Hemostatic dressing with antibacterial effect

Abstract

The application discloses hemostatic dressings with antibacterial effect, and belongs to the technical field of medical and health materials. The hemostatic dressings are obtained by freeze-drying hydroxypropyl methylcellulose, calcium sodium edetate and ciprofloxacin hydrochloride in a suitable ratio, and then mixing the obtained product with excipients, so that stable and sustained release of ciprofloxacin hydrochloride is realized, and the clinical requirement of long-acting antibacterial effect on a wound surface can be met.

Description

Technical Field

[0001] This invention belongs to the field of sanitary materials technology, specifically relating to a powder of a hemostatic dressing containing a drug-containing sustained-release matrix that can rapidly gel and slowly release antibacterial drugs, and its preparation method. Background Technology

[0002] Traumatic bleeding can easily lead to critical conditions and reduced survival rates in injured individuals. Hemostatic dressings are an important tool in trauma treatment, and extensive research has been conducted both domestically and internationally on this topic. Current hemostatic dressings are mainly classified into the following categories: chitosan-based, zeolite / kaolin-based inorganic materials, oxidized cellulose-based, and alginate-based dressings. An ideal hemostatic dressing should not only possess the ability to quickly stop bleeding but also have antibacterial and wound-healing-promoting functions. Therefore, loading antibacterial drugs into the dressing matrix, enabling the dressing to simultaneously possess hemostatic and anti-infection functions, has become a research hotspot in this field.

[0003] Ciprofloxacin hydrochloride, a third-generation fluoroquinolone broad-spectrum antibacterial agent, exhibits strong antibacterial activity against common wound infection bacteria such as Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. Based on its excellent antibacterial spectrum and activity, ciprofloxacin has been extensively studied for its application in the development of wound dressings.

[0004] For example, patent CN106149203B discloses a drug-loaded nanofiber membrane and its application, using polylactic acid caprolactone as a carrier and ciprofloxacin as the drug. The nanofiber membrane is prepared using electrospinning technology and can be used as a wound dressing. Patent CN111317865A discloses a method for preparing a double-layer antibacterial composite film. This method uses low-power electron beam deposition technology to prepare a double-layer antibacterial composite film with a bottom layer of polylactic acid and ciprofloxacin and an upper layer of polyurethane and ciprofloxacin, exhibiting good antibacterial and sustained-release properties. All of the above-mentioned prior art involves loading ciprofloxacin into molded products such as sheets and nanofiber membranes; there are no reports of loading ciprofloxacin into powder-based hemostatic dressings.

[0005] Powder-based hemostatic dressings have irreplaceable clinical value in trauma treatment. In deep trunk or junctional areas (such as the groin and axilla), conventional hemostasis methods often fail due to the complex location of the wound and the inability to apply effective pressure. Traditional hemostatic patches, due to their planar structure, are difficult to apply tightly to deep or irregular wounds. Powder, however, can adapt to wounds of any shape due to its free-flowing properties. Developing powder-based hemostatic dressings with antibacterial functions is of significant clinical importance. However, loading antibacterial drugs into powder-based hemostatic dressings faces unique technical challenges: the drug exists in a particulate form, with a large specific surface area and lacking a continuous matrix framework as a physical barrier, making it difficult to effectively control drug release: often resulting in severe initial release followed by a rapid decline in effective concentration.

[0006] Therefore, how to overcome the technical obstacles of uncontrollable drug release and poor resistance to exudate impact while maintaining the advantages of powder form, and provide a powder-based hemostatic dressing that has both rapid hemostasis and continuous antibacterial functions, can effectively control drug release behavior, improve drug stability, and reduce toxic side effects caused by impurities absorbed through broken skin, is a technical problem that urgently needs to be solved in this field. Summary of the Invention

[0007] To achieve stable antibacterial function in powder-based hemostatic dressings, the inventors, through continuous research into solving numerous problems such as the uncontrollable release behavior of the antibacterial drug ciprofloxacin hydrochloride in powder formulations and the easy growth of related substances during storage, creatively adjusted the formula and screened the process methods. They finally determined to combine hydroxypropyl methylcellulose, sodium edetate, and ciprofloxacin hydrochloride with appropriate viscosity. High-viscosity hydroxypropyl methylcellulose, as a hydrophilic polymer backbone material, can quickly form a hydrated gel layer upon contact with water, "anchoring" ciprofloxacin to the local wound surface and effectively resisting the physical erosion of tissue exudate. At the same time, the freeze-drying process endows it with the ability to quickly gel upon contact with water, which can delay the release pathway of ciprofloxacin hydrochloride, reduce the burst release effect, and achieve sustained drug release.

[0008] Furthermore, the appropriate formulation provided by this invention possesses multiple functional properties, including thickening, binding, and dispersing. When formulated into a powder, it exhibits excellent flowability and spreadability, and helps to slow down the degradation of ciprofloxacin hydrochloride during storage, thus improving formulation stability. Through these synergistic effects, this invention effectively overcomes the long-standing technical obstacles faced by powder-based antibacterial hemostatic dressings.

[0009] This invention is achieved through the following means:

[0010] In a first aspect, the present invention provides a hemostatic dressing with antibacterial properties, which is a powder composed of ciprofloxacin hydrochloride, a sustained-release matrix and an acceptable excipient; and the ciprofloxacin hydrochloride and the sustained-release matrix are used after freeze-drying.

[0011] The sustained-release matrix is ​​composed of hydroxypropyl methylcellulose and sodium edetate.

[0012] The excipients include one or more of the following: skeleton material, crosslinking agent, filler, inorganic hemostatic material, and lubricant.

[0013] Furthermore, the weight ratio of ciprofloxacin hydrochloride, hydroxypropyl methylcellulose, and sodium edetate is 1:3-10:0.2-1.0; the viscosity of the hydroxypropyl methylcellulose is 80,000 mPa·s-120,000 mPa·s.

[0014] Furthermore, the skeleton material is selected from one or more of sodium alginate, sodium carboxymethyl cellulose, carboxymethyl chitosan, sodium hyaluronate, gelatin, collagen, starch, pregelatinized starch, and hydroxyethyl starch;

[0015] The crosslinking agent is selected from one or more of calcium chloride, glutaraldehyde, and sodium trimetaphosphate;

[0016] The filler is selected from one or more of mannitol, microcrystalline cellulose, lactose, sorbitol, dextrin, calcium sulfate, and calcium phosphate;

[0017] The inorganic hemostatic material is selected from one or more of kaolin, zeolite, silica, bentonite, diatomaceous earth, and basic ferric sulfate.

[0018] The lubricant is selected from one or more of magnesium stearate and talc.

[0019] Furthermore, the hemostatic dressing, by weight, is composed of the following components:

[0020] Ciprofloxacin hydrochloride 1-10 parts

[0021] Sustained-release materials: 10-50 parts of hydroxypropyl methylcellulose and sodium edetate

[0022] 5-40 parts of skeleton material

[0023] 0-30 parts of filler

[0024] Crosslinking agent 0.5-5 parts

[0025] Inorganic hemostatic material 0-20 parts

[0026] Lubricant 0.1-1 part.

[0027] Furthermore, as the most preferred embodiment, the hemostatic dressing is formulated with the following components in parts by weight:

[0028] 5 parts of ciprofloxacin hydrochloride

[0029] 30 parts of hydroxypropyl methylcellulose

[0030] 2 parts of calcium sodium edetate

[0031] 20 parts sodium alginate

[0032] 2 parts calcium chloride

[0033] 0.5 parts magnesium stearate.

[0034] Secondly, the present invention also provides a method for preparing the hemostatic dressing, which comprises the following steps:

[0035] S1. Add ciprofloxacin hydrochloride, hydroxypropyl methylcellulose and calcium sodium edetate to water for injection, stir until completely dissolved, adjust the pH to 3-7 to obtain a drug-containing solution; freeze-dry the drug-containing solution to obtain a block; pulverize and sieve the block to obtain a drug-containing lyophilized powder;

[0036] S2. Initially mix the skeleton material, filler, crosslinking agent, surfactant, and inorganic hemostatic material through a 60-mesh sieve, then add the lyophilized drug-containing powder and mix thoroughly.

[0037] S3. Add lubricant, mix well, and package into polyester / aluminum / polyethylene pharmaceutical composite film bags to obtain the hemostatic dressing.

[0038] Furthermore, in the preparation steps of this hemostatic dressing, the pH value in step S1 is adjusted to 5-6, and the pH value is adjusted using hydrochloric acid or sodium hydroxide solution.

[0039] Furthermore, in the preparation steps of this hemostatic dressing, the freeze-drying in step S1 specifically involves a pre-freezing temperature of -40℃ to -80℃ for 2 to 4 hours; the sublimation drying involves a vacuum degree of 10 to 30 Pa, a temperature of -30℃ to -10℃, and a time of 10 to 20 hours; and the desorption drying involves a vacuum degree of ≤10 Pa, a temperature of 20℃ to 40℃, and a time of 4 to 10 hours.

[0040] Furthermore, in the preparation steps of this hemostatic dressing, the mixing parameters in step S2 are as follows: a three-dimensional motion mixer or a V-type mixer is used, the mixing speed is 10-30 rpm, the initial mixing time is 10-20 minutes, and the mixing time after adding the lyophilized drug powder is 10-60 minutes.

[0041] Furthermore, in the preparation steps of this hemostatic dressing, the mixing parameters in step S3 are as follows: a three-dimensional motion mixer or a V-type mixer is used, the mixing speed is 10-30 rpm, and the initial mixing time is 3-15 minutes.

[0042] The technical solution provided by this invention has the following advantages compared to the prior art:

[0043] 1. To realize antibacterial and hemostatic dressings in powder form.

[0044] The powder formulation containing antibacterial drugs provided by this invention fully leverages the inherent advantages of powder's free flow and adaptability to wounds of any shape. For complex wounds in deep trunk or junctional areas (such as the groin and armpit) where effective compression cannot be applied, traditional pre-formed dressings such as gauze and films are difficult to apply tightly. However, the powder of this invention can quickly cover the wound due to its excellent flowability and spreadability. Sodium calcium edetate assists in hemostasis by locally chelating calcium ions, synergizing with the sustained antibacterial function of ciprofloxacin hydrochloride. This gives the dressing both rapid hemostasis and long-lasting anti-infection properties, filling the gap in the existing technology for ciprofloxacin powder-based hemostatic dressings.

[0045] 2. Effectively control drug release behavior and achieve sustained release.

[0046] This invention utilizes a specific process to process high-viscosity hydroxypropyl methylcellulose, sodium calcium edetate, and ciprofloxacin hydrochloride in a suitable ratio. The high-viscosity hydroxypropyl methylcellulose, acting as a hydrophilic polymer backbone, rapidly forms a hydrated gel layer upon contact with water, "anchoring" ciprofloxacin to the local wound surface and effectively resisting the physical erosion of tissue exudate. Combined with a suitable freeze-drying process, the dressing rapidly gels upon contact with water, delaying the release pathway of ciprofloxacin and significantly reducing the initial burst release effect in powder form, thus achieving sustained drug release.

[0047] 3. Improves the storage stability of the formulation and reduces the risk of use.

[0048] This invention also reveals that the sodium edetate used in this technical solution not only improves the gelation rate of the sustained-release matrix hydroxypropyl methylcellulose, but also improves the stability of the product, resulting in a smaller increase in related substances and a slower increase in impurities. This reduces the chance of impurities being directly exposed to broken wounds and lowers the risk of the drug being absorbed into the systemic circulation through broken skin. Furthermore, the powder form requires no solvents or excipients before use, avoiding further damage to the skin barrier caused by penetration enhancers that may be present in existing ointments and gels. This effectively reduces the risk of systemic toxicity caused by the absorption of ciprofloxacin degradation impurities through broken skin.

[0049] 4. The preparation process is simple and suitable for industrial production.

[0050] The powder hemostatic dressing provided by this invention is prepared by dissolving the prescribed amounts of ciprofloxacin hydrochloride, hydroxypropyl methylcellulose, and sodium edetate in water, followed by freeze-drying, pulverizing, sieving, and mixing. The process is short, the operating conditions are mild, and no organic solvents are used. This avoids the complex steps of existing electrospinning technology (which requires organic solvents and high-voltage electric fields) and the introduction of multiple components in hydrogel preparation, making it suitable for industrial-scale production. Attached Figure Description

[0051] Figure 1X-ray diffraction crystal pattern of the drug-containing lyophilized powder in Example 1.

[0052] Figure 2 X-ray diffraction crystal pattern of the powder in Comparative Example 1

[0053] Figure 3 The in vitro release curves for each embodiment in Experimental Example 2.

[0054] Figure 4 The in vitro release curves for Example 1 and the comparative example in Experimental Example 2 are shown. Detailed Implementation

[0055] The following description illustrates exemplary embodiments of the present invention, including various details to aid understanding, and should be considered merely exemplary. Therefore, those skilled in the art will recognize that various changes and modifications can be made to the embodiments described herein without departing from the scope and spirit of the invention. Similarly, for clarity and brevity, descriptions of well-known functions, operations, and structures are omitted in the following description.

[0056] Unless otherwise defined, the technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art. While similar or identical methods and materials may be applied in experimental or practical applications, the present invention describes materials and methods hereinafter. In case of conflict, the definitions included herein shall prevail.

[0057] Unless otherwise specified, all experiments in the following experiments were conducted under standard conditions or conditions recommended by the manufacturer. Raw materials, reagents, and instruments used, unless otherwise specified, are all commercially available products. Unless otherwise stated, all percentages, ratios, proportions, or parts are by weight. Unless otherwise specified, all materials in this invention are commercially available pharmaceutical raw materials or pharmaceutical excipients, provided they do not significantly affect the overall efficacy of the formulation.

[0058] Example 1: Preparation of hemostatic dressing

[0059] formula:

[0060]

[0061] The viscosity of hydroxypropyl methylcellulose was determined according to the method in Part IV of the 2025 edition of the Chinese Pharmacopoeia.

[0062] Preparation process:

[0063] S1. Preparation of drug-containing lyophilized powder

[0064] Take approximately 20 L of water for injection and place it in a mixing vessel. Add the prescribed amounts of ciprofloxacin hydrochloride, hydroxypropyl methylcellulose, and calcium sodium edetate, and stir until completely dissolved. Add water for injection to a final volume of 25 L. Adjust the pH to 5.5 with 0.1 mol / L hydrochloric acid solution to obtain the drug-containing solution.

[0065] The above-mentioned drug-containing solution was dispensed into lyophilization trays and placed in a freeze dryer for freeze drying.

[0066] Pre-freezing: Set the temperature to -50℃ and hold for 3 hours; Sublimation drying: Control the vacuum degree to 20 Pa and the temperature to -20℃, and maintain for 15 hours; Desorption drying: Control the vacuum degree to ≤10 Pa and the temperature to 30℃, and maintain for 6 hours.

[0067] After freeze-drying, the block was removed, crushed in a pulverizer, and passed through an 80-mesh sieve to obtain a drug-containing freeze-dried powder.

[0068] S2, Initial Mixing

[0069] Take the prescribed amounts of sodium alginate and calcium chloride, pass them through a 60-mesh sieve, and put them into a three-dimensional motion mixer. Mix at 20 rpm for 15 minutes. Then add the lyophilized drug powder prepared in S1 and continue mixing for 30 minutes.

[0070] S3, Blending and Packaging

[0071] Add the prescribed amount of magnesium stearate to the mixture in S2 and mix at 20 rpm for 10 minutes. Dispense the final mixture into polyester / aluminum / polyethylene pharmaceutical packaging composite film bags to obtain the powdered hemostatic dressing.

[0072] Example 2: Preparation of hemostatic dressings with different proportions of sustained-release matrix

[0073] formula:

[0074]

[0075] The proportion of sustained-release matrix in the formulations of the above embodiments differs from that in Example 1. In Example 2, the weight ratio of ciprofloxacin hydrochloride, hydroxypropyl methylcellulose, and sodium edetate is 1:4:0.25.

[0076] Preparation process:

[0077] S1. Preparation of drug-containing lyophilized powder

[0078] Take approximately 20 L of water for injection and place it in a mixing vessel. Add the prescribed amounts of ciprofloxacin hydrochloride, hydroxypropyl methylcellulose, and calcium sodium edetate, and stir until completely dissolved. Add water for injection to a final volume of 25 L. Adjust the pH to 5.0 with 0.1 mol / L hydrochloric acid solution to obtain the drug-containing solution.

[0079] The above-mentioned drug-containing solution was dispensed into lyophilization trays and placed in a freeze dryer for freeze drying.

[0080] Pre-freezing: Set the temperature to -40℃ and hold for 4 hours; Sublimation drying: Control the vacuum degree to 30 Pa and the temperature to -10℃, and maintain for 12 hours; Desorption drying: Control the vacuum degree to ≤10 Pa and the temperature to 20℃, and maintain for 10 hours.

[0081] After freeze-drying, the block was removed, crushed in a pulverizer, and passed through an 80-mesh sieve to obtain a drug-containing freeze-dried powder.

[0082] S2, Initial Mixing

[0083] Take the prescribed amounts of sodium alginate and calcium chloride, pass them through a 60-mesh sieve, and put them into a three-dimensional motion mixer. Mix at 10 rpm for 20 minutes. Then add the lyophilized drug powder prepared in S1 and continue mixing for 50 minutes.

[0084] S3, Blending and Packaging

[0085] Add the prescribed amount of magnesium stearate to the mixture in S2 and mix at 20 rpm for 15 minutes. Dispense the final mixture into polyester / aluminum / polyethylene pharmaceutical packaging composite film bags to obtain the powdered hemostatic dressing.

[0086] Example 3: Preparation of hemostatic dressings with different proportions of sustained-release matrix

[0087] formula:

[0088]

[0089] The proportion of sustained-release matrix in the formulations of the above embodiments differs from that in Example 1. In Example 3, the weight ratio of ciprofloxacin hydrochloride, hydroxypropyl methylcellulose, and sodium edetate is 1:8:0.6.

[0090] Preparation process:

[0091] S1. Preparation of drug-containing lyophilized powder

[0092] Take approximately 20 L of water for injection and place it in a mixing vessel. Add the prescribed amounts of ciprofloxacin hydrochloride, hydroxypropyl methylcellulose, and calcium sodium edetate. Add water for injection to a final volume of 25 L and stir until completely dissolved. Adjust the pH to 5.9 with 0.1 mol / L hydrochloric acid solution to obtain the drug-containing solution.

[0093] The above-mentioned drug-containing solution was dispensed into lyophilization trays and placed in a freeze dryer for freeze drying.

[0094] Pre-freezing: Set the temperature to -70℃ and hold for 2 hours; Sublimation drying: Control the vacuum degree to 10 Pa and the temperature to -30℃, and maintain for 20 hours; Desorption drying: Control the vacuum degree to ≤10 Pa and the temperature to 30℃, and maintain for 4 hours.

[0095] After freeze-drying, the block was removed, crushed in a pulverizer, and passed through an 80-mesh sieve to obtain a drug-containing freeze-dried powder.

[0096] S2, Initial Mixing

[0097] Take the prescribed amounts of sodium alginate and calcium chloride, pass them through a 60-mesh sieve, and put them into a three-dimensional motion mixer. Mix at 20 rpm for 30 minutes. Then add the lyophilized drug powder prepared in S1 and continue mixing for 15 minutes.

[0098] S3, Blending and Packaging

[0099] Add the prescribed amount of magnesium stearate to the mixture in S2 and mix at 20 rpm for 3 minutes. Dispense the final mixture into polyester / aluminum / polyethylene pharmaceutical composite film bags to obtain the powdered hemostatic dressing.

[0100] Examples 4-5: Preparation of hemostatic dressings with different viscosity grades of HPMC

[0101] formula:

[0102]

[0103] The viscosity of hydroxypropyl methylcellulose was determined according to the method in Part IV of the 2025 edition of the Chinese Pharmacopoeia. Examples 4 and 5 show hydroxypropyl methylcellulose products with different viscosity grades.

[0104] Preparation process:

[0105] Same as in Example 1.

[0106] Comparative Example 1: Preparation of hemostatic dressings using non-lyophilized processes

[0107] formula:

[0108] Same as in Example 1.

[0109] Preparation process:

[0110] Except for the different preparation process of the medicinal powder in S1, the rest is the same as in Example 1.

[0111] The preparation process of S1 containing medicinal powder is as follows:

[0112] The prescribed amounts of ciprofloxacin hydrochloride, hydroxypropyl methylcellulose, and calcium sodium edetate were added to a three-dimensional motion mixer and mixed at 20 rpm for 5 minutes for initial mixing. The mixture was then discharged and passed through an 80-mesh sieve three times. It was then added back to the three-dimensional motion mixer and mixed at 20 rpm for 25 minutes to obtain the drug-containing powder.

[0113] Comparative Example 2: Preparation of a hemostatic dressing with sodium alginate as a sustained-release matrix

[0114] formula:

[0115]

[0116] Preparation process:

[0117] S1. Preparation of drug-containing lyophilized powder

[0118] Take approximately 20 L of water for injection and place it in a mixing vessel. Add the prescribed amounts of ciprofloxacin hydrochloride, sodium alginate (3 kg), and calcium sodium edetate. Add water for injection to a final volume of 25 L and stir until completely dissolved. Adjust the pH to 5.5 with 0.1 mol / L hydrochloric acid solution to obtain the drug-containing solution.

[0119] The above-mentioned drug-containing solution was dispensed into lyophilization trays and placed in a freeze dryer for freeze drying.

[0120] Pre-freezing: Set the temperature to -50℃ and hold for 3 hours; Sublimation drying: Control the vacuum degree to 20 Pa and the temperature to -20℃, and maintain for 15 hours; Desorption drying: Control the vacuum degree to ≤10 Pa and the temperature to 30℃, and maintain for 6 hours.

[0121] After freeze-drying, the block was removed, crushed in a pulverizer, and passed through an 80-mesh sieve to obtain a drug-containing freeze-dried powder.

[0122] S2, Initial Mixing

[0123] Take the prescribed amounts of sodium alginate and calcium chloride, pass them through a 60-mesh sieve, and put them into a three-dimensional motion mixer. Mix at 20 rpm for 15 minutes. Then add the lyophilized drug powder prepared in S1 and continue mixing for 30 minutes.

[0124] S3, Blending and Packaging

[0125] Add the prescribed amount of magnesium stearate to the mixture in S2 and mix at 20 rpm for 10 minutes. Dispense the final mixture into polyester / aluminum / polyethylene pharmaceutical packaging composite film bags to obtain the powdered hemostatic dressing.

[0126] Comparative Example 3: Preparation of a hemostatic dressing without sodium edetate

[0127] formula:

[0128]

[0129] The viscosity of hydroxypropyl methylcellulose was determined according to the method in Part IV of the 2025 edition of the Chinese Pharmacopoeia.

[0130] Preparation process:

[0131] S1. Preparation of drug-containing lyophilized powder

[0132] Take approximately 20 L of water for injection and place it in a mixing vessel. Add the prescribed amounts of ciprofloxacin hydrochloride and hydroxypropyl methylcellulose, then add water for injection to a final volume of 25 L. Stir until completely dissolved. Adjust the pH to 5.5 with 0.1 mol / L hydrochloric acid solution to obtain the drug-containing solution.

[0133] The above-mentioned drug-containing solution was dispensed into lyophilization trays and placed in a freeze dryer for freeze drying.

[0134] Pre-freezing: Set the temperature to -50℃ and hold for 3 hours; Sublimation drying: Control the vacuum degree to 20 Pa and the temperature to -20℃, and maintain for 15 hours; Desorption drying: Control the vacuum degree to ≤10 Pa and the temperature to 30℃, and maintain for 6 hours.

[0135] After freeze-drying, the solid material is removed, pulverized in a grinder, and passed through an 80-mesh sieve to obtain a drug-containing freeze-dried powder. S2, Initial Mixing

[0136] Take the prescribed amounts of sodium alginate and calcium chloride, pass them through a 60-mesh sieve, and put them into a three-dimensional motion mixer. Mix at 20 rpm for 15 minutes. Then add the lyophilized drug powder prepared in S1 and continue mixing for 30 minutes.

[0137] S3, Blending and Packaging

[0138] Add the prescribed amount of magnesium stearate to the mixture in S2 and mix at 20 rpm for 10 minutes. Dispense the final mixture into polyester / aluminum / polyethylene pharmaceutical packaging composite film bags to obtain the powdered hemostatic dressing.

[0139] Comparative Example 4: Preparation of hemostatic dressing without acid-base adjustment

[0140] formula:

[0141] Same as in Example 1.

[0142] Preparation process:

[0143] S1. Preparation of drug-containing lyophilized powder

[0144] Take about 20 L of water for injection and place it in a mixing tank. Add the prescribed amounts of ciprofloxacin hydrochloride and hydroxypropyl methylcellulose, and then add water for injection to a final volume of 25 L. Stir until completely dissolved to obtain a drug-containing solution.

[0145] The above-mentioned drug-containing solution was dispensed into lyophilization trays and placed in a freeze dryer for freeze drying.

[0146] Pre-freezing: Set the temperature to -50℃ and hold for 3 hours; Sublimation drying: Control the vacuum degree to 20 Pa and the temperature to -20℃, and maintain for 15 hours; Desorption drying: Control the vacuum degree to ≤10 Pa and the temperature to 30℃, and maintain for 6 hours.

[0147] After freeze-drying, the block was removed, crushed in a pulverizer, and passed through an 80-mesh sieve to obtain a drug-containing freeze-dried powder.

[0148] S2, Initial Mixing

[0149] Take the prescribed amounts of sodium alginate and calcium chloride, pass them through a 60-mesh sieve, and put them into a three-dimensional motion mixer. Mix at 20 rpm for 15 minutes. Then add the lyophilized drug powder prepared in S1 and continue mixing for 30 minutes.

[0150] S3, Blending and Packaging

[0151] Add the prescribed amount of magnesium stearate to the mixture in S2 and mix at 20 rpm for 10 minutes. Dispense the final mixture into polyester / aluminum / polyethylene pharmaceutical packaging composite film bags to obtain the powdered hemostatic dressing.

[0152] Experimental Example 1: Evaluation of Powder Properties and Spreadability

[0153] In clinical use, the spreadability of powder hemostatic dressings directly determines whether the powder can be evenly and quickly applied to the wound, thus affecting hemostatic efficiency and the uniformity of drug distribution. Powder spreadability is mainly influenced by multiple factors, including particle shape, particle size distribution, surface energy, and flowability. To fully demonstrate the differences in powder spreadability among the powder hemostatic dressings prepared in the various embodiments and comparative examples of this invention, the spreadability of the above samples was evaluated.

[0154] Test basis:

[0155] Chinese Pharmacopoeia 2025 Edition, Part IV, 9604: Guidelines for Determination of Powder Flowability, with reference to ASTM E2044-99 (2012).

[0156] Test method:

[0157] Angle of repose determination: The fixed funnel method (pouring method) is used. Take an appropriate amount of the sample to be tested, and slowly pour the powder through the funnel onto a horizontal circular base. Keep the bottom of the funnel 2-4 cm away from the tip of the powder cone until the height of the resulting powder cone no longer increases. Measure the height of the cone (h) and the radius of the base (r), and calculate the angle of repose. Each sample is measured in triplicate, and the average value is taken.

[0158] The relationship between powder flowability and the corresponding angle of repose is as follows:

[0159]

[0160] Spreadability testing was conducted according to the core principle of spreading radius determination in ASTM E2044-99(2025), using the natural fall method. A precise 1.0g sample was placed in a separatory funnel fixed at a height of 20cm. The stopcock was opened to allow the powder to fall freely onto the center of a horizontal, smooth glass plate (300mm × 300mm). After the powder stopped flowing and formed a stable accumulation, the maximum diameter (Dmax) and minimum diameter (Dmin) of the spreading area were measured, and the spreading area S = π × (Dmax / 2) × (Dmin / 2) was calculated. This area reflects the powder's natural spreading ability under its own weight; a larger area indicates better powder flowability and easier spreading on the wound surface. Each sample was measured in triplicate, and the average value was taken.

[0161] Measurement results:

[0162]

[0163] in conclusion:

[0164] Examples 1-5 all have an angle of repose of less than 35° and a spreading area of ​​more than 9 cm². They have good overall fluidity and spreading properties, which can meet the clinical needs for uniform coverage of wounds.

[0165] Example 1 has a repose angle of 28° and a spreading area of ​​13.8 cm². 2 The flowability of Example 1 was rated as "very good," while Comparative Example 2, which used sodium alginate, a commonly used material in existing technologies, instead of hydroxypropyl methylcellulose, showed inferior powder and spreading properties compared to Example 1. Comparative Example 1, which used a non-lyophilized process, exhibited the worst results. The experimental results indicate that the skeletal structure formed by HPMC as a slow-release matrix after lyophilization is more conducive to improving powder flowability, possibly due to the reduced surface energy and increased sphericity of the particles after lyophilization.

[0166] Also refer to the accompanying drawings in the instruction manual. Figure 1 , Figure 2 It is evident that, after freeze-drying, the drug-containing mixed powder, in addition to differences in powder properties, also exhibits an amorphous crystalline form. This amorphous form allows the drug-containing powder to rapidly absorb water and swell to form a gel layer upon contact with water. On one hand, this gel layer can quickly adhere to, spread, and fix itself to the wound surface after contact with wound exudate, forming a physical barrier that is beneficial for hemostasis and wound protection. On the other hand, the formed gel layer can act as a controlled-release barrier for drug diffusion, achieving slow release and continuously maintaining an effective antibacterial concentration.

[0167] Experimental Example 2: In Vitro Release Behavior Test

[0168] When powder-based hemostatic dressings are applied to wounds, the drug release behavior directly affects the duration of local antibacterial concentration and the persistence of hemostatic effect. An ideal sustained-release formulation should achieve stable and continuous drug release within the wound's exudate environment, avoiding excessively high local concentrations that could cause tissue irritation due to initial burst release, while ensuring the maintenance of an effective antibacterial concentration throughout the entire dressing change interval. To evaluate the differences in in vitro release behavior of the powder-based hemostatic dressings prepared in the relevant embodiments and comparative examples of this invention, the release rate of the above samples was measured.

[0169] Test standards: Chinese Pharmacopoeia 2025 Edition, Part IV, General Chapter 0931, "Determination of Dissolution and Release Rate"; United States Pharmacopeia (USP) General Chapter <1724> "Semi-solid pharmaceutical products - performance testing" - vertical diffusion cell (i.e., Franz diffusion cell method)

[0170] Test method:

[0171] The measurements were performed using the vertical diffusion cell method (Franz diffusion cell). The supply and receiving cells of the diffusion cell were separated by a cellulose acetate membrane (0.45 μm pore size). 7 mL of phosphate buffer (pH 7.4, simulating wound exudate) was injected into the receiving cell, and the temperature of the receiving cell was controlled at 32 ± 0.5 °C (simulating wound surface temperature) by a circulating water bath. The cells were stirred at 300 rpm using a magnetic stirrer.

[0172] Accurately weigh 0.2 g of each sample powder and evenly spread it on the membrane surface of the feed cell. Take 0.5 mL samples from the receiving cell at 0.5, 2, 4, 8, 12, and 24 h, and simultaneously add an equal volume of fresh medium. Determine the concentration of ciprofloxacin hydrochloride in the medium using the ciprofloxacin hydrochloride tablet dissolution assay (Chinese Pharmacopoeia 2025 Edition, Part II, Main Text), and calculate the cumulative release rate (%) at each time point. Each sample was measured in parallel in six diffusion cells (n=6), and the results were averaged.

[0173] Measurement results: (n=6);

[0174]

[0175] Conclusion: The release of the samples in each embodiment was relatively stable, and the cumulative release RSD between each group of samples within the batch was small. In clinical dressing change practice, infected wounds are usually dressed once a day, and those with less exudation can be dressed once every 2-3 days. The antibacterial drug release endpoint of the samples in Examples 1-3 of this invention was 24 hours, which completely covered the treatment interval between two dressing changes.

[0176] Among them, Comparative Example 1 (direct mixing process of drug and sustained-release matrix) showed burst release and exhibited rapid release characteristics, while Examples 1-3 of the present invention showed significantly delayed release and good uniformity. This indicates that the freeze-drying process enables HPMC to form a porous framework, which rapidly hydrates upon contact with water to form a dense gel layer, effectively delaying the drug release pathway and realizing the transformation from rapid release to sustained release. This solves the problem of slow release when adding antibacterial drugs to powder.

[0177] Examples 4 (too low viscosity) and 5 (too high viscosity) exhibited slight burst release and incomplete release anomalies, indicating that the viscosity selection of HPMC is also important. Comparative Example 2, which replaced HPMC with sodium alginate, showed a release plateau in the middle time period, and the final release amount was <80%, indicating that the density of the gel layer formed by the hydration of sodium alginate was worse than that of the present invention. Comparative Example 3 (without sodium edetate) had a larger cumulative release RSD at each measurement time point. This was because the lack of sodium edetate resulted in poor uniformity of skeleton formation during the freeze-drying process, leading to increased release differences between the diffusion cells.

[0178] For details regarding the in vitro release curves of the above embodiments and comparative samples, please refer to the accompanying drawings in the specification. Figure 3 , Figure 4 .

[0179] In summary, the sustained-release hemostatic dressing prepared by the technical solution of this invention can achieve stable, continuous, and uniform release behavior, which can meet the clinical needs of long-term local antibacterial effect on wounds.

[0180] Experiment 3 Stability Study

[0181] The chemical stability of ciprofloxacin hydrochloride in powder-based hemostatic dressings directly affects the product's efficacy and safety. The piperazine ring and quinolone core in the ciprofloxacin hydrochloride molecule are prone to oxidative degradation under light and high-temperature catalytic conditions, generating various degradation impurities. This invention found that calcium sodium edetate can significantly improve the product's storage stability and effectively control the increase of related substances; simultaneously, adjusting the pH to a suitable range during the preparation of the drug-containing solution can further ensure the chemical stability of the drug during lyophilization and storage. To verify these beneficial effects, accelerated stability studies were conducted on representative samples of this invention, and related substances were determined.

[0182] Test basis:

[0183] Accelerated testing is performed according to the "Guiding Principles for Stability Testing of Raw Materials and Preparations" in General Chapter 9001 of Part IV of the Chinese Pharmacopoeia 2025 Edition; the determination of related substances is performed according to the related substances test method under "Ciprofloxacin Hydrochloride" in Part II of the Chinese Pharmacopoeia 2025 Edition, using high performance liquid chromatography (General Chapter 0512 of Part IV of the Chinese Pharmacopoeia 2025 Edition).

[0184] Total impurity test results:

[0185]

[0186] Conclusion: The above results show that the samples without sodium edetate (Comparative Example 3) and those without pH adjustment within a suitable range (Comparative Example 4) exhibited a significant increase in impurities during accelerated stability testing. The results indicate that sodium edetate effectively inhibits oxidative degradation by chelating trace metal ions, and pH adjustment keeps the drug within its optimal stability range. The synergistic effect of these two factors ensures controllable impurity levels within the formulation's shelf life, reducing the safety risk of impurities being exposed to broken wounds.

Claims

1. A hemostatic dressing with antibacterial properties, characterized in that, It is a powder composed of ciprofloxacin hydrochloride, a sustained-release matrix, and acceptable excipients. The ciprofloxacin hydrochloride and the sustained-release matrix are freeze-dried to form a drug-containing lyophilized powder. The specific manufacturing method of the drug-containing lyophilized powder is as follows: Ciprofloxacin hydrochloride, hydroxypropyl methylcellulose, and calcium sodium edetate were added to water for injection and stirred until completely dissolved. The pH was adjusted to 3-6 to obtain a drug-containing solution. The drug-containing solution was freeze-dried to obtain a block. The block was crushed and sieved to obtain a drug-containing lyophilized powder. The sustained-release matrix is ​​composed of hydroxypropyl methylcellulose and sodium edetate; the weight ratio of ciprofloxacin hydrochloride, hydroxypropyl methylcellulose, and sodium edetate is 1:3-10:0.2-1.0; the viscosity of the hydroxypropyl methylcellulose is 80000mPa·s-120000mPa·s. The excipients include one or more of the following: skeleton material, crosslinking agent, filler, inorganic hemostatic material, and lubricant; It consists of the following components in parts by weight: Ciprofloxacin hydrochloride 1-10 parts Sustained-release matrix: 10-50 parts of hydroxypropyl methylcellulose and sodium edetate 5-40 pieces of skeleton material 0-30 parts of filler Crosslinking agent 0.5-5 parts Inorganic hemostatic material 0-20 parts Lubricant 0.1-1 part.

2. The hemostatic dressing according to claim 1, characterized in that, The skeleton material is selected from one or more of sodium alginate, sodium carboxymethyl cellulose, carboxymethyl chitosan, sodium hyaluronate, gelatin, collagen, starch, pregelatinized starch, and hydroxyethyl starch; The crosslinking agent is selected from one or more of calcium chloride, glutaraldehyde, and sodium trimetaphosphate; The filler is selected from one or more of mannitol, microcrystalline cellulose, lactose, sorbitol, dextrin, calcium sulfate, and calcium phosphate; The inorganic hemostatic material is selected from one or more of kaolin, zeolite, silica, bentonite, diatomaceous earth, and basic ferric sulfate. The lubricant is selected from one or more of magnesium stearate and talc.

3. The hemostatic dressing according to claim 1, characterized in that, It consists of the following components in parts by weight: 5 parts of ciprofloxacin hydrochloride 30 parts of hydroxypropyl methylcellulose 2 parts of calcium sodium edetate 20 parts sodium alginate 2 parts calcium chloride 0.5 parts magnesium stearate.

4. A method for preparing a hemostatic dressing as described in claim 1, characterized in that, It consists of the following steps: S1. Add ciprofloxacin hydrochloride, hydroxypropyl methylcellulose and calcium sodium edetate to water for injection, stir until completely dissolved, adjust the pH to 3-6 to obtain a drug-containing solution; freeze-dry the drug-containing solution to obtain a block; pulverize and sieve the block to obtain a drug-containing lyophilized powder; S2. Initially mix the skeleton material, filler, crosslinking agent, surfactant, and inorganic hemostatic material through a 60-mesh sieve, then add the lyophilized drug-containing powder and mix thoroughly. S3. Add lubricant, mix well, and package to obtain the hemostatic dressing.

5. The method for preparing the hemostatic dressing according to claim 4, characterized in that, In step S1, the pH value is adjusted to 5-6, and the pH adjuster is hydrochloric acid.

6. The method for preparing the hemostatic dressing according to claim 4, characterized in that, The freeze-drying process described in step S1 specifically involves pre-freezing, sublimation drying, and desorption drying: the pre-freezing temperature is -40℃ to -80℃, and the time is 2 to 4 hours; the sublimation drying vacuum degree is 10 to 30 Pa, the temperature is -30℃ to -10℃, and the time is 10 to 20 hours; the desorption drying vacuum degree is ≤10 Pa, the temperature is 20℃ to 40℃, and the time is 4 to 10 hours.

7. The method for preparing the hemostatic dressing according to claim 4, characterized in that, The mixing parameters in step S2 are as follows: a three-dimensional motion mixer or a V-type mixer is used, the mixing speed is 10-30 rpm, the initial mixing time is 10-20 minutes, and the mixing time after adding the lyophilized drug powder is 10-60 minutes.

8. The method for preparing the hemostatic dressing according to claim 4, characterized in that, The mixing parameters in step S3 are as follows: a three-dimensional motion mixer or a V-type mixer is used, the mixing speed is 10-30 rpm, and the mixing time is 3-15 minutes.

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