WO1995011697A1 - Cure accelerator in chondroplasty - Google Patents

Cure accelerator in chondroplasty Download PDF

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Publication number
WO1995011697A1
WO1995011697A1 PCT/JP1994/001803 JP9401803W WO9511697A1 WO 1995011697 A1 WO1995011697 A1 WO 1995011697A1 JP 9401803 W JP9401803 W JP 9401803W WO 9511697 A1 WO9511697 A1 WO 9511697A1
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Prior art keywords
pth
cartilage
bone
human
parathyroid hormone
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PCT/JP1994/001803
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French (fr)
Japanese (ja)
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Takashi Mori
Sayumi Higashi
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Chugai Seiyaku Kabushiki Kaisha
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Priority to AU80029/94A priority Critical patent/AU8002994A/en
Publication of WO1995011697A1 publication Critical patent/WO1995011697A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/29—Parathyroid hormone (parathormone); Parathyroid hormone-related peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/635—Parathyroid hormone (parathormone); Parathyroid hormone-related peptides

Definitions

  • the present invention relates to a therapeutic accelerator in cartilage reduction. More particularly, the present invention relates to a drug that promotes healing, ie, bone regeneration and cartilage repair, in cartilage reduction surgery in which a defect is formed in the subchondral bone and articular cartilage.
  • Articular cartilage has a role as a cushion against loads and impacts, and is also important as guaranteeing mobility in joints.However, even with the same cartilage, growth plate cartilage plays an important role in skeletal growth. Be distinguished. In other words, the growth plate and bone cells present at the epiphysis and other parts achieve their physiological significance by proliferating and differentiating and then calcifying and replacing bone, whereas calcification is a desired function in articular cartilage. Contrary to this and usually does not cause calcification. This is why articular cartilage is called permanent or stationary cartilage.
  • Articular cartilage disorders can occur for a variety of reasons. These include joint overuse, joint trauma, fractures, infection, chronic arthritis, endocrine abnormalities, and metabolic abnormalities. It is often thought to be closely related to aging and aging, for which the cause cannot be identified.
  • This joint condition which is collectively called osteoarthritis and is based on the degenerative degeneration of joint components centered on articular cartilage, has become a serious social problem due to the aging society and the number of patients is growing rapidly. ing.
  • cartilage matrix destruction progresses, the cartilage layer becomes thinner, and subchondral bone hardens in the load area, which further increases the stress on cartilage, and further degenerates and destroys cartilage. Go.
  • the cartilage layer is completely lost locally, and the subchondral bone is exposed, and is worn and dentinized by frictional motion.
  • cartilage reduction procedures include arthroscopic perforation by drilling the affected area where the cartilage layer is damaged, recurrence to the subchondral bone, and removal of necrotic tissue.
  • Chen Yongzhen, Joint Surgery, 8, 113-121 (1989) Ch i 1 der, El ll wo o ⁇ C lin. O rt ho p.. 144, 114—120 (1979)) performed perforation in patients with extra-knee cartilage disorders, and Good results have been obtained.
  • S workede et al. (Clin. Orthop., 144, 74—83 (1979)) reported that degenerative arthritic knees were subjected to debridement and resection in 73% of patients. I see joint stiffness and pain relief.
  • Surgery to create defects in the bone for surgical treatment includes, for example, benign bone tumors and osteomas, when harvesting bone grafts (eg, iliac bones), joint contractures, open fractures, complex fractures, bone atrophy, It is performed due to osteonecrosis, osteomyelitis, etc., and cartilage reduction can be considered as a surgical technique in which the surgical site is limited to the joint.
  • bone grafts eg, iliac bones
  • joint contractures eg, open fractures, complex fractures, bone atrophy
  • cartilage reduction can be considered as a surgical technique in which the surgical site is limited to the joint.
  • the present inventors have continued research on drugs that promote bone regeneration and cartilage repair in surgical cartilage reduction, and as a result, parathyroid hormone ( ⁇ ⁇ ⁇ ⁇ ) showed such a useful effect.
  • PTH is the most important hormone involved in bone metabolism secreted by the parathyroid gland, its pharmacological effects are diverse. In short, its effect is to promote bone turnover, and in recent years, in addition to the long-known activity of promoting bone absorption, bone formation has also attracted attention, and its potential as a therapeutic agent for osteoporosis is being investigated. .
  • the present inventors suggest that PTH promotes the differentiation of various undifferentiated cells derived from blood in surgical cartilage reduction with hemorrhage, repairs bone defects, and helps regeneration of cartilage tissue.
  • Animal experiments were performed based on the hypothesis. In other words, when repairing a hole drilled from the surface of the cartilage at the distal end of the egret femur, the subchondral bone grew faster in the PTH-administered group than in the control group, and the cartilage layer was almost normal in regeneration. Was found to be fast.
  • Fig. 1 is a photograph of the HE-stained tissue specimen at the 21st postoperative day in the PTH administration group.
  • FIG. 2 is a photograph of the HE-stained tissue specimen of the control group 21 days after the operation.
  • FIG. 3 is a photograph of the HE-stained tissue specimen of the control group on day 42 after the operation.
  • Figure 4 is a photograph of the 21st post-operative Alshan blue stained tissue specimen in the PTH-administered group.
  • FIG. 5 is a photograph of the 21st post-operative Alshan blue stained tissue specimen of the control group.
  • FIG. 6 is a photograph of the Alshambre single-stained tissue specimen of the control group on day 42 after the operation.
  • the parathyroid hormone (PTH) in the present invention includes natural PTH, PTH produced by a genetic method, and PTH chemically synthesized, and preferably comprises human PTH comprising 84 amino acid residues.
  • the PTH derivative means a peptide having the same activity as the above-mentioned partial peptide of PTH or a peptide in which the amino acid constituting PTH itself or its partial peptide is partially replaced with another amino acid.
  • Examples of the partial peptide of PTH include, for example, human 1-34PTH and peptide 1-34PTH.
  • 1-34 PTH means the partial peptide of PTH consisting of 34 amino acids from the N-terminal to the 34th amino acid of PTH.
  • Parathyroid hormone used as a therapeutic accelerator in bone reduction according to the present invention is used as a therapeutic accelerator in bone reduction according to the present invention.
  • Preferred examples of (PTH) or PTH derivatives human 1-84PTH, human 1 one 34PTH, human 1 one 38PTH, human 1 one 37 PTH, such as human 1-34P TH- NH 2 and the like, More preferred are human 1-84 PTH and human 1-34 PTH, and most preferred is human 1-84 PTH.
  • Cartilage repair such as drilling a hole in the affected area where the cartilage layer is damaged under arthroscopic vision, recurrence to the subchondral bone, and removal of necrotic tissue. It means the intended surgical treatment of cartilage and subchondral bone.
  • the dosage form of the drug of the present invention in addition to an injection prepared by a usual preparation method of a peptide, localization and delayed action such as encapsulation in a microcapsule or inclusion in a gel sheet were expected. Dosage forms are also possible. In the case of a liquid preparation, it is preferable to add an appropriate protein or an appropriate anti-adhesion agent.
  • the method of administering the agent of the present invention can be performed by systemic administration or local administration. Preferred examples include whole injection such as local injection into the joint cavity or into a lesion by injection, or subcutaneous administration.
  • the dosage of PTH of the present invention, the adaptive diseases, varies depending on such conditions, 10 7 M from 10-15 at the tissue level by topical administration, from 10 to 1000 gZ head is preferable than systemic administration.
  • the administration timing may be either before or after cartilage reduction surgery, but administration after surgery is more preferable.
  • PTH used in the examples was prepared by using a modified method of the method described in Japanese Patent Publication No. 505259/1992 and J. Biol. Chem., 265, 15854 (1990).
  • the following experiment was performed as an experiment using an animal model of cartilage reduction.
  • JWZCSK Japanese White Heron
  • the darkly stained portion with HE staining in Fig. 1, Fig. 2 and Fig. 3 is the bone (subchondral bone), and the darkly stained portion with Alshan blue staining in Fig. 4, Fig. 5 and Fig. 6.
  • the repair of the hole drilled from the ⁇ distal end of the heron's femur ⁇ bone surface was performed in the PTH-administered group not only at the same time as the control group (21 after surgery) but also in the control group. 42 Compared to 42 days after the operation, ⁇ the growth of the subosseous bone was faster, near normal, and the regeneration of the cartilage layer was much faster '.
  • the drug containing the PTH or PTH derivative of the present invention as an active ingredient is useful for promoting healing in surgical cartilage reduction surgery.

Abstract

A cure accelerator in chondroplasty containing a parathyroid hormone (PTH) or a derivative thereof as the active ingredient.

Description

明 細 書  Specification
軟骨整復術治療促進剤 技術分野  Cartilage reduction treatment accelerator Technical field
本発明は、 軟骨整復術における治療促進剤に関する。 さらに詳しくは外科的に 軟骨下骨と関節軟骨に欠損部を作成する軟骨整復術における治癒すなわち骨新生 と軟骨修復を促進する薬剤に関する。  The present invention relates to a therapeutic accelerator in cartilage reduction. More particularly, the present invention relates to a drug that promotes healing, ie, bone regeneration and cartilage repair, in cartilage reduction surgery in which a defect is formed in the subchondral bone and articular cartilage.
背景技術 Background art
関節軟骨は、 荷重や衝撃に対するクッションの役割を有するとともに、 関節で の易可動性を保証するものとして重要であるが、 同じ軟骨でも骨格成長に重要な 役割を果たす成長板軟骨などとは厳密に区別される。 すなわち、 骨端部などに存 在する成長板软骨細胞では、 増殖、 分化した後石灰化して骨に置き換わることで その生理的意義を完遂するのに対し、 関節軟骨では、 石灰化は目的機能に反する ものであり、 通常石灰化は起こさない。 これが関節軟骨が永久軟骨あるいは静止 軟骨と言われる所以である。  Articular cartilage has a role as a cushion against loads and impacts, and is also important as guaranteeing mobility in joints.However, even with the same cartilage, growth plate cartilage plays an important role in skeletal growth. Be distinguished. In other words, the growth plate and bone cells present at the epiphysis and other parts achieve their physiological significance by proliferating and differentiating and then calcifying and replacing bone, whereas calcification is a desired function in articular cartilage. Contrary to this and usually does not cause calcification. This is why articular cartilage is called permanent or stationary cartilage.
関節軟骨の障害は種々の原因で起こり得る。 すなわち、 関節の酷使、 関節外傷、 骨折、 感染、 慢性関節炎、 内分泌異常、 代謝異常等である。 また、 原因を特定し 得ない経年変性や老化と密接に関係すると思われる場合も多い。 変形性関節症と 総称されるこの関節軟骨を中心とした関節構成体の退行性変性を基盤とする関節 病態は、 高齢化社会を迎え患者数も急速に伸びており、 重大な社会問題となって いる。 病態の進展とともに、 軟骨マトリックスの破壊が進行し、 軟骨層は薄くな り、 荷重部では軟骨下骨の硬化が起こり、 これがさらに軟骨にかかるストレスを 増大させ、 さらに軟骨の変性破壊が進行していく。 やがては局所的に軟骨層が全 く消失し、 軟骨下骨が露出し、 摩擦運動により摩耗し象牙質化したりする。  Articular cartilage disorders can occur for a variety of reasons. These include joint overuse, joint trauma, fractures, infection, chronic arthritis, endocrine abnormalities, and metabolic abnormalities. It is often thought to be closely related to aging and aging, for which the cause cannot be identified. This joint condition, which is collectively called osteoarthritis and is based on the degenerative degeneration of joint components centered on articular cartilage, has become a serious social problem due to the aging society and the number of patients is growing rapidly. ing. As the disease progresses, cartilage matrix destruction progresses, the cartilage layer becomes thinner, and subchondral bone hardens in the load area, which further increases the stress on cartilage, and further degenerates and destroys cartilage. Go. Eventually, the cartilage layer is completely lost locally, and the subchondral bone is exposed, and is worn and dentinized by frictional motion.
関節軟骨のうけた障害は、 一般にきわめて修復が困難であり、 整形外科領域に おける大きな問題となっている。 軟骨が血管により栄養の補給をうけない組織で あることが、 この修復の難しさと関係していると思われる。 H. K. W. K i m ら （J. Bo n e a n d J o i n t S u r g e r y, 73 A, 1301— Damage to articular cartilage is generally extremely difficult to repair and poses a major problem in the orthopedic field. The fact that cartilage is a tissue that is no longer vascularly nourished appears to be associated with this difficulty in repair. H.K.W.Kim et al. (J. Bonean dJointSurg ery, 73 A, 1301—
1315 (1991) ) のゥサギを用いた実験がこの間の事情を端的に物語って いる。 すなわち、 ゥサギの関節軟骨表層に浅い搔爬傷をつけた場合は、 12週間 経過後もほとんど修復が認められないのに対して、 軟骨下骨にまで達する深い搔 爬傷の場合は、 4週間でほとんど修復することを観察している。 この一見逆説的 に見える現象は、 深い傷の場合、 骨髄からの出血により血液由来の種々の細胞が 供給され骨欠損部の骨新生とともに血管のない軟骨組織の修復に関与するためで あると解釈できる。 通常極めて困難な軟骨修復への一つのアプローチとして現在 行われている軟骨整復術 （c ho n d r o p l a s t y) は、 このような考え方 に基づくものであるといえる。 1315 (1991)), an experiment using egrets tells the story during this period. I have. That is, 浅 shallow reptiles on the surface of the articular cartilage of the egret hardly show any repair after 12 weeks, whereas 搔 repeats that reach the subchondral bone 4 weeks It has been observed that most repairs are made. This seemingly paradoxical phenomenon can be interpreted as that, in the case of deep wounds, bleeding from the bone marrow supplies a variety of blood-derived cells and contributes to the regeneration of cartilage tissue without blood vessels as well as the regeneration of bone in the bone defect. it can. The current practice of chondroplasty, which is one of the most difficult approaches to cartilage repair, is based on this concept.
現在、 軟骨整復術としては関節鏡視下に軟骨層が障害をうけている患部にドリ ルで穴をあける穿孔術や、 軟骨下骨に達する搔爬術、 壊死組織の切除術などが行 われている （陳永振、 関節外科、 8、 113— 121 (1989) ) 。 Ch i 1 d e r, E l l wo o ^ C l i n. O r t ho p. . 144, 114— 12 0 (1979) ) は、 膝外軟骨障害患者に対し穿孔術を行い、 80%以上の患者 で良好な結果を得ている。 S p r a gu eら （C l i n. O r t ho p. , 14 4, 74— 83 (1979) ) は、 退行性関節炎の膝に、 壊死組織切除、 搔爬術 を施し、 73%の患者に関節の硬さ、 疼痛の軽減を見ている。  At present, cartilage reduction procedures include arthroscopic perforation by drilling the affected area where the cartilage layer is damaged, recurrence to the subchondral bone, and removal of necrotic tissue. (Chen Yongzhen, Joint Surgery, 8, 113-121 (1989)). Ch i 1 der, El ll wo o ^ C lin. O rt ho p.. 144, 114—120 (1979)) performed perforation in patients with extra-knee cartilage disorders, and Good results have been obtained. S prague et al. (Clin. Orthop., 144, 74—83 (1979)) reported that degenerative arthritic knees were subjected to debridement and resection in 73% of patients. I see joint stiffness and pain relief.
外科的治療の目的で骨に欠損を作成する手術は、 例えば良性骨腫瘍ならびに骨 囊腫、 移植骨の採取時 （腸骨など） 、 関節拘縮、 開放骨折、 複雑骨折、 骨萎縮、 無腐性骨壊死、 骨炎等で行われており、 軟骨整復術は手術部位を関節部に限定し た術式ととらえることもできる。  Surgery to create defects in the bone for surgical treatment includes, for example, benign bone tumors and osteomas, when harvesting bone grafts (eg, iliac bones), joint contractures, open fractures, complex fractures, bone atrophy, It is performed due to osteonecrosis, osteomyelitis, etc., and cartilage reduction can be considered as a surgical technique in which the surgical site is limited to the joint.
発明の開示 Disclosure of the invention
このように一般には修復の困難な軟骨の障害に、 外科的软骨整復術がある程度 効果があるが、 この術式における治癒を促進するような薬剤は未だ知られていな い。 またこの軟骨整復術には、 賛否両論があり、 短期的にはある程度の効果はあ- ても、 長期的にはメリッ トはないという説もある。 この術式における骨新生と軟 骨の修復を促進し得る薬剤があれば、 この術式そのものの評価をも高め、 関節軟 骨障害の治癒に貢献するものと思われる。  As described above, surgical bone reduction is effective to some extent in repairing cartilage disorders that are generally difficult to repair, but there is no known drug that promotes healing in this surgical procedure. There are pros and cons to this cartilage reduction procedure, and there is a theory that although there are some effects in the short term, there is no merit in the long term. Drugs that could enhance bone regeneration and cartilage repair in this procedure would enhance the reputation of the procedure and contribute to the healing of articular cartilage disorders.
本発明者らは、 外科的軟骨整復術における骨新生と軟骨修復を促す薬剤を求め て研究を続けてきた結果、 副甲状腺ホルモン （ΡΤΗ) がこのような有用な作用  The present inventors have continued research on drugs that promote bone regeneration and cartilage repair in surgical cartilage reduction, and as a result, parathyroid hormone (ホ ル モ ン) showed such a useful effect.
- - を有することを発見し、 本発明を完成するに至った。 PTHは副甲状腺より分泌 される骨代謝にかかわる最も重要なホルモンであるが、 その薬理作用は多岐にわ たる。 その作用は一言でいえば、 骨代謝回転促進作用で、 古くより知られた骨吸 収促進作用に加えて、 近年骨形成作用も注目され、 骨粗鬆症治療薬としての可能 性が検討されている。 -- To complete the present invention. Although PTH is the most important hormone involved in bone metabolism secreted by the parathyroid gland, its pharmacological effects are diverse. In short, its effect is to promote bone turnover, and in recent years, in addition to the long-known activity of promoting bone absorption, bone formation has also attracted attention, and its potential as a therapeutic agent for osteoporosis is being investigated. .
PTHの軟骨に対する作用はまだ不明の点が多い。 これまでに、 PTHが i n V i t r oの実験系で軟骨細胞の增殖や分化機能に影響を与えることが報告さ れている （Kawa s h i ma e t a 1 , En d o c r i no l . J pn, 27, 349-356 (1983) ； Bu r c h e t a 1 , C a 1 c i f . T i s s u e I n t. ， 35， 526 - 532 (1983) : S u z uk i e t a 1 , FEBS L e t t. , 70， 155- 158 (1976) ； T a k i g a w a e t a 1 , P r o. a t l . Ac a d. S c i. USA, 7 7, 1481-1485 (1980) ； K a t o e t a 1 , Endo c r i n o 1 o gy, 122, 1991— 1997 (1988) など） 。 しかし、 軟骨 細胞の増殖に関する作用については、 胎仔期軟骨細胞には促進的であっても、 出 生後は作用がないという報告が多く、 さらに PTHの軟骨細胞分化機能促進の作 用は、 成長板軟骨細胞で明かでも、 関節軟骨細胞では認められないというものが ほとんどである。 PTHが関節軟骨に対して、 実際にその修復や增生を促すこと を報告したという例はまだな 、。  The effects of PTH on cartilage remain largely unknown. So far, it has been reported that PTH affects the growth and differentiation of chondrocytes in an in vitro experimental system (Kawa shima eta 1, En docri no l. Jpn, 27, 349- 356 (1983); Burcheta 1, Ca1 cif. T issue Int., 35, 526-532 (1983): Suz uk ieta 1, FEBS Lett., 70, 155-158 (1976) USA, 77, 1481-1485 (1980); Katoeta 1, Endo crino 1 ogy, 122, 1991-1997 (1988), etc .; ). However, there are many reports that chondrocyte proliferation is promoted in fetal chondrocytes but not after birth, and PTH promotes chondrocyte differentiation. Most are apparent in chondrocytes but not in articular chondrocytes. There are no reports that PTH actually promotes repair or regeneration of articular cartilage.
本発明者らは P T Hが出血を伴う外科的軟骨整復術における血液由来の種々の 未分化細胞の分化を促進し、 骨欠損部を修復するとともに、 軟骨組織の再生を助 けるのではないかという仮説に基づき、 動物実験を行った。 すなわち、 ゥサギ大 腿骨遠位端軟骨表面より ドリルであけた穴の修復を観察したところ、 PTH投与 群では対照群に比べ、 軟骨下骨の増生が速く、 正常に近い軟骨層の再生もはるか に速いことが認められた。  The present inventors suggest that PTH promotes the differentiation of various undifferentiated cells derived from blood in surgical cartilage reduction with hemorrhage, repairs bone defects, and helps regeneration of cartilage tissue. Animal experiments were performed based on the hypothesis. In other words, when repairing a hole drilled from the surface of the cartilage at the distal end of the egret femur, the subchondral bone grew faster in the PTH-administered group than in the control group, and the cartilage layer was almost normal in regeneration. Was found to be fast.
図面の簡単な説明 BRIEF DESCRIPTION OF THE FIGURES
図 1は PTH投与群の術後 21曰目の HE染色組織標本の写真である。  Fig. 1 is a photograph of the HE-stained tissue specimen at the 21st postoperative day in the PTH administration group.
図 2は対照群の術後 21日目の HE染色組織標本の写真である。  FIG. 2 is a photograph of the HE-stained tissue specimen of the control group 21 days after the operation.
図 3は対照群の術後 42日目の HE染色組織標本の写真である。 図 4は PTH投与群の術後 21曰目のアルシャンブルー染色組織標本の写真で ある。 FIG. 3 is a photograph of the HE-stained tissue specimen of the control group on day 42 after the operation. Figure 4 is a photograph of the 21st post-operative Alshan blue stained tissue specimen in the PTH-administered group.
図 5は対照群の術後 21曰目のアルシャンブルー染色組織標本の写真である。 図 6は対照群の術後 42日目のアルシャンブル一染色組織標本の写真である。 発明を実施するための最良の形態  FIG. 5 is a photograph of the 21st post-operative Alshan blue stained tissue specimen of the control group. FIG. 6 is a photograph of the Alshambre single-stained tissue specimen of the control group on day 42 after the operation. BEST MODE FOR CARRYING OUT THE INVENTION
本発明における副甲状腺ホルモン （PTH) とは、 天然型の PTH、 遺伝子ェ 学的手法で作成された PTH、 化学的に合成された PTHを包含し、 好ましくは 84アミノ酸残基より成るヒト PTH (ヒト 1一 84PTH) を示す。 また PT H誘導体とは、 前記の PTHの部分ペプチドや、 PTHそのものあるいはその部 分べプチドの構成ァミノ酸を一部他のァミノ酸に置き換えたぺプチドなどで同様 の活性を有するペプチドを意味し、 PTHの部分ペプチドとしては、 たとえばヒ ト 1一 34PTH、 ゥシ 1— 34PTHなどがあげられる。 1— 34PTHとは PTHのN末端から34番目のアミノ酸までの 34個のァミノ酸からなる PTH の部分べプチドを意味する。  The parathyroid hormone (PTH) in the present invention includes natural PTH, PTH produced by a genetic method, and PTH chemically synthesized, and preferably comprises human PTH comprising 84 amino acid residues. (Human-84PTH). The PTH derivative means a peptide having the same activity as the above-mentioned partial peptide of PTH or a peptide in which the amino acid constituting PTH itself or its partial peptide is partially replaced with another amino acid. Examples of the partial peptide of PTH include, for example, human 1-34PTH and peptide 1-34PTH. 1-34 PTH means the partial peptide of PTH consisting of 34 amino acids from the N-terminal to the 34th amino acid of PTH.
本発明で软骨整復術における治療促進剤として用いられる副甲状腺ホルモン Parathyroid hormone used as a therapeutic accelerator in bone reduction according to the present invention
(PTH) または PTH誘導体の好ましい例としては、 ヒト 1— 84PTH、 ヒ ト 1一 34PTH、 ヒ ト 1一 38PTH、 ヒ ト 1一 37 PTH、 ヒ ト 1— 34P TH— NH2などがあげられ、 さらに好ましくはヒト 1一 84 PTH, ヒト 1一 34 PTHであり、 最も好ましいものとしてヒト 1—84 PTHがあげられる。 軟骨整復術とは関節鏡視下に軟骨層が障害をうけている患部にドリルで穴をあ ける穿孔術や、 軟骨下骨に達する搔爬術、 壊死組織の切除術など、 軟骨の修復を 目的とした外科的な軟骨や軟骨下骨への処置を意味する。 Preferred examples of (PTH) or PTH derivatives, human 1-84PTH, human 1 one 34PTH, human 1 one 38PTH, human 1 one 37 PTH, such as human 1-34P TH- NH 2 and the like, More preferred are human 1-84 PTH and human 1-34 PTH, and most preferred is human 1-84 PTH. What is cartilage reduction? Cartilage repair, such as drilling a hole in the affected area where the cartilage layer is damaged under arthroscopic vision, recurrence to the subchondral bone, and removal of necrotic tissue. It means the intended surgical treatment of cartilage and subchondral bone.
本発明の薬剤の剤形としてはべプチドの通常の製剤方法により製造される注射 剤の他に、 例えばマイクロカプセルへの封入あるいはゲル状のシー卜に含ませる など局所化および遅効性を期待した剤形も可能である。 液剤の場合には、 適当な 蛋白質を添加したり、 あるいは適当な付着防止剤を添加することが好ましい。 本発明の薬剤の投与方法は、 全身投与でも局所投与でも行い得るが、 好ましい 例として、 注射により関節腔内あるいは病変部への局所注入や皮下投与などの全 身投与などがあげられる。 本発明の PTHの投与量は、 適応疾患、 症状などにより異なるが、 局所投与で は組織レベルで 10— 15から 10— 7Mが、 全身投与では 10から 1000 gZ h e a dが好ましい。 また、 投与時期としては軟骨整復術の術前、 術後の何れで もよいが、 術後投与する方がより好ましい。 As the dosage form of the drug of the present invention, in addition to an injection prepared by a usual preparation method of a peptide, localization and delayed action such as encapsulation in a microcapsule or inclusion in a gel sheet were expected. Dosage forms are also possible. In the case of a liquid preparation, it is preferable to add an appropriate protein or an appropriate anti-adhesion agent. The method of administering the agent of the present invention can be performed by systemic administration or local administration. Preferred examples include whole injection such as local injection into the joint cavity or into a lesion by injection, or subcutaneous administration. The dosage of PTH of the present invention, the adaptive diseases, varies depending on such conditions, 10 7 M from 10-15 at the tissue level by topical administration, from 10 to 1000 gZ head is preferable than systemic administration. The administration timing may be either before or after cartilage reduction surgery, but administration after surgery is more preferable.
実施例 Example
以下に本発明の実施例を示す。 実施例で使用した PTHは、 特表平 4一 505 259号公報および J . B i o l. C h em. ， 265, 15854 (1990) に記載された方法の改良法を用いて製造されたヒト 1一 84 PTHである。  Hereinafter, examples of the present invention will be described. PTH used in the examples was prepared by using a modified method of the method described in Japanese Patent Publication No. 505259/1992 and J. Biol. Chem., 265, 15854 (1990). One is 84 PTH.
(実施例 1 )  (Example 1)
軟骨整復術の動物モデルによる実験として以下のような実験を行った。  The following experiment was performed as an experiment using an animal model of cartilage reduction.
日本白色種ゥサギ （JWZCSK) の左後肢内側から切開し、 大腿骨遠位端を 露出し、 遠位端内側に滅菌したドリルを用いて直径 3 mm、 深さ 2 mmにわたり、 軟骨および硬骨の切除を行う。 切開部を縫合し、 術後 1曰めより、 1曰おきに週 3回、 関節腔内へ PTH 100 g/m 1溶液 0. 5mlを投与する。 術後 21 日めおよび対照群は 42日めに大腿骨遠位端を摘出し、 直ちに 10%ホルマリン 液を用いて固定する。 脱灰後、 へマトキシリン一ェォジン染色 （HE染色） 、 ァ ルシャンブルー染色 （軟骨が青く染まる） 、 そしてサフラニン一 0染色を行い、 組織標本を作成した。  An incision was made from the inside of the left hind limb of the Japanese White Heron (JWZCSK), exposing the distal end of the femur, and using a sterilized drill on the inside of the distal end to remove cartilage and hard bone over a diameter of 3 mm and a depth of 2 mm. I do. Suture the incision and administer 0.5 ml of the PTH 100 g / m1 solution into the joint cavity three times a week, every other word, after the first word. On the 21st postoperative day and in the control group, the distal end of the femur is removed on the 42nd day and immediately fixed with 10% formalin solution. After decalcification, hematoxylin and eosin staining (HE staining), Alcian blue staining (cartilage stains blue), and safranin-10 staining were performed to prepare tissue specimens.
結果を図 1〜図 6に示す。  The results are shown in FIGS.
図 1、 図 2、 図 3の HE染色で濃く染まっている部分は、 骨 （軟骨下骨） の部 分であり、 図 4、 図 5、 図 6のアルシャンブルー染色で濃く染まっている部分は 軟骨部分である。  The darkly stained portion with HE staining in Fig. 1, Fig. 2 and Fig. 3 is the bone (subchondral bone), and the darkly stained portion with Alshan blue staining in Fig. 4, Fig. 5 and Fig. 6. The cartilage part.
図より明らかなように、 ゥサギ大腿骨遠位端钦骨表面より ドリルであけた穴の 修復は、 PTH投与群では対照群の同時期 （術後 21曰め） のものはもとより、 対照群の術後 42日経過したものに比べても、 钦骨下骨の増生が速く、 正常に近 、軟骨層の再生もはるかに速い'ことが認められた。  As is evident from the figure, the repair of the hole drilled from the 钦 distal end of the heron's femur 钦 bone surface was performed in the PTH-administered group not only at the same time as the control group (21 after surgery) but also in the control group. 42 Compared to 42 days after the operation, 钦 the growth of the subosseous bone was faster, near normal, and the regeneration of the cartilage layer was much faster '.
産業上の利用可能性 Industrial applicability
本発明の PTHまたは PTH誘導体を有効成分として含有する薬剤は、 外科的 軟骨整復術における治癒の促進に有用である。  The drug containing the PTH or PTH derivative of the present invention as an active ingredient is useful for promoting healing in surgical cartilage reduction surgery.

Claims

s冃 求 の 範 囲 s 冃 Scope of request
1. 副甲状腺ホルモン （PTH) または PTH誘導体を有効成分として含有す ることを特徴とする、 軟骨整復術における治療促進剤。 1. A therapeutic agent for cartilage reduction surgery, characterized by containing parathyroid hormone (PTH) or a PTH derivative as an active ingredient.
2. 副甲状腺ホルモン （PTH) がヒ ト PTH (1-84) であることを特徴 とする請求項 1記載の軟骨整復術における治療促進剤。  2. The therapeutic accelerator in cartilage reduction according to claim 1, wherein the parathyroid hormone (PTH) is human PTH (1-84).
3. PTH誘導体がヒ 卜 PTH (1-34) であることを特徴とする請求項 1 記載の軟骨整復術における治療促進剤。  3. The therapeutic accelerator for cartilage reduction according to claim 1, wherein the PTH derivative is human PTH (1-34).
4. 副甲状腺ホルモン （PTH) を有効成分として含有することを特徴とする 請求項 1記載の軟骨整復術における治療促進剤。  4. The therapeutic accelerator for cartilage reduction according to claim 1, comprising parathyroid hormone (PTH) as an active ingredient.
5. 副甲状腺ホルモン （PTH) がヒト PTH (1— 84) であることを特徴 とする請求項 4記載の軟骨整復術における治療促進剤。  5. The treatment promoting agent for cartilage reduction according to claim 4, wherein the parathyroid hormone (PTH) is human PTH (1-84).
6. 副甲状腺ホルモン （PTH) 誘導体を有効成分として含有することを特徴 とする、 軟骨整復術における治療促進剤。  6. A therapeutic agent for cartilage reduction, comprising a parathyroid hormone (PTH) derivative as an active ingredient.
7. PTH誘導体がヒ 卜 PTH (1-34) であることを特徴とする請求項 6 記載の軟骨整復術における治療促進剤。  7. The therapeutic agent for cartilage reduction according to claim 6, wherein the PTH derivative is human PTH (1-34).
8. 軟骨整復術が、 穿孔術、 搔爬術または切除術であることを特徴とする請求 項 1記載の軟骨整復術における治療促進剤。  8. The therapeutic agent for cartilage reduction according to claim 1, wherein the cartilage reduction is perforation, recurrence, or resection.
PCT/JP1994/001803 1993-10-27 1994-10-27 Cure accelerator in chondroplasty WO1995011697A1 (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998024471A1 (en) * 1996-12-05 1998-06-11 Société De Conseils De Recherches Et D'applications Scientifiques S.A.; Treatment of bone fracture
WO1999012561A2 (en) * 1997-09-09 1999-03-18 F. Hoffman-La Roche Ag FRACTURE HEALING USING PTHrP ANALOGS
EP0811383A4 (en) * 1995-02-20 2000-02-09 Yukio Kato Remedies for arthrosis deformans and inflammatory joint diseases
WO2010045229A2 (en) 2008-10-13 2010-04-22 University Of Rochester Protecting and repairing cartilage and musculoskeletal soft tissues

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0532696A (en) * 1990-09-28 1993-02-09 Takeda Chem Ind Ltd Parathyroid hormone derivative
JPH05320193A (en) * 1992-03-19 1993-12-03 Takeda Chem Ind Ltd Parathyroidal hormone derivative
JPH0687897A (en) * 1991-05-23 1994-03-29 Allelix Biopharmaceut Inc Essentially pure human parathroid hormone
JPH06184198A (en) * 1992-07-15 1994-07-05 Sandoz Ag Peptide

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0532696A (en) * 1990-09-28 1993-02-09 Takeda Chem Ind Ltd Parathyroid hormone derivative
JPH0687897A (en) * 1991-05-23 1994-03-29 Allelix Biopharmaceut Inc Essentially pure human parathroid hormone
JPH05320193A (en) * 1992-03-19 1993-12-03 Takeda Chem Ind Ltd Parathyroidal hormone derivative
JPH06184198A (en) * 1992-07-15 1994-07-05 Sandoz Ag Peptide

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0811383A4 (en) * 1995-02-20 2000-02-09 Yukio Kato Remedies for arthrosis deformans and inflammatory joint diseases
WO1998024471A1 (en) * 1996-12-05 1998-06-11 Société De Conseils De Recherches Et D'applications Scientifiques S.A.; Treatment of bone fracture
WO1999012561A2 (en) * 1997-09-09 1999-03-18 F. Hoffman-La Roche Ag FRACTURE HEALING USING PTHrP ANALOGS
WO1999012561A3 (en) * 1997-09-09 1999-05-14 Hoffmann La Roche FRACTURE HEALING USING PTHrP ANALOGS
AU752925B2 (en) * 1997-09-09 2002-10-03 F. Hoffmann-La Roche Ag Fracture healing using PTHrP analogs
US6583114B2 (en) 1997-09-09 2003-06-24 Roche Palo Alto Llc Fracture healing using pthrp analogs
WO2010045229A2 (en) 2008-10-13 2010-04-22 University Of Rochester Protecting and repairing cartilage and musculoskeletal soft tissues
EP2349325A4 (en) * 2008-10-13 2012-08-29 Univ Rochester Protecting and repairing cartilage and musculoskeletal soft tissues
US8513193B2 (en) 2008-10-13 2013-08-20 University Of Rochester Protecting and repairing cartilage and musculoskeletal soft tissues
US9192653B2 (en) 2008-10-13 2015-11-24 University Of Rochester Protecting and repairing cartilage and musculoskeletal soft tissues

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