The compound formulations for the treatment and delivery of drugs on open wounds, closed wounds and donor site wounds

Abstract

The compound formulations for the treatment and administration of drugs in open wounds, closed wounds and skin graft donor site wounds consists of the following: bupivacaine, tranexamic acid, adrenaline and hydrogel in the form of solution, hydrogel amorphous or hydrogel sheets. The hydrogel form consists of main ingredient drugs combined with one or more of hydrogel-forming polymers selected from a group consisting of one or more combinations of carboxymethyl cellulose, gelatin and pectin. The method for treating wounds in patients consists of applying the compound formula to the wound. The wounds are selected from a group consisting of surgical wounds, injury wounds, chronic and burn wounds. The compound formula is applied to wounds in the form of solution, hydrogel amorphous or hydrogel sheets.

Description

[0001] THE COMPOUND FORMULATIONS FOR THE TREATMENT AND DELIVERY OF DRUGS ON OPEN WOUNDS, CLOSED WOUNDS AND DONOR SITE WOUNDS

[0002] Technical Field

[0003] Pharmaceutical sciences, medications for treating disease, anaesthesiology, and medical devices involving compound formulations for the treatment and delivery of drugs in open wounds, closed wounds, and donor site wounds.

[0004] Background Art

[0005] Both external and internal wound care continu to be a major clinical challenge for healthcare professionals from past to present. Common problems in wound care include the following:

[0006] 1. Post-injury or postoperative pain, which triggers the secretion of stress hormones that hinder wound healing.

[0007] 2. Amount of fluid leakage from severed small lymphatic and other capillaries, thereby leading to the development of hematoma or seroma.

[0008] 3. Complications such as localized bacterial infection, incision separation, and slower healing than usual according to the natural wound healing mechanism.

[0009] 4. Abnormal scarring, such as keloid scarring, raised scars and poor wound quality.

[0010] The wound healing process consists of 4 main stages: the hemostasis phase, the inflammation phase, the proliferation phase, and the remodelling phase. The inflammation phase is a key phase involving pain, the amount of secretions, infection and wound healing time. Therefore, proper control of the inflammatory process is necessary in promoting wound healing and good clinical outcomes.

[0011] Bum wounds continue to be a current major public health and medical problem, particularly severe bum wounds that cause pain, inflammation, infection and delayed wound healing. It affects patients physically and mentally in addition to affecting quality of life and being an economic burden on the health care system. The bum wound dressing materials currently used also have numerous limitations such as inability to achieve effective pain management, inability to properly control inflammation and bum wound environment as well as inadequate to prevent infection.

[0012] During the inflammation phase (first 3-5 days), the donor site of a split-skin graft wound involves a large amount of bloody lymph fluid. The use of gauze alone to cover the wound does not reduce the amount of secretions. Instead, it creates a moist environment that promotes bacterial infections and causes wounds to heal naturally more slowly than usual. Proper materials for covering the donor sites of split-skin graft wound sites should have pain relief properties, inhibit inflammation and reduce the amount of bloody lymp fluid, while promoting tissue regeneration, preventing bacterial infection, promoting quality scarring and being easy to use.

[0013] Axillary lymph node dissection and inguinal lymph node dissection are important parts of treatment for breast and other cancers that have metastasized to the lymph nodes. Although it is useful for disease control and reduction of recurrence, it is often accompanied by major postoperative complications, particularly the occurrence of seroma in 30-80% of all cases, and potentially leadng to other subsequent problems such as infection, incision separation and seroma, which greatly and negatively affects the patient's recovery and quality of life. [4]

[0014] Breast surgery, abdominal surgery and tumor removal are all procedures that carry the risk of surgical complications such as infection, incision separation, and delayed healing, which affect the treatment outcomes and quality of life of patients.

[0015] Although there are currently various types of wound care products such as gauze, hydrocolloid, foam, alginate and hydrogel, there are still limitations in solving these problems comprehensively. Current treatments often focus on managing the absorption of secretions and reducing pain during the changing of wound dressing materials, which is only part of the wound healing process. There is still a gap in the development of wound care products that help manage pain, decrease the amount of secretions, inhibit inflammation and reduce bacterial infections, while promoting wound healing and quality scarring. [6]

[0016] Recent research on postoperative wound pain management has found that good pain control can reduce the incidence of hematoma or seroma, because pain causes contractions of the small muscles around blood vessels and lymphatic vessels, which increases pressure in the capillaries. As a result, blood clots are released and the formation of new blood clots is prevented, which increases wound seepage. Therefore, effective pain relief methods are important in preventing these complications.

[0017] Research over the past 5 years has, therefore, focused on managing pain after skin graft harvesting surgery, which is often highly severe during the first 3-5 days as a result of sensory nerve ending injury causing hot, stinging pain at the site of the wound. The visual analog pain score is usually as high as 7-9 points (visual analog pain score) in the early stages. The use of paracetamol analgesics and non-steroidal anti-inflammatory drugs (NSAIDs) alone is frequently insufficient. Thus, there is a need to rely on opioids, which have major side effects such as nausea and vomiting. In addition, the adrenaline naturally secreted by the body when there is stress or pain can trigger inflammatory mechanisms, increase sensitivity to pain reduce peripheral blood flow and slow wound healing.

[0018] Tranexamic acid is an antithrombotic drug and a synthetic substance similar to lysine that can inhibit fibrin dissolution. The transformation of plasminogen to plasmin helps prevent the breakdown of blood clots, helps prevent bleeding disorders, reduces inflammation, and supports wound repair. Significant reductions in blood loss, support of hemostasis, and postoperative complications in various areas of surgery have been widely studied. Direct application of drugs to the wound site is likely to be as effective as intravenous administration, but with fewer side effects. [9]

[0019] A study on the use of topical tranexamic acid before stitching sutures in axillary lymph node surgery found this method to reduce the seepage of residual fluids from surgical wounds and reduce the number and duration of drainage tube usage including postoperative complications with statistical significance when compared to the control group in terms of complications.

[0020] The research of Huang et al. conducted a systematic literature review and a metaanalysis of the use of tranexamic acid in knee replacement surgery, finding that topical medications can reduce blood loss, the need for blood transfusions and postoperative anemia with statistical significance without increasing the risk of thrombosis.

[0021] In addition, a study by Ausen et al. found that moistening breast cancer lesions with tranexamic acid before suturing can reduce fluid retention in the wound and shorten the duration of insertion of the drainage tubes without increasing the risk of other complications or side effects. However, in the case of axillary lymph node dissection, no benefit of tranexamic acid was found to affect the amount of postoperative seroma, which provides an opportunity to continue searching for new methods.

[0022] Later on, Lohani et al. conducted a prospective study in 93 patients undergoing breast cancer surgery with axillary lymph node dissection by randomly administering intravenous tranexamic acid at a dose of 15 mg / kg before surgery and 1000 mg daily for 5 days after surgery. Compared with the control group, the results showed that the group administered tranexamic acid had a significantly lower lymph yield at 24 hours and a statistically significant lower total lymph yield with ability to remove the drainage tubes faster, with a lower but not statistically significant tendency to develop postoperative seroma. In addition, intravenous administration of tranexamic acid may increase the risk of complications and may not be appropriate in some patients.

[0023] Later on, Weissler et al. conducted a retrospective study comparing the use of topical tranexamic acid during breast augmentation surgery with artificial breast sacs. The patients were administered topical tranexamic acid to heal the surgical wound before suturing. The results showed that the group administered topical tranexamic acid had a lower postoperative seroma incidence rate that the group not administered topical tranexamic acid and a slightly shorter duration of drainage tube insertion without increasing the risk of other complications. This study supports the idea that the use of topical tranexamic acid is likely to have a positive effect in terms of reducing zero-tolerance compared to intravenous administration and offers greater safety.

[0024] Research on pain management in surgical wounds has found that the use of local anesthetics such as bupivacaine to control postoperative pain can have the effect of reducing the occurrence of postoperative seroma. By relieving pain, it reduces the secretion of stress hormones, which have the effect of increasing inflammation, capillary leakage and fibrin dissolution. In addition, pain triggers spasms of the small muscles, which results in more blood and lymph leakage. The type of usage can be either a solution moistened with gauze to cover the wound or injected into the surgical site.

[0025] According to a study by Tauzin et al., injecting bupivacaine into foot surgery wounds can efficiently reduce the formation of subdural blood clots and lymph fluid in comparison to the use of medications in general. Furthermore, a study by Yao et al. found that the use of local anesthesia reduced the occurrence of seroma following radical mastectomy with axillary lymph node dissection with statistical significance. Therefore, the use of analgesics with anti-inflammatory effects, such as bupivacaine, is important in preventing this complication.

[0026] Use of vasoconstrictor drugs such as adrenaline, a hormone that triggers the contraction of blood vessels and capillaries, is used to control bleeding and reduce swelling at the wound sites for many types of surgery. This method is widely used in the form of both intradermal injections and topical application to the wound site. There is data to support the safety and efficacy of the above method in inhibiting seepage and reducing complications caused by blood loss and reducing blood and lymph seepage following axillary node dissection. Dissolving adrenaline in saline at a concentration of no more than 1:1000 is effective in achieving hemostasis without adversely affecting the cardiovascular system.

[0027] Although each drug is efficient in treating specific symptoms, there are significant limitations. For example, bupivacaine alone may not be sufficient to control severe pain and has no anti-inflammatory or hemostatic effects. Tranexamic acid reduces the breakdown of blood clots but does not have an analgesic effect, and adrenaline helps stop bleeding but can cause tachycardia if used in large doses. Mixing the three drugs together in the right proportions is a potential approach to properly addressing these limitations and increasing wound healing efficiency.

[0028] The formula of 3 compounds, namely bupivacaine, tranexamic acid, and adrenaline, is useful for management and promotion of healing in open wounds, closed wounds, split-skin thickness graft donor site wounds, bum wounds, and other surgical incision wounds, with comprehensive and synergistic mechanisms of action for pain relief, hemostasis, antiinflammatory effects, and triggering of wound repair; In addition to the direct effects of each active ingredient, mixing substances together in different ways will also enhance the properties suitable for use on various wounds more effectively.

[0029] Hydrogel is a highly interesting pharmaceutical form of drug delivery through surgical wounds and is gaining more attention in today’s wound care due to its abilities to absorb excess fluid, maintain a moist environment, exchange gases, relieve pain, promote wound healing, and gradually release important drugs continuously, including having mechanical properties suitable for use. It adheres well to wounds, peels off easily, and does not irritate the skin. In addition, other active ingredients can be easily added to the gel or hydrogel such as antibiotics, natural extracts, or tissue growth enhancers to boost healing efficiency.

[0030] Hydrogel is made of a hydrophilic polymer network with high flexibility and water retention properties (> 90% by weight). Usage options include sheet and amorphous types. The latest research has studied the addition of drugs to hydrogel to increase efficiency. For example, Boonprasertpoh et al. found that hydrogel with hyaluronic acid and ascorbic acid stimulates collagen production and increases wound healing rates in mice, while Gupta et al. reported that hydrogel with the addition of natural aloe vera extract reduces inflammation, increases collagen and promotes bum wound healing in mice better than hydrogel alone.

[0031] There is also research on the addition of tranexamic acid, bupivacaine or adrenaline to hydrogel, as reported by Chang et al., who studied hydrogel mixed with 5% tranexamic acid in the control of bleeding after spinal surgery. Patients who were administered hydrogel with tranexamic acid had less bleeding than those administered only hydrogel. Zhang et al. developed hydrogel to gradually release bupivacaine and were able to relieve postoperative pain in mice for more than 48 hours. Furthermore, the research of Zhao et al. found that hydrogel with adrenaline was able to inhibit blood seepage from surgical wounds following lymph dissection in dogs better than in the control group. These results suggest that the addition of anti-inflammatory drugs, analgesics and hemostatic agents to hydrogel may help enhance wound care more efficiently and potentially apply hydrogel technology in the administration of drugs in surgery.

[0032] Most of the hydrogel used in medicine is prepared from biopolymers, including propylene glycol, carboxymethyl cellulose, pectin, alginate, collagen, chitosan, hyaluronic acid and cellulose. Other additives might include stabilizing agents, pH adjusters and preservatives to give hydrogel suitable properties for use and storage. A study by Koehler et al. found that propylene glycol is relatively safe when used through the skin, while carboxymethyl cellulose and pectin are reported to be non-irritating and are well accepted when used in appropriate doses.

[0033] All of the above suggests that the main components in hydrogel are likely to be safe enough for use in wound care and reducing lymphatic seepage. The design is aimed at obtaining an easy-to-use form of water, gel, and bandage sheets to overcome the limitations of existing wound dressings and meet unresolved clinical needs, such as commonly used paraffin-soaked gauze that often attaches to wounds.

[0034] In addition, hydrogel sheets represent another interesting option for administering medication and managing wounds because they are convenient to use, adhere well to the wounds, release medication continuously, and are easy to remove. The production of hydrogel sheets is done by pouring a polymer solution into a mold, adding a cross-linking agent, allowing it to hold its shape, then drying it into sheets. Hydrogel sheet properties such as mechanical strength, ability to retain water and medication release rate, ability to be customized by selecting the type and amount of polymer, cross-linking agents and additives. Examples of biopolymers used to produce hydrogel sheets include alginate, chitosan, gelatin, and cellulose.

[0028]

[0035] For example, Lee et al.'s research developed silk-particle mixed hydrocolloid sheets and compared them with standard hydrocolloid sheets and found that the sheets developed had a more stable structure with the ability to retain shape at 80% when exposed to water, while standard sheets retained only 72% of their shape. Dave et al. compared bandage sheets containing collagen with the previous type of bandage sheets and found the collagen sheets to be significantly more convenient to use and to offer greater patient satisfaction. In addition, the use of hydrogel pads in the administration of antibiotics for wound infections such as metronidazole and silver sulfadiazine has been reported [29,30].

[0036] Apart from the impact on patient health, chronic wounds and complications from surgical wounds also have a significant economic impact. According to a 2023 study, the global cost of treating chronic wounds ulcers reaches USD 50 billion per year and is expected to increase to USD 70-80 billion within the next decade.

[0067] In Thailand, the cost of treating pressure sores alone has been reported to be as high as 1.4 billion baht per year.

[0068] Furthermore, surgical wound complications, such as surgical site infections, also increase medical costs by an average of USD 20,785 per patient and extend hospital stays by an average of 11.2 days.

[0069] . For this reason, the development of effective wound treatment methods is of great importance, both in terms of improving clinical outcomes and reducing the economic burden on the public health system.

[0037] The inventors conducted a literature review related to the care of open, closed and surgical wounds. Frequently encountered problems include pain, high amounts of secretions from wounds, infection and delayed healing. This remains a major clinical challenge for healthcare professionals, despite the wide range of wound care products currently available. However, most available options continue to have significant limitations. For example, gauze absorbs only limited secretions and needs to be changed frequently. Hydrocolloids can cause skin flaking when used for a long time. Foam is often expensive and not suitable for wounds with low secretion. Alginate might become dry and easily stick to the wound. Most currently available hydrogel does not have analgesic or anti-inflammatory effects.

[0033] In addition, there is no product that can deal with pain, inflammation, stop bleeding and promote wound healing at the same time.

[0038] Based on the abovementioned research data, this is the reason why the inventor came up with the idea of developing a compound formula containing bupivacaine, tranexamic acid and adrenaline. It is important to form a hydrogel solution and hydrogel sheets as an attractive alternative to local drug administration and promote wound healing. By designing an appropriate composition and physical properties, including the selection of effective active ingredients such as analgesics, antimicrobials, or tissue regeneration stimulants, bleeding and lymph infiltration can be reduced, while controlling inflammation, which better meets the needs of a wide range of wound care.

[0039] This is particularly true for skin graft donor wound sites and is expected to increase the efficiency of pain relief, control inflammation, promote wound healing, prevent localized bacterial infections and promote quality scarring. Furthermore, it may be useful in effectively reducing the occurrence of seroma and related complications in lymph node surgery, which is a major clinical problem that still needs to be solved.

[0040] The invention can also be used in the form of hydrogel amorphous and hydrogel sheets to help address the limitations of existing wound closure materials and meet unresolved clinical needs. It is also convenient for further clinical use.

[0041] In conclusion, the inclusion of a full range of anti-inflammatory, analgesic and hemostatic active ingredients in the same formula for use in wound care has not be covered in studies. For this reason, the inventor came up with the idea of developing a compound formula containing bupivacaine, tranexamic acid and adrenaline with comprehensive effects on pain management, reducing bleeding, and controlling inflammation in the form of solution, hydrogel amorphous and hydrogel sheets to be used to treat and promote the healing of open and closed wounds more effectively.

[0042] This is particularly true for donor sites of split thickness skin graft wounds, scalding bum wounds, and breast surgery wounds, and axillary and groin lymph nodes, which often lead to postoperative pain. Large amounts of lymph fluid mixed with blood and delayed natural recovery are frequent. Relying on a variety of drug delivery modalities, such as hydrogel solution and hydrogel wound bandage sheets, which have advantages over single drug or intravenous administration, and are expected to improve treatment efficiency, reduce pain, reduce complications, decrease the time it takes to use the liquid drainage tubes and promote wound healing.

[0043] The properties of hydrogel enable it to balance the wound environment, absorb secretions and gradually release key medications, which will help enhance the effective treatment of wounds, while preventing and treating seroma effectively. In particular, the properties of hydrogel that can administer drugs for a long time and continuously, in addition to having properties suitable for use in various surgical wounds, will help solve problems that have been encountered with single or intravenous drug administration, and are expected to increase effectiveness in reducing complications, further reducing the duration of insertion of the drains and promoting wound healing in this group of patients. This will lead to benefits in terms of better clinical outcomes, increase the quality of life of patients, and reduce the economic burden on the health system, are of which are considered significant challenges and goals for the development of surgical wound care methods in the future.

[0044] Description of Embodiments

[0045] The compound formulations for the treatment and administration of drugs in open wounds, closed wounds and skin graft donor wound sites include the following: bupivacaine, tranexamic acid and adrenaline. The formula is in the form of hydrogel solution or hydrogel sheets in which the hydrogel consists active ingredients in combination with one or more polymers that form hydrogel, selected from a group containing carboxymethyl, cellulose, gelatin and pectin, from which one or a combination of several is selected. The method for treating wounds in patients consists of applying a compound formula to the wound, with the wound selected from the group consisting of surgical wounds, wounds from injuries, chronic sores, and bum wounds. The compound is applied to the wound in a hydrogel solution form or hydrogel sheets. The purpose of this invention is to provide a convenient formulation for closed wounds, open wounds, and split thickness skin graft donor wound sites to reduce the sensation of pain, reduce the breakdown of blood clots and prevent bleeding, and to constrict capillaries and reduce lymph seepage in the form of liquid, gel or convenient sheets.

[0046] Full Disclosure of Inventioii

[0047] The compound formulations for the treatment and administration of drugs in open wounds, closed wounds and skin graft donor wound sites include the following: a) Bupivacaine at 0.1 -0.5% by weight. b) Tranexamic acid at 1-5% by weight. c) Adrenaline at 1:10,000-1:200,000.

[0048] The formula is in the form of a solution, hydrogel amorphous or hydrogel sheets.

[0049] The solution form consists of a main ingredient drug dissolved in a suitable solvent that can be selected from liquid for injection or balanced saline.

[0050] The hydrogel form consists of a a main ingredient drug in combination with one or more of the polymers that form hydrogel, selected from a group consisting of one or more combinations of carboxymethyl cellulose, gelatin and pectin.

[0051] The hydrogel form consists of a main ingredient drug in combination with one or more of the polymers that form a hydrogel, selected from a group consisting of the following:

[0052] Carboxymethyl cellulose at 1-5% by weight.

[0053] Gelatin at 1-10% by weight.

[0054] Pectin at 3-10% by weight.

[0055] Hydrogel sheets consist of a porous backing material soaked in a solution of the main ingredient drug, or hydrogel.

[0056] The porous backing material is selected from a group consisting of polyester fiber and collagen matrix. The formulation also contains one or more additives selected from a group consisting of pH adjusters, preservatives, and emulsifiers.

[0057] The method for treating wounds in patients consists of applying a compound formula to the wound, with the wound selected from the group consisting of surgical wounds, injury wounds, chronic sores, and bum wounds with compound formulations applied to wounds in the form of hydrogel solution or hydrogel sheets.

[0058] The compound formulations for the treatment and administration of drugs in open wounds, closed wounds and donor site wounds are applied in the treatment process as follows: a) Solubility of bupivacaine, tranexamic acid and adrenaline in a suitable solvent to obtain a solution. b) Adding one or more types of hydrogel-forming polymers to a solution to obtain a hydrogel (this procedure is optional) and c) Soaking in support materials with hydrogel solution or to obtain hydrogel sheets (this procedure is optional).

[0059] The polymers that form hydrogel are selected from a group consisting of carboxymethyl cellulose, gelatin and pectin.

[0060] The polymers that form hydrogel are selected from a group consisting of the following:

[0061] Carboxymethyl Cellulose at 1-5% by weight.

[0062] Gelatin at 1-10% by weight.

[0063] PECTIN at 3-10% by weight

[0064] The porous backing material is selected from a group consisting of polyester fiber and collagen matrix.

[0065] The compound formulation also contains one or more additives selected from a group consisting of pH adjusters, preservatives, and emulsifiers. The weight ratios of bupivacaine: tranexamic acid: adrenaline range from 1:10-50:0.001- 0.01.

[0066] The concentration of bupivacaine is within a range of 0.25-0.5%, while the concentration of tranexamic acid is within a range of 3-5% by weight, and the concentration of adrenaline is within a range of 1 : 10,000-1 :200,000.

[0067] The quality control methods for the compound formulas in Claim 1 are composed of the following: a) Examination of the purity and quality of all types of raw materials before they are used in production. b) Control of the temperature and humidity in the production room within a designated range. c) Examination of the accuracy of weighing and dosing every time. d) Testing of the pH and viscosity of the product during the production process. e) Examination of the sterility of finished products. f) Testing of drug release in finished products.

[0068] The method for testing the stability of compound formulas in Claim 1 consists of the following: a) Testing of physical stability by observing changes in the external characteristics, color, odor and viscosity of the product at temperatures of 25 and 40 degrees Celsius for 6 months. b) Testing of chemical stability by analyzing the amounts of main ingredient drugs by the HPLC technique at 0, 1, 3 and 6 months. c) Testing of pH stability by measuring the pH of the product at 0, 1, 3 and 6 months.

[0069] Brief Description of Drawings Best Invention Method

[0070] As stated in the Full Disclosure of Invention.

Claims

Claims1 . The compound formulations for the treatment and administration of drugs in open wounds, closed wounds and skin graft donor site wounds consist of the following: a) Bupivacaine at 0.1 -0.5% by weight. b) Tranexamic acid at 1-5% by weight. c) Adrenaline at 1:10,000-1:200,000.

2. The compound formulations for the treatment and administration of drugs in open wounds, closed wounds and skin graft donor site wounds in Claim 1 is such that the formula is in the form of a hydrogel solution or hydrogel sheets.3 . The compound formulations for the treatment and administration of drugs in open wounds, closed wounds and skin graft donor site wounds in Claim 2 is such that the solution form consists of a main ingredient drug dissolved in a suitable solvent that can be selected from fluids for injection or balanced saline.

4. The compound formulations for the treatment and administration of drugs in open wounds, closed wounds and skin graft donor site wounds in Claim 2 is such that the hydrogel form consists of a main ingredient drug combined with one or more hydrogelforming polymers selected from a group consisting of one or more combinations of carboxymethyl cellulose, gelatin or pectin.

5. The compound formulations for the treatment and administration of drugs in open wounds, closed wounds and skin graft donor site wounds in Claim 4 is such that the hydrogel form consists of a main ingredient drug combined with one or more polymers that form a hydrogel selected from a group consisting of the following:Carboxymethyl Cellulose at 1-5% by weight.Gelatin at 1-10% by weight.Pectin at 3-10% by weight.

6. The compound formulations for the treatment and administration of drugs in openwounds, closed wounds and skin graft donor site wounds in Claim 2 is such that the hydrogel sheets consist of a porous support material soaked in a solution of the main ingredient drug or hydrogel.

7. The compound formulations for the treatment and administration of drugs in open wounds, closed wounds and skin graft donor site wounds in Claim 6 is such that the porous support material is selected from a group consisting of polyester fibre sheets and collagen matrix.

8. The compound formulations for the treatment and administration of drugs in open wounds, closed wounds and skin graft donor site wounds in Claim 7 is such that the formula also contains one or more additives selected from a group consisting of pH adjusters, preservatives, and emulsifiers.

9. The compound formulations for the treatment and administration of drugs in open wounds, closed wounds and skin graft donor site wounds in Claim 1 is such that the method for treating wounds in patients consists of applying the compound mixture to the wound.

10. The compound formulations for the treatment and administration of drugs in open wounds, closed wounds and skin graft donor site wounds in Claim 9 is such that the wounds are selected from a group consisting of surgical wounds, injury wounds from injuries, chronic sores, and bum wounds.

11. The compound formulations for the treatment and administration of drugs in open wounds, closed wounds and skin graft donor site wounds in Claim 9 is such that, the compound formula is applied to the wound in the form of a hydrogel solution or hydrogel sheets.

12. The compound formulations for the treatment and administration of drugs in open wounds, closed wounds and skin graft donor site wounds in Claim 9 is such that the treatment procedures are as follows: a) Dissolving bupivacaine, tranexamic acid and adrenaline in a suitable solvent to obtain a solution. b) Adding one or more types of hydrogel-forming polymers to a solution to obtain ahydrogel (this procedure is optional) and c) Soaking porous support materials with solution or hydrogel to obtain hydrogel sheets (this procedure is optional).

13. The compound formulations for the treatment and administration of drugs in open wounds, closed wounds and skin graft donor site wounds in Claim 12 is such that, the hydrogen-forming polymers that are selected from a group consisting of carboxymethyl cellulose, gelatin and pectin.

14. The compound formulations for the treatment and administration of drugs in open wounds, closed wounds and skin graft donor site wounds in Claim 13 is such that the hydrogel-forming polymers are selected from a group consisting of the following:Carboxymethyl Cellulose at 1-5% by weight.Gelatin at 1-10% by weight.Pectin at 3-10% by weight.

15. The compound formulations for the treatment and administration of drugs in open wounds, closed wounds and skin graft donor site wounds in Claim 9 is such that the porous support material is selected from a group consisting of polyester fibre sheets and collagen matrix.

16. The compound formulations for the treatment and administration of drugs in open wounds, closed wounds and skin graft donor site wounds in Claim 12 is such that, the compound formula also contains at least one of the additives selected from a group consisting of pH adjusters, preservatives, and emulsifiers.

17. The compound formulations for the treatment and administration of drugs in open wounds, closed wounds and skin graft donor site wounds in Claim 12 is such that, the byweight ratios of bupivacaine: tranexamic acid: adrenaline are within a range of 1 : 1 0 - 50:0.001-0.01.

18. The compound formulations for the treatment and administration of drugs in open wounds, closed wounds and skin graft donor site wounds in Claim 17 is such that, theconcentration of bupivacaine is within a range of 0.25-0.5%, the concentration of tranexamic acid is in the range of 3-5% by weight, and the concentration of adrenaline is within a range of 1:10,000-1:200,000.

19. The compound formulations for the treatment and administration of drugs in open wounds, closed wounds and skin graft donor site wounds in Claims 1 - 18 is such that the quality control method for the formulation of the compound in Claim 1 consists of the following: a) Examination of the purity and quality of all types of raw materials before use in production. b) Control of the temperature and humidity in the production room within the designated range. c) Examination of the accuracy of weighing and dosing every time. d) Testing the pH and viscosity of the product during the production process. e) Examination of the sterility finished products. f) Testing of the drug release of finished products.

20. The compound formulations for the treatment and administration of drugs in open wounds, closed wounds and skin graft donor site wounds in Claims 1 - 18 is such that the method for testing the stability of the compound formula in Claim 1 consists of the following: a) Testing physical stability by observing changes in the external characteristics, color, odor and viscosity of the product at temperatures of 25 and 40 degrees Celsius for 6 months. b) Testing chemical stability by analyzing the amounts of main ingredient drugs by the HPLC technique at 0, 1, 3 and 6 months. c) Testing pH stability by measuring the pH of the product at 0, 1, 3 and 6 months.