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 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.

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

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.

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)

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.

Injury 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

The 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

Seller 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.

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).

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

The 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

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"

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 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)

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: cocaine, 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.

• 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)

ALDTNYCFRNLEENCCVRPLYIDFRQDLGWKWVHEPKGYYANFCSGPCPYLRSADT

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 Sequence Listing

<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> Homo sapiens <400> 1

Ala 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 30

Val 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 60

Tyr 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 95

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

Claims (1)

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.doc