How to improve non-surgical treatments

Abstract

A method for enhancing non-surgical treatment, comprising applying an antifibrinolytic agent to an area of ​​skin to be treated non-surgically prior to the non-surgical treatment, initiating non-surgical treatment on the area of ​​skin, and continuing the non-surgical treatment until the non-surgical treatment is completed. Further, a composition for enhancing non-surgical treatment, comprising an antifibrinolytic agent. Finally, a method for enhancing non-surgical treatment, comprising initiating non-surgical treatment on an area of ​​skin, continuing the non-surgical treatment until the non-surgical treatment is completed, and applying an antifibrinolytic agent to the area of ​​skin, wherein the application is at least one of before, during, and after the non-surgical treatment has begun. [Selection diagram] None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This patent application claims priority from U.S. Provisional Patent Application No. 62 / 481,162, filed April 4, 2017, the entire disclosure of which is incorporated herein by reference.

[0002] The present disclosure relates generally to non-surgical treatments and more particularly, but not exclusively, to methods and compositions for improving non-surgical treatments. [Background technology]

[0003] History of Related Technologies During the course of non-surgical treatments, such as those related to cosmetic or dermatological procedures, patients may experience unwanted swelling, inflammation and / or subcutaneous bleeding associated with treatments, such as injections of fillers or neurotoxins, or application of chemical peels, acne treatments, dermabrasion and laser skin treatments. For injection-type treatments, needles and pressure may cause slight bleeding. To counter this effect, certain vasoconstrictors, such as epinephrine, may be applied to tissues prior to injection to reduce the size of blood vessels, thereby reducing the likelihood that blood vessels will be injured during treatment, and the reduced blood vessel size may reduce the amount of bleeding. However, vasoconstrictors, such as epinephrine, may have a "rebound effect" that may result in unwanted effects as the drug wears off and blood vessels return to normal. Summary of the Invention

[0004] 1. A method of enhancing a non-surgical treatment, comprising applying an antifibrinolytic agent to an area of ​​skin prior to the non-surgical treatment, initiating non-surgical treatment on said area of ​​skin, and continuing the non-surgical treatment until the non-surgical treatment is completed.

[0005] A composition for enhancing non-surgical treatment, the composition comprising an antifibrinolytic agent.

[0006] A method of improving the treatment of a non-surgical treatment, comprising initiating a non-surgical treatment on an area of ​​skin, continuing the non-surgical treatment until the non-surgical treatment is completed, and applying an anti-fibrinolytic agent to the area of ​​skin, the application being at least one of before, during, and after the non-surgical treatment has begun. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0007] In various embodiments, the methods and compositions are used to improve non-surgical treatments that are prone to hemorrhage, swelling, inflammation or similar events, and the methods include applying an antifibrinolytic agent to an area of ​​the skin where the non-surgical treatment is performed, by applying the antifibrinolytic agent before, during and / or after the non-surgical treatment.In certain embodiments, there are several additional non-surgical cosmetic and dermatological treatments, such as chemical peels, skin excisions, acne treatments and laser skin treatments, that include hemorrhage, swelling and inflammation.

[0008] Various embodiments of the present invention will now be described more fully with reference to the accompanying tables, however, the present invention may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein.

[0009] An object of the present invention is to provide a method and composition that minimizes or reduces swelling, inflammation, bruising, or a combination of the same and similar that results from non-surgical treatment, thereby improving non-surgical treatment.An additional object of the present invention is to improve non-surgical treatment by using dermal fillers and toxins to extend the duration / function of non-surgical treatment.In certain embodiments, the present invention may be utilized with some non-surgical cosmetic and dermatological treatments, such as chemical peels, skin excision, acne treatments, and laser skin treatments, including bruising, swelling, and inflammation.As used herein, non-surgical treatments may include a variety of treatments, including but not limited to cosmetic procedures for improving physical appearance for aesthetic reasons, medicines, physical therapy, and radiation therapy for repairing the effects of injury, disease, or dysfunction, and are typically non-invasive in nature, such as treatments that do not involve linear incision of the skin.

[0010] According to the present invention, non-surgical treatment is enhanced by administration of one or more antifibrinolytic drugs before, during and / or after non-surgical treatment of human patients. As used herein, the term "enhance" means to minimize or reduce swelling, inflammation, bruising, or a combination of the same and similar, and may also include extending the duration / function of dermal fillers and toxins. The implementation of the present invention may be to utilize one or more antifibrinolytic drugs before non-surgical treatment to provide reduced swelling, inflammation and / or bruising, while still providing rapid and effective healing, for example, by limiting fibrinolytic activity, such as the conversion of plasminogen to plasmin, in or around the treatment area, thereby enhancing non-surgical treatment.

[0011] The antifibrinolytic agent may be provided to reduce swelling, inflammation, bruising, or combinations of the same and similar that may be associated with non-surgical treatments, such as injection and / or application of therapeutic, cosmetic, or dermatological treatments. The antifibrinolytic agent may be a simple aqueous solution or may be mixed with a pharma- ceutically acceptable carrier, such as a gel, lotion, or cream, and may optionally contain other active or inactive therapeutic ingredients and / or preservatives. The solution and / or compound may be administered directly onto or into the skin days, hours, or minutes before, during, and / or after the injection or application of the non-surgical treatment, to minimize swelling, inflammation, and / or bruising following the treatment. The antifibrinolytic agent may also be delivered systemically to provide similar cosmetic and / or healing benefits in non-surgical medical procedures. In certain embodiments, a combination of local and systemic administration may be used.

[0012] For intravenous administration of tranexamic acid (TA), one of the common antifibrinolytic drugs, the minimum dose of this antifibrinolytic drug is about 10 mg / kg body weight. More common doses are about 10 mg / kg body weight before treatment and 1 mg / kg / hour 12 hours later if continuous infusion is used. If continuous infusion is not used, a second bolus of 10 mg / kg is administered either at the end of treatment or about 8 hours after the first dose. The maximum total dose administered over the course of treatment is about 80 mg / kg. The dose should be administered about 10 to 30 minutes before the start of treatment. For traumatic episodes, dosing should be administered within 3 hours of onset.

[0013] With oral administration, approximately half of the TA taken does not enter the bloodstream, so the minimum and maximum doses are twice that of IV administration. For indications such as heavy menstrual bleeding, repeated doses should be administered approximately every 8 hours for up to 5 days. The dosage of another common antifibrinolytic, epsilon aminocaproic acid, is approximately 10 times that of tranexamic acid.

[0014] For the purposes of the present invention, the antifibrinolytic agent can act prophylactically, by its continuous action in tissue, to prepare and protect the treatment area for subsequent non-surgical treatment, and promote a rapid and improved healing process after non-surgical treatment.The antifibrinolytic agent may be applied and configured in such a way that it does not negatively affect the treatment and / or injection material.In various embodiments, the antifibrinolytic agent may be delivered following injection to continue therapy throughout the post-treatment period, for example, for 2 to 7 days, during which delayed subcutaneous bleeding, inflammation and / or swelling may occur.

[0015] The present invention may be implemented when the antifibrinolytic agent is administered after the non-surgical treatment is started without pre-administration of the antifibrinolytic agent. In such implementation, the antifibrinolytic agent will be administered during and / or after the non-surgical treatment. If administered after the non-surgical treatment, such administration should be performed promptly, for example, within one hour after the non-surgical treatment is completed. Furthermore, the present invention may be implemented by mixing the antifibrinolytic agent with the treatment material to be injected. For example, tranexamic acid and hyaluronic acid may be mixed to form an injection material with or without pre-administration of the antifibrinolytic agent. In some embodiments, the antifibrinolytic agent may be aprotinin, tranexamic acid, epsilon aminocaproic acid (EACA), Kunitz domain (KD1) inhibitors, AZD 6564, and analogs or derivatives thereof.

[0016] Antifibrinolytics have been shown to improve the hemostatic process during surgery because they can reduce the dissolution or breakdown of blood clots. Antifibrinolytics have also been shown to be effective in reducing bleeding and blood transfusions in hemophilia patients undergoing dental extractions. Additionally, antifibrinolytics have been shown to reduce heavy menstrual bleeding when administered orally.

[0017] The present invention utilizes the activity of antifibrinolytic agents before, during and / or optionally after treatment to avoid or reduce unwanted bruising, inflammation and / or swelling in non-surgical procedures. The present invention recognizes that the activity of the present antifibrinolytic agents to reduce inflammation, bruising and / or swelling is not necessarily solely an antifibrinolytic function or solely related to reduced bleeding, but can also include preventative and healing effects by improving the tissue environment in the non-surgical treatment area such that healing is accelerated and the return to a more normal pre-treatment state is encouraged.

[0018] In various embodiments, the method of treating a human with an antifibrinolytic agent prior to non-surgical treatment may be used to reduce inflammation, subcutaneous bleeding, and / or swelling after treatment.In certain embodiments, the method includes using a pharmaceutical composition comprising an antifibrinolytic agent.In some embodiments, the pharmaceutical composition is a solution having an antifibrinolytic agent concentration of 30% (weight / volume) or less, optionally in a pharma- ceutically acceptable carrier in which the solution is suitable for use on human skin.In various embodiments, the concentration may be 60% (weight / volume) or less of the antifibrinolytic agent.

[0019] In certain embodiments, the pharmaceutical composition antifibrinolytic agent is tranexamic acid, and tranexamic acid can also be optionally in a pharma- ceutically acceptable carrier that can be applied to human skin.In other embodiments, antifibrinolytic agent can be administered prior to the injection of non-surgical treatment to reduce inflammation, subcutaneous bleeding and / or swelling after injection.In other embodiments, antifibrinolytic agent can be applied and configured in such a way that it does not negatively affect subsequent treatment.

[0020] In various embodiments, the method of treating a human with an antifibrinolytic agent before, during and / or after non-surgical treatment may be used to reduce inflammation, subcutaneous bleeding, and / or swelling.In certain embodiments, non-surgical treatment may be enhanced by an antifibrinolytic agent, thereby providing the benefit of extending the duration / function of dermal fillers and toxins.In various embodiments, a solution containing an antifibrinolytic agent may be used to reduce inflammation, subcutaneous bleeding, and / or swelling, and may have a limited application time, for example, 3 minutes.In other embodiments, the solution may have an application time ranging from about 2 to 5 minutes.In certain embodiments, the application time of the solution may range from 3 to 10 minutes.

[0021] Dermal fillers used in cosmetic / dermatological treatments, such as JUVEDERM® and RESTYLANE®, typically contain hyaluronic acid. Dermal fillers are typically injected into the skin (e.g., mid to deep dermis of the cheek, periocular or perilip / oral area) and act to add volume to the injection area, leaving a more youthful appearance. The effects of a dermal filler treatment usually last for 6 to 12 months. Toxins used in cosmetic / dermatological treatments typically contain neurotoxins, such as BOTOX®. These toxins are typically injected into the skin (e.g., glabella area) and act to relax facial muscles, thereby reducing lines and wrinkles around the injection area, with effects usually lasting for 3 to 6 months.

[0022] It is believed that antifibrinolytic drugs can prolong the time it takes for the body to break down injected substances, such as hyaluronic acid and / or various neurotoxins, by inhibiting the conversion of plasminogen to plasmin, which breaks down various substances such as fibrin and collagen.By prolonging the time it takes for the body to break down injected substances, the present invention aims to improve the performance of injections.In certain embodiments, antifibrinolytic drugs such as tranexamic acid can be utilized before non-surgical treatment, such as dermal filler injection, to reduce the swelling and bruising that typically results from treatment.In other embodiments, antifibrinolytic drugs such as tranexamic acid can be utilized after treatment (e.g., after dermal filler injection) to reduce bruising in the treatment area.

[0023] To further explore the role of antifibrinolytics in non-surgical treatments, high performance liquid chromatography (HPLC) analysis was performed on tranexamic acid and a carrier containing hyaluronic acid (i.e., hyaluronan), a common substance used to create a gel-like consistency in products applied topically to the skin and a potential carrier for antifibrinolytics in non-surgical treatments, as well as a common hyaluronic acid dermal filler containing cross-linked hyaluronic acid polymers for better longevity, to determine whether there was a change in each form of hyaluronic acid when mixed with tranexamic acid.First, ERACLEA® Skin Care skin care products containing 1% (w / v) hyaluronic acid polymers and preservatives were tested.After establishing the HPLC profiles of tranexamic acid and ERACLEA® products, tranexamic acid was added to the ERACLEA® products in an amount that resulted in a tranexamic acid concentration of 3% (w / v). Analyses were performed on fresh sample preparations that were mixed and immediately injected into the analytical HPLC system as well as on sample preparations that were mixed and allowed to stand for 20 minutes before injection.

[0024] Further HPLC analysis was performed on samples of the same ERACLEA® product with 0.5% (w / v) and 3% (w / v) tranexamic acid concentrations added several weeks prior. Further HPLC analysis was performed on hyaluronic acid dermal fillers, more specifically JUVEDERM® fillers, with 3% (w / v) tranexamic acid added. As with the previous studies, analysis of JUVEDERM® was performed using fresh sample preparations that were injected immediately for analysis as well as sample preparations that were left for 20 minutes before injection. No analysis showed any interaction between tranexamic acid and any form of hyaluronic acid polymer.

[0025] Additionally, HPLC analyses were performed on hyaluronic acid fillers, specifically JUVEDERM®, when mixed with human plasmin and when mixed with saline. The purpose of these analyses was to demonstrate the degradation of the hyaluronic acid fillers, specifically the complete degradation of the hyaluronic acid fillers in samples after treatment with human plasmin, with no effect when mixed with saline. The aforementioned analyses are described below in more detail for each analysis.

[0026] Development of an HPLC method for tranexamic acid. The sample preparation was as follows: 100 μL of tranexamic acid (source: AUROMEDICS®, concentration 100 mg / mL sterile solution) was taken from the vial with a syringe and diluted to a volume of 1000 μL by adding a 60:40 volume ratio of distilled water / acetonitrile aqueous solution. This stock solution was used multiple times to develop an HPLC method for comparison with hyaluronic acid polymers, bulking agents and human plasmin. Table 1 shown below represents the ultraviolet (UV) results of tranexamic acid performed by HPLC with a flow rate of 1 mL / min, a sample concentration of 10 mg / mL, an injection volume of 10 μL, a wavelength of 205 nm, and a solvent system of 40:60 volume ratio of acetonitrile / distilled water. As can be seen below, the retention time of tranexamic acid is 2.280 minutes. TIFF0007675501000001.tif36170

[0027] Development of an HPLC method for hyaluronic acid polymers. Sample preparation was performed as follows: 10 mg of hyaluronic acid polymer (source: ERACLEA®, pure hydrate) was weighed into a 2.5 mL autosampler vial and diluted to a volume of 1000 μL with a 60:40 volume ratio of distilled water / aqueous acetonitrile to be used as a standard stock solution. Table 2 below shows the UV results of hyaluronic acid polymer, which was performed by HPLC with a flow rate of 1 mL / min, a sample concentration of 10 mg / mL, and an injection volume of 10 μL, a wavelength of 205 nm, and a solvent system of 40:60 volume ratio of acetonitrile / distilled water. As can be seen below, the retention time of hyaluronic acid polymer is 7.467 minutes. TIFF0007675501000002.tif36170

[0028] Using the retention time of tranexamic acid of 2.280 min and the retention time of hyaluronic acid polymer of 7.467 min, the retention time difference calculated between tranexamic acid and hyaluronic acid polymer was 5.187 min.

[0029] HPLC assay to detect any binding interactions between tranexamic acid and hyaluronic acid polymers Table 3, shown below, presents the UV results for 3% (weight / volume) tranexamic acid in hyaluronic acid polymer, freshly prepared and immediately injected, and run on HPLC with a flow rate of 1 mL / min, a sample concentration of 10 mg / mL, and an injection volume of 10 μL, a wavelength of 205 nm, and a solvent system of acetonitrile / distilled water in a volume ratio of 40:60. As can be seen below, the retention times are 2.217 minutes and 7.577 minutes for tranexamic acid and hyaluronic acid polymer, respectively. TIFF0007675501000003.tif42170

[0030] Table 4, shown below, presents the UV results for 3% (wt / vol) tranexamic acid in freshly prepared hyaluronic acid polymer, allowed to sit for 20 minutes before injection, and run on HPLC at a flow rate of 1 mL / min, a sample concentration of 10 mg / mL, and an injection volume of 10 μL, a wavelength of 205 nm, and a solvent system of acetonitrile / distilled water in a volume ratio of 40:60. As can be seen below, the retention times are 2.217 minutes and 7.577 minutes for tranexamic acid and hyaluronic acid polymer, respectively. TIFF0007675501000004.tif42170

[0031] Based on data collected from samples of tranexamic acid in hyaluronic acid polymers that were immediately injected and subjected to HPLC, and samples of tranexamic acid in hyaluronic acid polymers that were left for 20 minutes before being injected and subjected to HPLC, there is no interaction between tranexamic acid and the hyaluronic acid polymer over a 20 minute period. To further illustrate the absence of an interaction between tranexamic acid and the hyaluronic acid polymer, HPLC analysis was performed on additional samples and at various concentrations.

[0032] Table 5, shown below, represents the UV results for 3% (wt / vol) tranexamic acid in a solution containing 1% (wt / vol) hyaluronic acid polymer, supplied by Hylaco, LLC. several weeks prior to conducting the HPLC analysis. The HPLC was performed at a flow rate of 1 mL / min, a sample concentration of 10 mg / mL, and an injection volume of 10 μL, a wavelength of 205 nm, and a solvent system of acetonitrile / distilled water in a volume ratio of 40:60. As can be seen below, the retention times are 2.210 minutes and 7.520 minutes for tranexamic acid and the hyaluronic acid polymer, respectively. Similarly, the data shown below suggests that there is no interaction between tranexamic acid and this hyaluronic acid polymer when mixed in solution. TIFF0007675501000005.tif41170

[0033] Table 6, shown below, represents the UV results for 0.5% (wt / vol) tranexamic acid in a solution containing 1% (wt / vol) hyaluronic acid polymer, supplied by Hylaco, LLC., several weeks prior to conducting the HPLC analysis. The HPLC was performed at a flow rate of 1 mL / min, a sample concentration of 12.0 mg / mL, and an injection volume of 10 μL, a wavelength of 205 nm, and a solvent system of acetonitrile / distilled water in a volume ratio of 60:40. As can be seen below, the retention times are 2.197 minutes and 7.593 minutes for tranexamic acid and hyaluronic acid polymer, respectively. TIFF0007675501000006.tif41170

[0034] Table 7, shown below, represents the UV results for 0.5% (wt / vol) tranexamic acid in hyaluronic acid polymer (scratch sample) supplied by Hylaco, LLC. several weeks prior to conducting the HPLC analysis. The HPLC was performed at a flow rate of 1 mL / min, a sample concentration of 11.6 mg / mL, and an injection volume of 10 μL, a wavelength of 205 nm, and a solvent system of acetonitrile / distilled water in a volume ratio of 40:60. As can be seen below, the retention times are 2.170 minutes and 7.497 minutes for tranexamic acid and hyaluronic acid polymer, respectively. TIFF0007675501000007.tif42170

[0035] The above data show that tranexamic acid does not appear to interact with this form of hyaluronic acid polymer in aqueous solution with a gel-like consistency for easy topical application. Thus, tranexamic acid is shown to be compatible with carriers used in topical preparations. Further analysis was performed to determine whether tranexamic acid interacts with the crosslinked form of hyaluronic acid used in dermal fillers, particularly one of the JUVEDERM® family of fillers, and therefore whether it is suitable for use before and after non-surgical treatments to reduce inflammation, subcutaneous bleeding and / or swelling when non-surgical treatments utilize hyaluronic acid dermal fillers.

[0036] Development of an HPLC method for hyaluronic acid fillers. The sample preparation was as follows: 13 mg of packing material (source: JUVEDERM® Vollere XC) was weighed into a 2.5 mL vial and diluted to a volume of 1000 μL with a 60:40 volume ratio of distilled water / aqueous acetonitrile. Table 8 shown below represents the UV results of JUVEDERM® Vollere XC, which was run on HPLC at a flow rate of 1 mL / min, a sample concentration of 13 mg / mL (from a syringe), and an injection volume of 10 μL, a wavelength of 205 nm, and a solvent system of 40:60 volume ratio of acetonitrile / distilled water. As seen below, the retention times for the packing material were 2.167 min, 3.420 min, and 9.953 min, with the maximum area obtained at retention time 3.420 min. TIFF0007675501000008.tif48170

[0037] Table 9, shown below, presents the UV results for 3% (wt / vol) tranexamic acid in JUVEDERM® packing material, freshly prepared and immediately injected, and run on HPLC with a flow rate of 1 mL / min, a sample concentration of 10 mg / mL, and an injection volume of 10 μL, a wavelength of 205 nm, and a solvent system of acetonitrile / distilled water in a volume ratio of 40:60. As can be seen below, the retention times are 2.327 minutes and 3.143 minutes for tranexamic acid and JUVEDERM® packing material, respectively. TIFF0007675501000009.tif41170

[0038] Table 10, shown below, presents the UV results for freshly prepared 3% (wt / vol) tranexamic acid in JUVEDERM® packing, allowed to sit for 20 minutes before injection, and run on HPLC at a flow rate of 1 mL / min, a sample concentration of 10 mg / mL, and an injection volume of 10 μL, a wavelength of 205 nm, and a solvent system of acetonitrile / distilled water in a volume ratio of 40:60. As can be seen below, the retention times are 2.327 minutes and 3.143 minutes for tranexamic acid and JUVEDERM® packing, respectively. TIFF0007675501000010.tif41170

[0039] Based on data collected from tranexamic acid in JUVEDERM® filler immediately injected and run on HPLC, and from samples left for 20 minutes before being injected and run on HPLC, there is no interaction between the tranexamic acid and the filler over a 20 minute period. The data suggests that if there is any interaction between tranexamic acid and the dermal filler material, it would be exhibited during direct contact between the two over a 20 minute period, especially since there was no interaction between tranexamic acid and hyaluronic acid in gel solution when in contact for several weeks.

[0040] To investigate the possibility of degradation of hyaluronic acid fillers due to human plasmin, hyaluronic acid fillers exposed to human plasmin and immersed in saline were analyzed by HPLC.

[0041] HPLC assay to measure the degradation of hyaluronic acid fillers exposed to human plasmin. The sample preparation was as follows: 13 mg of packing material (source: JUVEDERM® Vollere XC) was weighed into a 2.5 mL vial and diluted to a volume of 1000 μL by adding a 60:40 volume ratio of distilled water / aqueous acetonitrile. From this stock solution, 100 μL was taken and mixed with 100 μL of 5 U (0.5 mL) of human plasmin (source: Sigma Aldrich, Lot #17148421), shaken slowly for 15 minutes, filtered, and injected into the HPLC system. Table 11 below shows the UV results of the sample that was subjected to HPLC with a flow rate of 1 mL / min, a sample concentration of 13 mg / mL, and an injection volume of 10 μL, a wavelength of 205 nm, and a solvent system of 40:60 volume ratio of acetonitrile / distilled water. The data below suggests that there is complete degradation of the filler hyaluronic acid polymer following treatment with human plasmin, as no retention peak is observed at 3.14 minutes (ie, the filler peak). TIFF0007675501000011.tif42170

[0042] Shown above are retention times of 3.003 and 3.900 minutes with the apparent absence of a retention peak at 3.14 minutes. Table 11 shows complete degradation of the filler hyaluronic acid polymer after treatment with human plasmin, as there is no retention peak at 3.14 minutes that would have appeared if filler had been present.

[0043] Comparison of the bulking agent data with that of the bulking agent treated with human plasmin shows that the retention peak at 3.14 is not present in the bulking agent treated with human plasmin, while this retention peak is clearly observable in the bulking agent. The data indicates complete degradation of the bulking agent hyaluronic acid polymer after treatment with human plasmin.

[0044] HPLC study to measure the degradation of hyaluronic acid fillers after immersion in saline The sample preparation was as follows: 10 mg of packing material (source: JUVEDERM® Vollere XC) was weighed into a 2.5 mL vial and diluted to a volume of 1000 μL by adding a 60:40 volume ratio of distilled water / aqueous acetonitrile. From this stock solution, 100 μL was taken and mixed with 100 μL of saline (source: Hospira, Inc., Lot 64-154-DK), shaken slowly for 15 minutes, filtered, and injected into the HPLC system. Table 12 shown below shows the UV results of the sample that was subjected to HPLC with a flow rate of 1 mL / min, a sample concentration of 10 mg / mL, and an injection volume of 10 μL, a wavelength of 205 nm, and a solvent system of 40:60 volume ratio of acetonitrile / distilled water. As seen below, the retention times are 2.353 min and 3.120 min. TIFF0007675501000012.tif41170

[0045] Summary of results As noted in the preceding discussion, tranexamic acid does not appear to interact with hyaluronic acid, whether in gel form or crosslinked form for use as a dermal filler, and therefore would be suitable for use before and after non-surgical treatments to reduce inflammation, subcutaneous bleeding and / or swelling when the non-surgical treatment involves a hyaluronic acid-based dermal filler.

[0046] As mentioned above, the mixture of tranexamic acid and JUVEDERM® was left for 20 minutes, indicating that there was no interaction between tranexamic acid and the dermal filler material. Furthermore, there was no interaction between tranexamic acid and the hyaluronic acid in the ERACLEA® product when left in contact for several weeks, and the cross-linked hyaluronic acid in the dermal filler is generally much more robust than non-cross-linked hyaluronic acid. In a dermal filler treatment, tranexamic acid will generally come into contact with the hyaluronic acid material in the skin within about 18 hours before the tranexamic acid is metabolized by the body.

[0047] Furthermore, the data indicate that since filler hyaluronic acid polymers are completely degraded by human plasmin, and antifibrinolytic agents such as tranexamic acid inhibit the conversion of plasminogen to plasmin, the use of tranexamic acid can actually increase the duration and effectiveness of in vivo filler treatments.

[0048] Furthermore, as discussed below, clinical trials show that the addition of tranexamic acid to non-surgical treatments has been shown to reduce subcutaneous bleeding and swelling compared to clinical trials conducted in the absence of antifibrinolytic agents such as tranexamic acid.

[0049] Clinical Trials A randomized controlled clinical evaluation of JUVEDERM® Ultra XC in the nasolabial fold was conducted over a two-week period (performed by Allergan) to determine common treatment site reactions by severity and duration. The most common injection site reactions to JUVEDERM® Ultra XC were redness, swelling, tenderness, firmness, lumps / bumps, discoloration, and bruising. Overall, the study found that 86% of subjects reported swelling and 59% reported bruising.

[0050] In a non-surgical study conducted over a period of approximately one year, 318 patients were exposed to a solution containing tranexamic acid at a concentration of 3% (weight / volume) before and after injection of hyaluronic acid dermal filler. Fewer than 1% of patients reported the occurrence of exponential and unexpected decline in subcutaneous bleeding and swelling compared to hyaluronic acid filler treatment without the use of tranexamic acid. Three of the 318 patients reported the occurrence of subcutaneous bleeding or swelling.

[0051] As mentioned above, in clinical use, tranexamic acid plays an important role in suppressing subcutaneous bleeding and swelling. This may be due to the activity of antifibrinolytic drugs at the injection site of non-surgical treatment. Furthermore, based on the above test data, antifibrinolytic drugs may play an important role in delaying the degradation of injected hyaluronic acid dermal fillers by inhibiting the conversion of plasminogen to plasmin.

[0052] In various embodiments, the antifibrinolytic agent may be aprotinin, tranexamic acid, epsilon aminocaproic acid (EACA), Kunitz domain (KD1) inhibitors, AZD 6564, and analogs or derivatives thereof. In various embodiments, the Kunitz domain inhibitor may be a Kunitz-type inhibitor similar to KD1.

[0053] In certain embodiments, EACA may be utilized as an antifibrinolytic agent in an EACA solution of 60% (w / v) or less. In some embodiments, the concentration of EACA may range from about 7% (w / v) to about 60% (w / v).

[0054] In other embodiments, tranexamic acid may be utilized as an antifibrinolytic agent in a tranexamic acid solution of up to 30% (w / v). In various embodiments, the concentration of tranexamic acid may range from about 0.7% (w / v) to about 30% (w / v).

[0055] In a further embodiment, aprotinin may be utilized as the antifibrinolytic agent in an aprotinin solution of at least 0.1% (weight / volume).

[0056] In still further embodiments, KD1 may be utilized as an antifibrinolytic agent in a solution of at least 0.1% (weight / volume) KD1.

[0057] In certain embodiments, AZD 6564 may be utilized as an antifibrinolytic agent in a solution of 15% (w / v) or less. In further embodiments, the concentration of AZD 6564 may range from about 0.35% (w / v) to about 15% (w / v).

[0058] Various embodiments of the disclosed methods and compositions are illustrated in the accompanying tables and figures, and described in the foregoing specification, but it will be understood that the invention is not limited to the disclosed embodiments, but is capable of numerous rearrangements, modifications, and substitutions without departing from the spirit and scope of the invention as set forth herein. The specification and examples are intended to be interpreted as illustrative only.

Claims

1. A medicament for improving the treatment of non-surgical therapy, comprising an antifibrinolytic agent, Non-surgical treatment is started on an area of ​​skin, Non-surgical treatment will continue until completion of non-surgical treatment. an antifibrinolytic agent is applied to said area of ​​skin, said application being at least one of before, during, and after non-surgical treatment has begun; A medicament, wherein the non-surgical treatment is an injection or application of a hyaluronic acid polymer, and the antifibrinolytic agent is tranexamic acid having a tranexamic acid concentration range of 0.7% to 3% (weight / volume), and applying the antifibrinolytic agent is for minimizing swelling, for minimizing inflammation, for minimizing subcutaneous bleeding, or for extending the duration / function of the non-surgical treatment.

2. The method of claim 1, wherein applying an antifibrinolytic agent minimizes swelling, minimizes inflammation, or minimizes subcutaneous bleeding.

3. an antifibrinolytic agent is mixed with the therapeutic material to form a mixed material; and The method of claim 1 , wherein the mixed material is injected into the area of ​​skin to be treated.

4. 2. The pharmaceutical of claim 1, wherein the antifibrinolytic agent is part of a solution, or is part of a solution that is applied topically, or is part of a solution having an antifibrinolytic agent concentration of 60% (weight / volume) or less.

5. 5. The method of claim 4, wherein the antifibrinolytic agent is tranexamic acid having a tranexamic acid concentration of 3% (weight / volume).

6. The pharmaceutical of claim 4, wherein the antifibrinolytic agent is applied as part of a pharma- ceutically acceptable carrier that renders the solution compatible with human skin or is delivered systemically.

7. 2. The method of claim 1, wherein applying comprises administering the antifibrinolytic agent directly onto or into human skin before, during, or after injection or application of the non-surgical treatment.

8. A composition for enhancing non-surgical treatment, comprising an antifibrinolytic agent, an antifibrinolytic agent is applied to an area of ​​skin, said application being at least one of before, during, and after the non-surgical treatment has been initiated; A composition wherein the non-surgical treatment is an injection or application of a hyaluronic acid polymer, the antifibrinolytic agent is tranexamic acid having a tranexamic acid concentration range of 0.7% to 3% (weight / volume), and applying the antifibrinolytic agent is for minimizing swelling, for minimizing inflammation, for minimizing subcutaneous bleeding, or for extending the duration / function of the non-surgical treatment.

9. 9. The composition of claim 8, wherein the antifibrinolytic agent is part of a solution or is part of a solution having an antifibrinolytic agent concentration of 60% (weight / volume) or less.

10. 10. The composition of claim 9, wherein the antifibrinolytic agent is applied topically as part of a pharma- ceutically acceptable carrier that renders the solution compatible with human skin.

11. 9. The composition of claim 8, wherein the antifibrinolytic agent is tranexamic acid having a tranexamic acid concentration of 3% (weight / volume).

12. The composition of claim 8 , wherein the composition is used in combination with a non-surgical treatment.

13. The composition of claim 8 , wherein application of the composition minimizes swelling, inflammation, or bruising.

14. 10. The composition of claim 8, which is administered directly onto or into human skin before, during, or after injection or application of a non-surgical treatment.

15. The composition of claim 8 mixed with a pharma- ceutically acceptable carrier, gel, lotion, or cream.

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