나노 구조의 서방성 국소 마취제의 발전

연장 방출 LA의 중합체 공식화

고분자 DDS에 대한 기본 지식

폴리머는 수천 개의 반복 단위(단량체)로 구성된 거대 분자입니다. Van der Waals의 힘과 수소 결합이 중요한 역할을 하는 리포솜과 달리 폴리머는 공유 결합에 의해 형성되어 선반 위에서뿐만 아니라 유리 LA와 함께 투여할 때도 더 나은 안정성을 제공합니다. 많은 종류의 생체 적합성 및 생분해성 고분자가 천연 물질뿐만 아니라 합성 물질도 포함하여 서방성 물질의 제조에 사용되었습니다. 아미드 및 에스테르 LA의 서로 다른 화학적 특성을 고려하여, 상응하는 로딩 방법을 사용하여 로딩 효율(정전기 상호작용, 공유 결합 및 캡슐화)을 최적화할 수 있습니다[8]. 또한, 나노입자, 나노캡슐, 나노겔, 나노필름 및 나노섬유와 같은 유연한 형태는 주입, 드레싱 또는 필름이 필요할 때 실제로 고분자 DDS의 적용을 확장합니다[7, 8]. 또한, 구조적 변형은 수술 전후 통증에 대한 수일, 만성 통증에 대한 수주, LA의 효능을 향상시키기 위한 두 번째 약물과의 공동 전달과 같은 고분자 DDS 조절 가능한 방출 프로필을 강화합니다[7].

가장 많이 사용되는 합성 고분자 중에는 폴리에스터가 있습니다. 이 범주에는 폴리(l-락티드), 폴리(글리콜산), 폴리(락트산-코-글리콜산) 및 폴리(e-카프로락톤)이 포함됩니다[95]. 대사 산물은 일반적으로 이산화탄소와 물과 같은 작은 분자이며 안전하게 재활용되거나 배설될 수 있습니다[96]. 반면에 생산 기술은 이중/단일 유제, 침전 및 분무 건조와 같은 전통적인 기술에서 미세 유체 플랫폼, 압출 및 비습윤 템플릿(PRINT)의 입자 복제로 크게 발전했습니다(그림 5a-g). 전기방사(electrospinning)와 같은 새로운 기술도 개발되어 제형 및 전달의 유연성을 가능하게 합니다(그림 5h) [95, 96].

폴리머좀의 고전적인 기술. 아 단일 에멀젼. ㄴ 더블 에멀젼. ㄷ 나노 침전. d 분무 건조. 이 미세유체학. 에 압출 유화. 지 비습윤 템플릿의 입자 복제(PRINT). 아 전기방사

약물 전달에 널리 활용되지는 않았지만 DDS의 미래 경로를 밝힐 수 있는 또 다른 생산 방법인 자가 조립이 있습니다. 자가 조립은 수성 환경에서 양친매성 고분자-제제 공중합체의 미셀로 자발적으로 조립된다는 점에서 다른 생산 절차와 다릅니다. 따라서 단순성, 고효율 및 우수한 수분산성을 나타냅니다[97, 98]. 공중합체는 원-포트 다성분 반응(2차 아미드와 포름알데히드에 의해 연결된 활성 수소 화합물 사이의 만니시 반응)[97, 99], 초분자 반응(사이클로덱스트린과 같은 호스트-게스트 상호작용)과 같은 다양한 반응을 통해 형성될 수 있습니다. 및 아다만틴)[100, 101], 에스테르화 및 개환 반응[102,103,104], 티올인 클릭 반응[105], 공중합체의 후개질[106]. 이 기술은 최근 형광 소광으로부터 보호하고 응집 유발 방출을 달성하기 위해 형광 고분자 입자에 주로 사용되지만 다양한 반응과 상호 작용으로 인해 다양한 소수성 약물이 반응성 고분자(특히 유기 고분자)를 찾아 자가 조립할 수 있습니다. 미셀 [107, 108]. 예를 들어, 아미드 LA의 2차 아미드는 만니시 반응에 의해 중합체와 반응하는 활성 부분으로 사용할 수 있습니다. 또는 약물을 공중 합체에 흡수하여 동시 영상화 및 치료를 달성할 수 있습니다[101]. 소수성 약물은 미셀의 코어에 캡슐화되어 있기 때문에 LA의 알칼리성 환경과 같은 약물 효능에 적합한 내부 환경을 제공할 수 있습니다. 한편, 훌륭한 세포 흡수 행동은 LA와 같은 세포 내 도메인을 표적으로 하는 약물을 향상시킬 수 있습니다[97, 100, 105]. 또한, 반응은 일반적으로 촉매가 없고 단순하며(예:마이크로파 및 초음파)[109, 110], 용매 경제적이고, 실험 조건이 가볍고, 시간이 절약되어 미래에 대량 생산이 가능합니다[97, 105 ].

고분자 DDS는 여러 경로를 통해 활성제를 방출합니다. 물이 처음에 고분자로 흘러들어갈 때 대류는 약물을 펌핑하는 삼투압을 생성합니다. 그러나 수성 환경에서 형성된 기공을 통한 확산이 주요 방법입니다. 이온화된 LA와 같은 친수성 약물의 누출을 돕습니다. 반대로 소수성 약물은 직접 확산될 수 있습니다. At the final stage of a typical tri-phase release profile, erosion of polymer dominates [111, 112].

Like liposomes, polymersomes also face the challenge of RES clearance. Morphology modification, stealth strategy, RES blockade, and macrophage depletion can be applied as well [40, 113,114,115]. Furthermore, the EPR effect facilitate tumor-target while auxiliary surface modification can help tissue specificity [43, 116]. Polymersomes do not induce significant systemic inflammation while some of natural polymers such as hyaluronan and laminin, and synthetic polymers such as negatively charged poly(lactic-co-glycolic acid) and polyurethane can reduce systemic inflammatory reaction [117,118,119]. Moreover, N -(2-hydroxypropyl) methacrylamide and polystyrene are reported to reduce neurotoxicity [120, 121].

Diverse Morphology and Applications

Particle is a common form of polymeric DDS. Polymeric particles are generally divided into two categories:nanosphere and nanocapsule. Nanosphere is an evenly disperse system, while nanocapsule is an embedding drug in polymeric cavity [95]. The earliest researches built nanoparticles with poor entrapment efficiency (< 60%) and release duration (< 30 h) [122, 123]. With finesses of technology, the drug entrapment efficiency reaches nearly 90% [124,125,126], the highest result is 93.3% [127]. In-vitro release can reach a maximal duration of 35 days [128]. There is another available form termed nanofiber, which is produced by electrospinning. Electrospinning technique has been widely applied in drug delivery, but limited usage in LAs. There is one research only using electrospinning technique to fabricate bupivacaine-loaded suture. It gained satisfactory results on extended release (over 12 days), while significant analgesia appeared from day 1 to day 9 in rat skin wound model [129]. Mostly in polymersomes, drugs are entrapped physically; in polymer-drug conjugate, drug is bonded to polymer covalently to enhance drug loading capacity and prolong release furthermore [130]. Apart from solid forms, amorphous forms such as gel show more versatility and malleability. A 60-day release was seen in the work of Daryl Sivakumaran and his colleagues (Table 4) [134]. Rapid burst release over 60% of LAs was observed in the work of Haibo Qu and his colleagues (Table 4) [135].

In order to make the release intelligent, responsive materials are used in situations where structural changes, volume-phase transitions, or sol-gel transitions are needed [137]. Inflammatory reaction is a major and initial process when trauma happens. Along with it is the changes of pH and temperature. Thus, pH and temperature are stimuli used commonly in LAs delivery. In the work of Todd Hoare and his colleagues, thermal aggregation can help control regional accumulation of thermal-responsive nanogel. However, larger precipitates after aggregation induced more severe local inflammation (Table 5) [139]. Teresa Alejo and his colleagues used sequential heat pulse to trigger the collapse of nanoparticle, fastening profound release in a spatiotemporal way (Table 5) [138]. A pH-responsive polymer (methacrylicacid–ethyl acrylate) was used by Jeremy P.K. Tan to achieve decreased release of procaine chloride with decrease of pH (Table 5) [140].

Despite the advantages of being responsive to stimuli, pH and temperature-responsive polymers do not act precisely enough to localize therapeutic agents. Moreover, acidic environment and high temperature may bring harm. Therefore, stimuli which are able to modulate therapeutic agents precisely without harm are wanted. Although there is no application so far in LAs delivery, ultrasound-responsive nanoparticles exhibiting harmless property have shown precise localization in tumor targeting and imaging [141, 142]. However, ultrasound signal can be influenced by air attenuation and bone structure. Magnetic responsive nanoparticles exhibit broader application such as in respiratory system which is filled with air and central nervous system covered with cranial bone [143]. Furthermore, magnetic responsive nanoparticles can help spatially and temporally localize actives without restriction by tissues depth [143]. Generally, there are three mechanisms underlying magnetic response, which are magnetic deformation, magnetic guidance, and magnetic-induced hyperthermia [144, 145]. Aginate-based ferrogel undergoes pore formation with magnetic stimulation [146]. In contrast, chitosan-based nanoparticle undergoes pore formation with the help of heat produced by magnetic field [147, 148]. In order to decrease thermal damage to surrounding tissues, Wei Chen and his colleagues produced a core-shell structure to embed heat-producing core and prevent thermal damage [143]. The guidance function can help the nanoparticle migrate long distance and penetrate biological barrier [149]. Combination of aforementioned mechanisms can create synergistic outcomes [150].

Polymeric carriers endow LAs extended-release, but unexpected burst release does exist. Long-term degradation may induce foreign body response. Versatility of materials and mature techniques are advantages of polymeric carriers. Acidic metabolites, however, may hamper the effect of LAs. Although responsive polymers make delivery more intelligent, they do not solve the aforementioned problems above completely. Therefore, further improvements are needed.

Lipid-Polymer Hybrid Carriers of Local Anesthetic

Liposomal and polymeric nanocarriers both have drawbacks such as low solubility, poor stability, undesired drug leakage. and diffusion [151,152,153]. Conventional liposomes are easily cleared out by enzymatic degradation and macrophage engulfing. Therefore, surface modification with inert and hydrophilic coats, such as PEG, ganglioside GM1, and phosphatidylinositol, have been used for protection against degradation by enzymes and macrophages. Furthermore, pegylation can enhance the negative charge of liposome and reinforce its attraction to cationic actives. In the work of Brett A. Howell and his colleagues, higher concentration and slower release of bupivacaine in human serum was observed in pegylated liposomes compared to conventional liposomes [154]. Alternatively, apolar cavity of biologically active compounds formed by cyclodextrins (a polymeric peptide), also known as an inclusion, in multi-vesicular liposomes can help achieve longer release. Inspired by various pioneer attempts to overcome drawbacks of liposome and polymeric nanoparticles, lipid-polymer hybrid nanoparticles come to the stage of controlled release [151, 155].

There are three systems of hybrid nanoparticles:lipid-core polymer-shell, polymer-core lipid-shell, and the polymer-lipid matrix. Lipid-core polymer-shell system using a polymeric coat improves the stability of liposome and delays clearance, while maintaining optimal biocompatibility of lipid core. The amphiphilic properties of some polymers can reduce surface tension of nanoparticles and decrease particle size to achieve better biocompatibility. Additionally, responsive polymers can enable liposomes more flexible behavior in various physical environment [152, 156]. Poly (acrylic acid) (Chol-PAA) is a pH-sensitive polymer, which tends to form globular structure from random coil in low pH. In poly (acrylic acid) (Chol-PAA)-caged liposome, the polymeric coat shrinks when environmental pH decreases, compressing core liposome to release significantly when liposome collapses [152]. Marina Sokolsky-Papkov and her colleagues used hybrid polymer (DL-lactic acid and castor oil) to formulate bupivacaine-loaded nanoparticles. This poly (fatty-ester) achieved relatively longer in-vitro release (beyond 1 week) and sensory blockade (> 72 h) compared to previous research [157]. Further research confirmed its release profile and extended its analgesic efficacy among thermal pain, mechanical pain, and rearing assessment [158]. Another research study explored the difference between oil nucleus on stability, release profile, and analgesia property, and found that a higher entrapment efficacy was observed compared to polymeric DDS [159].

Polymer-core lipid-shell system is commonly used in intravenous administration of drugs, especially anticancer drugs [151, 155]. The two components together help inhibit water infiltration and slow hydrolysis down, and as a result prevent drug diffusion and burst leakage. Lipid shell also enhances biocompatibility of nanoparticle with similarity to cell membrane [160]; this is promising in achieving simultaneous co-delivery of multiple drugs [151, 152, 160]. On the other hand, polymeric core can facilitate mechanical stability, shape control, and size distribution. Additionally, it can increase drug entrapment efficacy. In the work of Jianguo Wang and his colleagues, nanoparticle showed a slower release speed, smaller particle diameter, and higher drug loading compared to traditional liposomes [161]. The work by Pengju Ma at el. showed that hybrid bupivacaine nanoparticle had better stability, analgesic efficacy, and cytotoxicity [162].

The third system is a polymer-lipid matrix which can be subdivided into polymerized liposomes and nano-in-micro type. As their names suggest, polymerized liposome is a covalently bound liposome which demonstrates better stability and modulated release as mentioned above with basic knowledge on polymeric DDS [154], while the nano-in-micro system gathers nanoparticles into a matrix to achieve controlled release as shown in the work of Khanal Manakamana and his colleagues [163]. Moreover, hybrid nanoparticle was used in transdermal route showing better skin permeation than free bupivacaine in three studies by Yaocun Yue and Aimei Li at el., which expands its clinical application of analgesia [161, 164, 165].