TW201023878A - Non-surgical improvement of scars - Google Patents

Abstract

The present invention relates to medicaments and methods for use in the non-surgical improvement of scars that have resulted from injury.

Description

201023878 六、發明說明： 【發明所屬之技術領域】 本發明係關於用於非外科改善由損傷造成之傷疤的藥物 及方法。 【先前技術】 許多不同過程在結疤反應期間起作用，且已進行大量研 究來發現此等過程受何介導且此等過程如何彼此相互作用 來產生最終結果。已發現影響傷疤最終形成之品質的許多 因素與創傷癒合過程早期發生之事件有關。 /在傷疤由創傷癒合產生之情況下，傷疤可定義為由於修 復反應而產生之結構。身體對於創傷之修復反應係作為生 理必然性的進化解決方法而產生以預防受損傷動物死亡。 為克服歸因於感染或失血之死亡風險，身體迅速反應以修 復受損傷區域’而非試圖再生受損傷組織。因為受損傷組 織不再生獲得創傷之前存在的相同組織結構，所以可藉助 於傷疱與未受傷組織相比之異常形態來對其加以鑑別。 結疤反應在所有成年哺乳動物t為普遍的。其涉及自損 傷最初時刻起許多相繼發生(有一定程度之重疊)的互相關 聯之階段’且最終導致形成稱為「傷疤」之替代組織。各 個階段彼此相互影響，且正县 箐且正疋此累積作用決定所產生傷疤 之特性。 創傷癒合過程之第一階埒盔I* e Α 階段為發炎反應。此係由血管損傷 觸發，隨後又引起凝血級聯。 1下马此級聯之部分發生的血 小板脫顆粒引起許多可滚w 夕了，谷性信唬傳導因子（包括TGF-β)之 145021.doc 201023878 釋放，其募集發炎細胞至損傷部位。此等發炎細胞（主要 為單核細胞/巨噬細胞或嗜中性白血球系）開始移除損傷留 下的碎片’在創傷空隙中沈積臨時細胞外基質（ECm)，且 釋放其自身信號傳導分子，使得募集對創傷癒合至關重要 之其他細胞類型。此等細胞、臨時基質及其他向内遷移之 細胞為創傷癒合第二階段（肉芽組織形成）所必需。 肉芽組織由於其肉眼可見的「肉芽」外觀而如此稱呼， 為填補創傷缺損而產生的發炎細胞、纖維母細胞、新細胞 外基質及新血管之混合物。視所涉及物種而定，肉芽組織 形成在創傷後3至7天「達到高峰」^細胞自周圍組織遷移 至創傷區中’且一旦就位後即沈積新基質組份。此過程期 間所沈積之基質替換發炎期間所沈積之臨時基質，且通常 沈積於臨時基質上部，臨時基質用作支架。 細胞外基質沈積在創傷之後持續大約兩至四週，且在此 時沈積之細胞外基質形成癒合過程完成後所留下傷疤的基 礎。 創傷收縮及上皮再形成造成創傷閉合，且使得再建立功 忐性覆蓋物。在創傷收縮期間，成肌纖維細胞中之收縮成 分減小受傷區之體積。同時，來自周圍未受傷組織（且若 存在，來自受傷區中保留之表皮附屬器）之角質細胞遷移 穿過肉芽組織表面，藉此再形成表皮障壁。 在創傷癒合之最終階段（傷疤重塑），由保留於傷疤中之 細胞釋放的酶緩慢使基質再成形，從而促進傷疤成熟。已 顯示傷疤重塑及成熟在損傷之後的十二個月期間之許多階 145021.doc 201023878 段中出現。 儘管結減應良好適於滿足其㈣損失組織及預防由於 失血或感染把成之其他損傷或死亡的主要目的，但存在許 夕與、、口症相關之有害影響。此等有害影響趨向於由於所產 生傷症組織之特性與其所替換之初始未受損傷組織之間的 “而產生。傷疤組織可干擾生長，引起變形，使功能受 損且顯示出美學上無吸引力。 士-所替換之未文傷結締組織，傷症主要由細胞外基質 組成。此物質由在癒合過程期間存在之細胞沈積，替換由 於損傷而受損或失去之組織。生理必然性表現為產生可填 、、知傷4位之n組織，而非使得精_替換受傷前組 織通*傷症將包含與未受傷组織相比結構異常的結締組 織，如皮膚傷症中所常常觀察到的。或者或另外，傷泡可 包含以異常增加量存在之結締組織。大部分傷疤由異常結 構且過量的結締組織組成，如下文進一步描述。 ❹ 在正常皮膚中’細胞外基質分子形成纖維，當在顯微鏡 下觀察時具有特徵性無規排列，通常稱為「籃式編織」。 此籃式編織排列在傷苑中受到破壞。傷疤中之纖維與正常 皮膚中纖維之無規排列相比呈現顯著程度之相互對準。— 般而言，在傷Μ觀察狀纖維直徑料於正Μ膚中所 見ECM之尺寸及排列均可能促使傷症與正常皮膚相比機 械特性改變，最顯著地硬度增加。 肉眼上看去，傷疤可凹陷低於周圍組織表面，或高出其 未受傷周圍物之表面。與正常組織相比’傷症顏色可相對 I4502I.doc 201023878 較冰（色素過多）或與其周圍物相比傷疤可具有較淡顏色（色 素過少）。在皮膚傷疤之情況下，色素過多或色素過少之 傷苑構成非常明顯之美容缺陷。亦已知皮膚傷症可能比未 受傷皮膚更紅，使其變得顯眼且美容上不可接受。已展示 傷疤外觀為造成傷疤對患病者心理上打擊之主要因素之 且此等影響可保持至傷症原因過去以後报久。 除其心理影響外，傷疤亦可對患病者產生有害生理影 響。此等影響通常由於傷疤與正常組織之間的機械差異而 產生。傷疤之異常結構及組成意謂其通常與其正常組織對 應物相比可撓性較低。因此，傷疤可使正常功能受損（諸 如在傷疤覆蓋關節之情況下，其可能限制可能的運動範 圍）且若在年齡小時出現，可能延遲正常生長。 傷疤在多個身體部位出現，且在此等部位處結疤之影響 通常與結疤區中功能喪失或破壞有關❶與皮膚結疤相關之 一些缺點已於上文中論述。内臟結疤可造成狹窄及黏連之 形成，顯著或完全損害所討論之器官功能。腱及韌帶結疤 可對此等器官產生持續損害，且藉此降低相關關節之活動 性或功能。與血管且尤其與心臟瓣膜相關之結疤可能在損 傷或手術之後出現。血管結疤可引起再狹窄，導致血管窄 化且因此減少通過該結绝區之血液流量。中樞及周邊神經 系統中之結疤可阻礙沿神經之傳遞且可阻礙或減少受損神 經組織之再連接及/或功能性神經元傳遞。 倘若結疤為一種通常發生之問題’且許多損傷效應與結 疤相關，則需要開發可用於避免或減少結疤之藥品及策 145021.doc 201023878 刖絕大多數意欲改善結疤之療法集中於降低回應 員傷之傷宛形成程度或物理處理已形成之傷症。 或許最常用於減少傷疤影響之方法為外科切除術。在此 . 彳法中’切除傷症且採取步驟來減少對藉由此切除所形成 ’ 丨傷癒σ可預期的傷症量。該等步驟包括使用整形外 科，術來減少傷疤形成’重新調整新形成之傷疤(以避免 —、張力其可導致結疤增加；或使新傷疤隱蔽於現 φ 有皮膚褶襞中)且施用可能最佳的術後護理。 ，熟習此項技術者已知用於外科修復傷苑之各種其他技 術。。舉例而言，藉由諸如擦皮法（其中藉由機械處理正好 磨損掉結苑區表面）之方式治療高出之傷宛；亦可使用雷 射（C〇2 Er.Yag ’脈衝染料）來使突出之傷絶「脫塊（仏 bUlk)」，且使傷症邊緣更精密地接近周圍區之高度。冷;東 療，為另一種可以手術方式修復傷苑之技術，其中使傷症 經文極端低溫以求減少傷疤塊及色差。 ❿ 另—傷症修復治療形式使用趾Yag雷射以求減少造成傷 疤視覺衝擊的紅度。此類治療意欲破壞傷苑中之血管，因 此減夕總血官數罝且減輕傷症紅度（亦稱為發紅（rub〇r))。 目前廣泛使狀外科修復技術具有有利❹，然而其並 .$普遍適用。尤其已遭受結疤外傷之患者常常極其不樂音 進行必然與進一步結絶有關之額外外科方法。此外，一^ 最迫切需要傷症修復者為具有不良或病理性結症體質之個 體。使該等患者經受另外創傷可能為不妥當的，以免所得 傷疤結果比已存在之彼等傷疤還差。 145021.doc 201023878 已開發了許多非外科傷疤修復方法來充當外科傷疤修復 之替代或輔助。此等非外科技術在不樂意手術之患者中越 來越受歡迎。其亦可在臨床上適用於患者傾向於有不良結 疤結果之情況。一些最常用非外科傷疤修復治療包括壓縮 療法（例如’石夕膠片/凝膠、加壓服、耳夾、水合乳膏/軟 膏）；皮質類固醇療法；放射線療法；抗贅生劑（例如，5_ · 氟尿嘴咬）；視黃酸；維拉帕米（Verapamil)及免疫調節劑 (諸如乙莫奎德（Imoqimod))。 為避免產生寬大傷疤而提出的最簡單方法或許為在創傷 ◎ 部位之上施用膠帶。已表明此治療可適用於維持創傷邊緣 相互接觸，且因此避免創傷「伸展」，否則可能產生更寬 之傷苑。 可使用通常藉由加壓繃帶或其他該種敷料來施加之長期 壓迫以試圖軟化硬性傷疤且降低傷疤突出超過周圍皮膚之 高度。用於類似紋理之另一治療係使用高壓水。此通常經 由軟管以近似體溫施用於結疤部位。 亦使用病灶内類固醇注射以試圖減少結疤，但此等治療 © 通常與覆蓋傷疤之皮膚變薄相關，此結果本身可能為美學 上不可接受的。 在傷疤凹陷低於未受傷周圍組織之表面的情況下，已提 出投與暫時性或永久性填充化合物作為可克服高度差異且 由此減少傷疤之美學衝擊的方法。 儘管非外科傷疤修復技術之範圍已發展，但其中無一者 被視為普遍適用。此外’迄今為止所鑑別之許多技術具有 145021.doc 201023878 低或有爭議之功效’需要高度患者順應性及/或多次臨床 就S多且與南傷症復發率相關聯。因此，仍需要用於傷疲之 非外科改善之新藥物及方法、替代藥物及方法以及改善之 . 藥物及方法。 . 經研究用於抑制結症之標乾之一為轉化生長因子 p3(TGF-03)。TGF-β為以三種哺乳動物同功異型物形式 (TGF-βΙ、TGFJ2及TGF_P3)存在之生長因子家族。此等 ❹同功異型物之生物作用通常在許多方面相似，但在創傷癒 合及結疤之情形中，其發揮極為不同之作用。 所有二種哺乳動物TGF-β同功異型物均在傷症形成中發 揮重要作用。TGF-βΙ及TGF-P2皆提高與傷疤形成相關之 生物活性（諸如細胞外基質組份之累積），而Τ〇ρ-β3用以減 少創傷後之傷症形成。 已在實驗上顯示TGF-p3抑制否則可在創傷癒合後出現之 傷疤形成。此已在許多科學研究中得以證明，在該等研究 • 中在創傷形成之時局部投與TGF-P3至需抑制結疤之部位。 以TGF-P3治療之創傷療合後產生不如彼等在對照或未經治 療創傷癒合後形成之傷疤顯著之傷疤。此在肉眼下（所形 成傷疤與環繞其之皮膚相比較不明顯）以及在顯微鏡下（修 . 復區所建立之結構更精密接近彼等未受傷皮膚結構）均顯 而易見。 咸信藉由TGFj3所獲抗結疤作用係由於此生長因子在創 傷癒合反應之關鍵早期引起的直接影響後續傷疤品質之變 而產生研究（shah等人，1995)已顯示向創傷投與TGF_ 145021.doc 201023878 β3減少在癒合之第一 始夕赵s 天中所存在的單核細胞及巨噬細 胞之數目。認為此等細胞# ^ ^ , 飑存在數目之減少有助於減輕受傷 Γ 因：Γ反應。否則此反應常由可溶性因子增強，可溶 ’、由向受傷區募集其他發炎細胞之此等細胞釋放。 減輕之發炎反應確保存 子在較j產生TGF-βΙ及TGF-P2之細 胞，否則將促使傷疤形成。 在，治療創傷中TGF_p3之存在及促結HGF_p同功異型 物含量降低建立有利於細胞外基質組份之更正常結構及沈201023878 VI. Description of the Invention: TECHNICAL FIELD OF THE INVENTION The present invention relates to a medicament and method for non-surgical improvement of scars caused by injury. [Prior Art] Many different processes work during the scab reaction, and extensive research has been conducted to discover how these processes are mediated and how these processes interact with one another to produce the final result. Many of the factors that have influenced the quality of the final formation of scars have been found to be associated with events that occur early in the wound healing process. / In the case where the scar is caused by wound healing, the scar can be defined as the structure resulting from the repair reaction. The body's repair response to trauma is produced as an evolutionary solution to the inevitable nature of the disease to prevent the death of the injured animal. To overcome the risk of death from infection or blood loss, the body responds quickly to repair the damaged area instead of attempting to regenerate the damaged tissue. Since the damaged tissue does not regenerate to obtain the same tissue structure that existed prior to the wound, it can be identified by the abnormal morphology of the wounded blister compared to the uninjured tissue. The scarring reaction is common in all adult mammals. It involves a number of successive (and somewhat overlapping) cross-correlation phases from the initial moment of injury, and ultimately leads to the formation of an alternative organization called "scar". Each stage interacts with each other, and Zhengxian County is in the process of determining the characteristics of the scars produced. The first stage of the wound healing process, the I* e Α stage, is the inflammatory response. This is triggered by vascular damage, which in turn causes a coagulation cascade. 1 The granule degranulation that occurs in this part of the cascade causes a lot of stagnation, and the release of the gluten-stimulating factor (including TGF-β) 145021.doc 201023878, which recruits inflammatory cells to the injured site. These inflammatory cells (mainly monocytes/macrophages or neutrophils) begin to remove the debris left by the lesion' depositing a temporary extracellular matrix (ECm) in the wound space and releasing its own signaling molecules. To recruit other cell types that are critical to wound healing. Such cells, temporary stroma and other inwardly migrating cells are required for the second stage of wound healing (granulation tissue formation). The granulation tissue is so called because of its visible "granulation" appearance, which is a mixture of inflammatory cells, fibroblasts, new extracellular matrix and new blood vessels produced to fill the wound defect. Depending on the species involved, granulation tissue formation "reaches peak" 3 to 7 days after wounding ^ cells migrate from surrounding tissue into the wound area' and deposits new matrix components once in place. The matrix deposited during this process replaces the temporary matrix deposited during inflammation and is typically deposited on top of the temporary matrix, which serves as a scaffold. Extracellular matrix deposition lasts for about two to four weeks after the wound, and the extracellular matrix deposited at this point forms the basis for scars left after the healing process is completed. Wound contraction and epithelial re-formation cause wound closure and re-establishment of a functional covering. During contraction of the wound, the contractile component in the myofibroblasts reduces the volume of the injured area. At the same time, keratinocytes from surrounding uninjured tissue (and, if present, from the epidermal appendage retained in the injured area) migrate through the surface of the granulation tissue, thereby re-forming the epidermal barrier. In the final stage of wound healing (scarred remodeling), the enzyme released by the cells retained in the scar slowly reshapes the matrix, thereby promoting scar maturation. It has been shown that scar remodeling and maturation occur in many stages during the twelve month period following injury, 145021.doc 201023878. Although the reduction should be well suited to meet its (4) loss of tissue and prevention of other causes of injury or death due to blood loss or infection, there are detrimental effects associated with the disease. These detrimental effects tend to occur as a result of the nature of the resulting wounded tissue and the initial unaffected tissue that it replaces. The scar tissue can interfere with growth, cause deformation, impair function, and exhibit aesthetic appeal. The replacement of the non-textual connective tissue, the injury consists mainly of the extracellular matrix. This substance is deposited by the cells that exist during the healing process, replacing the tissue damaged or lost due to injury. Physiological inequality is manifested as Can fill, and damage the 4th n tissue, instead of making the spermatozoon replace the pre-injury tissue. The injury will contain connective tissue that is structurally abnormal compared to the uninjured tissue, as is often observed in skin injuries. Alternatively or additionally, the wound may comprise connective tissue present in an abnormally increasing amount. Most of the scar is composed of abnormal structures and excess connective tissue, as further described below. ❹ In normal skin, 'extracellular matrix molecules form fibers, when It has a characteristic random arrangement when viewed under a microscope, and is often referred to as "basket weaving." This basket weaving arrangement was damaged in the wounded garden. The fibers in the scar exhibit a significant degree of mutual alignment compared to the random arrangement of fibers in normal skin. — In general, the size and arrangement of the ECM seen in the scar diameter of the observed fiber diameter may cause the mechanical properties of the injury to change compared with normal skin, with the most significant increase in hardness. From the naked eye, the scar can be recessed below the surface of the surrounding tissue or above the surface of the uninjured surrounding. Compared with normal tissue, the color of the injury can be lighter (small color) compared to I4502I.doc 201023878 compared to ice (hyperpigmentation) or compared with its surroundings. In the case of skin scars, the hyperpigmentation or hypopigmentation of the injured garden constitutes a very obvious cosmetic defect. It is also known that skin injuries may be redder than uninjured skin, making it conspicuous and cosmetically unacceptable. It has been shown that the appearance of scars is the main cause of the psychological impact of scars on the sick and that these effects can be maintained until the cause of the injury has passed. In addition to its psychological effects, scars can also have harmful physiological effects on the affected person. These effects are usually due to mechanical differences between scars and normal tissues. The abnormal structure and composition of scars means that they are generally less flexible than their normal tissue counterparts. As a result, scars can impair normal function (such as in the case of scars covering the joint, which may limit the range of possible motion) and, if occurring at an age, may delay normal growth. Scars appear in multiple body parts, and the effects of scarring at these sites are often associated with loss of function or destruction in the scarring area. Some of the disadvantages associated with skin scarring are discussed above. Visceral scarring can result in the formation of stenosis and adhesions that significantly or completely impair the organ function in question. Ankles and ligament scars can cause sustained damage to these organs and thereby reduce the activity or function of the associated joints. Scarring associated with blood vessels and especially with heart valves may occur after injury or surgery. Vascular scarring can cause restenosis, resulting in narrowing of the blood vessels and thus reducing blood flow through the junction. The scars in the central and peripheral nervous systems can block the transmission along the nerve and can impede or reduce the reconnection and/or functional neuronal transmission of damaged nerve tissue. If crusting is a common problem' and many of the damage effects are related to scarring, then you need to develop a drug that can be used to avoid or reduce scarring. 145021.doc 201023878 刖 Most of the therapies intended to improve scarring focus on reducing In response to a wounded injury, the degree of formation or physical treatment has formed a wound. Perhaps the most common method used to reduce the effects of scars is surgical resection. Here, the injury is removed and steps are taken to reduce the amount of injury that can be expected from the resulting injury. These steps include the use of orthopedics to reduce scar formation 're-adjusting newly formed scars (to avoid - tension can lead to increased scar formation; or to conceal new scars in existing φ skin folds) and to apply The best postoperative care. Various other techniques known to those skilled in the art for surgical repair of wounded gardens. . For example, a high-risk treatment can be treated by means such as a rubbing method in which the surface of the knot garden is worn away by mechanical treatment; a laser (C〇2 Er.Yag 'pulse dye) can also be used. Make the outstanding injury "de-blocking (仏bUlk)", and make the edge of the injury more closely close to the height of the surrounding area. Cold; East treatment, another technique that can repair the wounded garden by surgery, which makes the injury scripture extremely low temperature in order to reduce the scars and chromatic aberration. ❿ Another - the form of injury repair treatment uses a toe Yag laser to reduce the redness of the visual impact of the injury. Such treatment is intended to destroy the blood vessels in the wounded garden, thus reducing the number of blood counts and reducing the redness of the injury (also known as redness (rub〇r)). At present, a wide range of surgical repair techniques are beneficial, however, they are generally applicable. In particular, patients who have suffered from crustal trauma are often extremely unhappy with additional surgical procedures that are necessarily associated with further stagnation. In addition, the most urgent need for a wound repairer is a person with a bad or pathological constitution. It may not be appropriate to subject these patients to additional trauma so that the resulting scars are worse than the existing scars. 145021.doc 201023878 A number of non-surgical scar repair methods have been developed to serve as an alternative or aid to surgical scar repair. These non-surgical techniques are becoming more and more popular among patients who are not willing to undergo surgery. It can also be clinically applied to situations in which patients tend to have poor outcomes. Some of the most commonly used non-surgical scar repair treatments include compression therapy (eg 'Shi Xi film / gel, compression suit, ear clip, hydrating cream / ointment); corticosteroid therapy; radiation therapy; antibiotics (eg, 5_ · Fluorine mouth bite; retinoic acid; Verapamil and immunomodulators (such as Imoqimod). The easiest way to avoid creating a large scar may be to apply a tape over the wound ◎ site. This treatment has been shown to be suitable for maintaining the edges of the wounds in contact with each other and thus avoiding "stretching" of the wound, which may result in a wider wounded court. Long-term compression, usually applied by compression bandages or other such dressings, can be used in an attempt to soften the scar and reduce the height of the scar beyond the surrounding skin. Another treatment for similar textures uses high pressure water. This is usually applied to the crust site by a hose at approximately body temperature. Intralesional steroid injections are also used in an attempt to reduce scarring, but such treatments are usually associated with thinning of the skin covering the scar and the results themselves may be aesthetically unacceptable. In the case where the scar sag is lower than the surface of the uninjured surrounding tissue, it has been proposed to apply a temporary or permanent filling compound as a method which can overcome the height difference and thereby reduce the aesthetic impact of the scar. Although the scope of non-surgical scar repair techniques has evolved, none of them are considered universally applicable. In addition, many of the techniques identified so far have a low or controversial effect of 145021.doc 201023878 requiring high patient compliance and/or multiple clinical multiples and associated with recurrence rates in southern injuries. Therefore, there is still a need for new drugs and methods for non-surgical improvement, alternative medicines and methods, and improvements for the treatment of injuries and injuries. One of the standard stems studied to inhibit the syndrome is transforming growth factor p3 (TGF-03). TGF-β is a family of growth factors present in three mammalian isoforms (TGF-βΙ, TGFJ2 and TGF_P3). The biological effects of these isoforms are often similar in many respects, but they play a very different role in the case of wound healing and crusting. All two mammalian TGF-β isoforms play an important role in the formation of the injury. Both TGF-βΙ and TGF-P2 increase the biological activity associated with scar formation (such as accumulation of extracellular matrix components), while Τ〇ρ-β3 is used to reduce post-traumatic injury formation. It has been experimentally shown that TGF-p3 inhibits the formation of scars that may otherwise occur after wound healing. This has been demonstrated in many scientific studies in which TGF-P3 is locally administered at the time of wound formation to the site where scab resistance is to be inhibited. Wound treatments treated with TGF-P3 produced significantly fewer scars than those formed after control or untreated wound healing. This is evident in the naked eye (the scar is less visible than the skin surrounding it) and under the microscope (the structure established in the repair zone is closer to the uninjured skin structure). The anti-crust effect obtained by TGFj3 is due to the fact that this growth factor directly affects the quality of subsequent scars caused by the critical early stage of wound healing response (Shah et al., 1995) has shown that TGF_145021 is administered to wounds. .doc 201023878 β3 reduces the number of monocytes and macrophages present in the first eve of healing. It is believed that the decrease in the number of such cells #^^, 有助于, helps to reduce the injury Γ: Γ reaction. Otherwise this reaction is often enhanced by soluble factors, soluble, and released by such cells that recruit other inflammatory cells to the injured area. The reduced inflammatory response ensures that the TGF-βΙ and TGF-P2 cells are produced at a higher level, which would otherwise contribute to the formation of scars. In the treatment of wounds, the presence of TGF_p3 and the decrease in the content of HGF_p isoforms in the wounds establish a more normal structure and precipitate for the extracellular matrix components.

積的局部條件。1 ^ rfc- A # σ之在癒合早期（在受傷後1天至7天 門）以TGF-P3冶療之創傷所含纖維結合蛋白膠原蛋 白1及膠原蛋自111含量低於未經治療對照物。 纖維結合蛋白為創傷癒合過程早期沈積之臨時基質的關 鍵組伤之-。纖維結合蛋白之主要來源為創傷區内之巨噬 細胞及纖維母細胞。在經TGF_p3治療之創傷中此等細胞數 目降低可促使所存在纖雉結合蛋白量降低。此纖維結合蛋 白減少在深部真皮中最顯著。纖維結合蛋白以及諸如纖維 蛋白之其他臨時基質組份一起形成在創傷癒合過程中稍後 沈積之其他ECM組份的支架，且因此此癒合早期對所產生 的更永久性修補結構之影響可持續至初始階段已完全之後 很久。 膠原蛋白I及膠原蛋白III構成為填補受傷區而產生之永 久性傷症結構的主要組份。在以TGF-β3治療之創傷瘢合之 第一個7天期間發現此等分子兩者之量均降低。在經tgf_ β3治療之創傷中膠原蛋白I之減少在深部真皮中最顯著（類 145021.doc -10- 201023878 似於纖維結合蛋白，且可能係由於臨時基質支架減少）， 而膠原蛋白III之減少在緊鄰表皮以下區域中最顯著。 有趣地是當將存在於經TGF-P3治療之創傷癒合後形成的 傷苑（受傷之後70天）中之膠原蛋白I及膠原蛋白hj之量與見 於各種對照組（在未經治療創傷或具有促結疤同功異型物 TGF-βΙ或TGF-P2之創傷癒合後形成之傷疤）中之量相比 時，發現所有均含有類似量之此等ECM組份，但傷疤之肉Local conditions of the product. 1 ^ rfc- A # σ In the early stage of healing (1 to 7 days after injury), the wound protein containing collagen-binding protein 1 and collagen from TGF-P3 was lower than the untreated control. . Fibronectin is a key group injury to the temporary matrix of early deposition in the wound healing process. The main source of fibronectin is macrophages and fibroblasts in the wound area. A decrease in the number of such cells in a TGF_p3 treated wound can result in a decrease in the amount of fibrin binding protein present. This fiber-binding protein reduction is most pronounced in the deep dermis. Fibronectin and other temporary matrix components such as fibrin together form a scaffold for other ECM components deposited later in the wound healing process, and thus the effect of this early healing on the resulting more permanent repair structure can be sustained The initial phase has been completely long after. Collagen I and collagen III constitute the main components of the permanent injury structure that fills the injured area. The amount of both molecules was found to decrease during the first 7 days of wound healing combined with TGF-β3. The decrease in collagen I in the wound treated with tgf_β3 was most pronounced in the deep dermis (class 145021.doc -10- 201023878 resembles fibronectin, and may be due to temporary matrix scaffold reduction), while collagen III is reduced It is most prominent in the area immediately below the epidermis. Interestingly, the amount of collagen I and collagen hj present in the wounded garden (70 days after injury) formed after healing of TGF-P3 treated wounds was found in various control groups (in untreated wounds or When compared with the amount of TGF-βΙ or TGF-P2 wound healing after wound healing, all of them were found to contain similar amounts of these ECM components, but the scars were

眼可見外觀極為不同（彼等經TGF_p3治療者明顯優於彼等 來自其他實驗組或對照組者）。此研究結果表明涉及於創 傷癒合之稍後階段中之許多過程（其中膠原蛋白沈積且 ECM成熟）在經TGF_P3治療及未治療創傷中共同存在。此 進一步表明TGF-P3能夠改變在創傷癒合早期發生之過程產 生所示有利結果。此等變化之作用在產生影響之事件結束 之後很久亦顯而易見。 【發明内容】 本發明之某些態樣及實施例 ’…、，α V、1费 之非外科改善的新藥物。本發明之某些態樣及實施例之一 目標在於提個於傷苑之非外科改#的新方法。此改善音 欲治療個體中由於個體之先前損傷或外傷而存在之傷心 =可由先前可選之過程造成，該過程經歷且完成正常自 …癒合過程且其㈣㈣束時已 本發明之一目標亦在於藉由以適 科方法治療來減少傷㈣紅度。本二療活性成份代替外 對比度。 纟發明亦旨在降低傷症之 145021.doc 201023878 在許多患者中，意欲改善傷疤彈性及血管形成之傷疤治 療未必減少傷疤之紅度及/或對比度。此係由於增加血管 形成之方法實際上導致先前創傷區域中灰管大小及或數目 增加。因此，儘管傷疤之彈性可得到改善，但就其紅度或 對比度而言之視覺衝擊未能改善。因此，本發明之進:步 目標在於治療此類型之患者，可藉由治療方式來治療該類 患者之傷疤紅度。一個注意點為該治療可能或可能不與傷 疤之彈性及/或血管形成的改善有關。The appearance of the eyes is very different (they are significantly better than those from other experimental groups or control groups) after TGF_p3 treatment. The results of this study indicate that many of the processes involved in the later stages of wound healing, in which collagen deposition and ECM maturation, coexist in TGF_P3 treated and untreated wounds. This further indicates that TGF-P3 is capable of altering the beneficial outcomes shown during the early stages of wound healing. The effects of these changes are also evident long after the end of the event. SUMMARY OF THE INVENTION Certain aspects and embodiments of the present invention are non-surgically improved new drugs of '..., α V, 1 . One of the aspects and embodiments of the present invention is directed to a new method of non-surgical modification of the wounded garden. This improvement in the desire to treat the individual's grief due to the previous injury or trauma of the individual = may be caused by a previously selectable process that undergoes and completes the normal healing process and that (4) (four) bundles have been Reduce the injury (4) redness by treatment with a medical method. This two-therapy active ingredient replaces the external contrast. The invention is also aimed at reducing injuries. 145021.doc 201023878 In many patients, the treatment of scars intended to improve scar elasticity and angiogenesis does not necessarily reduce the redness and/or contrast of scars. This is due to the fact that the method of increasing blood vessel formation actually results in an increase in the size and/or number of gray tubes in the previously wounded area. Therefore, although the elasticity of the scar can be improved, the visual impact in terms of its redness or contrast cannot be improved. Thus, the goal of the present invention is to treat patients of this type by treating the scar redness of such patients by treatment. One point to note is that the treatment may or may not be associated with an improvement in the elasticity and/or vascularization of the wound.

在本發明之第-態樣中’提供適用作向傷症提供用於其 非外科改善之藥物的TGF_P3。本發明之此態樣亦提供適用 於衣la向傷疤提供用於其非外科改善之藥物的。該 :症可為由於在至少二至六個月以前，例如在投與藥物： 刖一—、四、五或六個月所造成之創傷而形成之傷疤。 向傷症投與TGF-P3可在創傷閉合之後至少二至六個月開 始該創傷之癒合已產生傷症（例如，在創傷閉合之後In the first aspect of the invention, 'providing TGF_P3 suitable for providing a drug for its non-surgical improvement to a wound. This aspect of the invention also provides for the use of a garment for providing scars with a non-surgical improvement. The condition may be due to a scar formed by at least two to six months prior to, for example, the administration of a drug: a wound caused by a first, a fourth, a fifth, or a six month. Administration of TGF-P3 to a wound may result in injury to the healing of the wound at least two to six months after the wound is closed (eg, after wound closure)

一、二、㈤、五或六個月）。根據本發明之第-態樣之藥 物可較佳經調配以供局部注射。 、 在第二^樣中，本發明亦提供一種非外科改善傷疤之 法該方法包含向需要該傷危之非外科改善之個體之 提供治療有效量之TGF m 4b r* . _β3。根據本發明之第二態樣之方 可包含向欲經非外斜# ¥ 1 卜科改善之傷疤投與治療有效量之Tc β3。本發明方法可句冬 匕3兩-人或兩次以上治療，於其中向 體提供TGF-P3。 本發明係基於本發明 者之驚人研究結果：TGF-p3在提供 145021.doc -12· 201023878 至見有傷症時月b夠w起傷疱特性之有利改變。此等有利改 變使得投與Τ〇Ρ-β3引起有效傷症改善而不需要外科干預。 經受改變之傷症特性可包括肉眼及顯微鏡下特性兩者。可 使用本晷月藥物及方法改善之特性包括(但不限於)獨立地 .冑自由以下組成之群的彼等特性：傷症寬度；傷症高摩； 傷症色素/儿著，傷症紅度；傷症體積及傷疮紋理。 TGF-P3可用以藉由非外科治療現有傷症來改善結症之研 • 究結果極其驚人’此係由於熟習此項技術者在考慮TGF-P3 在大約又傷之時施用影響創傷癒合之早期以抑制結症的方 式時，未預期在傷苑已形成之後，結症過程之如此晚期提 供TGF-P3會有任何益處。 如上所述，先前已展示TGF_p3能夠影響創傷癒合過程之 早期以產生發炎反應減輕，且細胞外基質組份以更精密接 L未又傷皮膚中所見者之方式沈積的局部創傷環境。此似 乎由於TGFj3「阻抑」沈積過多異常結構之基質物質以填 ❹ 補損傷留下之空隙的身體自然反應而發生。 創傷癒合過程為動態過程，其中癒合過程早期發生之作 用為隨後發生作用之基礎，且因此能夠影響後續事件。因 此，TGF-|33在創傷癒合反應第一天中建立受控有序修復之 • 條件的事實足以使癒合及結疤過程之稍後階段以有利方式 發生。因為癒合過程早期對表徵反應之性質及所形成替換 組織而言為至關重要的，所以在此早期之相對較小改變可 在過程之稍後階段引起程度大得多之改變。 瞭解所有此等要點之熟習此項技術者未能預期使用tgf_ 145021.doc 13 201023878 β3干預來改變已形成傷苑之特性會具有任何有利作用。認 為此生長因子產生發炎活性及基質沈積減少之局部環境的 能力在過晚階段發揮以致不能具有任何作用。在將提供 TGFj3以引起根據本發明之非外科改善之該類型現有傷症 中，發炎反應已有效地按其常規發展。此外，傷疤之細胞 外基質組份在很久以前已沈積，且—旦此等組份就位後， 則不預期TGF-P3會以任何方式有利地對其具有影響。 因此，可見先前技術無法使熟習此項技術者認為TGF_p3 可適用於在可非外科改善傷疤之藥物或方法中提供至傷 疤。認識到TGF-P3具有相對較窄之治療時間窗（大約結疤 之時），在該時間窗中其可有利地影響癒合過程之進程以 減少結疤，且本發明提出之用途恰好落於該時間窗之外。 此外，所報導之TGF_p3對創傷癒合反應之影響的某些特 定態樣將使熟習此項技術者認為其相當不適合以本發明提 出之方式使用。舉例而言，已顯示TGF-P3增加經提供 TGF-03之創傷中的血管數目（Shah等人J〇umai 〇f Cell Science 1〇8, 985-1002 (1995))。熟習此項技術者會由此認 為TGF-03相當不適合用於希望減少傷疤紅度之情況，因為 會預期其將具有相反作用。 在一項實施例中’ TGF-p3係用於減少傷疤之紅度。傷疤 為例如在形成傷疤之創傷癒合之後2_6個月之間（或6個月以 上）之傷疤。在一項實施例中，TGF-P3不恢復傷疤之彈性 但減少傷疤之紅度。認為TGF-P3可降低傷疤與相鄰「正 常」亦即無傷疤皮膚相比之顏色對比度，且詳言之紅度。 145021.doc -14- 201023878 紅度及/或對比度之降低可以肉眼測量。 在一項實施例中’傷疤不為硬化之傷疤且Τ〇Ρ_β3不用於 恢復傷疤之彈性。在一項實施例中，TGF_p3不用於降低肥 • 厚性傷苑或瘢痕瘤傷症之硬度。 • 先前已報導添加TGF-P之前纖維變性形式（亦即TGF-β 1 或TGF-P2)不足以使在不存在初始創傷損傷下結疤。出於 同樣原因，熟習此項技術者一般不認為已形成之傷疤可藉 由施用TGF-p3而改善。 此外’先前已發現需要在創傷癒合早期添加能夠中和 TGF-βΙ及TGF-P2之藥劑（諸如抗體），若其有利地影響傷疤 形成之程度。此進一步表明一般熟習此項技術者咸信TgF_ β活性之早期干預對於設法減少結疤為重要的。 不希望受缚於任何假設’本發明者咸信TGF-P3之有利作 用使其適用於傷疤之非外科改善中係由於生長因子促進且 加速經提供TGF-p3之傷疤成熟的能力而產生。成熟涉及多 φ 個過程，包括傷疤内ECM成分之重排及血管網之成熟/修 剪。 出於本發明之目的，TGFj3可包含含有以序列ID No. 1 顯不之胺基酸序列的蛋白質。具有以序列ID No. 1顯示之 • 序列的TGF-P3代表用於本發明藥物或方法中的較佳形式 TGF-P3。然而，使用此TGF_p3形式所獲的非外科傷疤減 少之優勢亦可由TGF-P3之治療有效片段或衍生物提供。因 此’除非上下文另外要求，否則在本發明之各個態樣或實 施例中提及之TGF-p3應視為亦涵蓋TGF-P3之治療有效片 145021.doc -15- 201023878 段或衍生物。此將在下文中更詳細討論。 在本發明之上下文中，傷宛之非外科改善可視為指示任 何非外科方法或治療方法，其中治療癒合過程結束後形成 之傷症以弱化傷症之外觀或減輕由傷㈣引起之功能障 礙。本發明藥物或方法可以唯一之傷疲之非外科改善模式 使用或可與此改善傷症之其他治療組合使用。僅舉例而 言，本發明藥物或方法可用作供非外科改善傷症用之組合 治療的部分，該組合治療亦包含一或多種以下治療：壓: 療法；皮質類固醇療法；放射線療法，·石夕膠片·抗贊生劑 (例如5-敦尿喷咬）；視黃酸；維拉帕米及免疫調節劑（諸如 乙莫奎德）。TGF-P3可獨立提供至接受其他非外科治療（諸 如上文所列舉之彼等治療）之傷苑。或者，根據本發明之 此實施例之適合藥物可包含與TGF_p3組合之活性劑，諸如 皮質類固醇；抗贅生劑；視黃酸；維拉帕米或免疫調節 劑。 本文中所用術語「傷症之非外科改善」應視為特別排除 傷症經切除、切割、重新調整或其他外科處理之傷症修復 方法。本發明藥物或方法可適用於進_步非外科改善由於 該等外科修復（或其他手術）產生之傷苑但僅在治療之外 科態樣相關創傷已癒合之後。 使用本發明藥物或方法非外科改善傷麵始之時間可參 考自產生傷疤之創傷形成後經過之時間計算。然而，此種 計算形式一般不適於癒合過程不尋常地延長的情形（例如 由於創傷癒合併發症）。在此情況下’非外科改善傷疤之 145021.doc 201023878 較佳參考引起傷症之創傷瘡合完成後經過的 、“2已在嗳傷部位上重建完整上皮覆蓋，即可 視創傷已癒合，且闲士 ρ太山 產生傷疤。此可例如由負責患者 …療之臨床醫師以肉眼評估確定。 傷症使用本發明藥物或方法的非外科改善較佳可在受傷 十，個月β’更佳受傷十個月内，更佳受傷人個月内 佳受傷六個月内’最佳受傷兩個月内起始。One, two, (five), five or six months). The drug according to the first aspect of the present invention can be preferably formulated for local injection. In a second aspect, the invention also provides a method of non-surgical improvement of scars comprising providing a therapeutically effective amount of TGF m 4b r* . _β3 to an individual in need of the surgically non-surgical improvement. According to a second aspect of the present invention, a therapeutically effective amount of Tc β3 can be administered to a wound that is to be improved by a non-exotropy #¥1. The method of the present invention can treat TGF-P3 to a body in two or more human or more than two treatments. The present invention is based on the surprising findings of the present inventors: TGF-p3 provides a favorable change in the characteristics of the wound at the time of providing 145021.doc -12·201023878 to the time of injury. These favorable changes have led to the administration of Τ〇Ρ-β3 to cause an effective injury improvement without the need for surgical intervention. The injury characteristics that are subject to change can include both macroscopic and submicroscopic properties. The characteristics that can be improved using this month's drugs and methods include, but are not limited to, the characteristics of the group consisting of: 伤 free: the width of the injury; the injury is high; the color of the injury/child, the redness of the injury Degree; the volume of the injury and the texture of the wound. TGF-P3 can be used to improve the symptoms of non-surgical treatment of existing injuries. The results are extremely amazing. This is due to the fact that those skilled in the art are considering the application of TGF-P3 at about the time of injury and affecting the early stage of wound healing. In the manner of inhibiting the syndrome, it is not expected that there will be any benefit in providing TGF-P3 in such a late stage of the healing process after the wounded garden has been formed. As noted above, it has previously been shown that TGF_p3 can affect the early stages of the wound healing process to produce a reduced localized wound environment in which the inflammatory response is reduced and the extracellular matrix component is deposited in a manner that is more precise and does not injure the skin. This seems to occur because TGFj3 "suppresses" the deposition of excessively abnormal matrix material to fill the body's natural response to the voids left by the damage. The wound healing process is a dynamic process in which the early action of the healing process is the basis for subsequent effects and can therefore influence subsequent events. Thus, the fact that TGF-|33 establishes a controlled and ordered repair condition on the first day of the wound healing response is sufficient to allow a later stage of the healing and scarring process to occur in an advantageous manner. Since the early stages of the healing process are critical to characterizing the nature of the reaction and the resulting replacement tissue, relatively small changes in the early stages can cause much greater changes in later stages of the process. Those who are familiar with all of these points are not expected to use the tgf_ 145021.doc 13 201023878 β3 intervention to change the characteristics of the formed wounded garden. It is believed that the ability of the growth factor to produce a local environment with reduced inflammatory activity and reduced matrix deposition does not play any role in the late stage. In the case of an existing injury of this type which will provide TGFj3 to cause non-surgical improvement according to the present invention, the inflammatory response has been effectively developed as usual. In addition, the extracellular matrix component of the scar has been deposited long ago, and once these components are in place, it is not expected that TGF-P3 will beneficially affect it in any way. Thus, it can be seen that prior art techniques have not made it known to those skilled in the art that TGF_p3 can be adapted to provide scars in drugs or methods that can be used to improve scars. Recognizing that TGF-P3 has a relatively narrow treatment window (approximately at the time of scarring), during which it can advantageously affect the progress of the healing process to reduce scarring, and the use of the present invention falls within the Outside the time window. In addition, certain specific aspects of the effect of the reported TGF_p3 on the wound healing response will be considered by those skilled in the art to be relatively unsuitable for use in the manner suggested by the present invention. For example, TGF-P3 has been shown to increase the number of blood vessels in wounds that provide TGF-03 (Shah et al. J〇umai 〇f Cell Science 1 〇 8, 985-1002 (1995)). Those skilled in the art would recognize that TGF-03 is quite unsuitable for situations where it is desirable to reduce the scarcity of the scar, as it would be expected to have the opposite effect. In one embodiment, 'TGF-p3 is used to reduce the redness of scars. Scars are, for example, scars between 2 and 6 months (or more than 6 months) after wound healing that forms scars. In one embodiment, TGF-P3 does not restore the elasticity of the scar but reduces the redness of the scar. It is believed that TGF-P3 reduces the color contrast of the scar compared to the adjacent "normal", ie, non-scarred skin, and the redness is detailed. 145021.doc -14- 201023878 Redness and/or contrast reduction can be measured visually. In one embodiment, the scar is not a sclerosis scar and Τ〇Ρ_β3 is not used to restore the elasticity of the scar. In one embodiment, TGF_p3 is not used to reduce the stiffness of a fat or thick scar or a keloid injury. • It has previously been reported that fibrotic forms (i.e., TGF-β 1 or TGF-P2) prior to the addition of TGF-P are insufficient to scarring in the absence of initial traumatic injury. For the same reason, those skilled in the art generally do not believe that the scars that have formed can be improved by administering TGF-p3. Furthermore, it has previously been found that it is necessary to add an agent (such as an antibody) capable of neutralizing TGF-βΙ and TGF-P2 in the early stage of wound healing, if it favorably affects the degree of scar formation. This further indicates that early intervention in the TgF_β activity of those skilled in the art is important to try to reduce scarring. It is not desirable to be bound to any hypothesis that the inventors' belief in the beneficial effects of TGF-P3 in the non-surgical improvement of scars is due to the growth factor-promoting and accelerated ability to provide TGF-p3 scar maturation. Maturity involves more than φ processes, including rearrangement of ECM components in the scar and maturation/repair of the vascular network. For the purposes of the present invention, TGFj3 may comprise a protein comprising an amino acid sequence which is not shown by sequence ID No. 1. TGF-P3 having the sequence shown in Sequence ID No. 1 represents the preferred form of TGF-P3 for use in the medicament or method of the present invention. However, the advantage of non-surgical scar reduction obtained with this TGF_p3 form can also be provided by a therapeutically effective fragment or derivative of TGF-P3. Thus, unless otherwise required by the context, TGF-p3 as referred to in various aspects or embodiments of the invention is considered to encompass a therapeutically effective fragment of TGF-P3, paragraph 145021.doc -15-201023878, or a derivative thereof. This will be discussed in more detail below. In the context of the present invention, a non-surgical improvement of the wound can be considered to indicate any non-surgical method or treatment in which the wound formed after the end of the healing process is treated to attenuate the appearance of the injury or to alleviate the dysfunction caused by the injury (4). The medicament or method of the present invention may be used in the non-surgical improvement mode of the sole injury or may be used in combination with other treatments for ameliorating the injury. By way of example only, the medicament or method of the invention may be used as part of a combination therapy for non-surgical improvement of a wound, which combination therapy also includes one or more of the following treatments: pressure: therapy; corticosteroid therapy; radiotherapy, stone夕 Film·Anti-Zansheng (such as 5-Dian squirt); retinoic acid; verapamil and immunomodulators (such as Emoquid). TGF-P3 can be independently provided to a wounded hospital that receives other non-surgical treatments (these treatments as listed above). Alternatively, a suitable drug according to this embodiment of the invention may comprise an active agent in combination with TGF_p3, such as a corticosteroid; an anti-neoplastic agent; retinoic acid; verapamil or an immunomodulator. The term "non-surgical improvement of injury" as used herein shall be considered as a method of repairing a wound that is specifically excluded from resection, cutting, readjustment or other surgical treatment of the injury. The medicament or method of the present invention is applicable to non-surgical improvement of the wounded garden resulting from such surgical repair (or other surgery) but only after the treatment has been healed. The time from the non-surgical improvement of the wound surface using the drug or method of the present invention can be calculated by referring to the time elapsed since the wound is formed. However, this form of calculation is generally not suitable for situations where the healing process is unusually prolonged (e. g. due to complications of wound healing). In this case, 'non-surgical improvement of scars 145021.doc 201023878 better reference to the traumatic wounds caused by the completion of the wound, "2 has been reconstructed in the wound site on the complete epithelial coverage, you can see the wound has healed, and leisure士太山 produces scars. This can be determined, for example, by visual assessment by the clinician responsible for the patient... The non-surgical improvement of the drug or method using the present invention is better at injury for 10 months, β' is better injured 10 Within a month, the better injured person was injured within six months of the injury within six months of the 'best injury' within two months.

傷症使用本發明藥物或方法的非外科改善可在受傷之後 至少兩個Μ始’或可在受傷之後至少四個月，受傷之後 至少六個月’受傷之後至少八個月，受傷之後至少十個 或甚至党傷之後十二個月或超過十二個月起始。 傷苑之非外科改善可在瘡合十二個月内，癒合十個月 内’癒合八個月内，癒合六個月β，或甚至癒合兩個月内 °亦即可在癒合十二個月内，例如癒合十個月内，戋 癒合八個月内’可能在癒合六個月内，或例如癒合兩個月 内提供TGFp-3至傷症。 為了產生根據本發明之傷疤之有效非外科改善，治療可 在導致形成傷疤之損傷癒合之後至少兩個月，癒合之後至 少四個月，癒合之後至少六個月，癒合之後至少八個月， 療口之後至少十個月，或甚至療合之後十二個月或超過十 二個月起始。 根據本發明之傷疤之非外科改善的方法較佳可包含兩次 或兩人以上治療。使用兩次或兩次以上治療一般將對傷疤 之非外科改善產生與單次治療相比更大有利作用。然而， 14502l.doc -17- 201023878 將治療次數限制為例如2次可能避免患者順應性降低（其可 能不樂意接受較多次重複注射，或可能發現難以安排較多 次就診以接受治療）且由此阻礙治療方案完成的風險。兩 -人以上之治療對於治療對治療具相對抗性之傷症，諸如病 理性傷症可能為理想的。亦即，根據本發明之傷范之非外 科改善的治療錢可藉由僅單:欠投與雨如至傷症而獲 得。在TGF-P3以使生長因子持續釋放至欲經非外科改善之 傷症之形式投與的情況下，此實施例可能尤其適合。 在採用本發明藥物或方法的傷疤之非外科改善中使用兩 次或兩次以上治療之情況τ，可能較佳控制個別次治療之 間的時間。治療之間的較佳時間可為大約6小時至大約48 小時。治療之間的定時更佳可為大約16小時至％小時，更 佳大約20小時至30小時且最佳可為約24小時。 可能較佳將本發明藥物及方法用於非外科改善先前未經 歷傷症修復或&結疲療法之傷症。詳言《，可能較佳將本 發明藥物及方法用於除彼等先前已提供TGF如作為抗結症 治療之部分的傷疤以外之傷疤。 受在本發明別處所述之任何附帶條件之限制，本發明藥 物及方法在非外科改善任何需要該治療之傷疤中可能為有 利的。本發明藥物及方法可用於非外科改善「正常」傷 症’或用於非外科改善「病理性傷疤」。 出於本發明之目的，「正常」傷疤可視為藉由正常創傷 癒合反應（亦即不受干擾使得產生病理性結疤之創傷療人 反應）所形成之任何傷症。 145021.doc •18- 201023878 病理性傷症」可視為包括彼等由於異常創傷癒合反應 而形成之傷症，諸如肥厚性傷症、瘋痕瘤傷症或翼狀裔肉 (眼睛中之病理性傷_式）。肥厚性或瘢痕瘤傷症皆為結 •症之不常見的嚴重形式，其產生顯著高出周圍組織之傷 .⑮’且其通常可具有與其周圍組織相比之色差。瘢痕瘤傷 症特徵性地生長超出初始損傷之邊界產生傷抱，而肥厚性 傷症常常遭受損傷性收縮。使用本發明藥物或方法治療病 • 雜傷症或許能改善所治療傷疤之外觀且由此減輕視覺衝 擊。 瘢痕瘤傷錢肥厚性傷宛亦可能與疼痛或㈣相關聯。 根據本發明之非外科修復亦可減少與此等錢相關的不 適’諸如疼痛或瘙癢。 本發明藥物或方法尤佳可用於非外科改善具有「發紅殘 留物」之傷疤（Bond等人以比121 (2M87 96’ 2008)。此傷疤之持久性紅度導致傷疤與其周 • 圍組織相比’比正常成熟及消退之傷症更為顯眼。已發現 2有「發紅殘留物」之傷症未經受長時間發炎反應（如先 前可能認為）且發炎似乎不是觀察到紅度之主要原因。本 . 發明者咸信使用根據本發明之傷疤之非外科改善可顯著改 • 善具有「發紅殘留物」之傷疤的外觀，導致經治療傷疤比 在受傷後或癒合後同時未經治療之傷疤更精密地接近未受 傷皮膚之顏色及外觀。 根據本發明之傷疤之非外科改善可能較佳在經歷重塑之 傷疤中進行。本發明者自己的公開案近來已證實重塑在人 145021.doc -19- 201023878 類皮膚創傷癒合之後進行至少一年（Bond等人尸/aW βαο似ir. May; 121(5):1650-8，2008)。本發明之一項 較佳實施例為將TGF-p3用作非外科改善經歷重塑之傷疤的 藥物及/或將TGF-p3用於非外科改善經歷重塑之傷疤的方 法中。 傷疤之重塑可持續至形成傷疤之創傷閉合之後至少一 年。在重塑過程中’傷疤内之ECM分子經歷特徵性成熟過 程’促使傷疤與初始創傷相比機械強度增加。 TGF-p3有效治療現有傷症之紅度或對比度是令人驚言牙 的’因為其先前僅在癒合過程之早期中涉及，且認為涉及 早期創傷癒合及傷疤重塑之生物過程彼此相當不同。 為避免疑義現將進一步描述用於本發明中之各種術語。 應理解為了簡潔起見，可僅參考本發明之某些態樣來描述 —些此等術語。然而，除非上下文中另有要求，否則以下 此等術語之描述可適用於本發明之所有態樣。 本發明藥物或方法 出於本發明之目的，提及「本發明藥物」應視為涵蓋根 據本發明之各種態樣或實施例所製造的含有TGF_p3之藥 物。此外，除非上下文中另有要求，否則本發明藥物在根 據本發明之第-態樣或此態樣之任何冑合實施例使用時應 視為包含TGF-P3(或其治療有效片段或衍生物）。本發明藥 物能夠提供TGF-P3至欲經非外科改善之傷疤。可能較佳將 本發明藥物投與欲經非外科改善之傷疤。 本發明方法應視為涵蓋根據本文中所闡明之本發明各種 14502l.doc •20· 201023878 =ΓΓ任何“之非外科改善方法，或其他相應 π療方法。㈣解本發”物_般代表㈣本 較佳組合物。 々&之 治療有效量 .〜在本發明之上下文中TGF-P3之「治療有效量」將為能夠 貫現非外科改善經提供生長因子之傷症的此生長因子之任 何量。根據本發明之TGF_p3之治療有效量將為引起所治療 ❹ 傷症與未經治療或對照治療傷症之外觀相比外觀改善（顯 微鏡下及/或肉眼評估）的彼等量。 本發明者已首次㈣該等治療有效量，且已進—步發現 特定治療有效量與意謂使用本發明藥物或方法可能特別有 利的特性或特徵相關聯。在說明書中別處更詳細考慮此等 較佳治療有效量。然而，一般而言，能夠非外科改善i公 分長度之真皮傷疤的TGF-P3之總治療有效量可在1〇〇至 1〇,〇〇〇吨之範圍内，更佳在200至5 000吨之範圍内，更佳 φ 在500至2,50〇 ng之範圍内，且甚至更佳在1000至2,〇〇〇 ng 之範圍内。TGF-p3之此等治療有效量及在本發明中別處提 及之TGF-P3之量一般較佳藉由定量酶聯免疫吸附檢定 (ELISA)測定，以英國國家生物標準及控制研究所（United ' Kingdom National Institute f〇r Biological Standards) (NIBSC)轉化生長因子β-3(源自人類rDNA)參考試劑碼 98/608校正，如下文中更詳細描述。 應理解此等治療有效量可在一或多次治療過程中投與且 此為本發明之一較佳實施例。在採用多次治療之情況中， 145021.doc -21 - 201023878 各次所提供的TGF-P3之量可相應地變化以便在多次治療過 程中提供已知比例之治療有效量（例如，在兩次治療中提 供治療有效量之TGF-P3的情況中，各次可包括提供所選治 療有效量之一半）。舉例而言，當需要在包含兩次投藥之 治療方案過程中提供大約100至10,000 ng之間的TGF-P3至 一公分之傷疤時，欲使用之適合藥物將為能夠每公分欲經 非外科改善之傷症提供大約50 ng至5,000 ng之間的TGF-P3 的藥物。因此，在其他實例中’本發明之適合藥物可用於 投與每公分欲經非外科改善之傷疤大約1〇〇至25〇〇 ng，大 約 250至 1250 ng，或大約 500至 1000 ng TGF-P3。 當經由本發明藥物或方法提供治療有效量之TGF-P3時， 母公分欲經改善之傷疤5〇〇 ng或1〇〇〇 ng TGF_p3代表每次 治療欲投與的TGF_P3之尤佳量。此等量可藉助於兩次治療 投與’因此每公分需要非外科改善之傷症分別提供總治療 量為 1,000 ng或 2,〇〇〇 ng之 TGF-p3。 本發明者咸信使用根據本發明之治療有效量的TGF_(33之 傷疤之非外科改善在最後一次治療之後十二個月内，在最 後-次治療八個月β，在最後—次㈣六個月内，或在最 後-次治療四個㈣，兩個月内或甚至—個月内引起 估之結疤減少。 用本發明藥物或方法的傷疤之非外科改善較佳可引 :症與適合對照物（例如，在治療之前的相同傷絶，同 '未Λ3療部刀’對照治療傷症或未經治療傷宛）相 心至少跳。根據本發明之錢之非外科改善較佳可 145021.doc 201023878 起結疤與適合對照物相比減少至少20%，更佳至少5〇%， 甚至更佳至少75%且更佳至少9〇%。實際上，根據本發。明 之傷症之非外科改善最佳可引起結宛與適合對照物相 少 100%。 傷症之公分 無論是^與本發明之藥物或方法有關，欲提供至欲經非 外科改善之傷疮的治療有效量之TGF_P3可參考欲治療傷苑 ❹Injury The non-surgical improvement using the drug or method of the invention may be initiated at least two after the injury' or at least four months after the injury, at least six months after the injury, at least eight months after the injury, and at least ten after the injury. Or even 12 weeks after the party injury or more than 12 months. The non-surgical improvement of the wounded garden can be healed within 12 months, healing within 10 months, healing within 8 months, healing for 6 months, or even healing within 2 months. During the month, for example, within 10 months of healing, the hemorrhoids heal within eight months 'may be within six months of healing, or for example, within two months of healing to provide TGFp-3 to the injury. In order to produce an effective non-surgical improvement of the scar according to the present invention, the treatment may be at least two months after healing of the wound causing the scar, at least four months after healing, at least six months after healing, and at least eight months after healing, Start at least ten months after the mouth, or even twelve months or more than twelve months after the treatment. The non-surgical improvement of the scar according to the present invention preferably comprises two or more treatments. The use of two or more treatments will generally result in a greater beneficial effect on the non-surgical improvement of the scar compared to a single treatment. However, limiting the number of treatments to, for example, 2 times may avoid a reduction in patient compliance (which may be unwilling to accept more repeated injections, or may find it more difficult to schedule more visits for treatment) and 14502l.doc -17-201023878 This hinders the risk of completion of the treatment plan. Two or more treatments may be desirable for treating a wound that is relatively resistant to treatment, such as a pathological injury. That is, the treatment cost for non-disciplinary improvement according to the present invention can be obtained by simply owing a lack of investment and rain as a result of injury. This embodiment may be particularly suitable where TGF-P3 is administered in a form such that sustained release of growth factors is desired to be a non-surgical improvement. In the case of using two or more treatments in the non-surgical improvement of scars using the medicament or method of the present invention, it may be preferable to control the time between individual treatments. A preferred time between treatments can range from about 6 hours to about 48 hours. The timing between treatments may preferably be from about 16 hours to about 100 hours, more preferably from about 20 hours to 30 hours, and most preferably about 24 hours. It may be preferred to use the medicaments and methods of the present invention for non-surgical improvement of previous injuries without history repair or & In particular, it may be preferred to use the medicaments and methods of the present invention in addition to scars other than those previously provided for TGF, as part of the treatment of anti-cause treatment. Subject to any of the attendant limitations described elsewhere herein, the agents and methods of the invention may be beneficial in non-surgical improvement of any scar requiring such treatment. The medicament and method of the present invention can be used for non-surgical improvement of "normal" injuries or for non-surgical improvement of "pathological scars". For the purposes of the present invention, a "normal" scar can be considered as any injury resulting from a normal wound healing response (i.e., a traumatic response that produces a pathological scar without interference). 145021.doc •18- 201023878 Pathological injuries can be considered as including injuries caused by abnormal wound healing reactions, such as hypertrophic injuries, maddenales or pterygium (pathological in the eye) Injury _ type). Hypertrophic or keloid lesions are uncommon severe forms of the disease that produce lesions that are significantly higher than surrounding tissue. 15' and which typically have a chromatic aberration compared to the surrounding tissue. Scar cancer lesions characteristically grow beyond the boundaries of the initial injury to produce wounds, while hypertrophic injuries often suffer from damaging contractions. Treatment of a disease using the medicament or method of the present invention may improve the appearance of the scar to be treated and thereby reduce visual impact. Scar hyperplasia can also be associated with pain or (4). Non-surgical repairs in accordance with the present invention may also reduce discomfort associated with such money, such as pain or itching. The medicament or method of the present invention is particularly preferably used for non-surgical improvement of scars having "redness residues" (Bond et al., 121 (2M87 96' 2008). The persistent redness of this scar causes scars and its peripheral tissues. It is more conspicuous than 'normally mature and regressed injuries. It has been found that 2 injuries with "redness residue" have not been affected by prolonged inflammatory reactions (as previously thought) and inflammation does not seem to be the main cause of observed redness. The inventor's belief that the non-surgical improvement of the scar according to the present invention can significantly improve the appearance of scars with "redness residues", resulting in treated scars that are untreated after injury or after healing. The scar more closely approaches the color and appearance of the uninjured skin. The non-surgical improvement of the scar according to the present invention may preferably be carried out in the scar undergoing remodeling. The inventor's own disclosure has recently been confirmed to be reshaped in human 145021. Doc -19- 201023878 The skin wound healing is carried out for at least one year (Bond et al. / aW βαο like ir. May; 121(5): 1650-8, 2008). A preferred embodiment of the present invention is TGF-p3 is used as a non-surgical agent for the treatment of remodeling scars and/or for the use of TGF-p3 for non-surgical improvement of wounds undergoing remodeling. The remodeling of scars can persist until at least the wounds that form scars are closed. One year. During the remodeling process, the ECM molecules in the scar undergo a characteristic maturation process, which promotes the increase in mechanical strength of the scar compared with the initial wound. TGF-p3 is effective in treating the redness or contrast of existing injuries. 'Because it was previously only involved in the early stages of the healing process, and the biological processes involved in early wound healing and scar remodeling are considered to be quite different from each other. For the avoidance of doubt, various terms used in the present invention will now be further described. For the sake of brevity, these terms may be described with reference only to certain aspects of the invention. However, the following description of such terms may apply to all aspects of the invention, unless the context requires otherwise. Pharmaceutics or Methods For the purposes of the present invention, reference to "the medicament of the invention" shall be taken to encompass the inclusion of TGF_p3 produced in accordance with various aspects or embodiments of the invention. In addition, unless otherwise required by the context, the medicament of the invention is considered to comprise TGF-P3 (or a therapeutically effective fragment thereof) when used in accordance with the first aspect of the invention or any of the conjugate embodiments of this aspect. Or a derivative). The medicament of the present invention is capable of providing TGF-P3 to a scar that is to be non-surgically improved. It may be preferred to administer the medicament of the present invention to a scar that is to be non-surgically improved. The method of the present invention is considered to be encompassed according to the present disclosure. Illustrating the various 14502l.doc •20· 201023878 of the present invention = ΓΓ any "non-surgical improvement method, or other corresponding π treatment method. (d) solution of the hair" _ general representative (four) the preferred composition. 治疗 & therapeutically effective amount ~ "Therapeutically Effective Amount" of TGF-P3 in the context of the present invention will be any amount that is capable of achieving non-surgical improvement of this growth factor that provides growth factor injury. The therapeutically effective amount of TGF_p3 according to the present invention will be such an amount that results in an improvement in appearance (microscopic and/or visual evaluation) of the treated spasticity compared to the appearance of the untreated or control treated wound. The inventors have for the first time (4) such therapeutically effective amounts, and have further discovered that a particular therapeutically effective amount is associated with a property or feature that may be particularly advantageous using the agents or methods of the invention. These preferred therapeutically effective amounts are considered in more detail elsewhere in the specification. However, in general, the total therapeutically effective amount of TGF-P3 capable of non-surgical improvement of dermal scars of i-cm length may range from 1 Torr to 1 Torr, preferably within the range of 〇〇〇 ton, more preferably from 200 to 5,000 ton. Within the range, more preferably φ is in the range of 500 to 2,50 ng, and even more preferably in the range of 1000 to 2, 〇〇〇ng. Such therapeutically effective amounts of TGF-p3 and the amount of TGF-P3 referred to elsewhere in the present invention are generally preferably determined by quantitative enzyme-linked immunosorbent assay (ELISA) to the National Institute of Biological Standards and Control (United Kingdom). ' Kingdom National Institute f〇r Biological Standards) (NIBSC) TGF-beta-3 (derived from human rDNA) reference reagent code 98/608, as described in more detail below. It will be understood that such therapeutically effective amounts can be administered in one or more treatment sessions and are a preferred embodiment of the invention. In the case of multiple treatments, the amount of TGF-P3 provided by each of 145021.doc -21 - 201023878 may be varied accordingly to provide a known ratio of therapeutically effective amount over multiple treatments (eg, in two In the case where a therapeutically effective amount of TGF-P3 is provided in a sub-treatment, each may include providing one and a half of the selected therapeutically effective amount). For example, when it is desired to provide between about 100 and 10,000 ng of TGF-P3 to one centimeter of scar during a two-dosing regimen, the appropriate drug to be used will be non-surgical improvement per cm. The injury provides approximately 50 ng to 5,000 ng of TGF-P3. Thus, in other examples, a suitable drug of the invention can be used to administer a scar of about 1 to 25 ng, about 250 to 1250 ng, or about 500 to 1000 ng of TGF-P3 per minute of non-surgical improvement. . When a therapeutically effective amount of TGF-P3 is provided via the medicament or method of the present invention, the mother's centimeters to be improved, 5 ng or 1 ng of TGF_p3 represents a particularly preferred amount of TGF_P3 to be administered per treatment. This amount can be administered by means of two treatments, thus providing a total therapeutic amount of 1,000 ng or 2, ng of TGF-p3, respectively, for each minute requiring non-surgical improvement. The inventors have used the therapeutically effective amount of TGF_ according to the present invention (33 non-surgical improvement of scars in the last 12 months after the last treatment, in the last - eight treatments of beta, in the last - (four) six During the month, or within the last four treatments (four), within two months or even within a month, the estimated crusting is reduced. The non-surgical improvement of the scar with the drug or method of the present invention is preferred: Suitable for the control (for example, the same injury before treatment, with the 'untreated 3 treatment knife' control treatment injury or untreated injury) at least jump. The non-surgical improvement of the money according to the present invention is preferably 145021.doc 201023878 The crusting is reduced by at least 20%, more preferably by at least 5%, even more preferably by at least 75% and more preferably by at least 9% compared to a suitable control. In fact, according to the present invention. Non-surgical improvement may result in a 100% less knot than the appropriate control. The nod of the injury is related to the drug or method of the present invention and is intended to be provided to a therapeutically effective amount of the wound that is to be non-surgically improved. TGF_P3 can refer to the treatment of wounded garden ❹

之長度或面積來限^。相關長度或面積可按照希望得到非 外科「改善的「傷疤之公分」數來測定。出於本發明之目 的，「傷疤之公分」表示可用於測量欲經非外科改善之結 疤部位的尺寸之單位β 一傷疤之公分可視為包含遭受結疤之體表(完全或部分任 -者)之平方公分。舉例而言，兩公分長度及一公分寬度 (亦即兩個平方公分之總表面積）之傷症將視為構成「兩個 傷苑公分」。出於同樣原因，兩公分長度但寬度可忽略（亦 即表面積可忽略）之線性傷疤若穿過兩個平方公分之身體 表面則出於本發明之目的將視為構成「兩個傷疤公分」。 相似地，具有兩公分長度及兩公分寬度（亦即四平方公分 之總表面積）之傷疤將構成四個傷疤公分。 以傷疤公分數計的部位之尺寸一般應在治療之前評估 (因為使用本發明藥物或方法的料科改善也許能減小傷 疤尺寸）。測量一般應在傷疤處於鬆弛狀態下（亦即，當具 有需要測量之部位的身體部分處於當身體靜止時採取之位 置時）進行。對於皮膚傷疤，應在皮膚不受外部張力時評 145021.doc -23- 201023878 估相關尺寸。 本發明者咸信可能較佳藉助於至少兩次（且争 v 又佳兩次）治 療將所選治療有效量之TGF-P3提供至欲經非外科改善之傷 疤。為了達成此目標，認識到本發明藥物可能較佳經調配 以便治療有效量之TGF-P3由提供至一公分傷疤之藥物量 (且延伸至患者）在至少兩次（且更佳兩次）治療過程中提 供。 TGF-P3之治療有效片段或衍生物 除非上下文中另外要求’否則提及之所有根據本發明藥 物或方法之TGF-P3亦應視為涵蓋TGF-P3之治療有效片段 或衍生物。TGF-p3之適合片段或衍生物可包含至少1〇個序 列ID No. 1之胺基酸殘基，較佳至少40個胺基酸殘基，更 佳至少70個胺基酸殘基，且最佳至少1〇〇個胺基酸殘基。 適合形式之衍生物之適合實例可選自（但不限於）由以下 組成之群·· TGF-p3之治療有效肽衍生物（或其片段）；包含 或基於本發明TGF-P3之藥效團的治療有效片段或衍生物； TGF-p3之治療有效類肽衍生物（或其片段）；TGF-P3之治療 有效D-胺基酸衍生物（或其片段）；基於TGF-P3之治療有效 肽模擬物（或其片段）；TGF-P3之治療有效肽類似物（或其 片段）；基於TGF-P3之治療有效偽肽（或其片段），·基於 TGF-P3之治療有效逆倒轉肽（或其片段）；基於TGF-P3之治 療有效縮肽衍生物（或其片段）；基於TGF-P3之治療有效β-肽衍生物（或其片段）；及基於TGF-P3之治療有效逆類肽衍 生物（或其片段）。 145021.doc •24· 201023878 如本文中所用術語「肽類似物」、「肽衍生物」及「肽模 擬物」意欲包括模擬肽之化學結構且保留肽之功能特性的 分子。設計肽類似物之方法在此項技術中已知。舉例而 言，參見Farmer, P. S. in Drug Design (E. J· Ariens,編） Academic Press，New York，1980，第 10卷，第 119-143 頁； Ball. J. B.及 Alewood，P. F. (1990) J. Mol. Recognition 3:55 ; Morgan, B. A.及 Gainor，J. A. (1989) Ann. Rep. Med_ Chem. 24:243 ；及 Freidinger，R. M. (1989) Trends Pharmacol. Sci. 10:270。肽類似物、衍生物及肽模擬物之 實例包括經一或多個笨并二氮呼分子取代之肽（參見，例 如 James, G. L.等人（1993) Science 260:1937-1942)、具有甲 基化醯胺鍵之肽及「逆-倒轉」肽（參見Sisto之美國專利第 4,522,752號）。 應理解出於本發明之目的’ TGF-P3可視為涵蓋蛋白質之 單體形式及二聚形式之任一者。令人驚訝地發現儘管TGF-β3通常以二聚體形式起作用’但TGF-P3能夠以單體形式及 二聚形式皆發揮其生物作用，且因此此等形式之任一者均 可用於本發明藥物或方法中以產生傷症之非外科改善。應 瞭解單體TGF-P3之分子量將低於相應二聚體，且因此應相 應地計算單體TGF-P3之治療有效量或劑量。 適用於本發明藥物或方法中的TGF-P3之治療有效片段或 衍生物較佳在提供至傷疤時可產生與適合對照物（舉例而 言，在治療之前的相同傷症，同一傷症之未治療部分，對 照治療傷疮或未經治療傷症）相比至少1 〇°/。之結症減少。適 145021.doc -25· 201023878 合根據本發明使用的TGF-P3之治療有效片段或衍生物較佳 在k供至傷症時可產生與適合對照物相比至少2〇%，更佳 至少50°/。’甚至更佳至少75°/。且更佳至少90%的結症減 少。實際上’ TGF-P3之治療有效片段或衍生物最佳在提供 至傷绝時能夠產生與適合對照物相比1〇〇%之結疤減少。 投藥之方法，調配物及组合物 本發明者咸信傷疤之非外科改善可根據本發明使用任何 適合投藥模式獲得，藉由該適當投藥模式可提供治療有效 量之TGF-P3至需要該改善之結疤部位。然而，一般將 TGF-p3直接投與需要治療之傷抱可能較佳。詳言之， TGF-P3之局部注射代表在本發明方法中之較佳投藥模式， 且適於局部注射之調配物代表用作本發明藥物的TGF_p3之 較佳形式。 局部注射直接投與τσρ-β3至欲經非外科改善之傷疤中的 能力提供許多優勢。不希望受缚於任何假設，咸信注射有 助於避免否則可與需要TGF_P3穿過表皮障壁相關聯的問 題。亦咸信TGF-P3經由可注射藥物投與至傷症中有助於為 傷疤之非外科改善創造尤其有利的局部條件。 -般可能較佳使用皮内注射針及注射器實施藉由注射投 與根據本發明之TGF_P3。然而，可投與根據本發明之藥物 的替代途徑係以液滴或;東乾粉末形式推進穿過皮膚。該推 進可為經由壓縮氣體之***性釋放（expiQsiveFeiease)的超 音推進。此投藥模式通常稱為「無針注射」且許多適合裝 置係市售的（例如，彼等以商標名「ρ〇λν(ΐ_Μ」、 145021.doc •26· 201023878The length or area is limited to ^. The relevant length or area can be determined by the number of non-surgical "improved "scores of scars" that are desired to be obtained. For the purposes of the present invention, "the scar of the scar" means a unit that can be used to measure the size of the scar site to be non-surgically improved. The centimeter of a scar can be regarded as containing a body surface that suffers from scarring (completely or partially) ) square centimeters. For example, an injury of two centimeters in length and one centimeter in width (ie, the total surface area of two square centimeters) will be considered to constitute "two wounded garden cents." For the same reason, a linear scar of two centimeters in length but negligibly wide (i.e., negligible in surface area) would be considered to constitute "two scars" if it passes through two square centimetres of body surface. Similarly, a scar having a length of two centimeters and a width of two centimeters (i.e., a total surface area of four square centimeters) will constitute four scars. The size of the site based on the scar score should generally be assessed prior to treatment (because the improvement in the material using the drug or method of the invention may reduce the size of the wound). Measurements should generally be made when the scar is in a relaxed state (i.e., when the body part with the part to be measured is in a position to take when the body is at rest). For skin scars, the relevant dimensions should be evaluated when the skin is not subject to external tension. The inventors may prefer to provide a selected therapeutically effective amount of TGF-P3 to a wound that is to be non-surgically modified by means of at least two (and two times better) treatments. In order to achieve this goal, it is recognized that the medicament of the present invention may preferably be formulated so that a therapeutically effective amount of TGF-P3 is treated at least twice (and preferably twice) from the amount of the drug provided to one centimeter of scar (and extended to the patient) Provided during the process. Therapeutically effective fragments or derivatives of TGF-P3, unless otherwise required by the context, otherwise all TGF-P3 according to the present invention may also be considered to comprise a therapeutically effective fragment or derivative of TGF-P3. A suitable fragment or derivative of TGF-p3 may comprise at least one amino acid residue of sequence ID No. 1, preferably at least 40 amino acid residues, more preferably at least 70 amino acid residues, and Preferably at least one amino acid residue is present. Suitable examples of suitable forms of derivatives may be selected from, but not limited to, a therapeutically effective peptide derivative (or a fragment thereof) of TGF-p3 consisting of: a pharmacophore comprising or based on TGF-P3 of the invention Therapeutic effective fragments or derivatives; therapeutically effective peptoid derivatives (or fragments thereof) of TGF-p3; therapeutically effective D-amino acid derivatives (or fragments thereof) of TGF-P3; therapeutically effective based on TGF-P3 Peptide mime (or a fragment thereof); a therapeutically effective peptide analog of TGF-P3 (or a fragment thereof); a therapeutically effective pseudopeptide based on TGF-P3 (or a fragment thereof), a therapeutically effective inverse peptide based on TGF-P3 (or a fragment thereof); a therapeutically effective depressor derivative (or a fragment thereof) based on TGF-P3; a therapeutically effective β-peptide derivative (or a fragment thereof) based on TGF-P3; and a therapeutically effective inverse based on TGF-P3 Peptoid derivatives (or fragments thereof). 145021.doc •24· 201023878 The terms “peptide analog”, “peptide derivative” and “peptide analog” as used herein are intended to include molecules that mimic the chemical structure of a peptide and retain the functional properties of the peptide. Methods of designing peptide analogs are known in the art. See, for example, Farmer, PS in Drug Design (E. J. Ariens, ed.) Academic Press, New York, 1980, Vol. 10, pp. 119-143; Ball. JB and Alewood, PF (1990) J. Mol. Recognition 3:55; Morgan, BA and Gainor, JA (1989) Ann. Rep. Med_Chem. 24:243; and Freidinger, RM (1989) Trends Pharmacol. Sci. 10:270. Examples of peptide analogs, derivatives, and peptidomimetics include peptides substituted with one or more benzodiazepine molecules (see, for example, James, GL et al. (1993) Science 260: 1937-1942), with a methyl group. A peptide of a guanamine bond and a "reverse-inverted" peptide (see U.S. Patent No. 4,522,752 to Sisto). It is to be understood that for the purposes of the present invention, TGF-P3 can be considered to encompass any of the monomeric and dimeric forms of the protein. Surprisingly, it has been found that although TGF-β3 usually functions in a dimeric form, TGF-P3 can exert its biological effects in both monomeric and dimeric forms, and thus any of these forms can be used in this form. A non-surgical improvement in the production of a drug or method to produce a wound. It will be appreciated that the molecular weight of the monomeric TGF-P3 will be lower than the corresponding dimer, and therefore the therapeutically effective amount or dose of the monomeric TGF-P3 should be calculated accordingly. A therapeutically effective fragment or derivative of TGF-P3 suitable for use in a medicament or method of the invention preferably produces a suitable control when administered to a scar (for example, the same wound prior to treatment, the same injury) The treatment part, compared with at least 1 / ° / compared with treatment for wounds or untreated injuries). The syndrome is reduced. 145145021.doc -25· 201023878 The therapeutically effective fragment or derivative of TGF-P3 for use in accordance with the present invention preferably produces at least 2%, more preferably at least 50, compared to a suitable control when supplied to a wound. °/. 'Either better at least 75°/. And preferably at least 90% of the symptoms are reduced. In fact, a therapeutically effective fragment or derivative of 'TGF-P3 is optimally capable of producing a reduction in scar formation of 1% compared to a suitable control when provided to the wound. Methods of Administration, Formulations, and Compositions The non-surgical improvement of the present inventors of the present invention can be obtained according to the present invention using any suitable mode of administration by which a therapeutically effective amount of TGF-P3 can be provided to the desired level of improvement. Scarring area. However, it is generally preferred that TGF-p3 is administered directly to the wound that requires treatment. In particular, topical injection of TGF-P3 represents a preferred mode of administration in the methods of the invention, and formulations suitable for topical injection represent a preferred form of TGF_p3 for use as a medicament of the invention. The ability of a local injection to directly administer τσρ-β3 to a scar that is not surgically improved provides many advantages. Without wishing to be bound to any hypothesis, Xianxin injection helps to avoid problems that might otherwise be associated with the need for TGF_P3 to cross the epidermal barrier. It is also believed that the administration of TGF-P3 via injectable drugs to the wound helps to create particularly favorable local conditions for the non-surgical improvement of scars. It is generally preferred to use an intradermal needle and a syringe to effect administration of TGF_P3 according to the present invention by injection. However, alternative routes to which the drug according to the present invention can be administered are advanced through the skin in the form of droplets or; This advancement can be an ultrasonic advancement via expiratory release of compressed gas (expiQsiveFeiease). This mode of administration is commonly referred to as "needle-free injection" and many suitable devices are commercially available (for example, they are under the trade name "ρ〇λν(ΐ_Μ", 145021.doc •26· 201023878

Jetpeel」、「Airgent」及其類似者出售者）。 應瞭解可藉由除注射以外之方式（例如，藉由說明書中 别處所考慮之表面藥物）將治療有效量之TGF_p3提供至傷 疤且仍可產生所需非外科改善。實際上，在某些情況下， . &面藥物可能較佳，因為注射通常造成患者不適，且需要 夕-人主射可能使得治療過程不能較好完成。在表面治療之 凊況下，必需提供傳遞TGFp3蛋白質穿過完整表皮的方 ❿ 例如藉由囊封於脂質體或傳遞體（transfersome)(Paul等 人〜Jan_Feb; 16(2_3):188-95 1998)内。 諸如本發明方法的治療方案可利用藉由注射及其他方式 之杈藥。舉例而言，傷疤之非外科改善可藉由涉及以注射 形式才又與TGF-p3之首次治療，接著進行涉及藉由表面藥物 杈一 TGF-p3之第二（且視情況後續）次治療來獲得。在臨床 醫師或其類似者投與首次治療（例如在醫院或診所）且患者 自己投與第二次及視情況後續治療（例如在其家中）之情況 下，此可能為較佳的。 在TGF-P3藉助於注射提供至患者之情況中，較佳投藥模 式可涉及在欲治療區域中彼此間隔大約一公分投與一系列 注射液。因此，在實質上線性傷疤之情況下可（例如使 用外科標記物）以一系列彼此間隔大約一公分之參考點來 ‘圮傷疤。在一項較佳實施例中，在傷疤任一端之參照點 應自欲治療之傷絶端延伸出至少半公分。此排列係示意性 地展示於圖2中。對於TGF_p3之投與，將皮下注射針皮内 ***位點B且前進至位點A，隨著針之取出，1〇〇 μ1之給藥 145021.doc -27- 201023878 溶液隨後注入至1 cm長度之真皮中，確保併入TGFp3之組 合物均勻分布在位點A與B之間。在溶液注入真皮中處將 看到變白之「皰隨後將針沿位點B之方向***位點c中 且重複給藥方法直至在欲經非外科修復之傷疤之所有部分 達成給藥。此投藥方式可視為沿傷疤產生注射線。類似投 藥可藉由使用注射器（預填充或在使用時填充）及特別為皮 . 内才又藥設计之針（Laurent 等人 Vaccine, 8833-8842，2007)， 例如Becton Dickinson SoluviaTM系統達成。 當TGF-P3投與至傷疤時，將其實質上投與至欲改善傷疤 參 之中心可能較佳。在長條形傷疤之情況下，此可涉及沿實 質上沿傷疤之縱向中心延伸之線來投藥。以此方式之投藥 可月b在傷症寬度為大約1公分或1公分以下之情況中尤其有 效。在傷疤寬度大於1 cm之情況下，可能較佳藉助於一系 列沿傷疤縱向延伸之大致平行線投與TGF_|33以便將治療有 效量之TGF-P3提供至各傷疤公分。 本發明者已發現治療有效量之TGF-P3於大約1〇〇 μΐ體積 之藥物中提供的調配物尤其有利，且進一步較佳本發明之 ® 此等實施例應涉及投與大約100 μ1在各注射液中包含TGF_ β3之藥物。較佳調配物可經設計以便治療有效量之tGF_ P3(或該量之所需部分）在大約1〇〇 μ1之體積中投與。本發 明者已發現大約1〇〇 μ1包含TGF_p3之藥物的體積為患者所 良好耐受。詳言之，在包含TGF-P3之藥物注射液的情況 下，一般每公分欲治療傷疤可投與1〇〇 μ1體積之該等藥 物’而不在該治療位點誘發其他損傷或其類似者。此外， I45021.doc -28- 201023878 100 μΐ體積包含TGF-P3之藥物可為投與其之傷疤充分吸 收，且此對於控制精確投與治療有效量之TGF_p3為有利 的。 . 根據本發明之TGF-P3之可注射調配物可較佳適用於皮内 注射。 雖然可能將由本發明提供之TGF J33用於任何形式之療 法，但可能較佳將其在醫藥調配物中投與，例如與關於預 φ 期投藥途徑及標準醫藥實踐而選擇的適合醫藥賦形劑、稀 釋劑或載劑混合。因此，在一態樣中，本發明提供包含至 少一種活性組合物或其醫藥學上可接受之衍生物以及醫藥 學上可接受之賦形劑、稀釋劑及/或載劑的醫藥組合物或 調配物。該賦形劑、稀釋劑及/或載劑在與調配物之其他 成份相容且不損害其接受者之意義上必須為「可接受 的」。 本發月組合物可經調配用於以任何適用於人類或獸醫藥 Φ 物之便利方式投藥。因此，本發明在其範疇之内包括醫藥 組合物，其包含適用於人類或獸醫藥物的本發明之產物。 供治療使用之可接受之賦形劑、稀釋劑及載劑在醫藥技 術中熟知且描述於例如Remingt〇n: The Seience andSeller of Jetpeel, "Airgent" and the like). It will be appreciated that a therapeutically effective amount of TGF_p3 can be provided to the wound by means other than injection (e.g., by surface medications considered elsewhere in the specification) and still produce the desired non-surgical improvement. In fact, in some cases, & facial medications may be preferred because injections often cause discomfort to the patient and the need for a priming-human main shot may make the treatment process less well done. In the case of topical treatment, it is necessary to provide a means for transferring TGFp3 protein across the intact epidermis, for example by encapsulation in liposomes or transfersomes (Paul et al.~Jan_Feb; 16(2_3): 188-95 1998 )Inside. A treatment regimen such as the method of the invention may utilize a remedy by injection and other means. For example, non-surgical improvement of scars can be achieved by first treatment with TGF-p3 in an injectable form, followed by a second (and optionally follow-up) treatment with a surface drug, TGF-p3. obtain. This may be preferred if the clinician or the like is to be treated for the first treatment (e.g., in a hospital or clinic) and the patient is on their own for a second and optionally follow-up treatment (e.g., at home). In the case where TGF-P3 is provided to the patient by injection, the preferred mode of administration may involve administering a series of injections about one centimeter apart from each other in the area to be treated. Thus, in the case of a substantially linear scar (e.g., using a surgical marker), a series of reference points spaced about one centimeter from each other can be 'scared. In a preferred embodiment, the reference point at either end of the scar should extend at least half a centimeter from the wound end of the wound to be treated. This arrangement is shown schematically in Figure 2. For the administration of TGF_p3, the subcutaneous injection needle was inserted into the site B and advanced to the site A. As the needle was removed, the administration of 1〇〇μ1 was 145021.doc -27-201023878 and the solution was subsequently injected to a length of 1 cm. In the dermis, it is ensured that the composition incorporating TGFp3 is evenly distributed between sites A and B. When the solution is injected into the dermis, the whitened "blistles" will then be inserted into the site c along the direction of the site B and the method of administration will be repeated until all parts of the scar to be repaired by non-surgical repair are achieved. The method of administration can be regarded as the injection line along the scar. Similar administration can be done by using a syringe (pre-filled or filled at the time of use) and a needle specially designed for the skin. Laurent et al. Vaccine, 8833-8842, 2007 For example, the Becton Dickinson SoluviaTM system is reached. When TGF-P3 is administered to the scar, it may be better to actually inject it to the center where the scar is to be improved. In the case of long scars, this may involve The medicine is applied along the line extending along the longitudinal center of the scar. The administration of this method can be particularly effective in the case where the width of the wound is about 1 cm or less, and the width of the scar is more than 1 cm. Preferably, TGF-|33 is administered by means of a series of substantially parallel lines extending longitudinally along the scar to provide a therapeutically effective amount of TGF-P3 to each scar. The inventors have discovered that a therapeutically effective amount of TGF-P3 is approximately Formulations provided in a 1 〇〇μ volume of the drug are particularly advantageous, and further preferred embodiments of the invention. These embodiments should involve administering about 100 μl of a drug comprising TGF_β3 in each injection. Preferred formulations may be administered. The therapeutically effective amount of tGF_P3 (or the desired portion of the amount) is designed to be administered in a volume of about 1 〇〇μ1. The inventors have found that the volume of the drug containing TGF_p3 of about 1 〇〇μ1 is good for the patient. Tolerance. In particular, in the case of a pharmaceutical injection comprising TGF-P3, typically 1 μl of the volume of the drug may be administered per minute for treating the scar' without inducing other damage at the treatment site or In addition, I45021.doc -28-201023878 100 μΐ volume of a drug comprising TGF-P3 can be fully absorbed by administration of the scar, and this is advantageous for controlling the precise administration of a therapeutically effective amount of TGF_p3. The injectable formulations of TGF-P3 are preferably suitable for intradermal injection. While TGF J33 provided by the present invention may be used in any form of therapy, it may be preferred to administer it in a pharmaceutical formulation, for example Suitable for mixing with a suitable pharmaceutical excipient, diluent or carrier for the pre- φ phase of administration route and standard pharmaceutical practice. Thus, in one aspect, the invention provides at least one active composition or pharmaceutically acceptable thereof A pharmaceutical composition or formulation of a derivative and a pharmaceutically acceptable excipient, diluent and/or carrier. The excipient, diluent and/or carrier are in admixture with other ingredients of the formulation. It must be "acceptable" in the sense that it does not harm its recipient. The present month composition can be formulated for administration in any convenient manner suitable for use in human or veterinary medicines. Accordingly, the invention includes within its scope pharmaceutical compositions comprising the products of the invention suitable for use in human or veterinary medicine. Acceptable excipients, diluents, and carriers for therapeutic use are well known in the art and are described, for example, in Remingt〇n: The Seience and

Practice of Pharmacy. Lippincott Williams & Wilkins (A.R.Practice of Pharmacy. Lippincott Williams & Wilkins (A.R.

Gennaro編2005)中。醫藥賦形劑、稀釋劑及載劑之選擇可 關於預期投藥途徑及標準醫藥實踐來選擇。 本發明者已發現諸如麥芽糖或海藻糖之糖代表適用於本 發明藥物的較佳賦形劑。諸如麥芽糖之糖可向併入糖之組 145021.doc -29- 201023878 "物提供許多優勢，包括提高生物活性糖自組合物中之回 收率°諸如麥芽糖之糖亦可用來減輕注射疼痛。適合調配 物之實例描述於以wo綱7GG7G95公開之本發明者同在申 請中之專利申請案中。 可能較佳將TGF-P3與諸如利多卡因（Ugn〇caine)或其類 似物之麻醉劑組合投與。因此，本發明藥物之—項較佳實 =例可能為本發明藥物與麻醉劑一起投與，且甚至該等組 口物進-步包含諸如利多卡因之麻醉劑。相似地，本發明 之/〇療方法之一項較佳實施例可能為在投與TGF-p3之前或 投與TGFJ3同時向患者投與諸如利多卡因之麻醉劑。 +適用於本發明藥物中的較佳調配物及該等藥物之較佳投 藥途控之更多細節在本說明書之別處提供。 醫藥學上可接受 广本文中所用，短語「醫藥學上可接受」係指當向人類 投與時「一般認為安全」（例如，生理上耐受且通常不產 生過敏或諸如胃部嗜雜、眩暈及其類似者之類似不良反 應）之刀子貫體及組合物。如本文中所用，術t吾「醫藥學 上可接受」較佳意謂由美國聯#或州政府之管理機構所許 可或列入美國藥典（u s pharmac〒e⑷或用於動物且更詳 言之人類之其他一般認可之藥典中。 計算TGF-P3含量、效能及所投舆量 TGF-P3之劑量及含有tgf_P3之藥物的蛋白質含量（且詳 人類TGF-β3，其為欲根據本發明使用之較佳形式 之TGFj3)較佳可藉由定量酶聯免疫吸附檢定（阳从）測 145021.doc 201023878 定，以英國國家生物標準及控制研究所（NIBSC)轉化生長 因子β-3(源自人類rDNA)參考試劑碼98/608校正。以此方 式測定蛋白質含量容許熟習此項技術者計算含有TGF-P3之 . 藥物的蛋白質含量且由此計算藉由給定量之該藥物提供至 一公分身體位點之TGF-03之量。 在本發明中所提及之TGF-P3之劑量及治療有效量較佳根 據此NIBSC參考試劑來計算。應相應地解釋在此申請案中 提及之TGF-P3之特定劑量或量。此方案已用於測定實驗結 ® 果部分中所用溶液之蛋白質含量。 在熟習此項技術者不能獲得NIBSC參考試劑碼98/608之 參考樣品的情況下，本發明者已發現ELIS A使用其自己的 TGF-P3產品（Lonza Bulk藥物批號205-0505-005)作為標準 得出為彼等由NIBSC參考試劑碼98/608所得到者大約52% 之值。在希望使用此替代標準代替NIBSC參考試劑碼 98/608之情況下，應相應地確定所需TGF-P3之量（例如， . 若需要使用對應於如參考NIBSC參考試劑碼98/608所評估 1 000 ng之治療有效量之TGF-P3，則此等於如參考Lonza Bulk藥物批號205-0505-005所評估 520 ng TGF-03)。 • 欲根據本發明使用之TGF-P3之生物活性（亦即效能）可藉 - 由抑制貂肺上皮細胞株（MLEC)(美國典型培養物保藏所 (ATCC)目錄號CCL-64)之增殖來測定。在一項較佳實施例 中，生物活性可藉助於使用上文所提及的英國國家生物標 準及控制研究所參考試劑碼98/608校正之檢定來定量。認 為參考試劑碼98/608具有每微克TGF-P3蛋白質10,000個任 145021.doc -31 - 201023878 意單位（AU)之特定生物活性，且藉由將相關樣品之mlec 抑制活性與參考試劑碼98/608之MLEC抑制活性相比較， 可易於測定以AU計之相關樣品之生物活性。 因此’ 500 ng TGF-P3之劑量（當以NIBSC參考試劑校正 時）提供 5,000 AU TGF-P3活性，且 l，〇〇〇 ng TGF_p3 之劑量 提供10,000 AU TGF-P3活性。應相應地解釋在本發明中提 及使用TGF-p3之特定劑量。 欲經非外科改善之傷疤 本發明藥物或方法可用以獲得男性及女性患者之傷疤的 非外科改善。此外，本發明者咸信本發明藥物或方法可用 於位於任何身體部位及任何組織或器官中的傷疤之非外科 改善。皮膚代表可經受使用本發明藥物或方法之非外科改 善之傷疤的較佳位置。應瞭解使用本發明藥物或方法的傷 疤之非外科改善將對傷疤之外觀產生顯著改善。因此，在 一項較佳實施例中，可使用本發明藥物或方法非外科改善 位於可見身體部分之傷疤。此等身體部分包括面部、頸部 及手部，且亦可涵蓋腿部及腹部。 除用於非外科改善皮膚傷疤之外，本發明者咸信本發明 藥物及方法可用於非外科改善在一系列位置中之傷疤，包 括（但不限於）彼等獨立地選自由以下組成之群之傷疤：血 管傷疤；中樞及周邊神經系統之傷疤；腱、韌帶或肌肉之 傷疤；包括唇及鰐之口腔傷疤；諸如肝臟、心臟、大腦、 消化組織及生殖組織之内臟傷疤；及在諸如腹腔、骨盆腔 及胸腔之體腔中的傷疤。 145021.doc -32^ 201023878 經治療傷疤」及「未經治療傷疤」 向傷疤提供治療有效量之TGF_P3將得到「經治療傷 疤」，其中結疤得到改善（亦即其中結疤程度降低卜與在治 - 療之前存在者相比且與可見於相似「未經治療傷疤」中的 • 肖錄度相比，結絲度將降低。若治療有效量之TGF_p3 僅對傷疤之一部分提供（其在此情況下將變為「經治療」 部分）且不向傷疤之另一部分提供（在此情況下為「未經治 ❹ 療」部分）時，則單-傷苑可包含「經治療」及「未經^ 療」部分。 經治療傷疤中與未經治療傷疤中之結疤程度的比較可有 益於評估本發明各種藥物或方法之功效，包括用以確定本 發明藥物或方法之較佳態樣的實驗藥物或方法及尤佳能產 生傷疤之最佳非外科改善的治療有效量之TGF_p3。 未經治療傷疤通常可用作評估在經治療傷疤中獲得非外 科改善之程度的比較物。此類型之適合比較物（未經治療 Φ 傷疤）較佳可參考一或多個獨立地選自由以下組成之群的 準則與經治療傷苑相匹配：傷抱年齡；傷疲尺寸；傷苑部 位’患者之體重心數，患者年齡；患者種族及患者性別。 傷疤之非外科改善之模型 •可直接關於需要該治療之患者評估能引起傷症之非外科 改善的TGF_P3之治療有效量。在此情況下，可藉由任何適 合當事人（諸如患者或臨床醫師）進行必要的測定。 然而，一般較佳參考傷疤之非外科改善之適合模型來測 定TGF-P3之治療有效量。該等模型可用以測定可用於適用 145021.doc -33 - 201023878 於各種各樣患者之藥物或方法中MGF_p3之治療有效量。 可如下在關於結料估之標題下所述以肉眼評估傷症。 因此，可使用所述程序評估在以TGF_p3治療前後傷苑之紅 度及/或對比度。 可利用活體内模型來評估健之非外科改善。該等模型 -般涉及評估且比較在㈣療健中獲得之傷苑之非外科 改善的程度與未經治療傷宛中所見之結疲程度。適合模型 包括彼等使用非人類動物之模型，但可能較佳使用在人類 個體中評估傷疤之非外科改善之模型。 傷疤之非外科改善的實驗模型亦可容許鑑別可投與TGF_ β+3之尤其有效途徑或方案。此等途徑或方案可在本發明之 藥物及方法的功效方面提供顯著優勢，且此等優勢可得到 本發明之其他態樣或實施例。 評估結疤及結疤之抑制 已根據本發明獲得之傷疤之非外科改善的程度可藉由評 估見於經治療傷疲中的結症程度及將此與見於治療之前相 同傷疤中或見於同-傷疤之未經治療部分中或在比較物未® 經治療或對照治療傷疤中的結疤程度相比較來測定。當經 治療傷疤之外觀經評估比治療之前相同傷疤之外觀或:: 治療或對照治療傷症之外觀更類似於未受傷組織時，表明 為傷症之有效非外科改善。 使用本發明藥物或方法獲得的傷疤之非外科改善之程度 可參考與治療之前的傷疤之顯微鏡下及/或肉眼外觀相比 經治療傷疤之顯微鏡下及/或肉眼外觀來評估及/或測量。 145021.doc •34- 201023878 使用本發明藥物或方法獲得的傷疤之非外科改善之程度亦 可適田地參考與未經治療傷苑之顯微鏡下及/或肉眼外觀 相比經治療傷疤之顯微鏡下及/或肉眼外觀來評估。 儘s結疤之評估可考慮傷疤之肉眼外觀及/或傷疤之顯 微鏡下外觀，但可能較佳參考肉眼外觀進行結症之評估。 :考肉艮外觀之評估可能較佳，此係由於傷疤之肉眼外觀 最直接反映患者或其他人感知傷疤之方式。 已開發出評估結症之許多方法，主要關於皮膚結疮（其 為身體最大器t，且該器官中之傷疤具有最大美容影 響）。因此，以下用於評估本發明藥物及方法的傷症抑制 活性之方法的描㈣主要參考皮膚中之料評估來描述。 然而’熟習此項技術者將即刻瞭解到評估皮膚巾之結宛時 相關的許多因素亦與評估其他器官或組織中的結苑有關。 因此，熟習此項技術者將認識到除非上下文中另有要求否 則下文在評估皮膚傷范上下文中提出之參數亦可適用於評 估除皮膚以外的組織中之結疤。 結疤之評估較佳可為提供指示存在結疤程度之可計量值 的評估。此容許對已獲得傷疤之非外科改善之程度的已完 成定量。 無論是經治療、未經治療或經對照治療傷宛之肉眼外觀 可參考許多參數來評估。適合參數可單獨或以組合形式考 慮。 結疤程度，且由此所獲任何傷疤之非外科改善所達成之 程度可藉由傷疤之肉眼臨床評估來評估。此可藉由對個體 145021.doc •35- 201023878 直接評估傷疤獲得；或藉由評估傷疤之照片影像；或獲自 傷症之聚矽氧模，或由該等模具製成之陽性石膏模型獲 得。當評估結疤時可考慮之傷疤肉眼特徵包括： i)傷症顏色通常就周圍皮膚來看’傷症可為色素過少 或色素過多。當經治療傷疤之色素沉著比未經治療傷 疤之色素沉著更精密接近無傷疤皮膚之色素沉著時， - 可表明為結疤之有效非外科修復。傷疤通常可比周圍 皮膚更紅。在此情況下，當與未經治療傷疤相比，經 治療傷疤之紅度更早消退，或更完全消退，或更精密 Θ 類似於周圍皮膚之外觀時，可表明為結疤之有效非外 科修復。顏色可易於例如藉由使用許多能夠提供關於 傷症，、無傷苑皮膚之色素以及傷症與無傷苑皮膚之紅 度之資料的非侵襲性比色裝置來測量。顏色亦可易於 藉由分析標準化臨床相片（如本說明書中別處更詳細 述）測量。傷疤顏色且詳言之傷疤紅度為欲用於結 疤評估中之較佳參數，無論係作為唯一評估參數亦或 與其他參數組合。 n ϋ) 傷宛高度。傷症通常與周圍皮膚相比可能突出或凹 陷。^經治療傷疮之高度與未經治療傷苑之高度相比 ^精进接近無傷症皮膚之高度（亦即既不突出又不凹 =時’可表明為結苑之有效非外科修復。傷症之高 二° ^患者直接（例如藉助於輪廓測定法），或間接（例 iii) 藉由獲自傷宛之模具的輪廟測定法）測量。 表面紋理。傷症表面可能比周圍皮膚相對更平 145021.doc -36- 201023878 滑u生具有「光亮」外觀之傷症）或比周圍皮膚 链。當經治療傷症之表面紋理比未經治療傷症之表面 紋理更精密接近無傷疲皮膚之表面紋理時，可表明為 結疱之有效非外科修復。表面紋理亦可對患者直接 (例如藉助於輪廓測定法），或間接（例如，藉由獲自傷 症之模具的輪廓測定法）測量。Gennaro, ed. 2005). The choice of pharmaceutical excipients, diluents and carriers can be selected with regard to the intended route of administration and standard pharmaceutical practice. The inventors have found that sugars such as maltose or trehalose represent preferred excipients for use in the medicament of the present invention. Sugars such as maltose can provide a number of advantages to the incorporation of sugars 145021.doc -29-201023878 ", including increasing the recovery of bioactive sugars from the composition. Sugars such as maltose can also be used to alleviate injection pain. An example of a suitable formulation is described in the patent application filed by the present inventor, the disclosure of which is incorporated herein by reference. It may be preferred to administer TGF-P3 in combination with an anesthetic such as lidocaine or its analog. Thus, the preferred embodiment of the medicament of the present invention may be administered with the medicament of the present invention together with an anesthetic, and even the components may further comprise an anesthetic such as lidocaine. Similarly, a preferred embodiment of the method of treatment of the present invention may be to administer an anesthetic such as lidocaine to a patient prior to administration of TGF-p3 or administration of TGFJ3. + Further details of preferred formulations for use in the medicaments of the invention and preferred routes of administration of such medicaments are provided elsewhere in this specification. Medically acceptable as used herein, the phrase "pharmaceutically acceptable" means "generally considered safe" when administered to humans (eg, physiologically tolerated and usually does not produce allergies or such as stomach hoarding) Knives and compositions of similar adverse reactions in dizziness and the like. As used herein, "medicalally acceptable" is preferably permitted by the United States or the governing body of the state government or included in the United States Pharmacopoeia (4) or for animals and more specifically humans. In other generally recognized pharmacopoeias. Calculate the TGF-P3 content, potency and dose of TGF-P3 and the protein content of the drug containing tgf_P3 (and detail human TGF-β3, which is intended to be used according to the invention) The preferred form of TGFj3) is preferably determined by quantitative enzyme-linked immunosorbent assay (Yang Cong) 145021.doc 201023878, with the National Institute of Biological Standards and Control (NIBSC) transforming growth factor β-3 (derived from human rDNA) Correction by reference reagent code 98/608. Determining the protein content in this manner allows the skilled artisan to calculate the protein content of the drug containing TGF-P3 and thereby calculate the amount of the drug to a one centimeter body site by a given amount The amount of TGF-P3 mentioned in the present invention is preferably calculated according to the NIBSC reference reagent. The TGF-P3 mentioned in this application should be interpreted accordingly. Specific agent Or the amount. This scheme has been used to determine the protein content of the solution used in the section of the experimental section. In the case where a reference sample of the NIBSC reference reagent code 98/608 is not available to those skilled in the art, the inventors have found that ELIS A Using its own TGF-P3 product (Lonza Bulk Drug Lot No. 205-0505-005) as a standard, it is approximately 52% of those obtained by NIBSC Reference Reagent Code 98/608. It is desirable to use this alternative standard instead. In the case of NIBSC reference reagent code 98/608, the amount of TGF-P3 required should be determined accordingly (eg, if needed, a therapeutically effective amount corresponding to 1 000 ng as assessed by reference to NIBSC Reference Reagent Code 98/608) TGF-P3, this is equal to 520 ng TGF-03 as assessed by reference to Lonza Bulk Drug Lot No. 205-0505-005. • The biological activity (ie, potency) of TGF-P3 to be used in accordance with the present invention can be inhibited by The proliferation of the silicosis epithelial cell line (MLEC) (American Type Culture Collection (ATCC) Cat. No. CCL-64) is determined. In a preferred embodiment, the biological activity can be achieved by using the above mentioned UK National Biological Standards and Control Research The reference reagent code 98/608 is calibrated to quantify. The reference reagent code 98/608 is considered to have a specific biological activity of 10,000 145021.doc -31 - 201023878 units (AU) per microgram of TGF-P3 protein, and by Comparing the mlec inhibitory activity of the relevant sample with the MLEC inhibitory activity of reference reagent code 98/608, the biological activity of the relevant sample in AU can be readily determined. Thus the dose of '500 ng TGF-P3 (when calibrated with the NIBSC reference reagent) provides 5,000 AU of TGF-P3 activity, and l, the dose of 〇〇〇ng TGF_p3 provides 10,000 AU of TGF-P3 activity. The specific dose of TGF-p3 used in the present invention should be interpreted accordingly. Scars that are intended to be non-surgically improved The drug or method of the present invention can be used to obtain non-surgical improvements in scars in male and female patients. Furthermore, the inventors believe that the medicament or method of the present invention can be used for non-surgical improvement of scars located in any body part and in any tissue or organ. Skin represents a preferred location for undergoing non-surgically modified scars using the medicaments or methods of the invention. It will be appreciated that non-surgical improvements in the use of the agents or methods of the invention will result in significant improvements in the appearance of scars. Thus, in a preferred embodiment, the medicament or method of the invention can be used to non-surgically improve the scar on the visible body part. These body parts include the face, neck and hands, and can also cover the legs and abdomen. In addition to being used for non-surgical improvement of skin scars, the inventors believe that the medicaments and methods of the present invention can be used for non-surgical improvement of scars in a range of locations including, but not limited to, those independently selected from the group consisting of Scars: vascular scars; scars of the central and peripheral nervous system; scars of tendons, ligaments or muscles; oral scars including the lips and crocodile; visceral scars such as the liver, heart, brain, digestive tissue and reproductive tissues; Scars in the body cavity of the abdominal cavity, pelvic cavity and chest cavity. 145021.doc -32^ 201023878 "Treatment of scars" and "untreated scars" A therapeutically effective amount of TGF_P3 to scars will result in "treated scars" in which the scarring is improved (ie, the degree of scarring is reduced) The degree of silk will be reduced compared to the presence of the pre-existing and compared to the • unrecorded “untreated scar”. If the therapeutically effective amount of TGF_p3 is only provided for one of the scars (which is here) In the case of a "treated" section and not provided to another part of the scar (in this case the "untreated" section), the single-injury court may include "treated" and "not" The treatment section. Comparison of the degree of scarring in the treatment of scars with untreated scars may be useful in assessing the efficacy of various drugs or methods of the invention, including determining the preferred aspect of the medicament or method of the invention. An experimental drug or method and a particularly non-surgicalally effective therapeutically effective amount of TGF_p3 that produces a scar. Untreated scars are often used to assess the extent of non-surgical improvement in treated scars. A suitable comparator of this type (untreated Φ scar) may preferably be matched with one or more criteria selected from the group consisting of: the age of the wound; the size of the wound; the wound Court site 'patient's weight, heart age; patient race and patient gender. Model of non-surgical improvement of scars • The therapeutically effective amount of non-surgical improved TGF_P3 that can cause injury can be assessed directly with the patient in need of the treatment. In this case, the necessary assays can be performed by any suitable party (such as a patient or clinician). However, it is generally preferred to determine the therapeutically effective amount of TGF-P3 by reference to a suitable model of non-surgical improvement of the scar. It can be used to determine the therapeutically effective amount of MGF_p3 that can be used in a drug or method for a variety of patients, 145021.doc -33 - 201023878. The injury can be assessed visually as described below under the heading of the assessment of the knot. The program was used to assess the redness and/or contrast of the injured field before and after treatment with TGF_p3. An in vivo model can be used to assess the non-surgical improvement of the health. The model generally involves assessing and comparing the degree of non-surgical improvement of the wounded court obtained in (4) healing with the degree of fatigue seen in untreated wounds. Suitable models include those models using non-human animals, but may It is preferred to use a non-surgical improvement model for assessing scars in human subjects. Non-surgical improved experimental models of scars may also allow for the identification of particularly effective pathways or protocols for administration of TGF_β+3. The advantages of the medicaments and methods of the invention provide significant advantages, and such advantages may result in other aspects or embodiments of the invention. Evaluating the inhibition of scars and scars The degree of non-surgical improvement of scars obtained according to the present invention may be By assessing the degree of stenosis seen in the treated injury and the scar in the same scar as seen before treatment or in the untreated portion of the same-scarlet or in the treatment of the wound or the control The degree is compared to determine. When the appearance of the treated scar is evaluated as the appearance of the same scar before treatment or:: The appearance of the treated or control treated wound is more similar to the uninjured tissue, indicating an effective non-surgical improvement of the injury. The degree of non-surgical improvement of the scar obtained using the medicament or method of the present invention can be evaluated and/or measured by microscopic and/or visual appearance of the treated scar compared to the microscopic and/or visual appearance of the scar prior to treatment. 145021.doc •34- 201023878 The degree of non-surgical improvement of the scar obtained by using the medicament or method of the present invention can also be adjusted to the microscope under the microscope and/or the naked eye of the untreated wounded garden. / or the appearance of the naked eye to assess. The evaluation of the sputum may take into account the appearance of the eye and/or the appearance of the scar under the microscope, but it may be better to evaluate the appearance of the eye with reference to the appearance of the naked eye. The evaluation of the appearance of the test meat may be better. This is because the appearance of the eye of the scar most directly reflects the way the patient or other person perceives the scar. A number of methods have been developed to assess the symptoms of the knot, primarily with skin sores (which are the largest body t, and the scars in the organ have the greatest cosmetic impact). Therefore, the following description of the method for evaluating the wound inhibitory activity of the medicaments and methods of the present invention is mainly described with reference to the evaluation of the material in the skin. However, those skilled in the art will immediately understand that many of the factors associated with assessing the knot of a skin towel are also related to assessing the knot in other organs or tissues. Thus, those skilled in the art will recognize that the parameters set forth below in the context of assessing skin injuries may also be applicable to assessing scarring in tissues other than skin, unless otherwise required by the context. Preferably, the assessment of scarring may provide an assessment of the measurable value indicative of the degree of scarring. This allows for the completion of quantified levels of non-surgical improvement in which scars have been obtained. The appearance of the naked eye, whether treated, untreated or treated with a control, can be evaluated with reference to a number of parameters. Suitable parameters can be considered individually or in combination. The degree of scarring, and the degree of non-surgical improvement of any scars obtained therefrom, can be assessed by visual assessment of the visual eye of the scar. This can be obtained by directly assessing the scars of the individual 145021.doc •35-201023878; or by assessing the photographic image of the scar; or obtaining the polyoxynium model from the injury, or a positive plaster model made from the mold . The characteristics of the eyelids that can be considered when assessing scarring include: i) The color of the injury is usually seen in the surrounding skin. The injury can be hypopigmentation or hyperpigmentation. When the pigmentation of the treated scar is more precise than the pigmentation of the untreated scar, the pigmentation of the skin without flaws can be indicated as an effective non-surgical repair of scarring. Scars are usually redder than the surrounding skin. In this case, the redness of the treated scar is earlier, or more completely resolved, or more precise, similar to the appearance of the surrounding skin, compared to untreated scars. repair. Color can be readily measured, for example, by the use of a number of non-invasive colorimetric devices that provide information about the injury, the pigmentation of the skin without injury, and the redness of the wounded and non-injured skin. Colors can also be easily measured by analyzing standardized clinical photographs (as described in more detail elsewhere in this specification). The scar color and the detailed scar redness are the preferred parameters to be used in the evaluation of the knot, either as a sole evaluation parameter or in combination with other parameters. n ϋ) Injury height. Injuries can often be prominent or concave compared to the surrounding skin. ^The height of the treated wound is compared with the height of the untreated wounded garden. ^The height of the skin close to the injury-free skin (that is, neither protruding nor concave = when it can be indicated as an effective non-surgical repair of the knot garden. The patient's height is measured directly (for example by means of profilometry) or indirectly (example iii) by means of a wheel temple measurement obtained from a wounded mold. Surface texture. The surface of the injury may be relatively flatter than the surrounding skin. 145021.doc -36- 201023878 The slippery skin has a "light" appearance of the wound or is more than the surrounding skin chain. An effective non-surgical repair of blistering can be indicated when the surface texture of the treated wound is more closely related to the surface texture of the uninjured skin than the surface texture of the untreated wound. The surface texture can also be measured directly to the patient (e.g., by means of profilometry), or indirectly (e.g., by profilometry of a mold obtained from a wound).

經治療傷純佳將呈現如參考至少—種本說明書中所閣 明之肉眼評估參數所㈣之有效料科結錢善。更佳 地，經治療傷疤可表明參考至少兩個參數，甚至更佳至少 三個參數，且最佳至少四個此等參數（例如，上文所闡明 之所有四個參數）之結疤之有效非外科改善。 肉眼評估傷疤之一較佳方法為整體評估。此可藉由專家 組或公民小組（lay panel)評估宏觀照片或臨床上 床醫師或患者自己肉眼評估來實現。評估可藉助於vas(視 覺模擬評分法）或分類評分法獲得。用於評估結疤（且藉此 評估結疤之非外科修復）之適合參數之實例描述如下。適 合參數之其他實例，及可獲得評估該等參數的方式係由 Duncan等人（2〇〇6)，Beausang 等人（1998)及 van Zuijlen等人 (2002)描述。 傷疤之顯微鏡下評估一般將採用傷疤微觀結構之組織學 分析。用於傷疤之顯微鏡下評估的適合參數可包括： i)細胞外基質（ECM)纖維之厚度。傷疤通常含有比見於 無傷疤皮膚中更薄之ECM纖維。當經治療傷疤中之 ECM纖維厚度比見於未經治療傷疤中之纖維厚度更精 145021.doc •37· 201023878 密接近無傷疤皮膚中所見之ECM纖維厚度時，可表明 為結疤之有效非外科修復。 ii) ECM纖維之定向。見於傷疤中之ECM纖維趨向於展現 比見於無傷疤皮膚中（其具有無規「籃式編織」定向） 更大程度之彼此對準。因此，當經治療傷疤中之ECM 纖維定向比見於未經治療傷疤中之該等纖維定向更精 密接近見於無傷症皮膚中之ECM纖維定向時，可證明 為有效非外科結疤修復。 iii) ECM組份之豐度。傷疤通常含有比無傷疤皮膚更多量 之ECM組份，諸如膠原蛋白。在此情況下，當經治療 傷症與未經治療或對照治療傷疤相比含有豐度降低之 ECM組份時’或當經治療傷疤與含於未經治療或對照 傷症中之豐度相比含有更類似於無傷疤皮膚之豐度的 ECM組份時，可表明為結疤之有效非外科修復。 iv) 傷疤之ECM組成。存在於傷疤中之ECM分子組成展示 與見於正常皮膚中之組成不同。因此，當經治療傷疤 真皮中之ECM纖維組成比見於未經治療傷症中之纖維 組成更精被接近見於無傷疤皮膚中之該等纖維組成 時’可表明為結疤之有效非外科修復。 v) 傷疤之細胞結構。傷疤趨向於含有比無傷疤皮膚相對 更少之細胞。因此，應瞭解當經治療傷疤之細胞結構 比未經治療傷疤之細胞結構更精密接近無傷疤皮膚之 細胞結構時，可表明為結疤之有效非外科結疤修復。 上文提出之一或多個參數可用以形成用於顯微鏡下評估 145021.doc 201023878 結疤之視覺模擬評分之基礎。當經治療傷疤之品質與未經 治療或對照傷症品質相比更接近無傷症皮膚之品質時，可 表明為結疤之有效非外科改善。 令人驚譯的是傷症（諸如彼等皮膚傷苑）之總體外觀幾乎 不受傷疤上皮覆蓋物之影響，即便此為最易於由觀察者發 現之傷疤部分。相反，本發明者已發現存在於傷疤内之結The purely treated wounds will be presented as a reference to at least the effective material of the visual assessment parameters specified in this manual (4). More preferably, the treated scar may indicate that at least two parameters are referenced, even better than at least three parameters, and the balance of at least four of these parameters (eg, all four of the parameters set forth above) is effective. Non-surgical improvement. One of the preferred methods for assessing scars by the naked eye is an overall assessment. This can be done by an expert panel or a lay panel to evaluate a macroscopic photograph or a clinical bedside physician or patient's own visual assessment. The assessment can be obtained by means of vas (visual analog scoring) or a classification scoring method. Examples of suitable parameters for assessing scarring (and thereby assessing non-surgical repair of scarring) are described below. Other examples of suitable parameters, and the manner in which such parameters can be evaluated, are described by Duncan et al. (2, 6), Beausang et al. (1998) and van Zuijlen et al. (2002). Microscopic evaluation of scars will generally involve histological analysis of the scar microstructure. Suitable parameters for microscopic evaluation of scars can include: i) Thickness of extracellular matrix (ECM) fibers. Scars usually contain thinner ECM fibers than those found in non-scarred skin. When the thickness of the ECM fiber in the treated scar is more refined than the thickness of the fiber found in the untreated scar, 145021.doc •37·201023878 is close to the thickness of the ECM fiber seen in the skin without scar, which can be indicated as effective non-surgical scarring. repair. Ii) Orientation of ECM fibers. ECM fibers found in scars tend to exhibit a greater degree of alignment with each other than in non-scarred skin, which has a random "basket weave" orientation. Thus, an effective non-surgical scar repair can be demonstrated when the ECM fiber orientation in the treated scar is more closely related to the ECM fiber orientation seen in the skin without injury in the untreated scar. Iii) Abundance of ECM components. Scars usually contain a greater amount of ECM components, such as collagen, than non-scarred skin. In this case, when the treated injury has an abundance-reducing ECM component compared to untreated or control-treated scars, or when the treated scar is in abundance with untreated or control wounds An effective non-surgical repair of scarring may be indicated when it contains an ECM component that is more similar to the abundance of skin without scars. Iv) ECM composition of scars. The composition of the ECM molecule present in the scar is different from the composition found in normal skin. Thus, when the composition of the ECM fibers in the treated dermis is more precise than the composition of the fibers found in the untreated wounds, which is close to those fibers found in the skin without scars, it can be shown to be an effective non-surgical repair of scarring. v) Cell structure of scars. Scars tend to contain relatively fewer cells than non-scarred skin. Therefore, it should be understood that when the cell structure of the treated scar is more closely related to the cell structure of the skin without the scar, the effective non-surgical scar repair of the scar is indicated. One or more of the parameters set forth above can be used to form the basis for a visual analog score for the evaluation of the underlying microscope 145021.doc 201023878. An effective non-surgical improvement of scarring is indicated when the quality of the treated scar is closer to the quality of the uninjured skin compared to the quality of the untreated or control wound. It is striking that the overall appearance of the injury (such as their skin wounded garden) is hardly affected by the epithelial covering, even if it is the scar most easily found by the observer. On the contrary, the inventors have found that the knot exists in the scar

締組織（諸如構成真皮或新真皮之結締組織）的特性對感知 結症程度以及結疤組織之功能有更大影響。因此，與諸如 真皮之結締組織而非諸如表皮之上皮的相關之準則的評估 可經證明最適用於評估結疤之有效非外科修復。在結締組 織内ECM纖維之厚度及ECM纖維之定向可為評估結疤之非 外科修復的有利參數。當考慮傷疤品質時，分別評估乳突 真皮及網狀真皮中之ECM結構及豐度可能為合乎需要的^ 經治療傷隸佳可表明如參考至少—個上文所闡明之顯 微鏡下評估參數所評估之有效非外科結錢善。更佳地， 經治療傷疤可表明參考至少兩個參數，甚至更佳至少三個 參數且最佳所有四個此等參數之料之非外科改善。肉眼 及顯微鏡下參數可組合用於評估有效非外科結錢善（亦 即評估至少一個用於肉眼評估參 鏡下評估之參數)。 I數及至）-個用於顯微 獲得得及定量結症評估的方式。可使用適合方法 獲仔結絶之肉眼或顯微鏡下評估， 或間接(對獲自患者之照片或祺具)執行。可獲直得接= 的方式之實例包括（但不限於）·· 獲得結以估 145021.doc -39- 201023878 使用視覺模擬評分（VAS)傷疤計分之評估 可使用基於結疤之VAS獲得傷疤之評估。用於評估傷疤 之適合VAS可基於由Duncan等人（2〇〇6)或Beausang等人 (1998)描述之方法。此通常為1〇 cm之線，其中將〇 cm視為 難以察覺之傷疤且10 cm視為極難看之肥厚性傷疤。以此 方式使用VA S容s午容易地獲得及定量結苑評估。va s計分 可用於肉眼及/或顯微鏡下評估結疤。 僅舉例而言，可使用VAS進行結疤之適合肉眼評估， VAS係由0-10 cm之線組成，代表自左至右〇(對應於正常皮 ® 膚）至10(指示不良傷症）之等級。可由評估者基於對傷苑之 總體評估在10 cm線上作出標記。此可考慮諸如傷疤之高 度、寬度、輪麻及顏色之參數。最佳傷苑（通常寬度小， 且顏色、高度及輪廓如同正常皮膚）可朝向評分表之「正 常皮膚」端（VAS線之左手側）記分且不良傷宛（通常寬度 大，輪麻突出且輪廓不規則且顏色比正常皮膚紅或白）可 朝向評分表之「不良傷疤」端（VAS線之右手側）記分。接 著可自左手側測量標記以提供以公分計傷疤評估之最終值 ® (至小數點後一位）。 涉及比較兩個傷疤或兩個傷疤區段（一區段經治療且另 一區段未經治療，或僅以安慰劑處理）以確定哪個具有較 佳外觀之替代性結疤肉眼評估可使用VAS進行，該VAS包 含兩個100 mm VAS線與垂直線交叉（綜合傷疤比較評分 (Global Scar Comparison Scale))。在此類 VAS 中，兩條 VAS線對應於所比較之兩個傷疤，而垂直線表示〇(表示所 145021.doc •40- 201023878 比較傷疤之間不存在可察覺之差異)。職之極端(在任一 VAS線末端10〇贿處)表示一個傷疤與周圍皮膚相 難以察覺。 曰使用此類VAS比較一對傷疤時，評估者必須首先確定 那個傷苑具有較佳外觀或在兩個傷症之間是否不存在可察 覺之差異。若不存在可察覺之差異，則藉由將標記至於〇 垂直線處對其記錄。若存在可察覺之差異，則評估者使用 兩個傷疱中之較為不良者作為固定物碟定見於較佳傷症中 ，改善程度且隨後在評分表之相關部分上標記分數。所標 記之點代表優於固定物傷疤之改善百分比。 曰本發明者已發現使用此類VAS測量評估傷苑之肉眼外觀 提供許多優勢。因為此等VAS#f上為直觀的，其⑽低 廣=訓練使用不同皮膚類型中不同傷症嚴重度之參考影像 之而求’使得此工具相對簡單用於大型3期試驗；2)減小 馨 資料之變化性：對各傷症對執行一次評估，而非藥物傷症 及安慰劑傷症之兩個獨立評估；3)併人已確立之VAS原理 (亦即資料之連續分布）及在同一評分表中分級的益處；及 句容許容易地與臨床醫師及患者交流藥物作用（改善百分 比）。 對於顯微鏡下評估而言，可將傷症自實驗個體切除(較 佳併入少量周圍正常、组織）且固_如在福馬林（f〇_叫 中）。固定組織可隨後經處理以供额織學。可使用適合 方案為組織載玻片染色以容許評估結疤(諸如馬松三色 (MaSS〇n,S &▲刪)或馬勒瑞氏三色（咖。的triehrome))， 145021.doc 201023878The characteristics of the tissue, such as the connective tissue that makes up the dermis or the new dermis, have a greater impact on the degree of perceptual stenosis and the function of the scar tissue. Therefore, an assessment of criteria associated with connective tissue such as the dermis rather than epithelial epithelium may prove to be most suitable for assessing effective non-surgical repair of scarring. The thickness of the ECM fibers within the connective tissue and the orientation of the ECM fibers can be advantageous parameters for assessing non-surgical repair of the scar. When considering the quality of scars, it may be desirable to separately evaluate the ECM structure and abundance in the mastoid dermis and reticular dermis. The therapeutic lesions may be as indicated by reference to at least one of the microscopic evaluation parameters set forth above. The evaluation is effective and non-surgical. More preferably, the treated scar may indicate a non-surgical improvement with reference to at least two parameters, even better than at least three parameters and preferably all four of these parameters. Visual and microscopic parameters can be combined to assess effective non-surgical outcomes (ie, to evaluate at least one parameter for visual assessment). I number and to) a method for microscopic acquisition and quantitative evaluation of the syndrome. It can be performed using a suitable method for visual or microscopic evaluation, or indirectly (for photos or cookware obtained from patients). Examples of ways in which direct access can be obtained include, but are not limited to, obtaining a knot to estimate 145021.doc -39- 201023878 Assessment using the visual analogue scale (VAS) scar score can be obtained using scar tissue based VAS Evaluation. Suitable VAS for assessing scars can be based on the method described by Duncan et al. (2〇〇6) or Beausang et al. (1998). This is usually a 1 cm line, with 〇 cm as an undetectable scar and 10 cm as a very unsightly hypertrophic scar. In this way, the VA S capacity is easily obtained and quantified using the VA S capacity. The va s score can be used to assess scarring under the naked eye and/or under the microscope. For example only, VAS can be used for the visual assessment of scab, VAS consists of a line of 0-10 cm, representing left to right 〇 (corresponding to normal skin®) to 10 (indicating bad injury). grade. The evaluator can mark the 10 cm line based on the overall assessment of the wounded garden. This can take into account parameters such as height, width, wheel and color of the scar. The best wounded garden (usually small in width and color, height and contour like normal skin) can be scored towards the "normal skin" end of the score sheet (left hand side of the VAS line) and bad injuries (usually large width, prominent The contour is irregular and the color is red or white than normal skin. It can be scored towards the "bad scar" side of the score sheet (the right hand side of the VAS line). The marker can then be measured from the left hand side to provide the final value of the injury assessment in centimeters ® (to one decimal place). Involving the comparison of two scars or two scar segments (one segment treated and the other segment untreated, or only placebo) to determine which of the alternative appearances have a better appearance. Visual assessment can use VAS In progress, the VAS consists of two 100 mm VAS lines intersecting the vertical line (Global Scar Comparison Scale). In this type of VAS, two VAS lines correspond to the two scars compared, while the vertical line represents 〇 (indicating that there is no discernible difference between the 145021.doc •40-201023878 comparison scars). The extremes of the job (10 bribes at the end of any VAS line) indicate that a scar is hard to detect with the surrounding skin.曰 When using this type of VAS to compare a pair of scars, the assessor must first determine if the wounded garden has a better appearance or if there is no discernible difference between the two injuries. If there is no discernible difference, record it by placing the marker on the vertical line. If there is a discernible difference, the evaluator uses the lesser of the two blister as a fixture to be seen in the better injury, the degree of improvement and subsequent marking of the score on the relevant part of the score. The marked points represent a percentage improvement over the fixed lesions. The present inventors have found that the use of such VAS measurements to assess the appearance of the naked eye of the wounded garden provides a number of advantages. Because these VAS#f are intuitive, their (10) low-wide = training uses reference images of different severity of injury in different skin types to make 'this tool relatively simple for large-scale phase 3 trials; 2) reduce Variability of Xin data: an assessment of each injury, not two independent assessments of drug-injury and placebo-injury; 3) the established VAS principle (ie, continuous distribution of data) and The benefits of grading in the same score sheet; and sentences allow for easy interaction with clinicians and patients (percent improvement). For microscopic evaluation, the injury can be excised from the experimental individual (preferably incorporated into a small amount of surrounding normal, tissue) and solid-like in formalin (f〇_叫). The fixed tissue can then be processed for the woven fabric. Tissue slides can be stained using a suitable protocol to allow for the assessment of scars (such as Mason's three colors (MaSS〇n, S & ▲ deleted) or Male's tricolor (triehrome), 145021.doc 201023878

且由評估者使用顯微鏡下VAS評估結疤。適合VAS可由〇_ 10 cm之線組成，其自左至右表示對應於正常皮膚）至 1〇(指不不良傷疤）之等級。可基於考慮諸如膠原蛋白纖維 間隔、定向及厚度之參數的傷疤總體評估在1〇 em線上作 出標記。最佳傷范（通常具有在纖維之間間隔正常之無規 結構厚膠原蛋白纖維的窄傷宛，類似於見於無傷疮真皮 中）將朝向評分表之「正常皮膚」端（VAS線之左手側）記分 且不良傷疤(通常具有稠密堆疊之平行薄膠原蛋白纖維的 寬傷症）將朝向評分表之「不良傷症」端（vas線之右手侧） 記分。可接著自左手侧測量標記以提供以公分計傷苑評估 之最終值(至小數點後一位同樣，可使用上述綜合傷症 比較評分之原理來比較評估兩個顯微鏡下影像。 使用總體分類評分之評估 '、》疤評估可藉由基於所評估傷疤之文字描述（例如「《 乎不能察覺」，「與正常皮膚良好摻混」，「與正常皮膚〉The sputum was evaluated by the evaluator using VAS under the microscope. Suitable for VAS can be composed of 〇 10 cm line, which represents the level from left to right corresponding to normal skin) to 1 〇 (referring to no bad scar). Marking can be performed on the 1 〇 em line based on the overall evaluation of the scar considering parameters such as collagen fiber spacing, orientation, and thickness. The best injury (usually a narrow wound with a regular thickness of collagen fibers that is normally spaced between the fibers, similar to that found in the acne-free dermis) will be toward the "normal skin" end of the score sheet (left hand side of the VAS line) Scores and bad scars (usually wide wounds with densely stacked parallel thin collagen fibers) will be scored towards the "bad injury" end of the score sheet (right hand side of the vas line). The marker can then be measured from the left hand side to provide the final value of the assessment of the injury center in centimeters (to the same decimal place, the same can be used to compare the two microscopic images using the principle of the composite injury comparison score above. Using the overall classification score The assessment ', ' evaluation can be based on the textual description of the scars assessed (eg "I can't detect", "mix well with normal skin", "with normal skin"

同」等）將傷苑分為不同錄翻十訪丄丨士 _ U種類或藉由比較經治療傷疤與j 、“療或對照傷疤’注意其之間的任何差異且將差異分^ 所選類型（例如，「微小差異」，「中等差異」，「重大差異」 等）而獲得。可參考所 一 厅°子估傷疤之總體外觀進行此等詞 估。當評估指示經治療傷痂 ’、胃 與未、、Ί〇療或對照傷苑相比分 入至少一個更有利種類時， 昍 j表明為結疤之有效非外科改 善。可由患者、研究去、链士，， 獨立小組或臨床醫師執行此類評 估。 評估傷疤高度、傷疤宽度 傷宛周長、傷疤面積或傷疤 145021.doc 42· 201023878 體積 可例如藉由使用諸如測徑器之人工測量裝置或藉由使用 輪廓測里儀自動地直接對個體測量傷症之高度及寬度。可 直接對個體’藉由傷疤照片之影像分析或使用傷疤壓痕石 膏模生來測量傷苑寬度、周長及面積。熟習此項技術者亦 瞭解可用於研究適合參數之其他非侵襲性方法及裝置包括 聚碎氧模m、光#三維輪廊測量及高解析度磁共振 成像❶所有該等測量均易於獲得及定量。 可藉由與未經治療傷疤相比經治療傷疤的高度、寬度、 面積、周長或體積（或其任何組合）減小來證明結疤之非外 科改善。 與無傷疤皮膚相比傷疤之外觀及/或顏色 經治療傷疤之外觀或顏色可與無傷疤皮膚及/或未經治 療或對照傷疤及無傷疤皮膚之外觀或顏色相比較。可參考 傷疤與無傷疤皮膚相比是否更亮或更暗、或更紅將傷症之 外觀與無傷疤皮膚相比較。 可將傷症及皮膚之外觀或顏色分類（例如，彼此完全相 匹配、稍微不匹配、明顯不匹配或非常不匹配）且記錄及/ 或定量此等分類。可基於視覺評估各別傷疤與無傷症皮膚 來進行適合比較。 替代視覺評估或除視覺評估之外，存在許多非侵襲性比 色裝置’其能夠提供關於傷症與無傷苑皮膚之色素沉著以 及皮膚之紅度（其可為存在於傷疤或皮膚中之血管供應程 度指標）的資料。该等裝置之實例包括X-rite SP-62分光光 145021.doc • 43- 201023878 度計、Minolta Chronometer CR-200/300 ; Labscan 600 ;Same as "etc." Divide the wounded garden into different recorded ten visits to the gentleman _ U type or by comparing the treated scar with j, "therapy or control scar" to pay attention to any difference between the two and select the difference ^ Types (for example, "minor differences", "medium differences", "significant differences", etc.). These terms can be evaluated by reference to the overall appearance of the sputum.评估 j indicates an effective non-surgical improvement of scarring when the assessment indicates that at least one more favorable species is classified as compared to treated scars, stomach and no, sputum, or control wounded courts. Such assessments can be performed by patients, research, chain, independent groups or clinicians. Assessing the height of the scar, the width of the scar, the area of the scar, or the scar 145021.doc 42· 201023878 The volume can be automatically measured directly by the individual, for example by using a manual measuring device such as a caliper or by using a profilometer. The height and width of the disease. The width, perimeter and area of the wounded garden can be measured directly by the individual's image analysis of the scarred photograph or by using the scar indentation plaster. Those skilled in the art are also aware of other non-invasive methods and devices that can be used to study suitable parameters, including poly- occlusion mode m, light #3D vernier measurement, and high-resolution magnetic resonance imaging. All such measurements are readily available and quantifiable. . Non-surgical improvement of scarring can be demonstrated by a reduction in the height, width, area, circumference or volume (or any combination thereof) of the treated scar compared to the untreated scar. Appearance and/or color of scars compared to non-scarred skin The appearance or color of treated scars can be compared to the appearance or color of non-scarred skin and/or untreated or control scars and scar-free skin. Reference can be made to whether the scar is brighter or darker than the skin without scars, or reddish to compare the appearance of the injury to the skin without scars. The appearance and color of the injury and skin can be categorized (e.g., completely matched, slightly mismatched, significantly mismatched, or very mismatched) and recorded and/or quantified. Appropriate comparisons can be made based on visual assessment of individual scars and non-injury skin. In addition to or in addition to visual assessment, there are a number of non-invasive colorimetric devices that are capable of providing pigmentation on the skin of the wounded and non-injured gardens and the redness of the skin (which may be the supply of blood vessels present in the scar or skin) Information on the degree indicator). Examples of such devices include X-rite SP-62 spectrophotolight 145021.doc • 43-201023878 metric, Minolta Chronometer CR-200/300; Labscan 600;

Dr. Lange Micro Colour ; Derma光譜儀；雷射-多普勒流量 計（laser-Doppler flow meter);及分光光度皮内分析（SIA) 示波儀。使用該等裝置獲得之結果亦可經記錄及定量。 與治療之前的基線傷疤相比傷疤之外觀及/或顏色 使用以上段落中所述設備、方法及儀器，可將治療之後 傷疤/傷疤區段之外觀與治療之前同一傷疤/傷疤區段之外 觀相比較。治療或對照治療前後之分析可對經治療傷疤/ 傷疤區段及對任何對照治療（例如投與安慰劑）進行且比較 © 其差異。 傷症扭曲 傷疤與無傷疤皮膚之間的差異可導致傷疤區域之扭曲。 此可由於包括傷疤超過或低於周圍皮膚表面之各種因素引 起。可藉由視覺比較傷疤與無傷疤皮膚及對扭曲之程度分 類（例如，分為不引起扭曲、輕度扭曲、中度扭曲或嚴重 扭曲）來評估傷疤扭曲。 ❿ 傷疤輪廓及傷疤紋理 可藉助於視覺評估研究傷絲廟’且使用適合未數對輪 廓及紋理分類1於分類之適合參數可包括傷^否盘^ 圍皮膚齊平、稍微突出、龍凹H否為肥厚性或瘢痕 瘤。 傷疤紋理可參考傷疤外觀評估，且此亦可藉由視覺評仕 且相應地分類（例如，^ ° 光m…▲ 皮膚相比是否暗淡或 先，ϋ或具有粗糙或平滑外觀）來進行。 145021.doc -44 - 201023878 除上文闡明之技術之外，存在許多使用光學或機械方法 之非侵襲性輪廓測量裝置來評估傷疤輪廓及/或紋理。該 等评估可直接或間接進行。以此方式之評估可得出可易於 獲得評估之代表值。 、 照片評估 可由任何適合評估者執行經治療與未經治療傷疤之照片 評估。適合評估者之實例包括獨立公民或專家小組、臨床 ^師或患者自[。經治療或未經治療傷症可與傷苑之標準 化及校正照片比較評估。 τ 傷苑之照片評估之有利應用在於評估傷絲色，特別是 傷疤紅度。此較佳可由比較標準化臨床照片（例如照片中 影響顏色之參數經控制的照片）進行。可標準化及校正臨 床影像以供該等應用之適合程序為熟習此項技術者所熟 知。 在-項較佳實施例中，傷苑（諸如經治療與非經治療名 # ⑧’或在治療之前、期間或之後各時間點之經治療傷症 之標準化影像可加載至任何影像分析或諸如AdQbe ph⑽ sh°p之適合數位照片編輯軟體中’且描㈣症輪廓（或箱 分析之傷病區域）。隨後總體顏色分析測量⑽、 •彳以在所描繪輪廓内部區域（傷疱區域）與㈣線外部區减 (周圍皮膚區域）之間叫亮度）、a(紅色/綠色值）及b(黃色 藍色）值之差計算。與周圍皮膚之總體色差cEab)之比較可 定量評估傷症顏色’且將此顏色直接與周圍皮膚比較。此 等顏色分析測量亦可用以提供關於傷症紅度之資訊，傷症 145021.doc • 45- 201023878 紅度之降低將由治療前後經治療傷疤之間的Aa值位移（使 得經治療傷絶所記錄之Aa值更接近周圍皮膚之^值）指 示。 傷症亦可由經訓練之臨床或獨立公民小組評估以提供分 類分級資料（例如，所給經治療傷疤與未經治療傷疤相比 「較佳」、「較差」、「無差異」）及/或如本說明書中別處描 . 述之定量資料（諸如藉由使用VAS)。此等資料之獲得可利 用如申請人同在申請中之專利申請案pct/GB2〇〇5/〇〇4787 中所述之適合軟體及/或電子系統。 ⑮ 適合評估可考慮經治療傷疤隨時間出現之外觀差異。此 可藉由比較所選經治療傷疤與未經治療傷疤的影像時程獲 得。對結疤隨時間進程之評估可考慮傷疤總體外觀之變化 及/或諸如本說明書中別處所考慮之特定準則（例如，傷疤 顏色、傷疤紋理、傷疤寬度）之變化。 上文所討論之評估及參數適用於評估在動物或人類中與 對照、安慰劑或標準護理治療相比TGF_P3(詳言之，相關 劑量或治療方案）非外科改善傷苑之能力。應瞭解此等評 © 估及參數可用於測^TGF_p3之治療有效量。可使用適當統 計檢定來分析由不同治療產生之資料集以研究結果顯著 性。 在評估皮膚中之結宛程度（且由此所獲結疲之任何非夕卜. 科改善程度）時可使用上述各種參數，但當評估除皮膚以 外之部位的結疤時，其他參數亦可具有特殊相關性。 僅舉例而言’腱或勤帶中結症之有效非外科改善可由以 145021.doc -46· 201023878 本發明藥物或方法治療的組織之功能恢復指示。功能之適 合指標可包括腱或韌帶載重、拉伸之能力等。該等評估可 例如使用電生理學反射檢驗、表面肌電描記術、超音波檢 ' 查術、超音波/MRI掃描及自述症狀及疼痛問卷進行。 相似地’發生在血管中的結疤之有效非外科改善可例如 使用超音波直接測量或藉助於血流量間接測量。使用本發 明藥物或方法獲得之非外科傷疤修復可導致血管腔窄化減 輕且使血流量更正常。 'Φ 根據本發明使用之較佳調配物 一般而言，本發明藥物可以容許向患者投與該藥物以便 向欲經非外科改善之傷疤提供治療有效量之TGF-P3之任何 形式調配及製造。 含有TGF-p3之適合組合物或藥物可詳言之視其使用方式 採用許多不同形式。因此，舉例而言，其可呈液體、軟 膏、乳膏、凝膠、水凝膠、粉末或氣溶膠之形式。所有該 • 等組合物適合於向需要非外科改善之傷疤局部投與。 然而，本發明者已發現本發明之傷疮之非外科改善當使 用經調配以供藉由注射投與之組合物時尤其有效。本發明 t藥物更佳可經調配以供皮内注射。適用於皮内注射之典 ' 型調配物將為熟習此項技術者熟知。 適用於局部非經腸投藥（例如皮内、肌肉内及皮下）之本 發明藥物可藉由將TGF,與視情況選用之生理上可接受之 載劑、賦形劑或穩定劑（包括糖，諸如麥芽糖或海藻糖又)混 合為康乾及非;東乾粉末調配物形式（以供在使用之前復 145021.doc -47- 201023878 原）、非水溶液及水溶液及半固體調配物形式來製備。包 括賦形劑之可接受之载劑在所用劑量及濃度下對接受者無 毒，且其包括（但不限於）緩衝液，諸如磷酸鹽、檸檬酸鹽 及其他有機酸；抗氧化劑，包括抗壞血酸及甲硫胺酸；張 力調節劑’諸如氣化納、甘油及其類似物；防腐劑，諸如 十八烷基二甲基苄基氣化銨；氣化六羥季銨；氣化苯二甲 烴銨、苄索氣銨；苯酚、丁醇或苄醇；對羥基苯甲酸烷 酯，諸如對羥基苯曱酸甲酯及/或對羥基苯甲酸丙酯及/或 對羥基笨甲酸丁酯；兒茶酚；間苯二酚；環己醇-戊❹ 醇；及間甲盼；低分子量多肽（包含小於約十個胺基酸殘 基）；蛋白質’諸如血清白蛋白、明膠或免疫球蛋白；親 X性聚0物，諸如聚乙烯吡咯啶鲖；胺基酸，諸如甘胺 酸、麵胺醯胺、天冬醯胺、組胺酸、精胺酸或離胺酸；碳 水化β物，包括糊精；螯合劑，諸如edta ;成鹽相對離 子諸如鈉，金屬錯合物（例如辞-蛋白質錯合物）；陰離子 界面活〖生劑，諸如脂肪酸皂類或醯基硫酸鹽；陽離子界面 活性劑’諸如烧基一級胺、二級胺、三級胺或四級胺；非© 離子界面活性劑’例如，酿基酸之脫水山梨糖醇醋或聚乙 氧基化酿、聚氧化乙烯與聚氧化丙烯之共聚物。 舉例而吕’ 1適於非經腸投藥之無菌溶液形式的本發明 醫藥組合物除TGF-P3之外亦可包括以下成分： 糖 氫氧化納 注射用水 145021.doc 48- 201023878 氮氣 可製備上述溶液之凍乾（冷凍乾燥）粉末「餅」。 本發明之該藥物可呈具有無菌溶液、無菌懸浮液或任何 '《他醫樂學上可接受之適合於局部非經腸藥物傳遞之呈遞 形式的小瓶、安瓿或預填充之注射器形式。 諸如束乾之技術可延長本發明藥物之存放期，且可用以 產生例如適於復原之無菌凍乾（冷凍乾燥）粉末。 •，本發明藥物可經調配用於眼睛之傷症（例如滴眼劑形 式），或為腹膜内滴注液形式。 或者或另外，本發明藥物可經調配以便局部投與。在 TGF-P3由患者或無醫學㈣實踐者投與料正在進行中之 非外科傷症治療之部分的方法之上下文中，本發明藥物之 局部投與可為尤佳。 適於局部投與（例如經皮/皮膚、眼、耳、鼻、咽、頰、 直腸、***、尿道）之本發明藥物可藉由將tgf心與視情 _ 況選:之生理上可接受之載劑、賦形劑或穩定劑（包括諸 如麥芽糖之糖）混合為;東乾或非滚乾粉末調配物、非水溶 H水溶液、非水性或水性分散浮液（包括乳液）及半 固體調配物形式來製備。包括賦形劑之可接受之載劑在所 •肖劑量及濃度下對接受者無毒，且其包括（但不限於）純 水、生理食鹽水 '碟酸鹽緩衝生理食鹽水_)，林格氏 溶液邮㈣S〇1Uti〇n)、林格氏乳酸鹽溶液、水-醇溶液、 聚乙二醇（PEG)、丙二醇（PG)、鱗酸鹽、乙酸鹽、明膠、 m白 ' carb_ 934TM(BF Goodrich c〇rp )、植物及合 145021.doc -49- 201023878 成油及蠟、陰離子界面活性劑，諸如脂肪酸皂類或醯基硫 酸鹽；陽離子界面活性劑，諸如烷基一級胺、二級胺、三 級胺或四級胺；非離子界面活性劑，例如醯基酸之脫水山 梨糖醇酯或聚乙氧基化酯、聚氧化乙稀與聚氧化丙稀之共 聚物及其類似物。本發明醫藥組合物可另外包括適合防腐 劑、穩定劑、抗氧化劑、抗微生物劑及緩衝劑，例如對羥 基苯曱酸曱酿及/或對羥基苯曱酸丙醋及/或對羥基苯甲酸 丁醋、丁基化經基菌香醚（BHA)、丁基化羥基曱笨 (BHT)、檸檬酸、抗壞血酸及其類似物。適用於調配物中 之乳液、乳膏或軟膏基劑可包括水基乳膏及乳液（水包 油）、油基乳膏及乳液（油包水）、軟膏（乳化及非乳化烴）、 凝膠、水凝膠及其類似物。或者，本發明藥物可併入或囊 封於適合聚合物基質或膜中，由此提供適於置放於需要非 外科修復之傷疤上的持續釋放傳遞裝置。適合囊封可使用 Paul 等人〜c^·似· Jan-Feb; 16(2_3):188·95 1998 中所涵蓋種 類之脂質體或傳遞體。 本發明適合藥物可呈具有無菌溶液、無时乾或非象乾 粉末(以供復原）、無菌分散液/懸浮液、無菌半固體或任何 其他醫藥學上可接受之適於表面藥物傳遞之呈遞形式的 瓶、罐、管、噴霧形式。 投藥途徑 治療有效量之τπβ3可藉由能夠獲得向需要非外科改善 之傷绝提供包含TGF’之藥物的所需效應之任何適合途徑 投與H -般可能較佳將藥物且由此咖心藉助於局 14502l.doc -50. 201023878 部投藥提供至欲經改善之傷疤。 該局部投藥之適合方法可視所討論之组織或器官之特性 而達成’且亦可受欲治療之組織或器官是否可讓所選藥物 渗透之影響。適合投藥途徑可選自由以下組成之群·注 射；應用噴霧劑、軟膏或乳f;吸人藥物；自生物材料或 其他固體藥物釋放。_般而言，較錢藥途徑可包括局部 庄射（例如，在希望料科改善皮膚傷症之情況下皮内注Dr. Lange Micro Colour; Derma spectrometer; laser-Doppler flow meter; and spectrophotometric intradermal analysis (SIA) oscilloscope. The results obtained using such devices can also be recorded and quantified. The appearance and/or color of the scar compared to the baseline scar before treatment. Using the equipment, methods and instruments described in the paragraph above, the appearance of the scar/scar area after treatment can be compared to the appearance of the same scar/scar area before treatment. Comparison. Analysis before and after treatment or control treatment can be performed on the treated scar/scar area and on any control treatment (eg, placebo) and compared © for differences. Distortion of the injury The difference between the scar and the skin without the scar can lead to distortion of the scar area. This can be caused by various factors including the scar being above or below the surface of the surrounding skin. Scar distortion can be assessed by visually comparing scar and non-scarred skin and classifying the degree of distortion (eg, without causing distortion, mild distortion, moderate distortion, or severe distortion).疤 The contour of the scar and the texture of the scar can be studied by visual evaluation of the wounded silk temple' and the suitable parameters for classification according to the classification and texture classification 1 can be used to include the injury ^ No disk ^ The skin is flush, slightly protruding, dragon concave H Whether it is hypertrophic or keloid. Scar texture can be evaluated by reference to the appearance of the scar, and this can also be done by visual review and corresponding classification (for example, ^ ° light m... ▲ whether the skin is dim or first, ϋ or has a rough or smooth appearance). 145021.doc -44 - 201023878 In addition to the techniques set forth above, there are many non-invasive profilometry devices that use optical or mechanical methods to assess scar contours and/or texture. These assessments can be made directly or indirectly. An evaluation in this way yields a representative value that can be easily obtained. , Photo Assessment The photo assessment of treated and untreated scars can be performed by any appropriate evaluator. Examples of suitable evaluators include independent citizens or groups of experts, clinicians, or patients. Treated or untreated injuries can be compared with standardized and corrected photographs of the injured garden. A good application of the photo assessment of τ Injury is to assess the color of the wound, especially the scar redness. This preferably can be performed by comparing standardized clinical photographs (e.g., photographs whose parameters affect color in the photograph are controlled). Suitable procedures for standardizing and calibrating clinical images for such applications are well known to those skilled in the art. In a preferred embodiment, a standardized image of a treated injury, such as treated and non-treated name #8' or at various time points before, during, or after treatment, can be loaded into any image analysis or such as AdQbe ph(10) sh°p is suitable for digital photo editing software 'and description (four) disease contour (or box analysis of the injury area). Then the overall color analysis measurement (10), • 彳 in the contoured interior area (scar area) and (4) The difference between the outer area of the line minus (the surrounding skin area) is called the brightness), the a (red/green value), and the b (yellow blue) value. A comparison with the overall color difference cEab) of the surrounding skin allows quantitative assessment of the color of the injury' and compares this color directly to the surrounding skin. These color analysis measurements can also be used to provide information on the redness of the injury, injury 145021.doc • 45- 201023878 The reduction in redness will be recorded by the Aa value between the treated scars before and after treatment (so that the treatment is recorded The Aa value is closer to the value of the surrounding skin) indication. The injury can also be assessed by a trained clinical or independent citizen group to provide classification and grading information (for example, "better", "poor", "no difference" compared to untreated scars) and/or Quantitative data as described elsewhere in this specification (such as by using VAS). Such information may be obtained by a suitable software and/or electronic system as described in the applicant's patent application pct/GB2〇〇5/〇〇4787. 15 Appropriate assessments may take into account differences in appearance of treated scars over time. This can be obtained by comparing the image time course of the selected treated scar with the untreated scar. The assessment of the progression of the scar over time may take into account changes in the overall appearance of the scar and/or changes in specific criteria such as scar color, scar texture, scar width, as considered elsewhere in this specification. The assessments and parameters discussed above are applicable to assessing the ability of TGF_P3 (in detail, related doses or treatment regimens) to improve non-surgical injury in animals or humans compared to controls, placebo or standard care. It should be understood that these evaluations and parameters can be used to measure the therapeutically effective amount of TGF_p3. Appropriate statistical tests can be used to analyze data sets generated by different treatments to determine the significance of the results. The above various parameters can be used in assessing the degree of knot in the skin (and any degree of improvement in the resulting fatigue), but when assessing scarring in areas other than the skin, other parameters may also be used. Has a special relevance. By way of example only, an effective non-surgical improvement of a sputum or a diligent tract can be indicated by a functional recovery of tissue treated with the drug or method of the invention of 145021.doc -46.201023878. Suitable indicators of function may include sputum or ligament load, ability to stretch, and the like. Such assessments can be performed, for example, using electrophysiological reflex tests, superficial electromyography, ultrasonography, ultrasonography/MRI scans, and self-reported symptoms and pain questionnaires. An effective non-surgical improvement of scarring that occurs similarly in a blood vessel can be measured, for example, directly using ultrasound or indirectly by means of blood flow. Non-surgical scar repair obtained using the drug or method of the present invention results in a narrowing of the lumen of the blood vessel and a more normal blood flow. 'Φ Preferred Formulations for Use According to the Invention In general, the medicament of the present invention may allow for the administration of the drug to a patient for providing a therapeutically effective amount of TGF-P3 in any form suitable for furrowing and manufacturing. Suitable compositions or medicaments containing TGF-p3 are described in a variety of different forms depending on the mode of use. Thus, for example, it may be in the form of a liquid, ointment, cream, gel, hydrogel, powder or aerosol. All such compositions are suitable for topical administration to scars that require non-surgical improvement. However, the inventors have found that the non-surgical improvement of the wound of the present invention is particularly effective when using a composition formulated for administration by injection. The t drug of the present invention is preferably formulated for intradermal injection. Formulations suitable for intradermal injection will be well known to those skilled in the art. The medicament of the present invention suitable for topical parenteral administration (for example, intradermal, intramuscular, and subcutaneous) can be obtained by using TGF, and optionally a physiologically acceptable carrier, excipient or stabilizer (including sugar, For example, maltose or trehalose is mixed with Kanggan and non-form; Donggan powder formulation (for reuse before 145021.doc -47-201023878), non-aqueous solution and aqueous solution and semi-solid formulation. An acceptable carrier comprising an excipient is non-toxic to the recipient at the dosages and concentrations employed, and includes, but is not limited to, buffers such as phosphates, citrates, and other organic acids; antioxidants, including ascorbic acid and Methionine; tonicity modifiers such as gasified sodium, glycerol and the like; preservatives such as octadecyldimethylbenzylammonium hydride; gasified hexahydroxy quaternary ammonium; gasified phthalic hydrocarbon Ammonium, benzethonium; phenol, butanol or benzyl alcohol; alkyl paraben, such as methyl p-hydroxybenzoate and / or propyl p-hydroxybenzoate and / or butyl p-hydroxybenzoate; Tea phenol; resorcinol; cyclohexanol-pentanol; and metaprine; low molecular weight polypeptide (containing less than about ten amino acid residues); protein 'such as serum albumin, gelatin or immunoglobulin; a pro-X poly-polymer such as polyvinylpyrrolidin; an amino acid such as glycine, a face amine, anthraquinone, histidine, arginine or lysine; a carbohydrate hydrated substance, Including dextrin; chelating agents such as edta; salt forming relative ions such as sodium, metal mismatch (eg, a word-protein complex); an anionic interface living agent such as a fatty acid soap or a sulfhydryl sulfate; a cationic surfactant such as a primary amine, a secondary amine, a tertiary amine or a quaternary amine; Non-ionic surfactants', for example, sorbitan-based sorbitan or polyethoxylated brewed, copolymers of polyethylene oxide and polypropylene oxide. For example, the pharmaceutical composition of the present invention in the form of a sterile solution suitable for parenteral administration may include the following components in addition to TGF-P3: sodium hydroxide water for injection 145021.doc 48-201023878 Lyophilized (freeze-dried) powder "cake". The medicament of the present invention may be in the form of a sterile solution, a sterile suspension or any "a medically acceptable vial, ampoule or prefilled syringe suitable for presentation of a local parenteral drug delivery. Techniques such as stem drying may extend the shelf life of the medicament of the present invention and may be used to produce, for example, a sterile lyophilized (freeze-dried) powder suitable for reconstitution. • The medicament of the present invention may be formulated for use in an eye injury (e.g., in the form of an eye drop) or in the form of an intraperitoneal drip. Alternatively or additionally, the medicament of the invention may be formulated for topical administration. The topical administration of the medicament of the present invention may be particularly preferred in the context of a method in which TGF-P3 is administered by a patient or a non-medical (4) practitioner in the ongoing treatment of non-surgical injury. The medicament of the present invention suitable for topical administration (for example, percutaneous/skin, eye, ear, nose, pharynx, buccal, rectal, vaginal, urethra) can be selected by physiologically acceptable by tgf heart and condition. Mixtures of carriers, excipients or stabilizers (including sugars such as maltose); East or non-dry powder formulations, non-aqueous H solutions, non-aqueous or aqueous dispersions (including emulsions) and semi-solid formulations The form is prepared. An acceptable carrier comprising an excipient is non-toxic to the recipient at the dose and concentration, and includes, but is not limited to, pure water, physiological saline 'salt buffered saline _), Ringer Solution (4) S〇1Uti〇n), Ringer's lactate solution, water-alcohol solution, polyethylene glycol (PEG), propylene glycol (PG), sulphate, acetate, gelatin, m white 'carb_ 934TM ( BF Goodrich c〇rp ), Plants and 145021.doc -49- 201023878 Oil and wax, anionic surfactants, such as fatty acid soaps or sulfhydryl sulfates; cationic surfactants, such as alkyl primary amines, secondary An amine, a tertiary amine or a quaternary amine; a nonionic surfactant such as a sorbitan or polyethoxylated ester of mercapto acid, a copolymer of polyethylene oxide and polyoxypropylene, and the like . The pharmaceutical composition of the present invention may additionally comprise a suitable preservative, stabilizer, antioxidant, antimicrobial agent and buffering agent, for example, p-hydroxybenzoic acid brewing and / or p-hydroxybenzoic acid propyl vinegar and / or p-hydroxybenzoic acid Butyl vinegar, butylated carbendyl ether (BHA), butylated hydroxy hydrazine (BHT), citric acid, ascorbic acid and the like. Suitable emulsion, cream or ointment bases for use in formulations may include water-based creams and lotions (oil-in-water), oil-based creams and lotions (water-in-oil), ointments (emulsified and non-emulsified hydrocarbons), and condensate Glues, hydrogels and the like. Alternatively, the medicament of the invention may be incorporated or encapsulated in a suitable polymeric matrix or membrane, thereby providing a sustained release delivery device suitable for placement on a scar requiring non-surgical repair. For encapsulation, liposomes or transfersomes of the type encompassed by Paul et al., et al., Jan-Feb; 16(2_3): 188.95, 1998 can be used. Suitable pharmaceuticals for the present invention may be presented as sterile solutions, dry or non-dry powders (for reconstitution), sterile dispersions/suspensions, sterile semi-solids or any other pharmaceutically acceptable delivery for surface drug delivery. Forms of bottles, cans, tubes, sprays. Administration of a therapeutically effective amount of τπβ3 may administer a drug by any suitable means capable of obtaining the desired effect of providing a drug comprising TGF' to a wound requiring non-surgical improvement. In the Department of 14502l.doc -50. 201023878, the administration of the drug is provided to the scar to be improved. Suitable methods for topical administration can be achieved depending on the characteristics of the tissue or organ in question' and can also be influenced by the penetration of the selected drug by the tissue or organ to be treated. Suitable for the route of administration can be selected from the group consisting of the following: injection; application of sprays, ointments or milk f; inhalation of drugs; release from biological materials or other solid drugs. In general, the more expensive drug route may include local smear (for example, in the case of a medical department that wants to improve skin injuries)

射）。在本說日月書中別處考慮用於本發日月之此等實施财 的適合調配物。 在血管傷疤之情況下，可藉由直接注射 _ , j柯田且设江牙r 局#施用裝置（諸如金管支架）投與TGF_p。 j發明藥物可在可用以覆蓋需要非外科改善之傷苑之無 威敷料或貼片上提供。 應瞭解本發明藥物之媒劑應為患者良好耐受且容許釋放 Γ=需要非外科改善之傷症的媒劑。該媒劑較佳為可 :物降解、可生物再溶解、可生物再吸收及/或非發炎 不發明樂物可併入緩慢或延 置於欲經改善之傷宛上且來^ 吧上且采自該裝置之TGF_P3 天、數週或甚至數月内釋放。 本發明藥物或方法可以單一療法（例如，瘦 本發明藥物或方法）心非外科改善傷苑。或者 = :法或藥物可與其他化合物或非外科治療組合用於傷:; 145021.doc •51 · 201023878 應瞭解由於對人類之非外科傷疤修復可獲得之許多優勢 亦可適用於其他動物，尤其獸醫動物或家畜（例如馬、 牛、狗、貓等）。因此’應認識到本發明藥物及方法亦可 用於非人類動物傷症的非外科改善。 【實施方式】 現將參考以下實驗結果及方案及圖進一步描述本發明， 其中： 實驗結果及方案 本發明藥物及方法產生傷疤之有效非外科改善的能力可 使用下文闡明之臨床研究或試驗證明。此類試驗亦用於研 究及鑑別適用於本發明藥物或方法中的TGF_p3之較佳治療 有效量。 簡言之，適合試驗可包括視情況選用之篩選就診（在此 期間，可證實患者對於包含於試驗中之適合性且建立相關 「基線」值），隨後進行一或多次治療。進行之此等治療 可涉及提供治療有效量之TGF_P3’或該治療有效量之已知 比例以及或者或另外投與相關量之TGF_P3。該等相關量可 為推定的治療有效量（在該情況下，此類試驗也許能鍛別 所討論之量是否提供所需治療作用)或可為欲與已知在治 療上有效之量比較的h在進行所選治療次數之後，接受 而如之個體可經歷許多「隨訪」，其可用來研究所存在 結疤之程度(且由此研究已出現之結疤之任何非外科改盖) 及/或其他相關細節，諸如所提供TGF似劑量的耐受 性。 145021.doc -52- 201023878 下文所列項構成作為試驗部分欲研究之較佳變數及評估 集合。然而’應瞭解適合試驗可僅使用上文所提及之一些 評估，或可視需要使用其他額外評估。 ‘ 篩選就診（第-28天至第-1天） 在篩選期間執行以下評估： •獲得患者參與試驗之知情同意書。 •記錄用藥史（包括在篩選就診之前一個月的伴隨藥療 法）、吸煙史及飲酒情況。 •〜' 者包含/排除準則之評估。 人口統计資料記錄。 •執行12-導程ECG。 身體檢查，包括身高、體重、血壓及靜息脈博。 •收集血樣及尿樣以供實驗室安全性篩選，包括以下參 數：血液學（包括分析血紅蛋白、紅血球、血容比、平 均細胞容積、白血球（包括分布）及血小板計數）；臨床化 • 學（包括總膽紅素、總蛋白、白蛋白、天冬胺酸轉胺 酶、丙胺酸轉胺酶、γ麩胺醯轉移酶、鹼性磷酸酶、尿 素、肌酐、鈉、鉀及鈣）；尿分析··（包括ΡΗ值、蛋白 質、葡萄糖、酮類及血液）；及藥物濫用（包括：*** (***e)、***（amphetamine)、甲基***、大 麻（cannabis)、鴉片劑（opiate)及苯并二氮呼在個體進 展至第0天之前審查此等测試結果。 •採集血樣用於免疫原性分析。 •自有姓娠可能之女性令收集尿樣以供進行㈣測試。 145021.doc -53. 201023878 水對患者執行皮膚斑貼 使用用於紋身之半永久性美容墨 試驗》 •記錄關於欲治療傷疤之以下資訊： 〇傷疤年齡（例如，傷疤是否為至少兩個月大？）。 〇傷症部位。 〇傷症定向。 〇傷疤原因。 〇先前治療。 〇記錄各傷疤區段之長度及最大寬度。 •由研究者對各傷疤區段進行患者臨床傷疤評估。 第〇天 在才又與TGF - β3之前第〇天執行以下評估： •常規身體檢查，包括血壓及靜息脈博。 . •收集血樣及尿樣以供實驗室安全性篩選。 •自有姓娘可能之女性患者中收集尿樣以供進行姓娘測 試。僅妊娠測試陰性之患者進行治療。 •圯錄自篩選就診以來伴隨藥療法之任何變化或患者狀況 之變化。 •獲得欲治療傷疤區段之聚矽氧模。 •審查皮膚斑貼試驗區域且具有過敏反應之患者不容許參 與該研究。 •將欲治療傷疤分成兩個相等區段且使用半永久性美容墨 水對其標記。以半永久性美容墨水點兩個點來標記傷疤 之中線，該等點垂直於該傷疤且距該傷疤丨em，且以一 145021.doc 201023878 個點標記傷疤之各端（如圖1中示意性地展示）。 根據以下分配規則將由中線分開之兩個傷疤區段標記為 「A」及「B」： , 只要可能，區段A分配給傷疤之近端且B分配給遠端。 若傷疤完全水平且其不可能使用近端-遠端規則，則A分 配給患者右側端且B分配給患者左側。 •為基線測量評估局部耐受性。 ^ •(在標記傷疤之後）為欲治療傷疤拍照。 •要求患者完成§平估其傷苑之問卷。 •準備欲治療之傷疤且使其麻醉。 •在麻醉之後，藉由根據隨機化時程皮内注射TGF_p3或安 慰劑對傷疤區段（A及B)給藥。沿傷疤進行注射使得每直 線公分傷疤投與100 μΐ。藉由使用具有〇 3 x 13 mm bD Microlance™ 3針或相等物之1() mi注射器沿傷疤皮内注 射投與劑量。 • 較佳投藥方法示意地展示於圖2中。如此圖中所示，使 用外科標記物以一系列彼此間隔丨em之點標記傷疤。在 傷症任一端之點自傷苑任一端延伸至少〇. 5 cm。將針在 位點B處皮内***且沿傷疤中心前進至位點隨後隨 著針的拔出，將100 μ1給藥溶液注入i cm長度之真皮 中，確保試驗劑量均勻分布在位點八與B之間。當溶液 注入真皮中時看到變白》隨後將針沿位點B之方向在位 點C處***且重複給藥方法直至為該區段全部經給藥。 隨後對另一區段重複該程序。投藥延伸達至傷疤中線且 145021.doc •55· 201023878 超過各傷疤區段末端至少0.5 cm但至多1 cm(至正常皮膚 中）。 •適用於此實施例之較佳藥物每100 μΐ藥物可包含5〇〇叫 或1000 ng之TGFj3(當相對於NISBC參考標準校正時） •記錄所投與TGF-P3及所用伴隨藥療法之細節。 在給藥之後執行以下程序及評估： •為經治療之傷疤拍照。Shoot). Appropriate formulations for such implementation of the current month and month are considered elsewhere in this book. In the case of vascular scars, TGF_p can be administered by direct injection of _ , j Ketian and Jiangya r bureau # applicator (such as a gold tube stent). The inventive drug can be provided on a non-volatile dressing or patch that can be used to cover a wound that requires non-surgical improvement. It should be understood that the vehicle of the medicament of the present invention should be well tolerated by the patient and allowed to release Γ = a vehicle requiring a non-surgical improvement of the wound. Preferably, the vehicle is: degradable, bioredissolvable, bioresorbable, and/or non-inflammable. The inventive article can be incorporated into the wound or the wound to be improved. TGF_P from the device is released within 3 days, weeks, or even months. The medicament or method of the present invention can be used in a single therapy (e.g., a thin drug or method of the present invention) to improve the wounded heart. Or = : The method or drug can be used in combination with other compounds or non-surgical treatments for injury: 145021.doc •51 · 201023878 It should be understood that many of the advantages that can be obtained from the repair of non-surgical scars in humans can also be applied to other animals, especially Veterinary animals or livestock (eg horses, cows, dogs, cats, etc.). Therefore, it should be recognized that the medicaments and methods of the present invention are also useful for non-surgical improvements in non-human animal injuries. [Embodiment] The present invention will now be further described with reference to the following experimental results and schemes and figures, in which: Experimental Results and Protocols The ability of the medicaments and methods of the present invention to produce effective non-surgical improvement of scars can be demonstrated using clinical studies or tests as set forth below. Such assays are also useful for studying and identifying preferred therapeutically effective amounts of TGF_p3 suitable for use in the medicament or method of the invention. Briefly, suitable tests may include screening visits as appropriate (in which case the patient may be confirmed for suitability for inclusion in the trial and a relevant "baseline" value is established) followed by one or more treatments. Such treatment may involve providing a therapeutically effective amount of TGF_P3' or a known ratio of the therapeutically effective amount and or or otherwise administering a related amount of TGF_P3. The relevant amount can be a putative therapeutically effective amount (in which case such an assay may be able to forge the amount of treatment provided to provide the desired therapeutic effect) or may be compared to an amount known to be therapeutically effective. After the selected number of treatments, the individual can undergo a number of "follow-ups" that can be used to study the extent of crusting (and any non-surgical alterations that have resulted in the scarring that has occurred) and/or Other relevant details, such as TGF-like dose tolerance provided. 145021.doc -52- 201023878 The items listed below constitute a set of preferred variables and assessments to be studied as part of the trial. However, it should be understood that suitable trials may use only some of the assessments mentioned above, or other additional assessments may be used as needed. ‘ Screening visits (Day -28 to Day -1) Perform the following assessments during screening: • Obtain informed consent from patients participating in the trial. • Record medication history (including one-month medications prior to screening visits), smoking history, and alcohol consumption. • ~' assessment of inclusion/exclusion criteria. Demographic records. • Perform a 12-lead ECG. Physical examination, including height, weight, blood pressure and resting pulse. • Collect blood samples and urine samples for laboratory safety screening, including the following parameters: hematology (including analysis of hemoglobin, red blood cells, blood volume ratio, mean cell volume, white blood cells (including distribution), and platelet count); clinicalization • Including total bilirubin, total protein, albumin, aspartate transaminase, alanine transaminase, gamma glutamine transferase, alkaline phosphatase, urea, creatinine, sodium, potassium and calcium); Analysis · (including devaluation, protein, glucose, ketones and blood); and drug abuse (including: ***e, amphetamine, methamphetamine, cannabis, opiate and benzene And diazepam examines these test results before the individual progresses to day 0. • Blood samples are collected for immunogenicity analysis • Females with their own surnames are allowed to collect urine samples for testing (4) 145021.doc -53. 201023878 Water performs a skin patch on patients using a semi-permanent cosmetic ink test for tattoos. • Record the following information about the treatment of scars: age of scars (eg Is the scar at least two months old?). The area of the bruises. The orientation of the bruises. The cause of the scars. 〇 Previous treatment. 〇 Record the length and maximum width of each scar section. • The wound area by the investigator The patient was assessed for clinical scars. The following assessments were performed on the third day before TGF-β3: • routine physical examination, including blood pressure and resting pulse. • Collection of blood and urine samples for laboratory safety Sexual screening • Urine samples collected from female patients with surnames for surname testing. Only patients with negative pregnancy tests are treated. • Any changes in concomitant medications or changes in patient status since screening visits • Obtain a polyoxymethane mold to treat the scar area. • Patients who have an allergic reaction in the skin patch test area are not allowed to participate in the study. • The lesion to be treated is divided into two equal sections and semi-permanent beauty ink is used. Mark it. Mark the midline of the scar with two points of semi-permanent cosmetic ink, which are perpendicular to the scar and from the scar, and one 145021.doc 201023878 points mark each end of the scar (shown schematically in Figure 1). Mark the two scar segments separated by the center line as "A" and "B" according to the following distribution rules: whenever possible, Segment A is assigned to the proximal end of the scar and B is assigned to the distal end. If the scar is completely level and it is not possible to use the proximal-distal rule, then A is assigned to the patient's right end and B is assigned to the patient's left side. Assess local tolerance. ^ • (after marking scars) Photographs for treatment of scars • Ask patients to complete a questionnaire to assess their injuries. • Prepare the scars to be treated and anesthetize them. • After anesthesia, borrow The scar segments (A and B) were administered by intradermal injection of TGF_p3 or placebo according to a randomized time course. Injection along the scar causes 100 μΐ per linear centimeter scar. The dose was injected along the scar by using a 1 () mi syringe with a 〇 3 x 13 mm bD MicrolanceTM 3 needle or equivalent. • A preferred method of administration is shown schematically in Figure 2. As shown in this figure, the surgical marker is used to mark the scar at a point that is spaced apart from each other by 丨em. At any point on the end of the injury, extend at least 〇. 5 cm from either end of the wounded garden. Insert the needle into the skin at site B and advance to the site along the center of the scar. Then, as the needle is pulled out, inject 100 μl of the solution into the dermis of i cm length to ensure that the test dose is evenly distributed at the locus of eight. Between B. The whitening is seen when the solution is injected into the dermis. The needle is then inserted at position C along the direction of site B and the method of administration is repeated until all of the segment is administered. This procedure is then repeated for another segment. The drug is extended to the midline of the scar and 145021.doc •55· 201023878 exceeds the end of each scar section by at least 0.5 cm but up to 1 cm (to normal skin). • The preferred drug for this example may contain 5 〇〇 or 1000 ng of TGFj3 per 100 μΐ of the drug (when corrected relative to the NISBC reference standard) • Record the details of the TGF-P3 administered and the concomitant medication used . The following procedures and assessments were performed after dosing: • Photographed for treated scars.

•記錄給藥之後任何不利事件（AE)及或伴隨藥療法之 化。 第1天（首次IMP投藥之後24+/-4小時） 執行以下程序： •記錄任何AE及/或伴隨藥療法之變化。 •評估局部耐受性。 •在適當麻醉之後，如以上第〇天所述對傷疤區段及B) 給藥。 如前所述，用於此實施例之較佳藥物每1〇〇…藥物可包 含500 ng或1000 ng2TGF_p3(當相對於见8]5(：參考標準 〇 校正時）。 •記錄所用IMP及伴隨藥療法之細節。 第7天（+/-2天） 執行以下評估： •記錄伴隨藥療法之任何變化。 •記錄任何AE。 •對局部耐受性進行評估。 145021.doc •56- 201023878 •為經治療之傷疤拍照。 第14天（+/-2天） 執行以下評估： ^ · 5己錄伴隨藥療法之任何變化。 • §己錄任何AE。 •身體檢查。 •血壓及脈博。 • 12 導程 ECG。 •對局部财受性進行評估。 •為經治療傷疤拍照。 •為實驗室安全性而採集血樣。 第1個月（4遇+/-4天） 執行以下評估： •記錄任何AE及/或伴隨藥療法之變化。 •採集血樣以供免疫原性分析。 φ •進行局部耐受性評估。 •對有妊娠可能之女性個體進行尿妊娠測試。 •為經治療傷疤拍照。 •對各個治療區段進行患者臨床傷疤評估。 ' #要求患者完成評估其經治療傷錢段之問卷 第2、3、4及5個月（+/_ι週） 執行以下評估： •記錄任何AE及/或伴隨藥療法之變化。 •評估局部财受性。 14502】.doc •57- 201023878 •為經治療傷疤拍照。 •對各個治療區段進行患者臨床傷疤評估。 •要求患者完成評估其經治療傷疤區段之問卷。 第6個月（22-26週+/-2週） 執行以下評估： •記錄任何AE及/或伴隨藥療法之變化。 •評估局部耐受性。 •為經治療傷疤區段拍照。 •獲得經治療傷疤區段之聚矽氧模。 •對各個治療區段進行患者臨床傷疤評估。 •要求患者完成評估其經治療傷疤區段之問卷。 第12個月（+/-2週） 執行以下評估： •記錄任何AE及/或伴隨藥療法之變化。 •評估局部耐受性。 •為經治療傷疤區段拍照。 •獲得經治療傷疤區段之聚矽氧模。 •對各個治療區段進行患者臨床傷疤評估。 •要求患者完成評估其經治療傷疤區段之問卷。 序列資訊 TGF-p3(序列 ID No. 1)• Record any adverse events (AE) and or concomitant medications after dosing. Day 1 (24 +/- 4 hours after the first IMP administration) The following procedure was performed: • Record any changes in AE and/or concomitant medication. • Assess local tolerance. • After appropriate anesthesia, the scar section and B) are administered as described on day 1-3 above. As mentioned above, the preferred drug for this embodiment may contain 500 ng or 1000 ng2 TGF_p3 per drug (when compared to see 8] 5 (: when reference standard 〇 is corrected). • Record the IMP used and accompanying Details of medication. Day 7 (+/- 2 days) Perform the following assessments: • Record any changes in concomitant medications • Record any AEs • Evaluate local tolerances 145021.doc •56- 201023878 • Photographed for treated scars Day 14 (+/- 2 days) Perform the following assessments: ^ · 5 Record any changes in concomitant medications. • Have recorded any AEs. • Physical examinations. • Blood pressure and pulse. • 12-lead ECG • Assessment of local financial acceptability • Photographing for treated scars • Blood samples for laboratory safety. 1st month (4 +/- 4 days) Perform the following assessments: • Record any changes in AE and/or concomitant medications • Collect blood samples for immunogenic analysis φ • Perform a local tolerance assessment • Perform a urine pregnancy test on women who are likely to have a pregnancy • Take photos of treated scars • For each treatment section Patient clinical scar assessment. ' # Ask the patient to complete the assessment of their treatment of the injured section of the questionnaire for the second, third, fourth and fifth months (+/_ι weeks) Perform the following assessments: • Record any AE and / or concomitant medication Change. • Evaluate local financial acceptability. 14502].doc •57- 201023878 • Photographed for treatment of scars • Assessment of clinical clinical scars for each treatment segment • Require patients to complete a questionnaire to assess their treated scar segments. Week 6 (22-26 weeks +/- 2 weeks) Perform the following assessments: • Record any changes in AE and/or concomitant medications • Evaluate local tolerance • Take photos of the treated scar section • Obtain Treatment of the sputum segment of the sputum segment. • Assessment of clinical scars in each treatment segment. • Require patients to complete a questionnaire to assess their treated scar segments. Week 12 (+/- 2 weeks) Perform the following Assessment: • Record any changes in AE and/or concomitant medications • Evaluate local tolerance • Take photographs of the treated scar section • Obtain a polypoxide model from the treated scar section • For each treatment segment Carrying on Clinical scar assessment. Assessment Questionnaire • which requires patients completed sections of the treated scar. Sequence information TGF-p3 (Sequence ID No. 1)

ALDTNYCFRNLEENCCVRPLYIDFRQDLGWKWVHEPKGYYANFCSGPCPYLRSADTALDTNYCFRNLEENCCVRPLYIDFRQDLGWKWVHEPKGYYANFCSGPCPYLRSADT

THSTVLGLYNTLNPEASASPCCVPQDLEPLTILYYVGRTPKVEQLSNMWKSCKCS 【圖式簡單說明】 145021.doc -58 - 201023878 圖1為治療之前傷症標記的圖示；及 圖2為可將本發明藥物投與需要非外科改善之傷疤的較 佳方案之圖示。THSTVLGLYNTLNPEASASPCCVPQDLEPLTILYYVGRTPKVEQLSNMWKSCKCS [Simplified Schematic] 145021.doc -58 - 201023878 Figure 1 is a graphical representation of a pre-treatment injury marker; and Figure 2 is a graphical representation of a preferred protocol for administering a medicament of the invention to a non-surgically modified scar. .

145021.doc -59- 201023878 序列表145021.doc -59- 201023878 Sequence Listing

<110>英商雷諾芙有限公司 <120>傷疤之非外科改善 <130> ICA/PM311033TM <140> 098141027 <141> 2009-12-01 <150> GB 0821941.2 <151〉 2008-12-01 <160> 1 <170> Patentln version 3. 3<110>British Reynolds Co., Ltd. <120> Non-surgical improvement of scars<130> ICA/PM311033TM <140> 098141027 <141> 2009-12-01 <150> GB 0821941.2 <151> 2008-12-01 <160> 1 <170> Patentln version 3. 3

<210〉 1 <211〉 112 <212〉 PRT <213〉智人 <400> 1<210〉 1 <211> 112 <212〉 PRT <213> Homo sapiens <400> 1

Ala Leu Asp Thr Asn Tyr Cys Phe Arg Asn Leu Glu Glu Asn Cys Cys 15 10 15Ala Leu Asp Thr Asn Tyr Cys Phe Arg Asn Leu Glu Glu Asn Cys Cys 15 10 15

Val Arg Pro Leu Tyr lie Asp Phe Arg Gin Asp Leu Gly Trp Lys Trp 20 25 30Val Arg Pro Leu Tyr lie Asp Phe Arg Gin Asp Leu Gly Trp Lys Trp 20 25 30

Val His Glu Pro Lys Gly Tyr Tyr Ala Asn Phe Cys Ser Gly Pro Cys 35 40 45Val His Glu Pro Lys Gly Tyr Tyr Ala Asn Phe Cys Ser Gly Pro Cys 35 40 45

Pro Tyr Leu Arg Ser Ala Asp Thr Thr His Ser Thr Val Leu Gly Leu 50 55 60Pro Tyr Leu Arg Ser Ala Asp Thr Thr His Ser Thr Val Leu Gly Leu 50 55 60

Tyr Asn Thr Leu Asn Pro Glu Ala Ser Ala Ser Pro Cys Cys Val Pro 65 70 75 80Tyr Asn Thr Leu Asn Pro Glu Ala Ser Ala Ser Pro Cys Cys Val Pro 65 70 75 80

Gin Asp Leu Glu Pro Leu Thr lie Leu Tyr Tyr Val Gly Arg Thr Pro 85 90 95Gin Asp Leu Glu Pro Leu Thr lie Leu Tyr Tyr Val Gly Arg Thr Pro 85 90 95

Lys Val Glu Gin Leu Ser Asn Met Val Yal Lys Ser Cys Lys Cys Ser 100 105 110 145021.docLys Val Glu Gin Leu Ser Asn Met Val Yal Lys Ser Cys Lys Cys Ser 100 105 110 145021.doc

Claims (1)

201023878 七、申請專利範圍： 1· 一種TGF_p3，其係用作提供傷苑非外科改善之藥物。 如叫求項1之TGF-P3，其係用作可注射藥物。 ， Y长項1或2iTGF_P3，其中該藥物提供每公分欲經非 文。之傷苑大約1〇〇 ng與10,000 ng之間的TGF_p3。 4. 如請求項3之TGF_P3,其中該藥物提供每公分欲經非外 科改善之傷疤大約500 ng與1000 ng之間的TGFp3。 5. 如請求項4之服#，其中該藥物提供每公分欲經非外 科改善之傷疤大約500 ng TGF-P3。 6. 如請求項4之TGF-P3,其中該藥物提料公分欲經非外 科改善之傷疤大約1000 ng TGF_p3。 7-如請求項！或2之TGF-P3,其巾該非外科改善包含減少該 傷疤之紅度。 8·如請求項⑷之TGF-P3,其係用於非外科改善皮膚之傷 疤。 響9.如言青求項⑷之TGF_p3,其係用於受傷後至少兩個月之 傷苑。 10·如請求項丨或2之TGF-P3,其係用於受傷後多達六個月之 ' 傷症。 Π·如請求項丨或2之TGF-P3,其係用於正進行傷症重塑之傷 絶。 12.如請求項丄或]之TGF-P3，其中該藥物係局部投至欲經非 外科改善之傷疤。 13· —種改善個體傷疤的醫藥組合物，其包含治療有效量之 145021.doc 201023878 ，其中該組合物係非外科投與需要該改善之個體 的傷苑。 14.如請求項13之醫藥組合物，其中向該個體施用兩次或兩 次以上提供TGF-p3之治療。 15·如請求項14之醫藥組合物，其中向該個體施用兩次提供 TGF-p3之治療。 16·如請求項13至15中任一項之醫藥組合物，其中該組合物 係由注射提供。 17. 如請求項16之醫藥組合物，其中該組合物係由皮内注射 提供。 18. 如請求項13至15中任一項之醫藥組合物，其中該組合物 係由局部投與提供。 19. 如請求項13至15中任一項之醫藥組合物，其中該組合物 實質上沿該傷癌之中心投與。 20. —種TGF-P3，其係用於減少先前存在之傷疤的紅度及/ 或對比度。 21. -種ΤΟΡ-β3之用冑，其係用於製造改善個體傷症之藥 物，其中該藥物係非外科投與需要該改善之個體的傷 苑。 2 2 .如請求項2 1之用途，其中而兮/田Π* r〇 j., 丹T ^ 6亥個體施用兩次或兩次以上 提供TGF-P3之治療。 23.如請求項22之用途，装φ内姑加祕…拍 、T向該個體施用兩次提供TG；p_p3 之治療。 其中該樂物係由注射 24.如請求項21至23中任一項之用途 145021.doc 201023878 提供。 25·如請求項24之用途，其中該藥物係由皮内注射提供。 26.如請求項21至23中任一項之用途，其中該藥物係由局部 , 投與提供。 ' 27.如請求項21至23中任一項之用途，其中該藥物實質上沿 該傷疤之中心投與。201023878 VII. Scope of application for patents: 1. A TGF_p3, which is used as a drug to provide non-surgical improvement in the wounded garden. For example, TGF-P3 of claim 1 is used as an injectable drug. , Y long term 1 or 2iTGF_P3, wherein the drug is provided per centimeter. The wounded garden is about 1 ng and 10,000 ng between TGF_p3. 4. TGF_P3 as in claim 3, wherein the drug provides between about 500 ng and 1000 ng of TGFp3 per cm of the wound to be treated with a non-surgical improvement. 5. As requested in item 4, Service #, which provides approximately 500 ng of TGF-P3 per minute for a non-surgical improvement of the scar. 6. TGF-P3 of claim 4, wherein the drug is about 1000 ng TGF_p3 for a non-medical improvement. 7- such as the request item! Or 2 of TGF-P3, the non-surgical improvement of the towel comprises reducing the redness of the scar. 8. TGF-P3 according to claim (4), which is used for non-surgical improvement of skin wounds. 9. The TGF_p3 of Yan Qing (4) is used for at least two months after the injury. 10. If TGF-P3 is requested, or 2, it is used for 'sickness' for up to six months after injury. Π·If you request item 丨 or 2 of TGF-P3, it is used for injury that is undergoing injury remodeling. 12. The TGF-P3 as claimed in claim </ RTI> or wherein the drug is administered topically to a scar that is to be non-surgically improved. 13. A pharmaceutical composition for improving an individual's scar comprising a therapeutically effective amount of 145021.doc 201023878, wherein the composition is non-surgically administered to a wounded individual in need of such improvement. 14. The pharmaceutical composition of claim 13, wherein the treatment of TGF-p3 is provided to the individual two or more times. 15. The pharmaceutical composition of claim 14, wherein the treatment of TGF-p3 is administered to the individual twice. The pharmaceutical composition according to any one of claims 13 to 15, wherein the composition is provided by injection. 17. The pharmaceutical composition of claim 16, wherein the composition is provided by intradermal injection. The pharmaceutical composition according to any one of claims 13 to 15, wherein the composition is provided by topical administration. The pharmaceutical composition according to any one of claims 13 to 15, wherein the composition is administered substantially along the center of the wound cancer. 20. A TGF-P3 for reducing the redness and/or contrast of previously existing scars. 21. A sputum-β3 sputum for use in the manufacture of a medicament for improving an individual's injury, wherein the medicament is non-surgically administered to an individual in need of such improvement. 2 2. The use of claim 2, wherein 兮/田Π* r〇 j., Dan T ^ 6H is administered twice or more to provide treatment for TGF-P3. 23. For the use of claim 22, φ 内 加 ... 拍 拍, T is administered to the individual twice to provide TG; p_p3 treatment. Wherein the item is provided by injection 24. The use of any of claims 21 to 23 is provided in 145021.doc 201023878. 25. The use of claim 24, wherein the medicament is provided by intradermal injection. The use of any one of claims 21 to 23, wherein the drug is provided by topical administration. The use of any one of claims 21 to 23, wherein the medicament is administered substantially along the center of the scar. 145021.doc145021.doc