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WO2023134146A1 - 乳酸在调节促进组织增长制品中的应用 - Google Patents

乳酸在调节促进组织增长制品中的应用 Download PDF

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Publication number
WO2023134146A1
WO2023134146A1 PCT/CN2022/108025 CN2022108025W WO2023134146A1 WO 2023134146 A1 WO2023134146 A1 WO 2023134146A1 CN 2022108025 W CN2022108025 W CN 2022108025W WO 2023134146 A1 WO2023134146 A1 WO 2023134146A1
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Prior art keywords
lactic acid
tissue
tendon
analogues
compounds
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PCT/CN2022/108025
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English (en)
French (fr)
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王晋岳
郑茜
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长春圣博玛生物材料有限公司
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Priority to MX2024008624A priority Critical patent/MX2024008624A/es
Priority to KR1020247026923A priority patent/KR20240134367A/ko
Priority to AU2022434160A priority patent/AU2022434160A1/en
Priority to JP2024562216A priority patent/JP2024547224A/ja
Priority to EP22919783.5A priority patent/EP4464315A1/en
Priority to IL314228A priority patent/IL314228A/en
Publication of WO2023134146A1 publication Critical patent/WO2023134146A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/765—Polymers containing oxygen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates to the technical field of medicine, specifically, the application of lactic acid in products for regulating and/or promoting tissue growth, regeneration and healing.
  • Poly-L-lactic acid is a degradable polymer material that has been developed rapidly since the 1990s. It is made of lactic acid as a monomer through catalytic polymerization. PLLA is widely used in the medical field. Unlike simple fillers (such as hyaluronic acid, calcium hydroxyapatite, etc.), PLLA is a synthetic dermal filler that can stimulate the growth of subcutaneous collagen. Conventional wisdom holds that PLLA induces a foreign body giant cell response that gradually produces collagen. In our research, we found that during the degradation process of PLLA, the molecular structure of PLLA was gradually destroyed, and slowly hydrolyzed into lactic acid.
  • Lactic acid can induce human fibroblasts to increase collagen production, resulting in the increase of collagen fibers in the dermis, resulting in a filling and repairing effect. . Over time, the dermis thickens. The PLLA in the filling part will eventually degrade into carbon dioxide and water, which will be replaced by new collagen to achieve long-term cosmetic effect.
  • the purpose of the present invention is to provide new applications of lactic acid and its analogues.
  • the research of the present invention finds that lactic acid and its analogs can regulate and promote tissue regeneration, growth and healing, and can effectively prevent and treat diseases of tissue damage.
  • One of the objectives of the present invention is to provide the application of lactic acid and its analogues in the preparation of products for regulating and/or promoting tissue growth.
  • the second object of the present invention is to provide the application of lactic acid and its analogues in the preparation of products for regulating and/or promoting tissue regeneration.
  • the third object of the present invention is to provide the application of lactic acid and its analogs in the preparation of products for promoting tissue healing.
  • the fourth object of the present invention is to provide products for regulating and/or promoting tissue regeneration and/or healing in the preparation of lactic acid and its analogues.
  • the tissue is selected from tissues rich in collagen, more preferably, the tissue is selected from one or more of muscle tissue, connective tissue, tendon, fascia, bone, cartilage, and nerve tissue Most preferably, the tissue is selected from one or more of muscle fiber tissue, tendon, cartilage, muscle tissue, connective tissue, bone, and nerve tissue.
  • the lactic acid and its analogs are selected from one or more of L-lactic acid degradable polymers, lactic acid and its related lactic acid salts, lactic acid compounds, and complexes of the above substances and other compounds, preferably lactic acid.
  • the lactate is a chemical derivative of lactic acid, which is a salt formed by combining with a positively charged substance after lactic acid releases hydrogen ions, including but not limited to sodium lactate, potassium lactate, lactic acid Lithium, Calcium Lactate, Magnesium Lactate, Ferrous Lactate, Zinc Lactate, Aluminum Lactate, Chitosan Lactate, Hemosanone Lactate, Trimethoprim Lactate, 1-Ethyl-3-Methylimidazole L One or more of -(+)-lactate, 2-hydroxyethyl-trimethylammonium L-(+)-lactate, L-lactate tetrabutylammonium salt.
  • the product is selected from one or more of medicines, kits, health care products, and medical devices.
  • the fifth object of the present invention is to provide the application of lactic acid and its analogs in the preparation of medicines and/or medical devices for preventing and/or treating tissue damage.
  • the tissue damage is selected from collagen-rich tissue damage. More preferably, the tissue damage is selected from one or more of bone, cartilage, connective tissue, tendon, fascia, nerve tissue, most preferably, the tissue damage is selected from muscle tissue, tendon, cartilage, Damage to one or more of the nerve tissues.
  • the lactic acid and its analogs are selected from one or more of L-lactic acid degradable polymers, lactic acid and its related lactic acid salts, lactic acid compounds, and complexes of the above substances and other compounds, preferably lactic acid.
  • lactic acid and its analogs are used as the active ingredient, preferably, lactic acid and its related analogs are used as the only active ingredient.
  • the lactic acid and its analogues can promote cells to secrete collagen and provide energy for cell activities.
  • the lactic acid and its analogues are injections.
  • the dosage of the lactic acid and its analogues is 25mmol/L-75mmol/L.
  • the sixth object of the present invention is to provide a product that regulates and/or promotes tissue and/or nerve tissue growth, regeneration and/or healing, said product is made of lactic acid and its analogs and acceptable carriers, Said tissue has the meaning as defined above.
  • the lactic acid and its analogs are selected from one or more of L-lactic acid degradable polymers, lactic acid and its related lactic acid salts, lactic acid compounds, and complexes of the above substances and other compounds; more Preferably, selected from lactic acid.
  • the product is selected from one or more of medicines, kits, health care products, and medical devices.
  • the present invention finds through animal experiments that lactic acid and its analogs can significantly regulate and promote tissue growth, regeneration and healing, especially for tissues rich in collagen, and then can be used to prepare products for preventing and/or treating tissue damage, Has broad medicinal value.
  • Fig. 1 is the impact of injecting 25mmol/L lactic acid solution on animal muscle tissue regeneration ability
  • the right side of the experimental mouse is the experimental side (injection of different concentrations of lactic acid solution)
  • the left side is the control side (injection of 0.9% sodium chloride injection).
  • Fig. 2 is the effect of injecting 50mmol/L lactic acid solution on animal muscle tissue regeneration ability.
  • Figure 3 is the effect of injecting 25mmol/L lactic acid solution on the growth of animal tendon.
  • Figure 4 is the effect of injecting 50mmol/L lactic acid solution on the growth of animal tendon.
  • Figure 5 is the effect of injecting 75mmol/L lactic acid solution on the growth of animal tendon.
  • Figure 6 is the effect of injecting 50mmol/L lactic acid solution on the growth of animal ear cartilage.
  • Figure 7 shows the experimental results of the sciatic nerve function index.
  • mice male experimental mice with a body weight of 23 ⁇ 4 g were selected and divided into several groups, 10 in each group.
  • mice for the test, specifically muscle-rectus femoris, tendon-Achilles tendon, cartilage-ear cartilage tissue.
  • mice were the right side of the experimental mice (injected with different concentrations of lactic acid solutions), and the left side was the control side (injected with 0.9% sodium chloride injection).
  • Average value (3 measured values of animal 1 + 3 measured values of animal 2 + 3 measured values of animal 3)/9
  • lactic acid solution has a significant, even extremely significant, promoting effect on the regeneration of animal muscle tissue.
  • the muscle tissue regeneration of animals in the injection 25mmol/L lactic acid aqueous solution group reached a significant level, and the animal muscle tissue regeneration in the injection 50mmol/L lactic acid aqueous solution group Muscle tissue regeneration even reached a very significant level (P ⁇ 0.01) promotion.
  • the Achilles tendon on the experimental side of the 50mmol/L lactic acid aqueous solution group was significantly thickened on the 14th day, and the diameter of the Achilles tendon was detected to increase.
  • the tendon values measured under a 100-fold optical microscope are shown in Table 4: the experimental group was significantly different from the control group at 14 days (P ⁇ 0.05).
  • the lactic acid solution can significantly promote the growth of the tendon, and with the increase of the solubility of the lactic acid solution, the duration of the growth of the tendon can be increased, and the effect is also significant.
  • the lactic acid solution also significantly promotes the growth of the ear cartilage tissue of animals.
  • mice male experimental mice with a body weight of 30-35 g were selected and divided into 3 groups, 26 in each group.
  • Figure 7 is the experimental results of the sciatic nerve function index.
  • the results showed that the SFI scores of the model group and the treatment group were significantly lower than those of the sham operation group 7 days after operation. On the 14th day after operation, the SFI score of the treatment group was significantly increased, and the difference was statistically significant (P ⁇ 0.01), which indicated that the recovery of sciatic nerve function was better after treatment with lactic acid solution.
  • the results of the toe extension experiment in Table 7 show that the score of the treatment group has a significantly higher trend than that of the model group, indicating that lactic acid treatment can effectively improve the mouse toe extension function.
  • lactic acid solution can significantly promote the growth and healing of animal soft tissue, bone tissue and nerve tissue, especially muscle, tendon, cartilage tissue and sciatic nerve tissue, and can effectively prevent, treat and Repair tissue damage disease.

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Abstract

本发明涉及乳酸或聚乳酸调节和促进机体组织增长、再生和愈合，提供一种新的组织损伤的预防和治疗方式，可用于组织的损伤修复，在组织或器官的缺损治疗和修复等方面具有广阔的应用前景。

Description

乳酸在调节促进组织增长制品中的应用
本申请要求享有于2022年01月11日向中国国家知识产权局提交的，专利申请号为202210028046.9，名称为“乳酸在调节促进组织增长制品中的应用”的在先申请的优先权。
技术领域
本发明涉及医药技术领域，具体地说，是乳酸在调节和/或促进组织增长、再生和愈合制品中的应用。
背景技术
聚左旋乳酸(Poly-L-lactic acid，PLLA)是20世纪90年代起迅速发展起来的一种可降解高分子材料，它是以乳酸为单体，经过催化聚合而成。PLLA在医疗领域较为广泛，与单纯的填充剂(如透明质酸、羟基磷灰石钙等)不同，PLLA是一种可以刺激皮下胶原蛋白生长的人工合成的真皮填充剂。传统观念认为PLLA可以引起一种异物巨细胞反应，从而逐渐生成胶原蛋白。而在我们的研究中发现在PLLA降解过程中，PLLA的分子结构逐渐被破坏，缓慢水解成为乳酸，乳酸可诱导人体成纤维细胞增加胶原蛋白的生成，导致真皮内胶原纤维增加，产生填充修复效果。随着时间的增加，使真皮层增厚。填充部位的PLLA最终降解为二氧化碳和水，被新生胶原蛋白所取代，达到长期美容的效果。
然而，尚未发现PLLA和乳酸及其相关乳酸盐化合物在修复软骨、结缔组织、肌腱、筋膜等组织方面的应用。
发明内容
本发明的目的是提供乳酸及其类似物的新用途。本发明研究发现，乳酸及其类似物能够调节和促进组织再生、增长和愈合，能有效预防和治疗组织损伤的疾病。
本发明的目的之一，是提供乳酸及其类似物在制备调节和/或促进组织增长制品中的应用。
本发明的目的之二，是提供乳酸及其类似物在制备调节和/或促进组织再生制品中的应用。
本发明的目的之三，是提供乳酸及其类似物在制备促进组织愈合制品中的应用。
本发明的目的之四，是提供乳酸及其类似物在制备调节和/或促进组织再生和/或愈合的制品。
根据本发明的优选技术方案，所述组织选自富含胶原蛋白的组织，更优选，所述组织选自肌肉组织、结缔组织、肌腱、筋膜、骨、软骨、神经组织中的一个或多个；最优选地，所述组织选自肌纤维组织、肌腱、软骨、肌肉组织、结缔组织、骨、神经组织中的一个或多个。
根据本发明，所述乳酸及其类似物选自左旋乳酸类可降解聚合物、乳酸及其相关乳酸盐、乳酸类化合物、及上述物质与其他化合物的复合物中的一个或多个，优选乳酸。
根据本发明，所述乳酸盐是乳酸的一种化学衍生物，是当乳酸释放出氢离子后，同带正电的物质相结合所形成的盐，包括但不限于乳酸钠、乳酸钾、乳酸锂、乳酸钙、乳酸镁、乳酸亚铁、乳酸锌、乳酸铝、壳聚糖乳酸盐、常山酮乳酸盐、甲氧苄啶乳酸盐、1-乙基-3-甲基咪唑L-(+)-乳酸盐、2-羟乙基-三甲基铵L-(+)-乳酸盐、L-乳酸四丁基铵盐中的一种或多种。
根据本发明，所述制品选自药物、试剂盒、保健品、医疗器械中的一个或多个。
本发明的目的之五，是提供乳酸及其类似物在制备预防和/或治疗组织损伤 的药物和/或医疗器械中的应用。
根据本发明的优选技术方案，所述组织损伤选自富含胶原蛋白的组织的损伤。更优选地，所述组织损伤选自骨、软骨、结缔组织、肌腱、筋膜、神经组织中的一个或多个的损伤，最优选地，所述组织损伤选自肌肉组织、肌腱、软骨、神经组织中的一个或多个的损伤。
根据本发明，所述乳酸及其类似物选自左旋乳酸类可降解聚合物、乳酸及其相关乳酸盐、乳酸类化合物、及上述物质与其他化合物的复合物中的一个或多个，优选乳酸。
在本申请优选的实施例中，乳酸及其类似物作为活性成分，优选，乳酸及其相关类似物作为唯一活性成分。
根据本发明，所述乳酸及其类似物能够促进细胞分泌胶原蛋白，为细胞活动提供能量。
在本发明优选的实施例中，所述乳酸及其类似物为注射剂。其中，所述乳酸及其类似物的用量为25mmol/L-75mmol/L。
本发明的目的之六，是提供一种调节和/或促进组织和/或神经组织增长、再生和/或愈合的制品，所述制品是由乳酸及其类似物和可接受的载体制成，所述组织具有如上文所述的含义。
根据本发明，所述乳酸及其类似物选自左旋乳酸类可降解聚合物、乳酸及其相关乳酸盐、乳酸类化合物、及上述物质与其他化合物的复合物中的一个或多个；更优选地，选自乳酸。
根据本发明，所述制品选自药物、试剂盒、保健品、医疗器械中的一个或多个。
有益效果
本发明通过动物实验发现，乳酸及其类似物能够显著调节和促进组织增长、再生和愈合，特别是对于富含胶原蛋白的组织，进而能够用于制备预防和/或治 疗组织损伤的制品中，具有广阔的药用价值。
附图说明
图1为注射25mmol/L乳酸溶液对于动物肌肉组织再生能力的影响，实验小鼠右侧为实验侧(注射不同浓度乳酸溶液)，左侧为对照侧(注射0.9％氯化钠注射液)。
图2为注射50mmol/L乳酸溶液对于动物肌肉组织再生能力的影响。
图3为注射25mmol/L乳酸溶液对于动物肌腱增长的影响。
图4为注射50mmol/L乳酸溶液对于动物肌腱增长的影响。
图5为注射75mmol/L乳酸溶液对于动物肌腱增长的影响。
图6为注射50mmol/L乳酸溶液对于动物耳软骨增长的影响。
图7为坐骨神经功能指数实验结果。
具体实施方式
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
1.实验设计：
实验动物：选择体重为23±4g的雄性实验用小鼠分成若干组，每组10只。
实验部位：选取小鼠不同的组织部位进行试验，具体为肌肉——股直肌、肌腱——跟腱、软骨——耳软骨组织。
实验分组：①25mmol/L乳酸水溶液  ②50mmol/L乳酸水溶液
          ③75mmol/L乳酸水溶液  ④0.9％氯化钠注射液
实验操作：实验小鼠右侧为实验侧(注射不同浓度乳酸溶液)，左侧为对 照侧(注射0.9％氯化钠注射液)。
实验在开始的1-7日每天在实验侧单点注射0.1ml对应的实验溶液，分别在术后3天、7天、14天每组处死3只小鼠，每只小鼠选取实验侧和对照侧进行固定、病理组织学检测。
2.检测方法：
1)切取观察的组织，组织固定后进行天狼星红染色，观察注射溶液对各部位组织产生的影响。
2)随机选取实验侧和对照侧进行切片，在100倍光学显微镜下测量各组织直径，通过下列公式计算实验侧与对照侧平均值：
平均值＝(①号动物3个测量值+②号动物3个测量值+③号动物3个测量值)/9
比较两侧直径，通过SSPS 21运算结果分析乳酸溶液对各组织部位的作用。实施例1乳酸对于动物肌肉组织再生能力的影响
1.实验结果：
(1)注射25mmol/L乳酸溶液对动物肌肉组织的影响
表1注射25mmol/L乳酸组与对照组测量数值比较
Figure PCTCN2022108025-appb-000001
如图1所示，注射25mmol/L乳酸水溶液组在植入后14天可见实验侧肌肉组织明显增粗，且肌肉组织排列紧密，说明乳酸有促进组织再生的作用。在100倍光学显微镜下测量肌肉组织数值如表1所示：在14天时实验侧与对照侧的实验检测数据达到差异显著(P＜0.05)。
(2)注射50mmol/L乳酸溶液对动物肌肉组织的影响
表2注射50mmol/L乳酸组与对照组测量数值比较
Figure PCTCN2022108025-appb-000002
如图2所示，注射50mmol/L乳酸水溶液组在植入7天时可见实验侧肌肉组织明显增粗。在100倍光学显微镜下测量肌肉组织数值如表2所示：在7天时实验侧与对照侧的实验数据差异极显著(P＜0.01)，在14天时表现显著差异(P＜0.05)。2.结论
由上述实验结果可以看出，乳酸溶液对于动物肌肉组织再生有显著的，甚至是极显著的促进作用，注射25mmol/L乳酸水溶液组动物肌肉组织再生达到显著水平，注射50mmol/L乳酸水溶液组动物肌肉组织再生甚至达到极显著水平(P＜0.01)的促进作用。
实施例2乳酸对于动物肌腱增长的影响
1.实验结果：
(1)注射25mmol/L乳酸溶液对动物肌腱组织的影响
表3注射25mmol/L乳酸组与对照组测量数值比较
Figure PCTCN2022108025-appb-000003
Figure PCTCN2022108025-appb-000004
如图3所示，25mmol/L乳酸水溶液组在注射3天时可见实验侧跟腱明显增粗，检测跟腱直径增大。在第7天检测时发现跟腱多处断裂，因而无法进行测量。在100倍光学显微镜下测量肌腱数值如表3所示：实验组初期跟腱增长迅速，与对照组相比达到显著差异(P＜0.05)。
(2)注射50mmol/L乳酸溶液对动物肌腱组织的影响
表4注射50mmol/L乳酸组与对照组测量数值比较
Figure PCTCN2022108025-appb-000005
如图4所示，50mmol/L乳酸水溶液组在第14天时实验侧跟腱明显增粗，检测跟腱直径增大。在100倍光学显微镜下测量肌腱数值如表4所示：实验组14天时与对照组达到显著差异(P＜0.05)。
(3)注射75mmol/L乳酸溶液对动物肌腱组织的影响
表5注射75mmol/L乳酸组与对照组测量数值比较
Figure PCTCN2022108025-appb-000006
如图5所示，75mmol/L乳酸水溶液组在第3天、7天、21天时均可见实验侧明显增粗，跟腱直径增大。在100倍光学显微镜下测量肌腱数值如表5所示：实验组与对照组，在第3天、7天、21天时均达到显著差异(P＜0.05)。
2.结论：
从上述结果可以看出，乳酸溶液对肌腱增长有显著的促进作用，并且随着乳酸溶液溶度的增长促进肌腱增长持续的时间增长，效果也显著。
实施例3乳酸对动物耳软骨组织的影响
1.实验结果：
注射50mmol/L乳酸溶液对动物耳软骨组织的影响
表6注射50mmol/L乳酸组与对照组测量数值比较
Figure PCTCN2022108025-appb-000007
如图6所示，注射50mmol/L乳酸水溶液组在植入第21天实验侧耳软骨横截面可见明显增厚。在100倍光学显微镜下测量耳软骨数值如表6所示：第21天实验侧与对照侧的实验检测数据差异显著(P＜0.05)。
2.结论：
从上述结果可以看出，乳酸溶液对于动物的耳软骨组织也有明显促进增长。
实施例4乳酸对动物神经组织的影响
1.实验设计：
实验动物：选择体重为30～35g的雄性实验用小鼠分成3组，每组26只。
实验部位：选取小鼠坐骨神经。
实验分组：①模型组(坐骨神经钳夹损伤)；②治疗组(坐骨神经钳夹损伤后，通过腹腔注射每次给予0.1ml的50mmol/L的乳酸水溶液)；③假手术组(仅游离坐骨神经)。
实验操作：治疗组连续给药14天，模型组、假手术组给予等量0.9％氯化钠注射液。
2.检测方法：
(1)分别在术后7天、14天，通过坐骨神经功能指数(SFI)对小鼠的坐骨神经功能经损伤后的功能恢复情况进行追踪评价。具体是：将小鼠双侧后足沾满墨水后在通道内留下脚印，对实验小鼠左损伤侧(E)，右正常侧(N)足印进行测量，记录足印长度(PL)、第1足趾到第5足趾的距离(TS)、第2足趾到第4足趾的距离(IT)、代入公司计算，正常值为O，神经功能损伤后为负值，功能完全丧失为-100.公式如下：
SFI＝109.5(ETS-NTS)/NTS-38.3(EPL-NPL)/NPL+13.3(EIT-NIT)/NIT-8.8
(2)分别在术后3天、7天、14天，记录损伤侧足趾展开程度，评价等级分为0～3分，不展开为0分，完全展开为3分。
3.实验结果：
图7是坐骨神经功能指数的实验结果。结果显示，术后7天模型组和治疗组SFI评分明显低于假手术组。术后14天，治疗组的SFI评分明显升高，且差异具有统计学意义(P＜0.01)，这表明给予乳酸溶液治疗后，坐骨神经功能恢复效果更好。表7的趾展实验结果表明，治疗组评分比模型组的评分具有明显升高的趋势，说明乳酸治疗能有效改善小鼠趾展功能。
表7小鼠趾展实验评分结果
  3天 7天 10天 14天
假手术组 2.7±0.6 2.9±0.2 3.0±0.0 3.0±0.0
模型组 0±0.5 0.2±0.1 0.8±0.4 1.3±0.7
治疗组 0±0.4 0.9±0.6 2±0.3 2.5±0.5
2.结论：
从上述结果可以看出，乳酸溶液对于动物的坐骨神经也有明显促进增长。
综上，本发明通过动物实验证明了乳酸溶液对于动物的软组织、骨组织和神经组织，特别是肌肉、肌腱、软骨组织和坐骨神经组织增长与愈合均有显著的促进作用，能够有效预防、治疗和修复组织损伤疾病。
以上，对本发明的实施方式进行了说明。但是，本发明不限定于上述实施方式。凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (10)

  1. 乳酸及其类似物在制备调节和/或促进组织增长、再生或愈合制品中的应用，其特征在于，所述组织选自富含胶原蛋白的组织。
  2. 根据权利要求1所述的应用，其特征在于，所述组织选自肌肉组织、结缔组织、肌腱、筋膜、骨、软骨、神经组织中的至少一种；
    优选地，所述组织选自肌腱、软骨、肌肉组织、结缔组织、骨、神经组织中的一个或多个；
    所述乳酸及其类似物选自左旋乳酸类可降解聚合物、乳酸及其相关乳酸盐、乳酸类化合物、及上述物质与其他化合物的复合物中的一个或多个；
    优选地，所述制品选自医用药物、试剂盒、保健品、医疗器械中的一个或多个。
  3. 乳酸及其类似物在制备预防和/或治疗组织损伤的医用药物和/或医疗器械中的应用其特征在于，所述组织损伤选自富含胶原蛋白的组织的损伤；
    优选地，所述组织损伤选自肌肉组织、结缔组织、肌腱、筋膜、骨、软骨、神经组织中的一个或多个的损伤；
    最优选地，所述组织损伤选自肌腱、软骨、肌肉组织、结缔组织、骨、神经组织中的一个或多个的损伤。
  4. 根据权利要求3所述的应用，其特征在于，所述乳酸及其类似物选自左旋乳酸类可降解聚合物、乳酸及其相关乳酸盐、乳酸类化合物、及上述物质与其他化合物的复合物中的一个或多个。
  5. 根据权利要求3或4所述的应用，其特征在于，所述医用药物还包括药学上可接受的载体。
  6. 根据权利要求3-5任一项所述的应用，其特征在于，所述乳酸及其类似物作为活性成分。
  7. 根据权利要求3-6任一项所述的应用，其特征在于，所述乳酸及其类似 物作为唯一活性成分。
  8. 根据权利要求3-7任一项所述的应用，其特征在于，所述乳酸及其类似物为注射剂。
  9. 根据权利要求3-8任一项所述的应用，其特征在于，所述乳酸及其类似物的用量为25mmol/L-75mmol/L。
  10. 一种调节和/或促进组织和/或神经组织增长、再生和/或愈合的制品，其特征在于，所述制品是由乳酸及其类似物和可接受的载体制成；所述组织具有如权利要求2中所述的含义；优选地，所述乳酸及其类似物选自左旋乳酸类可降解聚合物、乳酸及其相关乳酸盐、乳酸类化合物、及上述物质与其他化合物的复合物中的一个或多个；所述制品选自药物、试剂盒、保健品、医疗器械中的一个或多个。
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Free format text: PRESENTAR, EM ATE 60 (SESSENTA) DIAS, NOVAS FOLHAS DOS DESENHOS ADAPTADAS AO ART. 39 DA INSTRUCAO NORMATIVA 31/2013 UMA VEZ QUE O CONTEUDO ENVIADO NA PETICAO NO 870240057967 DE 09/07/2024 ENCONTRA-SE FORA DA NORMA.

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