Tedizolid gel as well as preparation method and application thereof

Abstract

The invention relates to tedizolid gel and a preparation method thereof. The tedizolid gel is prepared from the following raw materials and auxiliary materials: an active component, a gel matrix, an alcohol solvent, a bacteriostatic agent, a pH regulator and water, the active component is tedizolid or ester thereof, or pharmaceutically acceptable salt thereof; the gel matrix is carbomer. The tedizolid gel can increase the local tissue free drug concentration of the skin of the bacterial infection part of an organism through transdermal absorption, so that the bacteriostatic activity of the tedizolid gel is better played, the treatment effect on local acute bacterial skin and skin soft tissue infection is improved, and the adverse reaction is reduced.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to a terdizolam gel, its preparation method, and its application. Background Technology

[0002] The US FDA's "Guidance for Industry Acute Bacterial Skin and SkinStructure Infections: Developing Drugs for Treatment" defines "Acute Bacterial Skin and Soft Tissue Infection (ABSSSI)" as "a bacterial skin infection with a lesion area of ​​at least 75 cm²". 2 (The size of the lesion is measured by the area of ​​redness, edema, or induration.)

[0003] Skin and soft tissue infections refer to infections involving the skin and subcutaneous soft tissues. Their general clinical manifestations include redness, swelling, heat, pain, and local functional impairment; severe infections may present with systemic symptoms. Under normal circumstances, the skin secretes low-pH lipid fluids and fatty acids that inhibit the growth of pathogens. Simultaneously, a large number of normal flora colonize the skin surface. These normal flora prevent the invasion of other pathogenic microorganisms through site competition and the production of antimicrobial agents. However, when the skin barrier is compromised, the number of bacteria increases, allowing bacteria to invade the epidermis and cause infection. In recent years, the isolation rate of Staphylococcus aureus in skin and soft tissue infections has been high, and community-acquired Staphylococcus aureus infections are becoming increasingly prevalent. Therefore, the effective prevention and treatment of acute bacterial skin and skin and soft tissue infections is a major problem that urgently needs to be addressed.

[0004] Terizolamide is a second-generation oxazolidinone antibiotic, a derivative of the first-generation oxazolidinone antibiotic linezolid. It was first developed by Dong-A Pharmaceutical in South Korea, and later transferred to Trius Therapeutics. Bayer was responsible for the market development of terizolamide phosphate. Trius Therapeutics was later acquired by Cubist (and subsequently by Merck).

[0005] Currently, terizolamide phosphate products are available in both tablet and injectable powder forms, with the indication being acute bacterial skin and soft tissue infections. After oral or intravenous administration, terizolamide phosphate tablets or injectable terizolamide is converted to terizolamide by intestinal or blood phosphatases, then binds to the 23S site of the ribosomal RNA on the bacterial 50S subunit, thereby preventing the formation of the 70S initiation complex and inhibiting bacterial protein synthesis. High oral or injectable doses may pose a risk of serious systemic adverse reactions for skin diseases. The most common adverse reactions are nausea (8%), headache (6%), diarrhea (4%), vomiting (3%), and dizziness (2%); other possible serious adverse reactions include bone marrow suppression, peripheral neuropathy and optic neuropathy, and allergic reactions.

[0006] Therefore, oral or injection administration is a far from ideal method of drug delivery, and its limitations urgently need to be addressed. Summary of the Invention

[0007] Based on this, the present invention provides a terdizolam gel that can be absorbed through the skin to increase the local tissue concentration of free drug at the site of bacterial infection, thereby better exerting its antibacterial activity, improving the therapeutic effect on local acute bacterial skin and soft tissue infections, and reducing adverse reactions.

[0008] The present invention includes the following technical solutions.

[0009] In a first aspect, the present invention provides a terdiazole gel, the raw and excipient materials of which include an active ingredient, a gel matrix, an alcohol solvent, an antibacterial agent, a pH adjuster, and water;

[0010] The active ingredient is terdizodil or its ester, or a pharmaceutically acceptable salt thereof;

[0011] The gel matrix is ​​carbomer, for example, it can be one or more of carbomer 5984EP, carbomer 974P NF, carbomer 980NF, carbomer 981NF, carbomer 971P NF, carbomer Ultrez 10 and carbomer ETD 2020.

[0012] Preferably, the carbomer in the terdizolam gel contains 0.5% to 2.0% by weight, more preferably 1.0% to 2.5%, 1.5% to 2.5%, or 1.8% to 2.2%.

[0013] Preferably, the terdiazole gel has a dynamic viscosity of 5000 mPa·s to 50000 mPa·s at 25°C.

[0014] Preferably, the pH of the terdiazole gel is adjusted to 6.5-8.5 using a pH adjuster, more preferably 6.5-8.0, and even more preferably 6.8-8.0.

[0015] Preferably, the alcohol solvent is one or more of a monohydric alcohol, an alcohol polymer, or a polyhydric alcohol; more preferably, it is one or more of isopropanol, polyethylene glycol, propylene glycol, and glycerin; the weight content of the alcohol solvent in the terdiazole gel is preferably 15% to 45%, more preferably 15% to 35%, 15% to 30%, or 25% to 30%.

[0016] Preferably, the alcohol solvent is a combination of a monohydric alcohol and a polyhydric alcohol, wherein the monohydric alcohol is preferably isopropanol, and the polyhydric alcohol is preferably propylene glycol and / or glycerol; the mass ratio of the monohydric alcohol to the polyhydric alcohol is preferably 1 to 8:1.

[0017] Preferably, the active ingredient is terdizolam, terdizolam phosphate, or other pharmaceutically acceptable salts or esters, and its weight content in the terdizolam gel is 0.1% to 5%, preferably 0.5% to 3.0%, more preferably 0.5% to 2.5%, and even more preferably 1.5% to 2.5%.

[0018] Preferably, the antibacterial agent is selected from at least one of methylparaben, ethylparaben, propylparaben, butylparaben, benzyl alcohol, phenoxyethanol, sodium benzoate, cresol, potassium sorbate, benzalkonium chloride, and benzalkonium bromide; and its weight content in the terdizolam gel is 0.005% to 0.5%, preferably 0.01% to 0.3%.

[0019] Preferably, the pH adjuster is selected from at least one of sodium hydroxide, potassium hydroxide, triethanolamine, diisopropanolamine, aminomethylpropanol, aminobutanetriol and tetra-2-hydroxypropylethylenediamine.

[0020] Preferably, the raw materials and excipients of the terdizolam gel, by weight percentage, include:

[0021]

[0022] The alcohol solvent is a combination of a monohydric alcohol and a polyhydric alcohol in a mass ratio of 2 to 7:1, wherein the monohydric alcohol is isopropanol and the polyhydric alcohol is propylene glycol and / or glycerol.

[0023] Secondly, the present invention also provides a method for preparing the aforementioned terdizolam gel, comprising the following steps:

[0024] a: Weigh the gel matrix, add water to swell, and obtain a matrix mixture;

[0025] b: Dissolve the antibacterial agent in an alcohol solvent to obtain an antibacterial agent solution;

[0026] c: Add the active ingredient to the alcohol solvent, stir and disperse evenly to obtain a drug mixture;

[0027] d: Add the antibacterial agent solution and drug mixture to the matrix mixture, stir and mix evenly, then adjust the pH with a pH adjuster, finally add water to determine the weight, stir and mix evenly to obtain the terdiazole gel.

[0028] Thirdly, the present invention provides the use of the aforementioned terdizolam gel in the preparation of a medicament for treating acute bacterial skin and soft tissue infections.

[0029] The present invention has the following beneficial effects:

[0030] This invention relates to a topical gel formulation prepared by combining terdizolam or its derivatives (e.g., esters) or pharmaceutically acceptable salts or mixtures thereof with specific gel matrices, alcohol solvents, and other excipients. This terdizolam gel can be absorbed transdermally, increasing the local tissue concentration of free drug at the site of bacterial infection, thus enhancing its therapeutic effect on acute bacterial skin and soft tissue infections and reducing adverse reactions. Extensive pharmacological experiments have demonstrated that the topical application of this terdizolam gel to the skin surface more effectively exerts the antibacterial activity of terdizolam, and its therapeutic effect on acute bacterial skin and soft tissue infections is significantly superior to terdizolam phosphate tablets and injectable terdizolam phosphate.

[0031] This invention creatively prepares terdizolamide or its derivatives or its salts or mixtures thereof into a gel for the first time, overcoming the technical prejudice that terdizolamide cannot penetrate the stratum corneum when applied topically, improving the therapeutic effect of terdizolamide, reducing its systemic adverse reactions, meeting the interests of a large number of patients, and has a very good application prospect.

[0032] Furthermore, by further optimizing and screening the gel matrix and its dosage, combined with further optimization of pH and alcohol solvent, the drug stability, drug release, and transdermal properties of terdizolam gel can be significantly improved. This ensures that the active drug does not degrade and its content remains stable during storage and administration. At the same time, it can stably release the drug within 24 hours and release it almost completely, thus guaranteeing its therapeutic concentration during administration and further improving its therapeutic effect. Detailed Implementation

[0033] To facilitate understanding of the present invention, a more complete description will be provided below. The present invention can be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided to provide a thorough and complete understanding of the disclosure of the present invention.

[0034] Unless otherwise specified, experimental methods in the following examples are generally performed under standard conditions or as recommended by the manufacturer. All commonly used chemical reagents used in the examples are commercially available products.

[0035] Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used in this specification is for the purpose of describing particular embodiments only and is not intended to limit the invention. The term "and / or" as used in this invention includes any and all combinations of one or more of the associated listed items.

[0036] Furthermore, as used herein, the term "or" is an inclusive "or" sign and is equivalent to the term "and / or" unless the context clearly specifies otherwise. The term "based on" is not exclusive and allows for basing on other factors not described unless the context clearly specifies otherwise. Additionally, throughout the specification, the meanings of "an," "a," and "the" include plural indicators. The meaning of "in" includes both "in" and "on."

[0037] Terizolamide inhibits bacterial growth by binding to the 23S site of the ribosomal RNA on the 50S subunit of bacteria, thereby preventing the formation of the 70S initiation complex and inhibiting bacterial protein synthesis. It is used to treat acute bacterial skin and soft tissue infections. Current dosage form research is mostly limited to terizolamide phosphate tablets or injectable terizolamide phosphate. After oral or intravenous administration, terizolamide phosphate is converted to terizolamide by intestinal or blood phosphatases, and then exerts its antibacterial effect through the aforementioned mechanism. However, both routes of administration carry the risk of systemic adverse reactions, and the drug concentration reaching the affected skin site after systemic circulation is limited, resulting in less than ideal therapeutic effects.

[0038] Meanwhile, current technology suggests that topical terizolamide cannot penetrate the stratum corneum of the skin and cannot reach an effective tissue concentration in the skin, thus failing to exert its therapeutic effect on acute bacterial skin and soft tissue infections. Therefore, although terizolamide or its pharmaceutically acceptable salts or mixtures thereof were launched in the United States as early as 2014, topical terizolamide formulations have not been available in China or abroad for nearly a decade.

[0039] In order to overcome the above-mentioned shortcomings of oral or intravenous administration, the inventors of this invention discovered through tireless research that by combining terdizolam or its derivatives or salts with suitable gel matrix, alcohol solvents and other excipients, a highly effective topical terdizolam gel can be prepared. In vitro pharmacodynamic studies have shown that it has unexpectedly excellent antibacterial activity in local skin bacterial infections, overcoming the technical prejudice that topical terdizolam cannot penetrate the stratum corneum of the skin.

[0040] This invention prepares terizolamide, its derivatives, its salts, or mixtures thereof into a topical gel. Extensive pharmacological experiments have demonstrated that this terizolamide gel, when applied topically to the skin, more effectively exerts the antibacterial activity of terizolamide. The terizolamide gel prepared by this invention, administered topically, exhibits excellent therapeutic effects on acute bacterial skin and soft tissue infections, significantly outperforming terizolamide phosphate tablets and injectable terizolamide phosphate. This indicates that the topical terizolamide phosphate gel prepared by this invention can be absorbed transdermally, increasing the local concentration of free drug in the skin at the site of bacterial infection, thus better exerting its therapeutic effect on acute local bacterial skin and soft tissue infections and reducing adverse reactions. This invention creatively and for the first time prepares terizolamide, its pharmaceutically acceptable salts, or mixtures thereof, into a gel, overcoming the technical limitation that terizolamide cannot penetrate the stratum corneum when applied topically. This improves the therapeutic effect of terizolamide, reduces its systemic adverse reactions, and is in the best interests of patients, showing great promise for application.

[0041] The above-mentioned effects of the terdiazole gel of the present invention are achieved through the following technical solutions.

[0042] In one embodiment of the present invention, a terdiazole gel is provided, comprising an active ingredient, a gel matrix, an alcohol solvent, an antibacterial agent, a pH adjuster, and water;

[0043] The active ingredient is terdizodil or its ester, or a pharmaceutically acceptable salt thereof;

[0044] The gel matrix is ​​carbomer.

[0045] The inventors discovered that the type of gel matrix has a significant impact on the stability of terdizolam phosphate gel. When carbomer is selected as the gel matrix, the stability of terdizolam phosphate gel can be improved. Among them, the carbomer type can be carbomer 5984EP, carbomer 974PNF, carbomer 980NF, carbomer 981NF, carbomer 971PNF, carbomer Ultrez 10NF, carbomer ETD 2020NF, etc.

[0046] The amount of carbomer in the terdizolam gel is sufficient to allow the gel to gel and achieve the required viscosity. The dynamic viscosity of the gel at 25°C should be between 5000 mPa·s and 50000 mPa·s. The inventors have also found that if the carbomer content in the terdizolam gel is too high, it will not only result in excessively high viscosity, which is detrimental to clinical use, but also affect the release rate of terdizolam. Conversely, if the content is too low, the terdizolam gel will have too low viscosity and be too fluid, failing to gel and resulting in poor adhesion, thus affecting the therapeutic effect. Terizolamide phosphate gels with a carbomer content of 0.5% to 2.0% (w / w) exhibit a 24-hour cumulative release rate of over 90%, and their viscosity falls within the range of 5000 mPa·s to 50000 mPa·s, meeting the requirements for gel use. However, when the carbomer content in the formulation is 2.5% (w / w), the 24-hour cumulative release rate of the terizolamide phosphate gel is only 70%, indicating incomplete drug release and excessive viscosity. Therefore, the preferred carbomer content in the terizolamide gel is 0.5% to 2.0% (w / w), more preferably 0.5% to 1.2% (w / w), and even more preferably 1.0% to 1.2% (w / w).

[0047] The content of the active ingredient (terdizolamide or its ester, or a pharmaceutically acceptable salt thereof) in the terdizolamide gel may be determined according to therapeutic needs, and may be 0.1% to 5% (w / w), preferably 0.5% to 3.0% (w / w), more preferably 0.5% to 2.5% (w / w), 1.0% to 2.5% (w / w), 1.5% to 2.5% (w / w), or 1.8% to 2.2% (w / w).

[0048] The active ingredient may be free terdizodil, terdizodil phosphate, or other pharmaceutically acceptable salts or esters.

[0049] The alcohol solvent in the terdiazole gel of the present invention can be a monohydric alcohol (e.g., isopropanol), an alcohol polymer (e.g., polyethylene glycol), or a polyhydric alcohol; the polyhydric alcohol can be a dihydric alcohol (e.g., propylene glycol) or a trihydric alcohol (e.g., glycerol).

[0050] In some embodiments, the alcohol solvent is preferably one or more of isopropanol, propylene glycol, and glycerol.

[0051] In some embodiments, the alcohol solvent content in the terdizolam gel can be 15%–45% (w / w), more preferably 15%–35% (w / w), even more preferably 15%–30% (w / w), and even more preferably 25%–30% (w / w). The alcohol solvent content also has a certain influence on the viscosity of the terdizolam gel. If the content is too high, the viscosity of the gel will be too low; if the content is too low, the viscosity of the gel will be too high. It will also affect the transdermal penetration and absorption of terdizolam phosphate. When its content is in the preferred range of 15%–45% (w / w), the terdizolam gel has a suitable viscosity and good transdermal absorption performance, thereby giving the terdizolam gel a better therapeutic effect.

[0052] In some embodiments, the alcohol solvent is a combination of a monohydric alcohol and a polyhydric alcohol; wherein the monohydric alcohol is preferably isopropanol, and the polyhydric alcohol is preferably propylene glycol and / or glycerol; the mass ratio of the monohydric alcohol to the polyhydric alcohol is 1 to 8:1, preferably 2 to 7:1; preferably, the alcohol solvent is a combination of a monohydric alcohol and a polyhydric alcohol with a mass ratio of 6 to 7:1.

[0053] The antibacterial agent described in this invention can be a commonly used antibacterial agent acceptable in pharmaceuticals, such as methylparaben, ethylparaben, propylparaben, butylparaben, benzyl alcohol, phenoxyethanol, sodium benzoate, cresol, potassium sorbate, benzalkonium chloride, benzalkonium bromide, etc., preferably one or more of cresol, benzalkonium chloride and benzalkonium bromide.

[0054] The content of the antibacterial agent in the terdiazole gel can be 0.005% to 0.5% (w / w), preferably 0.01% to 0.3% (w / w); when cresol is used as the antibacterial agent, its content is preferably 0.1% to 0.3% (w / w); when benzalkonium chloride and / or benzalkonium bromide are used as the antibacterial agent, its content is preferably 0.01% to 0.03% (w / w).

[0055] The pH adjuster described in this invention can be an inorganic base or an organic base; the inorganic base can be, for example, sodium hydroxide, potassium hydroxide, etc.; the organic base can be a low-molecular-weight amine compound, such as triethanolamine, diisopropanolamine, aminomethylpropanol, aminobutanetriol, tetra-2-hydroxypropylethylenediamine; preferably, it is one or two of sodium hydroxide, potassium hydroxide, and triethanolamine.

[0056] The inventors discovered that the pH of terizolamide gel has a significant impact on its stability. Terizolamide gel with a pH of 6.5–8.5 exhibits better stability. When the pH is 6.2 or lower, or 8.8 or higher, the stability of terizolamide phosphate gel decreases significantly. After 6 months of accelerated testing (40°C / 75% RH), the API content degrades severely, and related substances increase significantly. Therefore, the pH of the terizolamide gel described in this invention needs to be adjusted using a pH adjuster. The preferred pH is 6.5–8.5, more preferably 6.5–8.0, or 7.0–8.5, even more preferably 6.8–8.0, or 7.5–8.5, or 8.0–8.5.

[0057] In some embodiments, the raw materials and excipients of the terdizolam gel, by weight percentage, include:

[0058]

[0059] The alcohol solvent is a combination of a monohydric alcohol and a polyhydric alcohol, wherein the monohydric alcohol is isopropanol, the polyhydric alcohol is propylene glycol and / or glycerol, and the mass ratio of the monohydric alcohol to the polyhydric alcohol is 2 to 7:1.

[0060] In some embodiments, the raw materials and excipients of the terdizolam gel, by weight percentage, include:

[0061]

[0062]

[0063] The alcohol solvent is a combination of a monohydric alcohol and a polyhydric alcohol, wherein the monohydric alcohol is isopropanol, the polyhydric alcohol is propylene glycol and / or glycerol, and the mass ratio of the monohydric alcohol to the polyhydric alcohol is 2 to 7:1.

[0064] The terdiazole gel of the present invention may also contain other excipients acceptable for gel formulations, such as one or more of antioxidants, chelating agents, and fragrances. The antioxidants may be sodium bisulfite, butylated hydroxyanisole, butylated hydroxytoluene, etc.; the chelating agents may be ethylenediaminetetraacetic acid, disodium ethylenediaminetetraacetate, dicalcium ethylenediaminetetraacetate, tartaric acid, citric acid, etc.

[0065] In another embodiment of the present invention, a method for preparing the terdiazole gel of the present invention is provided, the method comprising the following steps:

[0066] a: Weigh the gel matrix, add water to swell, and obtain a matrix mixture;

[0067] b: Dissolve the antibacterial agent in an alcohol solvent to obtain an antibacterial agent solution;

[0068] c: Add the active ingredient to the alcohol solvent, stir and disperse evenly to obtain a drug mixture;

[0069] d: Add the antibacterial agent solution and drug mixture to the matrix mixture, stir and mix evenly, then adjust the pH with a pH adjuster, finally add water to determine the weight, stir and mix evenly to obtain the terdiazole gel.

[0070] In another embodiment of the invention, the application of the terdizolam gel described herein is provided, which can be used for the treatment of acute bacterial skin and soft tissue infections or related diseases.

[0071] The present invention will be further described in detail below with reference to specific embodiments.

[0072] Example 1

[0073] The preparation method of the terdizolam phosphate gel provided in this embodiment is as follows:

[0074] Weigh 12g of carbomer 981NF and add 660g of water to swell, thus preparing a matrix mixture; dissolve 0.2g of benzalkonium chloride in 40g of propylene glycol to obtain an antibacterial agent solution; add 20g of terdizolam phosphate to 250g of isopropanol and stir to disperse evenly, thus obtaining a drug mixture; add the antibacterial agent solution and drug mixture to the matrix mixture and stir to mix evenly; adjust the pH to 8.0 with triethanolamine, add an appropriate amount of purified water to make the total mass of the mixture 1000g, and stir to mix evenly to obtain the terdizolam phosphate gel.

[0075] Example 2

[0076] The terdizolam phosphate gel provided in this embodiment differs from that in Example 1 in that the carbomer used is carbomer 5984EP, and its dosage is 1.0% (w / w). The other components, dosages, and preparation methods are the same as in Example 1.

[0077] Example 3

[0078] The terdiazole phosphate gel provided in this embodiment differs from that in Example 1 in that the carbomer used is carbomer 974PNF, and its dosage is 1.0% (w / w). The other components, dosages, and preparation methods are the same as in Example 1.

[0079] Example 4

[0080] The terdiazole phosphate gel provided in this embodiment differs from that in Example 1 in that the carbomer used is carbomer 980NF, and its dosage is 0.8% (w / w). The other components, dosages, and preparation methods are the same as in Example 1.

[0081] Example 5

[0082] The terdiazole phosphate gel provided in this embodiment differs from that in Example 1 in that the carbomer is carbomer 971PNF, while the other components, dosages, and preparation methods are the same as in Example 1.

[0083] Example 6

[0084] The terdizolam phosphate gel provided in this embodiment differs from that in Example 1 in that the carbomer used is carbomer Ultraz 10 NF, and its dosage is 0.7% (w / w). The other components, dosages, and preparation methods are the same as in Example 1.

[0085] Example 7

[0086] The terdizolam phosphate gel provided in this embodiment differs from that in Example 1 in that the carbomer used is carbomer ETD 2020NF, and its dosage is 0.6% (w / w). The other components, dosages, and preparation methods are the same as in Example 1.

[0087] Example 8

[0088] The terdiazole phosphate gel provided in this embodiment differs from that in Example 1 in that the pH of the finished product is adjusted to 6.5, while the other components, dosages, and preparation methods are the same as in Example 1.

[0089] Example 9

[0090] The terdiazole phosphate gel provided in this embodiment differs from that in Example 1 in that the pH of the finished product is adjusted to 8.5, while the other components, dosages, and preparation methods are the same as in Example 1.

[0091] Example 10

[0092] The terdizolam phosphate gel provided in this embodiment differs from that in Example 1 in that the carbomer content is 0.5% (w / w), while the other components, dosages, and preparation methods are the same as in Example 1.

[0093] Example 11

[0094] The terdiazole phosphate gel provided in this embodiment differs from that in Example 1 in that the carbomer content is 2.0% (w / w), while the other components, dosages, and preparation methods are the same as in Example 1.

[0095] Example 12

[0096] The terdiazole phosphate gel provided in this embodiment differs from that in Example 1 in that the pH adjuster is sodium hydroxide, while the other components, dosages, and preparation methods are the same as in Example 1.

[0097] Example 13

[0098] The terdiazole phosphate gel provided in this embodiment differs from that in Example 1 in that the pH adjuster is potassium hydroxide, while the other components, dosages, and preparation methods are the same as in Example 1.

[0099] Example 14

[0100] The terdizolam phosphate gel provided in this embodiment differs from that in Example 1 in that the pH adjuster is triethanolamine and sodium hydroxide, and the specific preparation method is as follows:

[0101] Weigh 12g of carbomer 981NF and add 560g of water to swell, preparing a matrix mixture; dissolve 0.2g of benzalkonium chloride in 40g of propylene glycol to obtain an antibacterial agent solution; disperse 20g of terdiazole phosphate in 100g of water, then add an appropriate amount of sodium hydroxide aqueous solution to adjust the pH to 6.6-6.8, obtaining a drug solution; add the antibacterial agent solution, drug solution, and 250g of isopropanol to the matrix mixture and stir to mix evenly; adjust the pH to 7.8-8.2 with triethanolamine, add an appropriate amount of purified water to make the total mass of the mixture 1000g, and stir to mix evenly to obtain the terdiazole phosphate gel.

[0102] Example 15

[0103] The terdiazole phosphate gel provided in this embodiment differs from that in Example 1 in that the amount of isopropanol is 38%, the amount of propylene glycol is 7%, and the other components, amounts, and preparation methods are the same as in Example 1.

[0104] Example 16

[0105] The terdizolam phosphate gel provided in this embodiment differs from that in Example 1 in that the proportion of isopropanol is 11%, while the other components, amounts, and preparation methods are the same as in Example 1.

[0106] Example 17

[0107] The terdiazole phosphate gel provided in this embodiment differs from that in Example 1 in that propylene glycol is replaced with an equal amount of glycerol, while the other components, amounts, and preparation methods are the same as in Example 1.

[0108] Example 18

[0109] The terdiazole phosphate gel provided in this embodiment differs from that in Example 1 in that the amount of benzalkonium chloride used is 0.01% (w / w), while the other components, amounts, and preparation methods are the same as in Example 1.

[0110] Example 19

[0111] The terdiazole phosphate gel provided in this embodiment differs from that in Example 1 in that the amount of benzalkonium chloride used is 0.03% (w / w), while the other components, amounts, and preparation methods are the same as in Example 1.

[0112] Example 20

[0113] The terdiazole phosphate gel provided in this embodiment differs from that in Example 1 in that the antibacterial agent benzalkonium chloride is replaced with cresol, which accounts for 0.1% (w / w). The other components, dosages, and preparation methods are the same as in Example 1.

[0114] Example 21

[0115] The terdiazole phosphate gel provided in this embodiment differs from that in Example 1 in that the antibacterial agent benzalkonium chloride is replaced with cresol, which accounts for 0.3% (w / w). The other components, dosages, and preparation methods are the same as in Example 1.

[0116] Example 22

[0117] The terdiazole phosphate gel provided in this embodiment differs from that in Example 1 in that the antibacterial agent benzalkonium chloride is replaced with benzalkonium bromide, with a dosage of 0.01% (w / w). The other components, dosages, and preparation methods are the same as in Example 1.

[0118] Example 23

[0119] The terdiazole phosphate gel provided in this embodiment differs from that in Example 1 in that the antibacterial agent benzalkonium chloride is replaced with benzalkonium bromide, with a dosage of 0.03% (w / w). The other components, dosages, and preparation methods are the same as in Example 1.

[0120] Comparative Example 1

[0121] The terdizolam phosphate gel provided in this comparative example differs from that in Example 1 in that the matrix carbomer 981NF is replaced with hydroxypropyl methylcellulose, while the other components, amounts, and preparation methods are the same as in Example 1.

[0122] Comparative Example 2

[0123] The terdiazole phosphate gel provided in this comparative example differs from that in Example 1 in that the pH of the finished product is adjusted to 6.2, while the other components, dosages, and preparation methods are the same as in Example 1.

[0124] Comparative Example 3

[0125] The terdiazole phosphate gel provided in this comparative example differs from that in Example 1 in that the pH of the finished product is adjusted to 8.8, while the other components, dosages, and preparation methods are the same as in Example 1.

[0126] Comparative Example 4

[0127] The terdiazole phosphate gel provided in this comparative example differs from that in Example 1 in that the amount of carbomer is 2.5% (w / w), while the other components, amounts, and preparation methods are the same as in Example 1.

[0128] Comparative Example 5

[0129] The terdiazole phosphate gel provided in this embodiment differs from that in Example 1 in that the amount of isopropanol is 43%, the amount of propylene glycol is 7%, and the other components, amounts, and preparation methods are the same as in Example 1.

[0130] Comparative Example 6

[0131] The terdiazole phosphate gel provided in this embodiment differs from that in Example 1 in that the amount of isopropanol is 8%, the amount of propylene glycol is 2%, and the other components, amounts, and preparation methods are the same as in Example 1.

[0132] Example 24 Viscosity Measurement

[0133] The viscosity of the terdiazole phosphate gels prepared in Examples 1-17, Comparative Examples 1, and Comparative Examples 4-6 was measured. The method is as follows:

[0134] Take an appropriate amount of the corresponding terdiazole phosphate gel and let it stand at 25°C for at least 30 minutes. Test the viscosity using a rotational viscometer according to the viscosity determination method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0633, Method III). Measure the same sample three times. The dynamic viscosity of the gel at 25°C should be 5000–50000 mPa·s.

[0135] The viscosity test data are shown in Table 1 below: Within the range of 0.5% to 2.0% (w / w) of carbomer, the viscosity of different types of carbomer for terdizolam phosphate gel meets the requirements. The viscosity of terdizolam phosphate gel with a carbomer content of 2.5% (w / w) is relatively high, making it difficult to spread and inconvenient to use. In addition, when the alcohol solvent content is too high, the viscosity of terdizolam phosphate gel will be too low, resulting in poor adhesion, easy flow and difficulty in retention.

[0136] Table 1

[0137]

[0138]

[0139] Note: The viscosity measurement temperature is 25℃.

[0140] Example 25 Stability Test

[0141] The terdiazole phosphate gels prepared in Examples 1, 8, 9, 12-17, Comparative Examples 1, 2, and 3 were subjected to accelerated stability testing (40℃ / 75%RH). The pH was determined according to the pH determination method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0631), and the related substances and contents of terdiazole phosphate in the gel were determined according to the high performance liquid chromatography method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512).

[0142] The experimental results are shown in Tables 2-5.

[0143] Stability tests of terdizolam phosphate gels with different matrices under the same pH conditions revealed that different matrices have a significant impact on the stability of terdizolam phosphate gels. Compared with terdizolam phosphate gels with carbomer as the matrix, terdizolam phosphate gels with hydroxypropyl methylcellulose as the matrix (Comparative Example 1) showed a significant decrease in API content and a significant increase in related substances under accelerated testing (40℃ / 75%RH). Using carbomer as the matrix can improve the stability of terdizolam phosphate gels.

[0144] Stability tests of terdiazole phosphate gel under different pH conditions revealed that the stability of terdiazole phosphate gel is significantly affected by pH. In contrast, terdiazole phosphate gels with pH values ​​of 6.2 and 8.8 (Comparative Example 2) showed severe degradation of API content and a significant increase in related substances after 6 months of accelerated testing (40℃ / 75%RH). However, in terdiazole phosphate gels with pH values ​​between 6.5 and 8.5, the content of related substances did not change significantly within 6 months under accelerated testing (40℃ / 75%RH), and the increase in related substances was controllable, indicating improved gel stability.

[0145] Under the same pH conditions, the stability of terdiazole phosphate gels prepared with different pH adjusters showed no significant difference after 6 months of accelerated testing (40℃ / 75%RH).

[0146] Terizazole phosphate gel containing 15%–45% (w / w) alcohol solvent in the formulation is stable, and there is no significant difference in stability after 6 months of accelerated testing (40℃ / 75%RH); there is no significant difference in stability of terizazole phosphate gel obtained by replacing propylene glycol with glycerin.

[0147] Table 2. Accelerated test results of terdiazole phosphate gel prepared in Examples 1 and 8-9.

[0148]

[0149]

[0150] Table 3. Accelerated test results of terdiazole phosphate gels prepared in Comparative Examples 1-3

[0151]

[0152] Table 4. Accelerated test results of terdiazole phosphate gels prepared in Examples 12-14

[0153]

[0154]

[0155] Table 5. Accelerated test results of terdiazole phosphate gels prepared in Examples 15-17

[0156]

[0157] Example 26 In vitro release experiment

[0158] In vitro release tests were conducted on the terdiazole phosphate gels prepared in Examples 1-7, Example 10, Example 11, and Comparative Example 4.

[0159] The in vitro release test was conducted using the Franz diffusion cell method, and the content of the test sample solution released in vitro was determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512).

[0160] In vitro release conditions: Release medium: pH 7.4 phosphate buffer (mix 250 ml of 0.2 mol / L potassium dihydrogen phosphate solution and 195.5 ml of 0.2 mol / L sodium hydroxide solution, dilute with water to 1000 ml, and shake well); Medium volume: 9 ml; Temperature: 32℃; Rotation speed: 600 rpm; Sampling method: total sampling and replenishment; Drug dosage: approximately 0.3 g; Artificial membrane: Nylon 66 (0.45 μm); Sampling time: 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 16 h, 20 h, 24 h.

[0161] The in vitro release data are shown in Table 6 below: Within the range of 0.5%–2.0% (w / w) of carbomer, different carbomer types had no significant effect on the drug release in terizolamide phosphate gel. The 24-hour cumulative release rate of terizolamide phosphate gel with a carbomer content of 0.5%–2.0% (w / w) could reach over 90%. When the carbomer content in the formulation was too high, the release rate of terizolamide phosphate in the gel would be slower. The 24-hour cumulative release rate of terizolamide phosphate gel with a carbomer content of 2.5% (w / w) was only 70%, indicating incomplete drug release.

[0162] Table 6. Cumulative release rate (%) from in vitro release

[0163]

[0164]

[0165] Example 27 Antibacterial efficacy test

[0166] The terdizazole phosphate gels prepared in Examples 1 and 18-23 were tested for antibacterial efficacy according to (General Chapters 1105 and 1121 of Part IV of the Chinese Pharmacopoeia 2020).

[0167] Judgment criteria:

[0168]

[0169] The test results are shown in Table 7 below: terdiazole phosphate gel with benzalkonium bromide content of 0.01%–0.03% (w / w), terdiazole phosphate gel with cresol content of 0.1%–0.3% (w / w), and terdiazole phosphate gel with benzalkonium bromide content of 0.01%–0.03% (w / w) all meet the requirements for antibacterial efficacy.

[0170] Table 7 Results of antibacterial efficacy test

[0171]

[0172]

[0173]

[0174] Example 28 In vitro transdermal experiment

[0175] In vitro transdermal tests were conducted on the terdiazole phosphate gels prepared in Examples 1, 15, 16, 17, Comparative Example 5, and Comparative Example 6.

[0176] In vitro transdermal testing was conducted using a vertical transdermal diffusion apparatus. The content of the test sample solution in the in vitro transdermal test was determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512).

[0177] In vitro transdermal conditions: Receiving medium: pH 7.4 phosphate buffer (mix 250 ml of 0.2 mol / L potassium dihydrogen phosphate solution and 195.5 ml of 0.2 mol / L sodium hydroxide solution, dilute with water to 1000 ml, and shake well); Temperature: 32℃; Rotation speed: 600 rpm; Drug dosage: approximately 0.3 g; Skin: porcine skin; Sampling time: 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, 16 h, 20 h, 24 h.

[0178] The in vitro transdermal data are shown in Table 8 below: the cumulative permeation of terdizolam gel with an alcohol solvent content of 15% to 45% (w / w) is above 10% in 24 hours. When the alcohol solvent content is too low, the permeation will be reduced and the intradermal retention will be low. However, when the alcohol solvent content exceeds 45%, the cumulative permeation of terdizolam gel in 24 hours does not increase significantly.

[0179] Table 8

[0180]

[0181] Example 29: The therapeutic effect of terdizolam phosphate gel on acute bacterial skin and soft tissue infections in rats.

[0182] In this embodiment, an acute skin infection model was established by combining incision with Staphylococcus aureus infection. The wound area, wound healing rate, and wound bacterial count in rats were detected at different time points after drug administration. The therapeutic effect of terdizolam phosphate gel on acute bacterial skin and soft tissue infections in rats was tested.

[0183] 1. Test drug: Terizazole phosphate gel prepared in Example 1;

[0184] A blank gel (negative control) without terdizolam phosphate was prepared in the same manner as in Example 1;

[0185] Terizazole phosphate tablets (original formulation);

[0186] Terizazole phosphate for injection (original formulation).

[0187] 2. Group setup: 25 qualified SPF-grade male SD rats were selected and randomly grouped according to Table 9.

[0188] Table 9

[0189]

[0190] 3. Modeling method: A 2cm x 2cm area of ​​skin was scratched with industrial sandpaper, and a cross-shaped incision (2cm x 2cm) was made with a blade. Staphylococcus aureus suspension (1×10⁻⁶) was then used. 9 CFU / mL was instilled into the wound and its surrounding area, 1 mL / day / rat, for 3 consecutive days to establish an acute bacterial skin and soft tissue infection model. The day after the last modeling, 20 rats were randomly divided into 4 groups according to Table 9.

[0191] 4. Experimental methods: The wound area of ​​rats in each group was measured before administration and on days 1, 3, and 6 after administration, and the wound healing rate was calculated. Purulent secretions from the wounds on the backs of the animals were collected on days 1, 3, and 6 after administration for bacterial counting.

[0192] 5. Test Results:

[0193] (1) Impact on wound area

[0194] As shown in Table 10, compared with the blank gel group, the wound area of ​​rats in the terdizolam phosphate gel group was significantly reduced on the 3rd and 6th days after administration (P≤0.05). Compared with the terdizolam phosphate tablet group and the terdizolam phosphate injection group, the wound area of ​​rats in the 6th day after administration was significantly reduced (P≤0.05).

[0195] Table 10 Effects of terdizolamide phosphate gel on wound area in model rats ( n=5)

[0196]

[0197] Note: Compared with the blank gel group + P≤0.05, compared with the blank gel group, terdizolamide phosphate tablet group, and terdizolamide phosphate injection group. ++ P≤0.05.

[0198] (2) Impact on wound healing rate

[0199] As shown in Table 11, compared with the blank gel group, the wound healing rate of rats in the terdizolamide phosphate gel group was significantly increased on days 1, 3 and 6 after administration (P≤0.05 or P≤0.01). Compared with the terdizolamide phosphate tablet group and the terdizolamide phosphate injection group, the wound healing rate of rats on days 3 and 6 after administration was significantly increased (P≤0.05).

[0200] Table 11: Effect of terdizolamide phosphate gel on wound healing rate in model rats ( n=5)

[0201]

[0202] Note: Compared with the blank gel group * P≤0.01; compared with the blank gel group + P≤0.01; compared with the terdizolamide phosphate tablet group and the terdizolamide phosphate injection group + P≤0.05; compared with the blank gel group, terdizolamide phosphate tablet group, and terdizolamide phosphate injection group. ++ P≤0.05.

[0203] (3) Effects on bacterial load in secretions

[0204] As shown in Table 12, the bacterial load on the wound surface of the blank gel group was significantly increased compared with the normal control group (P≤0.01). Compared with the blank gel group, the terdizolam phosphate tablet group, and the terdizolam phosphate injection group, the bacterial load on the wound surface of rats was significantly reduced on days 3 and 6 after administration (P≤0.05).

[0205] Table 12 Effects of terdizolam phosphate gel on bacterial load in model rat wounds ( n=5)

[0206]

[0207]

[0208] Note: Compared with the blank gel group, terdizolamide phosphate tablet group, and terdizolamide phosphate injection group. + P≤0.05.

[0209] Conclusion: (1) By detecting changes in wound area, wound healing rate, and bacterial load of secretions at different times, the severity of acute bacterial skin and soft tissue infection can be predicted. After the rats were treated with abrasions and Staphylococcus aureus, the wound area and bacterial load of secretions increased significantly, indicating that the acute bacterial skin and soft tissue infection model was successfully constructed.

[0210] (2) Terizolamide phosphate gel can significantly reduce the wound area and bacterial load of secretions in model rats and improve the wound healing rate, indicating that terizolamide phosphate gel has a significant therapeutic effect on acute bacterial skin and soft tissue infections.

[0211] (3) Compared with terdizolamide phosphate tablets and terdizolamide phosphate for injection, the therapeutic effect of terdizolamide phosphate gel prepared in this invention is significantly better than that of terdizolamide phosphate tablets and terdizolamide phosphate for injection at the same dosage.

[0212] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims.

Claims

1. A terdiazole gel, characterized in that, Its raw and auxiliary materials include active ingredients, gel matrix, alcohol solvent, antibacterial agent, pH adjuster, and water; The active ingredient is terdizodil or its ester, or a pharmaceutically acceptable salt thereof; The gel matrix is ​​carbomer.

2. The terdiazole gel according to claim 1, characterized in that, The carbomer is selected from one or more of the following: carbomer 5984EP, carbomer 974P NF, carbomer 980NF, carbomer 981NF, carbomer 971PNF, carbomer Ultrez 10NF, and carbomer ETD 2020NF.

3. The terdiazole gel according to claim 1, characterized in that, The carbomer content in the terdizolam gel is 0.5%–2.0%, 1.0%–2.5%, 1.5%–2.5%, or 1.8%–2.2% by weight; and / or, The terdiazole gel has a dynamic viscosity of 5000 mPa·s to 50000 mPa·s at 25°C.

4. The terdiazole gel according to claim 1, characterized in that, The pH of the terdizolam gel is adjusted to 6.5-8.5 using a pH adjuster, preferably 6.5-8.0, and more preferably 6.8-8.

0.

5. The terdizolam gel according to any one of claims 1-4, characterized in that, The alcohol solvent is one or more of a monohydric alcohol, an alcohol polymer, or a polyhydric alcohol; Preferably, the alcohol solvent is selected from one or more of isopropanol, polyethylene glycol, propylene glycol, and glycerol; Preferably, the alcohol solvent is a combination of a monohydric alcohol and a polyhydric alcohol, wherein the monohydric alcohol is preferably isopropanol, and the polyhydric alcohol is preferably propylene glycol and / or glycerol; the mass ratio of the monohydric alcohol to the polyhydric alcohol is preferably 1 to 8:1; Preferably, the alcohol solvent has a weight content of 15% to 45% in the terdiazole gel, more preferably 15% to 35%, 15% to 30%, or 25% to 30%.

6. The terdizolam gel according to any one of claims 1-4, characterized in that, The active ingredient is terdizolamide, terdizolamide phosphate, or other pharmaceutically acceptable salts or esters; and / or, The antibacterial agent is selected from at least one of methylparaben, ethylparaben, propylparaben, butylparaben, benzyl alcohol, phenoxyethanol, sodium benzoate, cresol, potassium sorbate, benzalkonium chloride, and benzalkonium bromide; and / or, The pH adjuster is selected from at least one of sodium hydroxide, potassium hydroxide, triethanolamine, diisopropanolamine, aminomethylpropanol, aminobutanetriol, and tetra-2-hydroxypropylethylenediamine.

7. The terdizolam gel according to any one of claims 1-4, characterized in that, The active ingredient in the terdiazole gel contains 0.1% to 5% by weight, preferably 0.5% to 3.0%, more preferably 0.5% to 2.5%, and even more preferably 1.5% to 2.5%; and / or, The antibacterial agent is present in the terdiazole gel at a weight content of 0.005% to 0.5%, preferably 0.01% to 0.3%.

8. The terdizolam gel according to any one of claims 1-4, characterized in that, The raw materials and excipients of the terdizolam gel, by weight percentage, include: Terizazole phosphate 0.5%–2.5%, Carbomer 0.5%–2.0%, Alcohol solvent 15%–45%, Antibacterial agent 0.01%–0.3%, An appropriate amount of pH adjuster is used to adjust the pH of the terdizolam gel to 6.5–8.5; Add water to 100%; The alcohol solvent is a combination of a monohydric alcohol and a polyhydric alcohol in a mass ratio of 2 to 7:1, wherein the monohydric alcohol is isopropanol and the polyhydric alcohol is propylene glycol and / or glycerol.

9. A method for preparing the terdiazole gel according to any one of claims 1-8, characterized in that, Includes the following steps: a: Weigh the gel matrix, add water to swell, and obtain a matrix mixture; b: Dissolve the antibacterial agent in an alcohol solvent to obtain an antibacterial agent solution; c: Add the active ingredient to the alcohol solvent, stir and disperse evenly to obtain a drug mixture; d: Add the antibacterial agent solution and drug mixture to the matrix mixture, stir and mix evenly, then adjust the pH with a pH adjuster, finally add water to determine the weight, stir and mix evenly to obtain the terdiazole gel.

10. The use of the terdizolam gel according to any one of claims 1-8 in the preparation of a medicament for treating acute bacterial skin and soft tissue infections.

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