Composition for treating renal dysfunction-associated diabetic foot ulcers in subject

Abstract

The present invention relates to use of a composition comprising a Plectranthus amboinicus extract in the preparation of a medicament for treating renal dysfunction-associated diabetic foot ulcers in a subject. The medicament of the present application demonstrates favorable therapeutic efficacy for diabetic foot ulcers with comorbid renal dysfunction, offers a good prognosis, is convenient to administer, involves a simple treatment method, and has high safety, making it suitable for broad clinical application.

Description

A composition for treating diabetic foot ulcer of the renal dysfunction type in a subject Technical Field

[0001] The present invention relates to the field of biomedicine, and in particular to a composition for treating diabetic foot ulcers of the renal dysfunction type in a subject. Background Art

[0002] Diabetes is one of the world's most serious diseases. According to the International Diabetes Federation (IDF), it is estimated to affect 693 million adults by 2045. Vascular complications such as cardiovascular disease (CVD), diabetic nephropathy (DKD), diabetic retinopathy, and neuropathy are the leading causes of morbidity and mortality in diabetic patients. DKD is also the leading cause of end-stage renal disease (ESRD), which occurs when patients lose kidney function and require lifelong dialysis or even a kidney transplant.

[0003] On the other hand, diabetic foot ulcers (DFUs) also affect up to 34% of diabetic patients, resulting in a significant economic burden and reduced quality of life. Studies have shown that hemodialysis is a key risk factor for the prevalence of foot ulcers in diabetic patients. The likelihood of developing a diabetic foot ulcer increases significantly in diabetic patients who also undergo renal dialysis. Furthermore, DFUs caused by renal impairment are the most difficult to manage. A retrospective study showed that reduced eGFR levels in patients with DFUs, indicating deteriorating renal function, are associated with poor limb prognosis and mortality. This observation suggests that impaired renal function or dialysis treatment prolongs the healing of diabetic foot ulcers. Furthermore, clinical data have also found that diabetic patients receiving dialysis have disproportionately high rates of foot-related hospitalizations. Since 2019, the International Working Group on the Diabetes Foot (IWGDF) has stated that patients with diabetes and ESRD should be categorized as foot risk category 3, even without a history of foot ulcers or lower limb amputation, based on the observation that diabetic patients receiving hemodialysis have a higher risk of DFUs and a worse prognosis than other diabetic patients. Therefore, the International Working Group on Diabetic Foot classified diabetic patients with ESRD separately as the third category of people with foot risk.

[0004] Existing treatments for diabetic foot ulcers, a type of renal dysfunction, are complex and expensive, involving foot wound care, infection control, revascularization, debridement and amputation, and the production of special footwear. Furthermore, the effectiveness of common medications effective for diabetic foot ulcers falls short of expectations, making this a challenging treatment issue that urgently needs to be addressed in this field.

[0005] Summary of the Invention

[0006] In response to the technical problems existing in the prior art, the present invention proposes a use of a composition comprising an extract of Osmanthus fragrans for preparing a medicament for treating diabetic foot ulcers of the renal dysfunction type in a subject.

[0007] In some embodiments, the renal dysfunction is renal insufficiency.

[0008] In some embodiments, the renal dysfunction is end-stage renal disease.

[0009] In some embodiments, the renal dysfunction is such that the subject requires dialysis.

[0010] In some embodiments, the diabetic foot ulcer is graded as TEXAS 1A or TEXAS 2A according to the University of Texas Wound Classification.

[0011] In some embodiments, the extract of the fragrant osmanthus fragrans comprises one or more of salvigenin, cirsimaritin, rosmarinic acid and carvacrol.

[0012] In some embodiments, the composition further comprises Centella asiatica extract.

[0013] In some embodiments, the Centella asiatica extract comprises asiaticoside and / or asiatic acid.

[0014] In some embodiments, the weight ratio of the Herba Citri Reticulatae Extract to the Centella Asiatica Extract in the composition is 1:(1-4), preferably 1:4.

[0015] In some embodiments, the composition comprises about 0.1-1% (w / w) of the Cibotium chinense extract and / or about 0.4-4% (w / w) of the Centella asiatica extract; preferably, the composition comprises about 0.25% (w / w) of the Cibotium chinense extract and / or about 1% (w / w) of the Centella asiatica extract.

[0016] In some embodiments, the composition comprises about 0.5-5% (w / w) of an active ingredient, wherein the active ingredient comprises an extract of Cibotium officinale and / or an extract of Centella asiatica.

[0017] In some embodiments, the composition comprises: 1.0-10% (w / w) viscosity increasing agent; 5-30% (w / w) ointment base; 0.01-0.2% (w / w) antibacterial agent; and / or 0.5-6% (w / w) emulsifier.

[0018] In some embodiments, the viscosity increasing agent is selected from one or more of the following components: ethanol stearyl alcohol, cholesterol, stearyl alcohol, chlorocresol, white wax, stearic acid, cetyl alcohol or a combination thereof; preferably, the viscosity increasing agent includes cetyl stearyl alcohol; the ointment base includes one or more vaseline compounds, preferably a combination of liquid vaseline and white vaseline; the antibacterial agent includes one or more paraben compounds, preferably a combination of methyl paraben and propyl paraben; and / or the emulsifier includes sorbitol and / or polysorbate, preferably sorbitol monostearate and polysorbate 60.

[0019] In some embodiments, the composition includes: 0.25% (w / w) Citrus aurantium extract; 1% (w / w) Centella asiatica extract; 4-6% (w / w) cetearyl alcohol; 20-30% (w / w) a combination of liquid petrolatum and white petrolatum; 0.08-0.15% (w / w) a combination of methylparaben and propylparaben; 2-4% (w / w) sorbitan monostearate and polysorbate 60.

[0020] In some embodiments, the composition further comprises one or more solvents, preferably propylene glycol and water.

[0021] In some embodiments, the drug is in the form of a cream, gel, dressing, spray, ointment, cream, paste, patch, mask or lotion.

[0022] In some embodiments, the drug is administered to the diabetic foot ulcer of the subject 1-4 times a day or once every 2-7 days according to the approved dosage.

[0023] In some embodiments, the subject is a human or non-human mammal.

[0024] A method for treating diabetic foot ulcers of the renal dysfunction type in a subject, comprising administering any of the above-described drugs to the diabetic foot ulcers in the subject.

[0025] The drug of the present application has a good therapeutic effect on diabetic foot ulcers combined with renal dysfunction, has a good prognosis, is easy to administer, has a simple treatment method, and is highly safe, and can be widely used in clinical practice. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Below, the preferred embodiments of the present invention will be further described in detail with reference to the accompanying drawings, in which:

[0027] FIG1A is a photograph of a diabetic foot ulcer treatment record of patient 1 according to one embodiment of the present invention;

[0028] FIG1B is a diabetic foot ulcer healing curve of patient 1 according to one embodiment of the present invention;

[0029] FIG2A is a photograph of a diabetic foot ulcer treatment record of patient 2 according to one embodiment of the present invention;

[0030] FIG2B is a diabetic foot ulcer healing curve of patient 2 according to one embodiment of the present invention;

[0031] FIG3A is a photograph of a diabetic foot ulcer treatment record of patient 3 according to one embodiment of the present invention;

[0032] FIG3B is a diabetic foot ulcer healing curve of patient 3 according to one embodiment of the present invention;

[0033] FIG4A is a photograph of a diabetic foot ulcer treatment record of patient 4 according to one embodiment of the present invention; and

[0034] FIG4B is a diabetic foot ulcer healing curve of patient 4 according to one embodiment of the present invention. DETAILED DESCRIPTION

[0035] To make the objectives, technical solutions, and advantages of the embodiments of the present invention more clear, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts shall fall within the scope of protection of the present invention.

[0036] In the detailed description that follows, reference is made to the accompanying drawings that form part of this application and illustrate specific embodiments of the present application. In the accompanying drawings, similar reference numerals describe substantially similar components in different figures. Each specific embodiment of the present application is described below in sufficient detail to enable a person of ordinary skill in the art to implement the technical solutions of the present application. It should be understood that other embodiments may also be utilized or that the embodiments of the present application may be modified.

[0037] The present application relates to a composition for treating diabetic foot ulcers of the renal dysfunction type in a subject. The components and preparation method of the composition, as well as the preparation method of the extract of Cibotium officinale and Centella asiatica in the composition can be referred to the following patents or patent applications, the relevant disclosures of each of which are incorporated by reference into the subject matter and purposes cited herein: Application No. PCT / CN2023074120, application date 2023.02.01; Application No. PCT / CN2023 / 102711, application date 2023.06.27; Application No. PCT / CN2023 / 096428, application date 2023.05.26; application number PCT / CN2022 / 101441, application date 2022.06.27; application number CN201780009172.7, application date 2017.07.17; application number CN201210128422.8, application date 2012.04.27; application number CN201480081762.7, application date 2014.09.05; and application number CN201410442909, application date 2014.09.02.

[0038] The phrase "and / or" as used in the specification and claims should be understood to mean "one or both" of the elements so connected, i.e., elements that are present in a connected manner in some cases and in a separated manner in other cases. Multiple elements listed with "and / or" should be interpreted in the same manner, i.e., "one or more" of the elements so connected. In addition to the elements specifically identified by the "and / or" clause, other elements may optionally be present, related or unrelated to those specifically identified. Thus, as a non-limiting example, when used with open language such as "comprising," a reference to "A and / or B" may, in one embodiment, refer to only A (optionally including elements other than B); in another embodiment, to only B (optionally including elements other than A); in another embodiment, to both A and B (optionally including other elements), etc.

[0039] As used in the specification and claims, "or" should be understood to have the same meaning as "and / or" defined above. For example, when separating items in a list, "or" or "and / or" should be interpreted as inclusive, i.e., including at least one, but also including a number or list of multiple elements, and optional additional unlisted items. Only terms that clearly indicate the contrary, such as "only one" or "exactly one", or when used in the claims, "consisting of..." will refer to the inclusion of exactly one element in a number or list of elements. In general, the term "or" as used herein should be interpreted as indicating exclusive substitution (i.e., "one or the other, but not both") only when preceded by an exclusive term, such as "any one", "one of", "only one of" or "exactly one of". "Substantially consisting of...", as used in the claims, should have the same ordinary meaning as used in the field of patent law.

[0040] As used in the specification and claims, when referring to a list of one or more elements, the phrase "at least one" should be understood to refer to at least one element selected from any one or more elements in the list of elements, but does not necessarily include at least one of each and every element specifically listed in the list of elements, and does not exclude any combination of elements in the list of elements. This definition also allows that elements may be selectively present in addition to the elements specifically identified in the list of elements to which the phrase "at least one" refers, whether related or unrelated to those specifically identified elements. Thus, as a non-limiting example, in one embodiment, "at least one of A and B" (or equivalently "at least one of A or B", or equivalently "at least one of A and / or B") may refer to at least one without B, optionally including multiple A (optionally including elements other than B); in another embodiment, to at least one, optionally including multiple, without A (optionally including elements other than A); in yet another embodiment, to at least one (optionally including multiple) A and at least one (optionally including multiple) B (optionally including other elements), etc.

[0041] It should also be understood that in any method claimed herein that includes more than one step or action, the order in which the method steps or actions are performed is not necessarily limited to the order in which the method steps or actions are recited unless explicitly stated to the contrary.

[0042] 1. External use preparations

[0043] The present invention provides topical formulations for promoting scar maturation or reducing the risk of scar formation in a subject. The topical formulations disclosed herein include a Psoralea corylifolia (PA) extract and suitable excipients and carriers as disclosed herein. In some embodiments, the topical formulations may further include a Centella asiatica (CA) extract.

[0044] (a) Fragrance extract

[0045] The scientific name of "Plectranthus amboinicus (Lour.) Spreng. (hereinafter referred to as PA), is also known as left-handed incense, Indian mint, prince incense, etc., and its aliases include resurrection grass and touch-and-go incense. It belongs to the perennial Lamiaceae (Lamiaceae, also known as Labiatae) herb and is native to southern and eastern Africa.

[0046] A polysaccharide (PA) extract refers to an extract obtained from a PA plant using one or more suitable solvents. In some embodiments, the PA extract is prepared using the aerial parts of the PA plant. In some cases, at least one of the solvents used to prepare the extract has a polarity index less than 7 (e.g., less than 5). For example, methods for preparing polysaccharide extracts can be found in patent applications US10,758,584, PCT / CN2022 / 101441, and / or PCT / CN2023074120, the relevant disclosures of each of which are incorporated by reference into the subject matter and purposes cited herein. As used herein, a solvent refers to a substance or mixture of substances that dissolves another substance to form a solution. A single solvent can be used to prepare the PA extract described herein. The solvent used in each extraction step for preparing the extracts described herein (including PA and CA extracts) can be a single solvent, or a mixture of two or more solvents.

[0047] The PA extract described herein may comprise terpenes (e.g., monoterpenes, diterpenes, triterpenes, and / or sesquiterpenes), flavonoids, phenols, essential oils, or combinations thereof. The PA extract used to prepare the pharmaceutical composition disclosed herein may comprise one or more of salvigenin, cirsimin, rosmarinic acid, and carvacrol.

[0048] The PA extract described herein can be prepared by extracting the entire PA plant or a portion thereof (e.g., an aerial part; further, for example, a leaf) with one or more suitable solvents to produce a solution, and then drying the solution to produce a PA extract. The PA plant can be a fresh plant or a processed PA material can be the entire PA or a portion thereof (e.g., an aerial part, such as a leaf), and can be prepared by conventional methods. The PA material can be a fresh plant or a portion thereof. Alternatively, the PA material can be in a dried form. The PA can optionally be dried to form a powder, which can be used as the PA material for preparing the PA extract.

[0049] Since the PA extract contains flavonoids, terpenoids (e.g., monoterpenes, diterpenes, triterpenes, and / or sesquiterpenes), phenolic compounds, or essential oils, which are non-polar molecules, at least one of the extraction solvents may have a relatively low polarity (e.g., having a polarity index of less than 7) to facilitate the dissolution of the non-polar molecules. The "extraction" can be performed by directly contacting the PA material with a suitable solvent or eluting the active ingredient of the PA from a resin to which the active ingredient is attached.

[0050] In some embodiments, solvents with a polarity index below 7 can be used to extract active ingredients from PA to produce PA extracts. Examples include solvents with a polarity index of < about 6.5, < about 6.0, < 5.5, < 5.0, < 4.9, < 4.8, < 4.7, < 4.6, < 4.5, etc. In some embodiments, the solvent can be ethyl acetate, methyl acetate, methanol, ethanol, propanol, butanol, acetone, or chloroform. In other embodiments, the solvent can be a mixture of one or more solvents with different polarity indices, such as, but not limited to, mixtures of ethanol and ethyl acetate, ethyl acetate and butanol, ethanol and propanol, or methyl acetate and butanol.

[0051] Any PA material described herein can be extracted one or more times with a suitable solvent to produce a crude extract. In some embodiments, the solvent used to prepare the crude extract can be a highly polar solvent, such as one with a polarity index greater than 5 and preferably less than 7 (e.g., >5.2, >5.5, >5.8, >6, or greater, preferably less than 7). For example, in some embodiments, the solvent includes, but is not limited to, ethanol, acetone, methanol, water, or combinations thereof. If necessary, the crude extract can be concentrated using conventional methods to produce a concentrated crude extract.

[0052] In some embodiments, the crude extract can be contacted with a suitable resin (e.g., a non-ionic absorbent resin) under suitable conditions that allow the active ingredients in the crude extract to be bound to the resin. Exemplary resins for preparing the hand fragrance extract include, but are not limited to, Amberlite TM XAD-2 or Amberlite TM XAD-4.

[0053] In some embodiments, the resin can be washed one or more times and eluted with a suitable solvent (e.g., a solvent with a polarity index less than 7) to produce a PA extract, which can then be dried by conventional methods (e.g., freeze drying, spray drying, or concentrated drying) to produce a dry PA extract, which can be in a semi-solid or paste form.

[0054] In some embodiments, the resin absorption step can be performed by mixing the crude extract with the resin in a container. In other embodiments, the resin separation step can be performed by a chromatography column setup.

[0055] In some embodiments, the extract of PA can be prepared as follows: take the aerial part of PA (about 1.5 g), including leaves and / or stems. In some embodiments, it can be collected and extracted at room temperature for 30 minutes to 6 hours with a solvent with a polarity of less than 7 (e.g., methanol, ethanol, acetone, ethyl acetate, butanol, dichloromethane, or a combination thereof). In some embodiments, the extraction process can be carried out at a temperature of about 50 to 80° C., and the resulting crude extract can be directly loaded onto a non-ionic adsorbent resin column and eluted with a solvent with a polarity of less than 6 (e.g., ethanol, ethyl acetate, butanol, dichloromethane, hexane, toluene, or a combination thereof). The eluted components can be collected and purified by extraction with a solvent with a polarity of less than 6 (such as those described herein). The resulting filtrate can be collected to produce a PA extract.

[0056] A specific example of a PA preparation process is provided in Example 1. In some cases, the PA extract used in any topical formulation disclosed herein can be prepared by the method described in Example 1.

[0057] (b) Centella asiatica extract

[0058] Centella asiatica (L.) Urb. (hereinafter referred to as CA), also known as Asian hydrocotyle (Hydrocotyle asiatica L.) and clover (Trisanthus cochinchinensis Lour.), is a perennial medicinal plant native to Asia, Africa and South America, belonging to the Machileneaceae family or the Machileneoideae subfamily of the Apiaceae family.

[0059] Centella asiatica extracts typically contain two main compounds: asiaticoside and synthetic asiatic acid.

[0060] In some embodiments, the topical formulation disclosed herein may further comprise a CA extract, which may comprise an asiaticoside compound. The CA extract described herein refers to an extract obtained from the whole CA plant or a portion thereof. The CA extract may comprise asiaticoside and optionally synthetic acetic acid.

[0061] CA extracts can be prepared according to conventional methods, such as those described in US Pat. Nos. 5,834,437, 6,417,349, 6,475,536, 6,267,996, CN1313124, CN1089497, and CN1194154.

[0062] In some embodiments, CA material can be prepared by routine practice. Such material can be fresh or dried CA plants or parts thereof. CA material can be extracted with a suitable solvent, such as water, ethanol or a mixture thereof, to produce a crude extract. The crude extract, which can be optionally concentrated, can be mixed with a suitable resin or loaded onto a column filled with resin. After washing once or multiple times, the resin can be eluted with a suitable solvent. The resulting eluate can be concentrated into a paste, which can be dried by conventional methods, such as vacuum drying, to produce a powder of CA extract. If necessary, the CA powder can be ground through a sieve (such as 100 mesh).

[0063] The CA extract can be prepared by the same or similar method as that used to prepare the PA extract. The PA extract and / or CA extract can be concentrated using a reduced pressure rotary evaporator.

[0064] (c) Suitable excipients and carriers

[0065] In some examples, the topical preparation may further comprise one or more suitable carriers or excipients, for example, one or more viscosity increasing agents (e.g., about 1.0-10%), one or more ointment bases (e.g., one or more cream bases), which may range from about 5-30%, one or more antimicrobial preservatives (e.g., about 0.005-0.2%, such as about 0.01-0.2% by weight), one or more emulsifiers (about 0.5-10%, such as about 0.5-6% by weight), or a combination thereof. These ingredients may be dissolved or dispensed in a suitable solvent.

[0066] As used herein, the term "about" means strict numerical boundaries (including upper and lower limits) of a specified parameter. Those skilled in the art have understood the meaning of "approximately" in the context of a specific context. In some cases, the term "about" refers to a specific value + / - 5% (e.g., + / - 3% or + / - 2%).

[0067] "Viscosifier" or "viscosity increasing agent" have the same meaning and refer to an agent used to thicken a formulation. For example, in some embodiments, the viscosity increasing agent may include cetyl alcohol, cholesterol, stearyl alcohol, chlorocresol, white wax, stearic acid, cetyl alcohol, or a combination thereof. The concentration of the viscosity increasing agent in the formulations described herein may be about 1.0-10% (w / w). For example, in some embodiments, the formulation includes about 1-1.5%, 1.5-2%, 2-2.5%, 2.5-3%, 3-3.5%, 3.5-4%, 4-4.5%, 4.5-5%, 5-5.5%, 5.5-6%, 6-6.5%, 6.5-7%, 7-7.5%, 7.5-8%, 8-8.5%, 8.5-9%, 9-9.5%, or 9.5-10% (w / w) of the viscosity increasing agent. Alternatively, the topical formulation may comprise about 1-5%, 2.5-7.5%, or 5-10% (w / w) of a viscosity increasing agent. In a specific embodiment, the topical formulation may comprise cetearyl alcohol as an emulsifier, which may be present in the topical formulation in an amount of about 4-6% (w / w).

[0068] "Ointment base" can be any semi-solid formulation or carrier into which an active agent can be incorporated. In some embodiments, ointment bases include, but are not limited to, oily ointment bases (such as white petrolatum or white ointment), absorbent ointment bases (such as hydrophilic petrolatum, anhydrous lanolin, Aquabase™, and ), water / oil emulsion ointment base (such as cold cream, aqueous lanolin, rose water ointment, Hydrocream TM 、 and ), oil / water emulsion ointment base (such as hydrophilic ointment, Dermabase TM 、 and ), and water-miscible ointment bases (e.g., polyethylene glycol ointment and Polybase TM ). The ointment base may be pharmacologically inert, but can trap water to provide an emollient protective film. In a specific embodiment, the ointment base can be any petrolatum compound (e.g., petrolatum, white petrolatum, white soft paraffin, liquid petrolatum, liquid paraffin, etc.). In a further specific embodiment, the ointment base includes white petrolatum (e.g., CAS No. 8009-03-8). In some embodiments, the ointment base for the topical formulations disclosed herein contains a combination of liquid petrolatum and white petrolatum.

[0069] In certain embodiments, in the topical preparation of the application, ointment base concentration is about 5-30% (w / w), for example, 10-30% (w / w). For example, in certain embodiments, topical preparation may include an ointment base of about 5-25%, 5-20%, 5-15%, 5-10%, 10-15%, 15-20%, 20-25% or 25-30% (w / w). Specifically, topical preparation may include an ointment base of about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29% or 30% (w / w). In a specific embodiment, the topical formulation may contain about 20-30% (w / w) of a combination of liquid petrolatum and white petrolatum as an ointment base.

[0070] In some embodiments, an "ointment base" as described herein contains less than 20% water and volatiles, and more than 50% hydrocarbons, waxes, or polyols as carriers.

[0071] In some embodiments, the "ointment base" described herein is a "cream base," which contains more than 20% water and volatiles and / or typically contains less than 50% hydrocarbons, waxes, or polyols as carriers for the drug substance. A cream base can be a multiphase formulation containing a lipophilic phase and an aqueous phase. In some cases, the cream base is a lipophilic cream base, which has a lipophilic phase as a continuous phase. Such cream bases typically contain oil-in-water emulsifiers, such as lanolin alcohol, sorbitan esters, and monoglycerides. In other cases, the cream base is a hydrophilic cream base, which has an aqueous phase as a continuous phase. Such cream bases typically contain oil-in-water emulsifiers, such as sodium or triamine soaps, fatty alcohol sulfates, polysorbates, and polyoxy fatty acids and fatty alcohol esters, and can be mixed with oil-in-water emulsifiers if necessary.

[0072] "Antibacterial preservative" can be any compound that can destroy microorganisms, prevent microbial reproduction or growth, or prevent microbial pathogenic effects. Exemplary antibacterial preservatives include, but are not limited to, paraben compounds (such as parabens, parabens, methylparaben, ethylparaben, propylparaben, butylparaben, heptylparaben, benzylparaben, isobutylparaben, benzylparaben, or their sodium salts), benzalkonium chloride, benzethonium chloride, benzyl alcohol, benzyl alcohol, propyl bromide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chlorocresol, cresol, ethanol, glycerol, hexylbutanol, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal. The concentration of the antibacterial preservative in the topical preparation is about 0.005-0.2%. In some embodiments, the concentration of the antimicrobial preservative in the topical formulation is about 0.01-0.2% (w / w). For example, in some embodiments, the topical formulation may contain about 0.005-0.01%, 0.01-0.05%, 0.05-0.1%, 0.1-0.15%, or 0.15-0.2% (w / w) of the antimicrobial preservative. Specifically, the topical formulation may include about 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19 or 0.2% (w / w) of an antimicrobial preservative. In some examples, the topical formulation contains about 0.08-0.15% (w / w) of a combination of methylparaben and propylparaben.

[0073] An "emulsifier" is a compound or substance that acts as a stabilizer for a mixture of two or more normally immiscible (immiscible or non-mixable) liquids. In some embodiments, the emulsifier may include, but is not limited to, natural emulsifiers (e.g., agar, alginic acid, sodium alginate, xanthan gum, cartilage, cholesterol, xanthan gum, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite [aluminum silicate] and magnesium aluminosilicate [magnesium aluminum silicate]), long-chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetate monostearate, ethylene glycol distearate, glycerol monostearate, propylene glycol monostearate, and polyvinyl alcohol), carbohydrates (e.g., carboxypolymethylene, polyacrylic acid, acrylic acid polymers, and carboxyvinyl polymers), carrageenan, cellulose derivatives (e.g., sodium carboxymethylcellulose, powdered cellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate Polyoxyethylene sorbitan monooleate Polyoxyethylene sorbitan monooleate Sorbitol monoaluminate Sorbitol monostearate Sorbitol tristearate Glyceryl monooleate and sorbitan monooleate ), polyoxyethylene esters (such as polyoxyethylene monostearate Polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene stearate and soluble alcohol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (such as ), polyoxyethylene ethers (such as polyoxyethylene lauryl ether ) and polyvinylpyrrolidone (vinylpyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, ethyl oleate, ethyl laurate, sodium lauryl sulfate, Pluronic F 68, Poloxamer 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium and / or a combination thereof. The emulsifier concentration in the topical preparation of the present application can be about 0.5-10% (w / w). For example, 0.5-6% (w / w). In some embodiments, the topical formulation may comprise about 0.5-1%, 1-1.5%, 1.5-2%, 2-2.5%, 2.5-3%, 3-3.5%, 3.5-4%, 4-4.5%, 4.5-5%, 5-5.5%, 5.5-6%, 5-10%, 6-10% or 8-10% (w / w) of an emulsifier. Specifically, the topical formulation may comprise about 0.5%, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5 or 10% (w / w) of an emulsifier. In some embodiments, the topical formulation may contain about 2-4% (w / w) of sorbitan monostearate and polysorbate 60 as emulsifiers.

[0074] The topical preparations of the present invention may further contain one or more solvents (e.g., non-aqueous solvents or water). In some embodiments, the non-aqueous solvent may include, but is not limited to, any known solvent, including propylene glycol, ethylene glycol, and mixtures thereof. The non-aqueous solvent may be present in the topical preparation at a concentration of about 2-65% (w / w). For example, the topical preparation may contain about 2-15%, 15-30%, 30-45%, or 45-65% (w / w) solvent. In some embodiments, the topical preparations disclosed herein may also contain water.

[0075] In some embodiments, the formulations of the present invention may further comprise one or more emollients, fragrances, or pigments (e.g., cyclohexane, n-hexane, n-decane, i-octane, octane, butyl ether, carbon tetrachloride, triethylamine, i-propyl ether, toluene, p-xylene, p-butyl methyl ether, benzene, phenyl ether, dichloroethane, 1-butanol, i-butanol, tetrahydrofuran, ethyl acetate, 1-propanol, 2-propanol, methyl acetate, cyclohexanone, methyl ethyl ketone (MEK), nitrobenzene, benzonitrile, 1,4-dioxane, or p-dioxane). In some embodiments, the formulations may also be used with wound dressings (e.g., adhesive bandages, plaster patches, etc.).

[0076] Additional information regarding topical formulations can be found, for example, in US Patent No. 10,758,584, the relevant disclosure of which is incorporated by reference herein for all purposes cited.

[0077] The topical preparations disclosed herein can be in any suitable format. Examples include, but are not limited to, creams, dressings, ointments, lotions, pastes, facial masks and gels. In some cases, the topical preparation can be placed on a device (e.g., a patch) for application to a site where a skin disease occurs. Wherein, skin diseases include, but are not limited to, wounds and scars on the skin surface caused by various causes, such as sunburn wounds, scald wounds, frostbite wounds, cut wounds, surgical wounds, ulcers caused by various causes, and scars caused by the above-mentioned wound healing, rash healing, etc. In some embodiments, the ulcer is caused by diabetes. Further, in some embodiments, the ulcer is caused by diabetes of the type of renal dysfunction.

[0078] 2. Methods to promote the recovery of diabetic foot ulcers of renal dysfunction type

[0079] Any of the topical formulations disclosed herein can be used to promote recovery of a diabetic foot ulcer of the renal dysfunction type, or to reduce the risk of further progression of the ulcer in a subject (eg, a human subject).

[0080] In some embodiments, an effective amount of the topical preparation can be administered to a subject in need of treatment (e.g., a diabetic foot patient with renal dysfunction) via an appropriate route, such as topically applying to a skin site that is ulcerated or about to form an ulcer (e.g., the foot).

[0081] The regimen of the method will depend on the nature and condition of the symptoms being treated, the age and condition of the patient, and any previous or concurrent treatments. In some cases, the topical formulation can be applied once a week, once every six days, once every five days, once every four days, once every three days, once every other day, once a day, twice a day, three times a day, or four times a day, etc., for a suitable period of time. In some embodiments, the topical formulation is applied to the diabetic foot ulcer of the subject 1-2 times a day in accordance with the approved instructions for use.

[0082] The subject treated by the topical formulation disclosed herein can be a human or non-human mammal. In some embodiments, the subject is a human patient with a diabetic foot ulcer of the type of renal dysfunction. Subjects with ulcers disclosed herein can be identified by routine medical examination.

[0083] As used herein, "effective amount" refers to the amount of each active agent required for producing a therapeutic effect on a subject, either alone or in combination with one or more other active agents. It will be apparent to those skilled in the art that the amount of the composition has achieved a therapeutic effect. As will be appreciated by those skilled in the art, the effective amount varies according to the specific condition being treated. Such as the severity of the disease, individual patient parameters, including age, physical condition, body shape, sex and weight, duration of treatment, the nature of concurrent treatment (if any), specific route of administration, and similar factors within the knowledge and expertise of the healthcare practitioner. These factors are well known to those of ordinary skill in the art and can be resolved by routine experimentation. It is generally preferred to use the maximum dose of a single component or a combination thereof, i.e., the highest safe dose according to reasonable medical judgment.

[0084] In some embodiments, the determination of dosage will generally be helpful for sales considerations. Dosage frequency can be determined and adjusted throughout the course of treatment, typically but not necessarily based on treating and / or suppressing and / or improving and / or delaying the target disease / disorder. Alternatively, a sustained continuous release formulation of the composition may be suitable. Various formulations and devices for achieving sustained release are known in the art.

[0085] Typically, for administration of any composition described herein, an initial candidate dose is administered to a subject. Repeated administration over several days or, depending on the condition, treatment is continued for a longer period of time until the desired symptom suppression occurs or until sufficient therapeutic levels are achieved to alleviate the target disease or disorder or its symptoms. The specific dosing regimen, i.e., dosage, timing, and frequency, will depend on the individual and the individual's medical history, as well as the properties of the individual agents (e.g., the half-life of the agent, and other considerations well known in the art).

[0086] For the purpose of the present application, the appropriate dosage of compositions described herein will depend on the specific active agent contained therein, the type and severity of the disease / illness, whether the compositions are used for prevention or for therapeutic purposes, previous treatment, the patient's clinical history and the reaction to treatment, and the judgment of the attending physician. Typically, the clinician will administer the composition until the dosage that reaches the desired result is reached. In certain embodiments, the desired result is a reduction in the severity of the disease (e.g., represented by a disease score). It will be apparent to those skilled in the art that the method for determining whether dosage produces the desired result. The administration of any compositions disclosed herein can be continuous or intermittent, depending on, for example, the physiological condition of the recipient, whether the purpose of administration is therapeutic or preventive and other factors known to technical practitioners. The administration of the compositions can be substantially continuous in a preselected time period, or can be in a series of spaced doses, e.g., before, during, or after the occurrence of target disease or obstacle.

[0087] As used herein, the term "treat," ...

[0088] Alleviation of the target disease / disorder includes slowing the development or progression of the disease or reducing the severity of the disease or prolonging survival. Alleviation of the disease or prolonging survival does not necessarily require a cure.

[0089] As used herein, "delaying" the development of a target disease or disorder means postponing, hindering, slowing, delaying, stabilizing, and / or postponing the progression of the disease. This delay can be for varying lengths of time, depending on the medical history and / or the individual being treated. "Delaying" or alleviating the development of a disease, or delaying the onset of a disease, refers to a method that reduces the likelihood of developing one or more symptoms of the disease within a given timeframe and / or reduces the extent of the symptoms of the disease within a given timeframe, compared to not using the method. Such comparisons are typically based on clinical studies using a sufficient number of subjects to provide statistically significant results.

[0090] The "development" or "progression" of a disease refers to the initial manifestation of the disease and / or the subsequent progression. The progression of the disease can be detected and assessed using standard clinical techniques well known in the art. However, progression also refers to progression that may not be detectable. For the purposes of this disclosure, development or progression refers to the biological course of symptoms. "Development" includes onset, recurrence, and onset. As used herein, "onset" or "occurrence" of a disease or disorder of interest includes initial onset and / or recurrence.

[0091] The particular dosing regimen, ie, dosage, timing, and frequency employed in the methods described herein will depend on the particular subject and that subject's medical history.

[0092] In some embodiments, any composition disclosed herein can be used in conjunction with one or more additional therapeutic agents for treating a target disease. In some cases, additional therapeutic agents can be used to enhance and / or supplement the effectiveness of the compositions disclosed herein.

[0093] The efficacy of a treatment against a target disease / disorder can be assessed by methods well known in the art.

[0094] 3. Kit for promoting recovery of diabetic foot ulcers of the renal dysfunction type

[0095] The present invention also provides a kit for promoting recovery of diabetic foot ulcers of the renal dysfunction type in a subject in need of treatment. Such a kit may include one or more units comprising any of the topical preparations described herein, the topical preparation comprising an extract of the Herba Centellae asiatica optionally combined with an extract of Centella asiatica, or one or more active agents thereof, such as those disclosed herein, and one or more suitable excipients and carriers.

[0096] In some embodiments, the unit may include instructions for use according to any of the methods described herein. The included instructions may include a description of administering a topical formulation for promoting recovery of a diabetic foot ulcer of the renal dysfunction type or inhibiting the risk of further ulcer development according to any of the methods described herein.

[0097] Instructions for use of topical preparations generally include information about the dosage, dosing schedule, and route of administration for the intended treatment. These may be unit doses, bulk packages (e.g., multi-dose packages), or subunit doses. The instructions provided in the kits of the present invention are typically written instructions on a label or package insert (e.g., a paper included in the kit), but machine-readable instructions (e.g., instructions on a magnetic or optical storage disk) are also acceptable.

[0098] The label or package insert indicates that the preparation is used to promote recovery of diabetic foot ulcers of the renal dysfunction type.

[0099] 4. Diabetic foot

[0100] The concept of "diabetic mellitus foot" (DMF) was first proposed by Oakley in 1956. According to the World Health Organization and the International Diabetic Foot Working Group, diabetic foot is caused by chronic hyperglycemia in diabetic patients, which leads to lesions in the nerves and blood vessels of the feet, insufficient blood supply to the feet, decreased sensory function, and a high risk of persistent foot ulcers. These ulcers are often accompanied by infection or damage to deeper tissues, and in severe cases, can affect muscles and bones.

[0101] The prevalence of foot ulcers among diabetic patients is 4%-10%. Diabetic foot ulcers are a serious complication that can lead to disability and death, and are difficult and expensive to treat. Without early treatment, outcomes are often dismal. Among all non-traumatic low-level amputations, diabetic foot ulcers account for 40%-60% of all cases.

[0102] Symptoms and signs of diabetic foot vary depending on the course of the disease and the severity of the lesions. Mild cases may present with only mild foot pain and superficial ulcers; moderate cases may develop deeper, penetrating ulcers with soft tissue inflammation; severe cases may present with ulcers accompanied by soft tissue abscesses, bone lesions, localized gangrene of the toes, heels, or forefoot, and even complete foot gangrene. Numerous methods exist for grading diabetic foot, including the Wagner system, the TEXAS staging system, and the Chinese Medical Association's Diabetic Foot Classification, all of which share similar principles and methods.

[0103] The diabetic foot classification system proposed by the University of Texas at Austin takes both severity and etiology into account. Lesion severity is categorized from 0 to 3: Grade 0 indicates a history of ulceration, Grade 1 is a superficial ulcer, Grade 2 involves the tendon, and Grade 3 involves bone and joint involvement. Based on the presence or absence of infection and ischemia (i.e., etiology), the system is divided into stages A to D: Stage A includes neither infection nor ischemia, Stage B includes infection, Stage C includes ischemia, and Stage D includes both infection and ischemia.

[0104] 5. General Technical and Reference Documents

[0105] Unless otherwise indicated, the experiments described herein will employ conventional techniques of molecular biology (including recombinant techniques), microbiology, cell biology, biochemistry, and immunology, which are within the skill of the art. These techniques are fully explained in the literature, such as Molecular Cloning: A Laboratory Manual, 2nd Edition (Sambrook, et al., 1989) Cold Spring Harbor Press, Oligonucleotide Synthesis (MJ Gait, ed. 1984), Methods in Molecular Biology: A Laboratory Notebook (JE Cellis, ed., 1989) Academic Press, Animal Cell Culture (RI Freshney, ed. 1987), Introduction to Cell and Tissue Culture (JP Mather and P.E. Roberts, 1998) Plenum Press, Cell and Tissue Culture: Laboratory Procedures (A. Doyle, JB Griffiths and DG Newell, eds.) J. Wiley and Sons, Methods in Enzymology (Academic Press, Inc.), Handbook of Experimental Immunology (D.M. Weir and C.C. Blackwell, eds.): Gene Transfer Vectors in Mammalian Cells (J.M. Miller and M.P. Calos, eds., 1987), Current Protocols in Molecular Biology (F.M. Ausubel, et al.). al. eds. 1987), PCR: Polymerase Chain Reaction (Mullis et al. eds. 1994), Current Protocols in Immunology (J.E. Coligan et al., 1991), Short Protocols in Molecular Biology (Wiley and Sons, 1999), Immunobiology (C.A. Janeway and P. Travers, 1997), Antibodies (P. Finch, 1997), Antibodies: A Practical Approach (D. Carty, 25th ed., IRL Press, 1988-1989), Monoclonal Antibodies: A Practical Approach (P. Shepherd and C. Dean eds., Oxford University Press, 2000), Using Antibodies: A Laboratory Manual (E. Harlow and D. Lane, Cold Spring Harbor Laboratory Press, 1999), Antibodies (M. Zanetti and J.D. Capra, eds. Harwood Academic Press, 1995), DNA Cloning: A Practical Approach, Volumes I and II (D.N. Glover, 1985 edition), Nucleic Acid Hybridization (B.D. Hames & S.J. Higgins, eds.; 1985), Transcription and Translation (B.D. Hames and S.J. Higgins, eds.) (1984), Animal Cell Culture (R.I. Freshney, ed. (1986), Immobilized Cells and Enzymes (I.R.L. Press, 1986), B. Perbal, A Practical Guide to Molecular Cloning (1984); Ausubel et al. (eds.).

[0106] The reference documents involved in this application are as follows:

[0107] Patents or patent applications with the following application numbers: CN201410442909.2, CN201480081762.7, CN201210128422.8, CN201780009172.7, WOCN22101441, WOCN23096428, WOCN23102711, WOCN23074120.

[0108] The following non-patent documents:

[0109] 1. Cho NH, Shaw JE, Karuranga S, et al. IDF Diabetes Atlas: Global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract 2018; 138 (271-281, doi: 10.1016 / j.diabres.2018.02.023.

[0110] 2. Cole JB, Florez JC. Genetics of diabetes mellitus and diabetes complications. Nat Rev Nephrol 2020; 16(7):377-390, doi:10.1038 / s41581-020-0278-5.

[0111] 3. Nacak H, Bolignano D, Van Diepen M, et al. Timing of start of dialysis in diabetes mellitus patients: a systematic literature review. Nephrol Dial Transplant 2016; 31(2): 306-16, doi:10.1093 / ndt / gfv431.

[0112] 4.Alalawi F,Bashier A.Management of diabetes mellitus in dialysis patients:Obstacles and challenges.Diabetes Metab Syndr 2021;15(3):1025-1036,doi:10.1016 / j.dsx.2021.05.007。

[0113] 5.Armstrong DG,Boulton AJM,Bus SA.Diabetic Foot Ulcers and Their Recurrence.N Engl J Med 2017;376(24):2367-2375,doi:10.1056 / NEJMra 1615439。

[0114] 6.Schaper NC,van Netten JJ,Apelqvist J,et al.Practical Guidelines on the prevention and management of diabetic foot disease(IWGDF 2019 update).Diabetes Metab Res Rev 2020;36 Suppl 1(e3266,doi:10.1002 / dmrr.3266。

[0115] 7.Ndip A,Rutter MK,Vileikyte L,et al.Dialysis treatment is an independent risk factor for foot ulceration in patients with diabetes and stage 4 or 5 chronic kidney disease.Diabetes Care 2010;33(8):1811-6,doi:10.2337 / dc10-0255。

[0116] 8. Game FL, Chipchase SY, Hubbard R, et al. Temporal association between the incidence of foot ulceration and the start of dialysis in diabetes mellitus. Nephrol Dial Transplant 2006; 21(11):3207-10, doi:10.1093 / ndt / gfl427.

[0117] 9. Lavery LA, Lavery DC, Hunt NA, et al. Amputations and foot-related hospitalisations disproportionately affect dialysis patients. Int Wound J 2015;12(5):523-6, doi:10.1111 / iwj.12146.

[0118] 10. He Y, Qian H, Xu L, et al. Association between estimated glomerular filtration rate and outcomes in patients with diabetic foot ulcers: a 3-year follow-up study. Eur J Endocrinol 2017;177(1):41-50, doi:10.1530 / EJE-17-0070.

[0119] Without further elaboration, it is believed that one skilled in the art can, based on the above description, utilize the present invention to its fullest extent. Therefore, the following specific examples are to be construed as merely illustrative and not limiting in any way the remainder of the present disclosure. All publications cited herein are incorporated by reference for the purposes or subject matter cited herein.

[0120] Example: Safety and efficacy of topical preparations for treating diabetic foot ulcers of the renal dysfunction type

[0121] The subjects of this example were 4 patients with renal dysfunction and diabetic foot ulcers who were admitted to Cathay Hospital in Taiwan, China. Among them, the diabetic foot of the patients was graded as TEXAS1A and TEXAS2A according to the University of Texas Wound Classification (TEXAS) method, and the ulcer area after debridement was 1 cm 2<Ulceration area ≤ 10 cm 2 , and the patient's affected limb has adequate blood perfusion, as confirmed by 1.3>ABI≥0.7, or TcPO2≥30mmHg, or Doppler-related instruments to confirm that there is no major vascular obstruction.

[0122] A topical cream formulation includes 1.25% (w / w) of herbal extracts, including 0.25% scutellaria baicalensis extract and 1% Centella asiatica extract. The scutellaria baicalensis extract includes one or more of salvigenin, cirsimin, rosmarinic acid, and carvacrol; and the Centella asiatica extract includes asiaticoside and / or asiatic acid. The topical cream further includes approximately 4-6% (w / w) cetearyl alcohol, approximately 20-30% (w / w) of a combination of liquid petrolatum and white petrolatum, approximately 0.08-0.15% (w / w) of a combination of methylparaben and propylparaben, and approximately 2-4% (w / w) of sorbitan monostearate and polysorbate 60.

[0123] Treatment Methods: In this example, treatment included three phases: a screening phase, a treatment phase, and a follow-up phase. Treatment was performed during all three phases. At the beginning of the screening phase, the patient's ulcer was cleaned and the slough removed. Following the clinician's instructions, the patient received standard of care (SOC) treatment once daily, using a dressing to completely cover the ulcer. The screening phase lasted approximately two weeks, and ulcer recovery was recorded at two points (V0 and V1) at the beginning and end of the screening phase to exclude patients with rapid healers.

[0124] The treatment period lasts up to 20 weeks. Apply the topical cream formulation of this application evenly to the ulcer twice daily, applying enough to completely cover the ulcer. During the treatment period, record ulcer healing at 10 points (V2-V11). If the patient's ulcer heals prematurely, the treatment period will be terminated early, and points will be taken and recorded during the treatment period.

[0125] The follow-up period lasts for 2 weeks. Based on the doctor's assessment of the treatment results, if the wound heals, the wound is covered with gauze; if the wound does not heal, standard of care (SOC) is received according to the instructions of the clinical physician. At the end of the follow-up period, one point (V12) is taken to observe whether the ulcer recurs. During the entire treatment process, the topical cream preparation of the present application is applied to the patient's ulcer and covered with dry gauze. The cream preparation and dry gauze are changed twice a day. During the treatment, the patient should reduce the force on the foot with the ulcer surface and try to avoid other infections.

[0126] Treatment results:

[0127] Table 1 shows the changes in ulcer area and diabetic foot grade of the four patients during treatment.

[0128] Patient 1 had a diabetic foot ulcer on the little toe of his right foot. He had difficulty moving and needed a wheelchair. His diabetic foot grade was 2A, and the ulcer area was approximately 8.74 cm. 2 Combining the data in Figure 1A, Figure 1B and Table 1, after 2 weeks of medication, the diabetic foot grade of patient 1 was reduced to 1A; after 10 weeks of medication, the ulcer was completely healed.

[0129] Patient 2 has a diabetic foot ulcer on his right ankle, which makes him unable to move around easily and requires the use of a wheelchair. He also has a bone screw in his foot. The wound circled in red in Figure 2 is the wound left after the bone screw was removed and sutured. Due to his diabetes and renal dysfunction, the wound has not healed and is not the target wound of this example. Patient 2's diabetic foot grade is 2A, and the ulcer area is 9.38cm 2 Combining the data in Figures 2A and 2B and Table 1, Patient 2 began to develop granulation tissue after 2 weeks of treatment, the wound began to shrink, and the diabetic foot grade was reduced to 1A; the ulcer wound was completely healed after 8 weeks of treatment.

[0130] Patient 3 had a diabetic foot ulcer on the left foot. The diabetic foot grade was 2A and the ulcer area was 7.33 cm. 2 Combining the data in Figures 3A and 3B and Table 1, after 2 weeks of medication, the diabetic foot grade of patient 3 was reduced to 1A; after 20 weeks of treatment, the ulcer wound was only 0.03 cm 2 , the wound was reduced by 99%.

[0131] Patient 4 had a diabetic foot ulcer on the left heel, which made him unable to move and required the use of a wheelchair. His diabetic foot grade was 2A, and the ulcer area was approximately 5.98 cm. 2 Combining the data in Figure 5A, Figure 5B and Table 1, the ulcer of patient 5 was completely healed after 10 weeks of medication treatment.

[0132] In summary, among the four patients, two patients’ diabetic foot ulcers healed within 10 weeks, one of whom healed within 8 weeks; one patient’s healing rate reached 99% within 20 weeks, and the unhealed ulcer area was only 0.03 cm 2 Taking into account the patient's own physical condition and external factors beyond their control, the complete healing rate of the topical cream preparation for diabetic foot ulcers with renal dysfunction is comparable to the healing rate of ordinary diabetic foot ulcers. The treatment method of the present application is more convenient, easy to operate, safer and less expensive.

[0133] The above embodiments are only used to illustrate the present invention, and are not intended to limit the present invention. Ordinary technicians in the relevant technical field can make various changes and modifications without departing from the scope of the present invention. Therefore, all equivalent technical solutions should also fall within the scope of the present invention.

Claims

1. Use of a composition comprising an extract of Rhizoma Cibotii in the preparation of a medicament for treating diabetic foot ulcers of the renal dysfunction type in a subject.

2. The use according to claim 1, wherein the renal dysfunction is renal insufficiency.

3. The use according to claim 1, wherein the renal dysfunction is end-stage renal disease.

4. The method according to claim 1, wherein the renal dysfunction is such that the subject needs to undergo dialysis treatment.

5. The use according to claim 1, wherein the diabetic foot ulcer is of TEXAS 1A or TEXAS 2A grade according to the University of Texas Wound Classification.

6. The use according to claim 1, wherein the extract of the Herba Citriodorae odoriferae comprises one or more of salvigenin, cirsimarin, rosmarinic acid and carvacrol.

7. The use according to claim 1, wherein the composition further comprises a Centella asiatica extract.

8. The use according to claim 7, wherein the Centella asiatica extract comprises asiaticoside and / or synthetic asiatic acid.

9. The use according to claim 6 or 7, wherein the weight ratio of the Herba Citri Rehmanniae extract to the Centella asiatica extract in the composition is 1:(1-4), preferably 1:

4.

10. The use according to claim 9, wherein the composition comprises about 0.1-1% (w / w) of the Fructus Citri Reticulatae Extract and / or about 0.4-4% (w / w) of the Centella asiatica extract; preferably, the composition comprises about 0.25% (w / w) of the Fructus Citri Reticulatae Extract and / or about 1% (w / w) of the Centella asiatica extract.

11. The use according to claim 6 or 7, wherein the composition comprises about 0.5-5% (w / w) of an active ingredient, wherein the active ingredient comprises an extract of Rhizoma Cibotii and / or an extract of Centella asiatica.

12. The use according to claim 1, wherein The composition comprises: 1.0-10% (w / w) viscosity increasing agent; 5-30% (w / w) ointment base; 0.01-0.2% (w / w) of an antimicrobial agent; and / or 0.5-6% (w / w) emulsifier.

13. The use according to claim 1, wherein the drug is in the form of a cream, gel, dressing, spray, ointment, cream, paste, patch, mask or lotion.

14. The use according to any one of claims 1 to 13, wherein the drug is administered to the diabetic foot ulcer of the subject 1 to 4 times a day or once every 2 to 7 days.

15. The use according to claim 1, wherein the subject is a human or a non-human mammal.

16. A method for treating diabetic foot ulcers of the renal dysfunction type in a subject, comprising administering the drug for use according to any one of claims 1 to 15 to the diabetic foot ulcer of the subject.

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