used.
- Self-assembly of the peptide occurs under the following conditions. (1) When a peptide molecule takes a ⁇ structure in an aqueous solution, a hydrophilic amino acid having a charge and a hydrophobic amino acid that is electrically neutral are unevenly distributed on two sides of the peptide molecule. (2) When the ⁇ structure is taken, the charge distribution is complementary to the neighboring molecule. (3) When a ⁇ structure is taken, a sufficient hydrophobic bond is formed with an adjacent molecule. (4) The amino acid side chain charge is screened with a monovalent inorganic salt. (5) The molecule becomes electrostatically neutral near the isoelectric point of the peptide.
- Nanofibers are ultrafine fibers with a thickness of about 10 nm to 20 nm, and are reported to aggregate on the network and macroscopically form a gel.
- the gel network structure is very similar to natural extracellular matrix (ECM) in fiber size and pore size, and its use as a scaffold for cell culture has been studied.
- ECM extracellular matrix
- This peptide hydrogel is biodegradable, the degradation product does not adversely affect the tissue, and is highly bioabsorbable, so it is suitable for cell engraftment and proliferation.
- the object of the present invention is to self-assembled peptides that can maintain the gastrointestinal mucosa uplifting and swelling clinically for a sufficient amount of time in large mammals including humans and are free from infectious concerns such as viruses. It is to provide a mucosa-elevating agent and a method for using the same.
- the present inventors have found that by applying a self-assembling peptide hydrogel, which is used as a scaffold for cell culture, to mucosal ridges, the present invention exhibits mucosal bulging effects that are equal to or better than existing mucosal bulging agents. completed. Moreover, when a 3% concentration aqueous peptide solution reported in Patent Document 1 is injected into the submucosa, the effect of raising the mucosa can be obtained, but the injection is difficult because the viscosity of the peptide solution itself is high.
- a mucosal bulge, which is a self-assembling peptide that is ⁇ -structured in aqueous solution in the presence of physiological pH and / or cations [2] The peptide has a repeating sequence of a sequence consisting of arginine, alanine, aspartic acid and alanine, a sequence consisting of isoleucine, glutamic acid, isoleucine and lysine, or a sequence consisting of lysine, leucine, aspartic acid and leucine.
- [1] mucosal bulging agent [3] The mucosa-elevating agent according to [1] or [2], wherein the peptide consists of the amino acid sequence described in SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3.
- the mucosa-elevating agent according to any one of [1] to [3], further comprising a drug, [5] The mucosa-elevating agent according to [4], wherein the drug is a pharmaceutically acceptable pigment, [6]
- the drug is glucose, sucrose, purified sucrose, lactose, maltose, trehalose, dextran, iodine, lysozyme chloride, dimethylisopropylazulene, tretinointocopheryl, popidone iodine, alprostadil alphadex, anis alcohol, isoamyl salicylate, ⁇ , ⁇ -dimethylphenylethyl alcohol, bagdanol, helional, silver sulfadine, sodium bucladecin, alprostadil alphadex, gentamicin sulfate, tetracycline hydrochloride, sodium fusidate, mupirocin calcium hydrate and
- the mucosa-elevating agent according to any one of [1] to [6], which has a scar prevention or stenosis prevention effect [15] The mucosa-elevating agent according to any one of [1] to [6], which has a hemostatic effect. In the present invention,% means weight / volume (w / v). [16] The mucosa-elevating agent according to any one of [1] to [6], which is in a liquid form and gels in the body.
- the dye is a pharmaceutically acceptable dye, and is preferably selected from indigo carmine, brilliant blue FCF, fast green FCF, and indocyanine green.
- the present invention provides a submucosal injecting agent for raising an excision / exfoliation part in EMR or ESD containing the above mucosal bulging agent, or a mucosal tissue part raised by injecting a liquid into the submucosal layer. It also relates to the method of excision.
- the self-assembling peptide which is the main component, can serve as a scaffold for migrating cells in addition to the role as a mucosal bulging agent, and can provide a higher healing effect after surgery.
- the self-assembling peptide that is the main component of the mucosa-elevating agent of the present invention can be produced by synthesis, there is no risk of infection with viruses or the like as compared with conventional bio-derived materials, and itself is a living body. Since it is absorbable, there is no need to worry about inflammation.
- the mucosa-elevating agent of the present invention is an amphipathic peptide having amino acid residues 8 to 200 in which hydrophilic amino acids and hydrophobic amino acids are alternately bonded, and in the presence of physiological pH and / or cation,
- the main component is a self-assembling peptide that exhibits a ⁇ structure in an aqueous solution.
- the physiological pH is pH 6 to pH 8, preferably pH 6.5 to pH 7.5, and more preferably pH 7.3 to pH 7.5.
- the cation is, for example, 5 mM to 5 M sodium ion or potassium ion.
- the self-assembling peptide used in the present invention can be represented by, for example, the following four general formulas.
- X represents an acidic amino acid
- Y represents a hydrophobic amino acid
- Z represents a basic amino acid
- l, m and n are all integers (n ⁇ (l + m) ⁇ 200)).
- the N terminal may be acetylated and the C terminal may be amidated.
- hydrophilic amino acid an acidic amino acid selected from aspartic acid and glutamic acid and a basic amino acid selected from arginine, lysine, histidine and ornithine can be used.
- hydrophobic amino acid alanine, valine, leucine, isoleucine, methionine, phenylalanine, tyrosine, tryptophan, serine, threonine or glycine can be used.
- a self-assembling peptide having a repetitive sequence of arginine, alanine, aspartic acid and alanine can be preferably used.
- the sequence of such a peptide is Ac- (RADA).
- p- CONH 2 (p 2 to 50).
- a self-assembling peptide having repeating sequences of lysine, leucine, aspartic acid and leucine can also be preferably used.
- These self-assembling peptides can be composed of 8 to 200 amino acid residues. Among them, 8-32 residue self-assembling peptides are preferable, and self-assembling peptides having 12 to 16 residues are more preferable. preferable.
- the self-assembling peptide in the present invention include peptides RAD16-I having the (Ac- (RADA) 4 -CONH 2 ) sequence (SEQ ID NO: 1), (Ac- (IEIK) 3 I-CONH 2 ) Peptide IEIK13 having the sequence (SEQ ID NO: 2), peptide KLD having the (Ac- (KLDL) 3 -CONH 2 ) sequence (SEQ ID NO: 3), and RAD16-I is designated as PuraMatrix (registered trademark) The 1% aqueous solution is commercialized by 3D Matrix. PuraMatrix (registered trademark) includes hydrogen ions and chloride ions in addition to a peptide having 1% (Ac- (RADA) 4 -CONH 2 ) sequence (SEQ ID NO: 1).
- PuraMatrix (registered trademark), IEIK13 and KLD are oligopeptides having 12 to 16 amino acids and a length of about 5 nm.
- the solution is liquid when it is acidic pH, but it is changed to neutral pH.
- self-assembly of the peptide occurs, and nanofibers having a diameter of about 10 nm are formed.
- the peptide solution gels.
- PuraMatrix (registered trademark) is an amphipathic peptide having an amino acid sequence in which residues of arginine positively charged and aspartic acid negatively charged as hydrophilic amino acids and alanine residues as hydrophobic amino acids are alternately repeated.
- IEIK13 is A hydrophilic amino acid is an amphiphilic peptide having a positively charged lysine and a negatively charged glutamic acid, a hydrophobic amino acid having an amino acid sequence in which isoleucine residues are alternately repeated, and KLD has a positive charge as a hydrophilic amino acid.
- amphiphilic peptide having an amino acid sequence in which lysine and negatively charged aspartic acid and leucine residues are alternately repeated as hydrophobic amino acids, and the self-assembly of peptides is between peptide molecules by the amino acids constituting the peptides. Hydrogen bonding and hydrophobicity Due to binding.
- the nanofiber has a diameter of 10 to 20 nm and a pore size of 5 to 200 nm. This numerical range is approximately the same size as collagen, which is a natural extracellular matrix.
- the self-assembling conditions of the self-assembling peptide used in the present invention include physiological conditions of pH and salt concentration.
- the presence of monovalent alkali metal ions is important. That is, sodium ions and potassium ions present in large amounts in the living body contribute to the promotion of gelation. Once gelled, the gel does not degrade even when using denaturing agents such as normal protein denaturing conditions such as high temperature, acid, alkali, proteolytic enzyme, urea, guanidine hydrochloride.
- these self-assembling peptides such as PuraMatrix (registered trademark) are peptide sequences that do not have an apparent bioactive motif, there is no concern that the original cell function is impaired.
- Bioactive motifs are involved in the control of many intracellular phenomena such as transcription, and when a bioactive motif is present, proteins in the cytoplasm and cell surface are phosphorylated by enzymes that recognize the motif. When a bioactive motif is present in the peptide mucosa-elevating agent, transcriptional activity of various functional proteins may be activated or suppressed. There is no such concern with self-assembling peptides such as PuraMatrix (registered trademark) that do not have a bioactive motif.
- the self-assembling peptide used in the present invention is produced by chemical synthesis, it does not contain unknown components derived from animal-derived extracellular matrix. This property indicates that there is no risk of infection such as BSE, and that it has high safety for medical use.
- the mucosal bulging agent of the present invention can improve the osmotic pressure of a solution from hypotonic to isotonic without adding to the sugar without lowering the mucosal bulging effect, and can further enhance biological safety.
- Examples of the form of the mucosa-elevating agent of the present invention include powder, solution, gel and the like. Since the self-assembling peptide gels due to changes in pH and salt concentration of the solution, it can be distributed as a liquid agent that gels when it is brought into contact with a living body at the time of application.
- a liquid medicine containing a component such as a self-assembling peptide is pre-filled in a syringe or pipette with a cylinder (in the form of a prefilled syringe), or the component is replenished from the opening of a syringe or pipette tip.
- a chemical solution is supplied to a syringe or pipette tip by means (aspirator or valve) and applied from the discharge part to the affected part.
- the syringe and pipette may be composed of two or more.
- ⁇ Material> Peptide aqueous solution 1.0.25% peptide aqueous solution (peptide sequence: Ac- (RADA) 4 -NH 2 , manufactured by CPC Scientific, Inc; concentration: weight / volume) 2. 0.5% aqueous peptide solution (peptide sequence: Ac- (RADA) 4 -NH 2 , manufactured by CPC Scientific, Inc; concentration: weight / volume) 3. 1.0% aqueous peptide solution (peptide sequence: Ac- (RADA) 4 -NH 2 , manufactured by CPC Scientific, Inc; concentration: weight / volume) 4).
- ⁇ Method> Rabbits were administered cekratal 2% injection solution (containing 2.0 g as xylazine in 100 mL, Bayer) subcutaneously (3 mg / kg), then ketamine (containing 50 mg as ketamine in 1 mL, Fuji Chemical Industry Co., Ltd.) Anesthesia was performed by intravenous administration (10 mg / kg). • The rabbit was laparotomized through a midline incision. The stomach body was incised with a scalpel to expose the gastric mucosa. -0.5 mL of peptide aqueous solution was inject
- the peptide aqueous solution, muco-up, or physiological saline of this example was administered subcutaneously to the abdomen of the rabbit, before administration (FIG. 4), immediately after administration (FIG. 5), 15 minutes after administration, and 30 minutes after administration.
- Table 2 shows an example in which the effect of raising the abdominal skin (FIG. 6) was evaluated. 15 minutes after administration and 30 minutes after administration, it was confirmed that the aqueous peptide solution had a bulging effect equivalent to mucoup, and the physical strength of the aqueous peptide solution was equivalent to mucoup.
- Gastric submucosal bulging effect by mini-pig gastric submucosal injection The gastric submucosal bulging effect in endoscopic mini-pig gastric submucosal dissection was evaluated with a 0.25% aqueous peptide solution.
- Peptide aqueous solution 1.0.25% peptide aqueous solution (peptide sequence: Ac- (RADA) 4 -NH 2 , manufactured by CPC Scientific, Inc) • Miniature pigs of strain NIBS (anises from Nissei Laboratories) 20-20 months old and weighing 20-40 kg. All animals were weighed (electronic balance: DUE600ST / ID3S-A, METTLER TOLEDO), observed by inspection, palpation, etc., and animals with no abnormalities were carried into the breeding room. Thereafter, a quarantine period of 7 days was provided, followed by an acclimation period of 11 days.
- body weight measurement (electronic balance: DUE600ST / ID3S-A, METTLER TOLEDO, Inc.) is measured 4 times, food consumption measurement (electronic balance: PB1501, PB3002-S / FACT is used, METTLER TOLEDO, Inc. )
- food consumption measurement (electronic balance: PB1501, PB3002-S / FACT is used, METTLER TOLEDO, Inc. )
- enteral nutrition (Elental, Ajinomoto Pharma Co., Ltd.) should be used 3 days before and 2 days before the treatment day (the treatment day shall be 0 days).
- the same calorie content (feeding amount: 628 g ⁇ 10 g) was fed and no feeding was started from the day before the treatment.
- the analysis results of the same lot as the solid feed (NS) used are the results obtained at Nissei Laboratories Co., Ltd. and the Shizurin Inspection Center Co., Ltd. It was confirmed.
- Tap water was freely taken as drinking water using an automatic water supply device.
- results obtained at Toyo Inspection Center Co., Ltd. were obtained almost every 6 months, and it was confirmed that the test results were within the standard value range set by the test facility.
- SAFER100 inhalation anesthesia machine
- the catheter was turned to the back, the whole was fixed to the body with an adhesive cloth elastic bandage, and further protected with an elastic net bandage.
- -An endoscopic instrument (Olympus) was orally inserted into the stomach.
- -A spray tube (manufactured by Olympus) was inserted from the forceps opening.
- the sample to be administered was locally injected into the stomach submucosa with 5 mL of a peptide aqueous solution to bulge the mucosal surface, and the bulging submucosa was peeled off using an electric knife.
- -An additional 5 mL of aqueous peptide solution was injected locally during exfoliation of the submucosa.
- the excised mucosal tissue was fixed in formalin, and pathological tissue evaluation was performed by hematoxylin / eosin staining.
- FIG. 4 shows an example of the mucosal bulging effect of the aqueous peptide solution in the endoscopic gastric submucosal dissection of this example.
- Table 3 a sufficient mucosal bulging effect for performing gastric submucosal dissection in a 0.25% aqueous peptide solution was confirmed.
- FIG. 5 it was confirmed from the pathological tissue section observation of the resected gastric mucosa specimen that the aqueous peptide solution was injected between the intrinsic muscle layer and the mucosa, and the submucosa was peeled off (FIG. 5).
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Abstract
Description
自己組織化ペプチドは、電荷を帯びた親水性アミノ酸と電気的に中性な疎水性アミノ酸が交互に並び、正電荷と負電荷が交互に分布する構造をもち、生理的なpHと塩濃度においてβ構造をとる。
(1)水溶液中でペプチド分子がβ構造を取ることで、電荷をもつ親水性アミノ酸と電気的に中性な疎水性アミノ酸がペプチド分子の2面に偏在する。
(2)β構造をとったとき、隣分子と相補的な電化分布になる。
(3)β構造をとったとき、隣分子と十分な疎水結合を形成する。
(4)1価の無機塩によりアミノ酸側鎖の電荷がスクリーニングされる。
(5)ペプチドの等電点近くで、分子が静電的に中性になる。
(1)交互に分布するペプチド分子の正電荷と負電荷によって分子同士が引き合って近づく。
(2)隣分子の中性アミノ酸側鎖間で疎水結合が形成される。
(3)正負の電化分布により隣分子同士の相対的な配置が整えられ、分子間の会合力が強まる。
(4)分子の集合体が徐々に伸長し、ナノファイバーを形成する
[1]ペプチドを0.1%から1.0%含有する粘膜隆起剤であって、該ペプチドが、親水性アミノ酸と疎水性アミノ酸とが交互に結合し、アミノ酸残基8~200を有する両親媒性のペプチドであり、生理的pHおよび/または陽イオンの存在下、水溶液中でβ構造を示す自己組織化ペプチドである粘膜隆起剤、
[2]前記ペプチドが、アルギニン、アラニン、アスパラギン酸およびアラニンからなる配列、イソロイシン、グルタミン酸、イソロイシン、およびリジンからなる配列、または、リジン、ロイシン、アスパラギン酸の及びロイシンからなる配列の繰り返し配列を有する、[1]記載の粘膜隆起剤、
[3]前記ペプチドが、配列番号1、配列番号2、または配列番号3記載のアミノ酸配列からなる、[1]または[2]記載の粘膜隆起剤、
[4]さらに、薬剤を含有する、[1]~[3]のいずれかに記載の粘膜隆起剤、
[5]前記薬剤が薬学的に許容され得る色素である、[4]記載の粘膜隆起剤、
[6]前記薬剤が、ブドウ糖、白糖、精製白糖、乳糖、麦芽糖、トレハロース、デキストラン、ヨウ素、塩化リゾチーム、ジメチルイソプロピルアズレン、トレチノイントコフェリル、ポピドンヨード、アルプロスタジルアルファデクス、アニスアルコール、サリチル酸イソアミル、α,α-ジメチルフェニルエチルアルコール、バグダノール、ヘリオナール、スルファジン銀、ブクラデシンナトリウム、アルプロスタジルアルファデクス、硫酸ゲンタマイシン、塩酸テトラサイクリン、フシジン酸ナトリウム、ムピロシンカルシウム水和物および安息香酸イソアミルからなる群から選択される、[4]記載の粘膜隆起材、
[7]粘膜と筋層の間に注入される、[1]~[6]のいずれかに記載の粘膜隆起剤、
[8]粘膜が消化器粘膜である、[1]~[6]のいずれかに記載の粘膜隆起剤、
[9]粘膜切除術に用いられる、[1]~[6]のいずれかに記載の粘膜隆起剤、
[10]粘膜下層剥離術の用いられる[1]~[6]のいずれかに記載の粘膜隆起剤、
[11]追加注入が可能である、[1]~[6]のいずれかに記載の粘膜隆起剤、
[12]シリンジに充填された形態にある、[1]~[6]のいずれかに記載の粘膜隆起剤、
[13]創傷治癒効果を有する、[1]~[6]のいずれかに記載の粘膜隆起剤。
[14]瘢痕予防又は狭窄予防効果を有する、[1]~[6]のいずれかに記載の粘膜隆起剤、
[15]止血効果を有する、[1]~[6]のいずれかに記載の粘膜隆起剤。
なお、本発明で%は、重量/容量(w/v)を意味する。
[16]液状の形態であり、体内ではゲル化する、[1]~[6]のいずれかに記載の粘膜隆起剤。
本発明において、生理的pHは、pH6からpH8、好ましくは、pH6.5からpH7.5、さらに好ましくは、pH7.3からpH7.5である。また、本発明において陽イオンとは、たとえば、5mM~5Mのナトリウムイオンまたはカリウムイオンである。
((XY)l-(ZY)m)n (I)
((YX)l-(YZ)m)n (II)
((ZY)l-(XY)m)n (III)
((YZ)l-(YX)m)n (IV)
(式(I)~(IV)中、Xは酸性アミノ酸、Yは疎水性アミノ酸、Zは塩基性アミノ酸を表し、l、mおよびnは共に整数(n×(l+m)<200)である。)
また、そのN末端はアセチル化されていてもよく、C末端はアミド化されていてもよい。
ウサギ生存したで胃粘膜下に0.25%ペプチド水溶液、0.5%ペプチド水溶液、1.0%ペプチド水溶液、ムコアップ(生化学工業株式会社)による粘膜隆起効果の評価を行った。
・ペプチド水溶液
1.0.25%ペプチド水溶液(ペプチド配列:Ac-(RADA)4-NH2、CPC Scientific, Inc社製;濃度:重量/体積)
2.0.5%ペプチド水溶液(ペプチド配列:Ac-(RADA)4-NH2、CPC Scientific, Inc社製;濃度:重量/体積)
3.1.0%ペプチド水溶液(ペプチド配列:Ac-(RADA)4-NH2、CPC Scientific, Inc社製;濃度:重量/体積)
4.ムコアップ(生化学工業株式会社、承認番号: 21800BZZ1012400)
・動物
日本白色種ウサギ(3.0-4.0kg、ジャパンホワイト、コンベンショナル、株式会社フナバシファーム社より購入)。室温25℃、湿度65%、照明時間12時間(7:00-19:00)で制御された飼育室内で飼育用ペレット(JA東日くみあい飼料株式会社)を給餌し、給水ボトルの自由摂水にて飼育した。絶食は試験当日の朝のみとし、給水は自由とした。
・ウサギは、セクラタール2%注射液(100mL中にキシラジンとして2.0g含有、バイエル社製)を皮下内投与後(3mg/kg)、ケタミン(1mL中にケタミンとして50mg含有、富士ケミカル工業株式会社製)を静脈内投与(10mg/kg)することで麻酔した。
・ウサギは正中切開により開腹した。胃体部をメスにて切開し、胃粘膜を露出させた。
・胃粘膜下に23G注射針(テルモ社製)にてペプチド水溶液0.5mLを注入した。
・ペプチド水溶液またはムコアップ注入直後および15分後にノギスにより肉眼的に粘膜隆起高を測定した。
ウサギ胃粘膜下層への投与前(図1)、投与直後(図2)、投与15分後(図3)、投与30分後において、本実施例のペプチド水溶液またはムコアップによる粘膜隆起効果の例を表1に示す。投与15分後の粘膜隆起高が50%以上維持されている場合、粘膜隆起材としての効果があるものと評価した。1%ペプチド水溶液、0.5%ペプチド水溶液、0.25%ペプチド水溶液、ムコアップにおいて粘膜隆起高の維持効果が認められた。
また、参考として、ウサギ腹皮下に本実施例のペプチド水溶液、ムコアップ、又は生理食塩水を投与し、投与前(図4)、投与直後(図5)、投与15分後、ならびに投与30分後(図6)の腹皮膚の隆起効果を評価した例を表2に示す。投与後15分後、ならびに投与30分後においてペプチド水溶液がムコアップと同等の隆起効果を有し、ペプチド水溶液の物理的強度がムコアップと同等であることを確認した。
内視鏡的ミニブタ胃粘膜下層剥離術における胃粘膜下層隆起効果を0.25%ペプチド水溶液にて評価した。
・ペプチド水溶液
1.0.25%ペプチド水溶液(ペプチド配列:Ac-(RADA)4-NH2、CPC Scientific, Inc社製)
・動物
20~21カ月齢の体重20~40kgの系統NIBSのミニブタ(日生研株式会社)。
動物入手時に全例の体重測定(電子天秤:DUE600ST/ID3S-A、メトラー・トレド株式会社)、視診、触診等による観察を行い、異常の認められない動物を飼育室へ搬入した。その後、7日間の検疫期間を設け、さらにその後11日間の馴化期間を設けた。この間に体重測定(電子天秤:DUE600ST/ID3S-A、メトラー・トレド株式会社)を4回、摂餌量測定(電子天秤:PB1501、PB3002-S/FACTのいずれかを使用、メトラー・トレド株式会社)を1日1回及び一般状態の観察を1日1回行って、検疫及び馴化とした。設定温度:23℃(許容範囲:20~28℃)、設定湿度:55%(許容範囲:30~80%)、明暗各12時間(照明:午前6時~午後6時)、換気回数10回/時(フィルターを通した新鮮な空気)に維持された飼育室で動物を飼育した。検疫・馴化期間中及び測定期間中ともステンレス製ケージ(W:590×D:840×H:740mmまたはW:630×D:1130×H:710mm)を用いて個別飼育した。製造後5ヵ月以内の固型飼料(NS、日生研株式会社)を給餌器を用いて1日500g±5g(100g当たり321kcal、1日当たり1605kcal、電子天秤:PB3002-S/FACT,PB1501のいずれかを使用)を午前中に与えた。ただし、内視鏡的粘膜下層剥離術処置の作業性を良くするため、処置日の3日前及び2日前(処置当日を0日とする)は経腸栄養剤(エレンタール、味の素ファルマ株式会社)を同カロリー分(給餌量:628g±10g)給餌し、処置前日からは給餌しないこととした。使用した固型飼料(NS)と同一ロットの分析結果は、日生研株式会社及び株式会社静環検査センターで実施した成績を入手し、分析結果が試験施設で定めた基準値の範囲内であることを確認した。水道水を飲料水として自動給水装置を用いて自由に摂取させた。飲料水の水質検査結果は、ほぼ6ヵ月毎に株式会社東洋検査センターで実施した成績を入手し、試験結果が試験施設で定めた基準値の範囲内であることを確認した。
・ミニブタはアトロピン硫酸塩0.05mg/kgおよびケタミン塩酸塩15mg/kgの頸背部筋肉内投与による導入麻酔後、吸入麻酔機(SAFER100、株式会社アネス)を用いてN2O:O2=1:1の混合ガス+0.5~1.5%イソフルランの条件下で麻酔を維持し、前大静脈洞にカテーテル[メディカットLCV-UKキット、日本シャーウッド株式会社、筒内をヘパリン加生理食塩液(約10unit/mL)で満たしたもの]を挿入、頸部に縫合固定した。カテーテルを背部に廻し、粘着性布伸縮包帯で全体を体に固定し、さらに伸縮ネット包帯で保護した。
・内視鏡用器具 (オリンパス社製)を経口的に胃に挿入した。
・鉗子口より散布チューブ(オリンパス社製)を挿入した。
・胃粘膜下層に投与検体を5mLのペプチド水溶液を局注し粘膜面を膨隆させ、電気メスを用いて、膨隆した粘膜下層を剥離した。
・粘膜下層剥離中に5mLのペプチド水溶液を追加局注した。
・剥離完了後、切除した粘膜組織をホルマリン固定し、ヘマトキシリン・エオシン染色による病理学的組織評価を行った。
図4において、本実施例の内視鏡的胃粘膜下層剥離術におけるペプチド水溶液の粘膜隆起効果の例を示す。表3に示したように、0.25%ペプチド水溶液において胃粘膜下層剥離術を実施するのに十分な粘膜隆起効果が確認された。また切除された胃粘膜検体の病理学組織切片観察よりペプチド水溶液が固有筋層と粘膜の間に注入され、粘膜下層が剥離されたことが確認された(図5)。
Claims (16)
- ペプチドを0.1%から1.0%含有する粘膜隆起剤であって、該ペプチドが、親水性アミノ酸と疎水性アミノ酸とが交互に結合し、アミノ酸残基8~200を有する両親媒性のペプチドであり、生理的pHおよび/または陽イオンの存在下、水溶液中でβ構造を示す自己組織化ペプチドである粘膜隆起剤。
- 前記ペプチドが、アルギニン、アラニン、アスパラギン酸およびアラニンからなる配列、イソロイシン、グルタミン酸、イソロイシン、およびリジンからなる配列、または、リジン、ロイシン、アスパラギン酸の及びロイシンからなる配列の繰り返し配列を有する、請求項1記載の粘膜隆起剤。
- 前記ペプチドが、配列番号1、配列番号2、または配列番号3記載のアミノ酸配列からなる、請求項1または2記載の粘膜隆起剤。
- さらに、薬剤を含有する、請求項1~3のいずれか1項に記載の粘膜隆起剤。
- 前記薬剤が薬学的に許容され得る色素である、請求項4記載の粘膜隆起剤。
- 前記薬剤が、ブドウ糖、白糖、精製白糖、乳糖、麦芽糖、トレハロース、デキストラン、ヨウ素、塩化リゾチーム、ジメチルイソプロピルアズレン、トレチノイントコフェリル、ポピドンヨード、アルプロスタジルアルファデクス、アニスアルコール、サリチル酸イソアミル、α,α-ジメチルフェニルエチルアルコール、バグダノール、ヘリオナール、スルファジン銀、ブクラデシンナトリウム、アルプロスタジルアルファデクス、硫酸ゲンタマイシン、塩酸テトラサイクリン、フシジン酸ナトリウム、ムピロシンカルシウム水和物および安息香酸イソアミルからなる群から選択される、請求項4記載の粘膜隆起材。
- 粘膜と筋層の間に注入される、請求項1~6のいずれか一項に記載の粘膜隆起剤。
- 粘膜が消化器粘膜である、請求項1~6のいずれか一項に記載の粘膜隆起剤。
- 粘膜切除術に用いられる、請求項1~6のいずれか一項に記載の粘膜隆起剤。
- 粘膜下層剥離術の用いられる請求項1~6のいずれか一項に記載の粘膜隆起剤。
- 追加注入が可能である、請求項1~6のいずれか一項に記載の粘膜隆起剤。
- シリンジに充填された形態にある、請求項1~6のいずれか一項に記載の粘膜隆起剤。
- 創傷治癒効果を有する、請求項1~6のいずれか一項に記載の粘膜隆起剤を含む、のある粘膜隆起剤。
- 瘢痕予防又は狭窄予防効果を有する、請求項1~6のいずれか一項に記載の粘膜隆起剤。
- 止血効果を有する、請求項1~6のいずれか一項に記載の粘膜隆起剤。
- 液状の形態であり、体内ではゲル化する、請求項1~6のいずれか一項に記載の粘膜隆起剤。
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US20150105336A1 (en) | 2015-04-16 |
EP2823830A1 (en) | 2015-01-14 |
EP2823830A4 (en) | 2015-11-18 |
JPWO2013133413A1 (ja) | 2015-07-30 |
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