Methods of treating epidermolysis bullosa

Abstract

The present disclosure provides a method for treating epidermolysis bullosa in a subject in need thereof, the method comprising administering to the subject an effective amount of adenine or a salt thereof. The present disclosure also provides a pharmaceutical composition for treating epidermolysis bullosa in a subject in need thereof.

Description

Technical Field

[0001] This disclosure relates to the treatment of epidermal blistering disease, and more particularly to a method of treating epidermal blistering disease by administering a pharmaceutical composition comprising adenine or a salt thereof to a subject in need. This disclosure also relates to a pharmaceutical composition for treating epidermal blistering disease in a subject in need. Background Technology

[0002] Epidermolysis bullosa (EB) is a rare, inherited skin condition that frequently leads to medical complications affecting various parts of the body, manifesting as blisters on the skin and mucous membranes. EB is characterized by extremely fragile skin, making it prone to tearing, ulceration, and blisters even from minor friction or impact. In more severe cases, blisters can also appear internally, posing a life-threatening risk when they occur in areas such as the mouth, esophagus, stomach, intestines, upper respiratory tract, bladder, and genitals.

[0003] Epidermal blistering syndrome arises from gene mutations following an autosomal dominant or autosomal recessive inheritance pattern. These mutations affect at least one of 16 genes responsible for producing up to 14 proteins related to skin cohesion and strength. Epidermal blistering syndrome encompasses a range of conditions characterized by painful blisters induced by mechanical trauma, resulting from the fragility, disruption, and breakage of the dermoepidermal junctions within the skin and other tissues lining or covering the epithelial surface.

[0004] Researchers have identified more than 30 subtypes of epidermolysis bullosa, which are classified into four main types based on the location of skin changes and the specific gene mutations involved: (1) simple epidermolysis bullosa (EBS), a common form of epidermolysis bullosa that affects the outermost layer of the skin (i.e., the epidermis) and causes skin fragility, blistering, and erosion; (2) junctional epidermolysis bullosa (JEB), which impacts proteins in the skin junction area, resulting in blisters and erosions mainly in the upper part of the basement membrane; (3) dystrophic epidermolysis bullosa (DEB), characterized by the formation of blisters in the upper dermis, caused by adhesion problems between the basement membrane and the upper dermis; and (4) Kindler epidermolysis bullosa (also known as Kindler syndrome). This syndrome often results in blisters between multiple layers of the skin, including the basement membrane.

[0005] In terms of symptoms, all types of epidermal bullous lesions (EBV) present with fragile skin prone to blisters and chronic inflammation. The severity of EBV depends on the specific mutations present in the patient's body and the precise location of the affected proteins at the ultrastructural level. Furthermore, unlike ordinary wounds, EBV exhibits a cyclical pattern; affected patients experience recurring symptoms, such as blisters and wounds, which may recur after a period of time rather than persisting as a continuous event. This recurring nature requires long-term, continuous medical management to address the intermittent symptoms. That is, even with aggressive treatment and care, patients with EBV may still experience cyclical symptoms. Therefore, EBV is a progressive disease that can lead to scarring and contractures, resulting in decreased mobility. It can even cause fusion of fingers and toes, resulting in mitten-like deformities and microstomia. EBV can also lead to severe disability and may even increase the risk of skin cancer.

[0006] In clinical settings, the applicability of various wound care products designed for normally healing skin to epidermal bullous disease (EBD) is highly limited. For example, a phase III clinical trial in EBD patients showed that the topical cream SD-101 containing 6% allantoin did not improve wound healing (Paller AS et al., Orphanet Journal of Rare Diseases. 2020; 15(1): 158). Prior to recent advances, there were no approved therapies specifically designed for the treatment of EBD.

[0007] Therefore, enhanced treatment options for epidermal varicella-zoster virus (EVV) are still needed to effectively reduce the risk of complications or death, effectively manage symptoms, and improve overall quality of life. Summary of the Invention

[0008] In view of this, the present disclosure provides a pharmaceutical composition for treating epidermal bullous eczema, comprising adenine or a salt thereof. The pharmaceutical composition of the present disclosure can effectively reduce the size of wounds associated with epidermal bullous eczema, shorten the time required for wound closure, and delay wound recurrence, thereby helping to relieve pain and itching, reduce the risk of complications from epidermal bullous eczema, and improve the quality of life for patients with epidermal bullous eczema.

[0009] In at least one specific embodiment of this disclosure, a pharmaceutical composition for treating epidermal blistering is provided, the pharmaceutical composition comprising adenine or a salt thereof and pharmaceutically acceptable excipients thereof.

[0010] In at least one specific embodiment of this disclosure, the epidermal blistering disease may be simple epidermal blistering disease, conjugated epidermal blistering disease, overt atrophic epidermal blistering disease, latent atrophic epidermal blistering disease, Kindle syndrome, or acquired epidermal blistering disease.

[0011] In at least one embodiment of this disclosure, the adenine or its salt in the pharmaceutical composition is present in an amount from 0.001% by weight to 80% by weight, for example, 0.001%, 0.002%, 0.005%, 0.01%, 0.02%, 0.05%, 0.08%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.75%, 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%, and 80% by weight. In some embodiments, the adenine or its salt in the pharmaceutical composition, by weight, has a lower limit selected from 0.001%, 0.005%, 0.01%, 0.05%, 0.1%, 0.5%, 1%, 5%, 10%, 15%, and 20%, and an upper limit selected from 80%, 70%, 60%, 50%, 40%, 30%, and 25%. In some specific embodiments, the adenine or its salt is present in the pharmaceutical composition at a concentration of 0.01% by weight to 50% by weight.

[0012] In at least one embodiment of this disclosure, the adenine or its salt is the sole active ingredient in the pharmaceutical composition for treating epidermal blistering. In some embodiments, the adenine or its salt may be combined with additional active ingredients for treating epidermal blistering (e.g., active ingredients other than adenine or its salt).

[0013] In at least one specific embodiment of this disclosure, the pharmaceutically acceptable excipient may be selected from fillers, binders, preservatives, disintegrants, lubricants, suspending agents, wetting agents, solvents, surfactants, acids, flavoring agents, polyethylene glycol (PEG), alkyl glycols, propylene glycol ethers, sebacic acid, dimethyl sulfoxide, alcohols, stearic acid, calcium stearate, sorbitan stearate, glyceryl monostearate, microcrystalline cellulose, silica, gelatin, fats, glycerol, dietary fiber, alginate, pectin, carrageenan gum, amidated pectin, xanthan gum, galvanic gum, ebony gum, rhamnose gum, vetiver gum, godiol, gum arabic, beeswax (cera alba), sorbitan palmitate, cetyl palmitate, cetyl 2-ethylhexanoate. The group consisting of hexanoate, sorbitan oleate, phenoxyethanol, paraffin oil, sodium chloride, methylparaben, propylparaben, cetearyl alcohol, and any combination thereof.

[0014] In at least one specific embodiment of this disclosure, the pharmaceutical composition may be in the form of a group selected from solutions, liniments, lotions, sprays, ointments, foams or foamable preparations, emulsions, creams, gels, pastes, patches, adhesives, films, powders, granules and wound dressings.

[0015] In at least one embodiment of this disclosure, a method is provided for treating epidermal blistering in a subject who requires it. In some embodiments, the method includes administering an effective amount of the above-described pharmaceutical composition to the subject. In some embodiments, the method includes administering an effective amount of adenine or a salt thereof to the subject.

[0016] In at least one embodiment of this disclosure, the pharmaceutical composition is applied topically to the subject. In some embodiments, the pharmaceutical composition is applied to a wound in the subject associated with epidermal blistering.

[0017] In at least one specific embodiment of this disclosure, the subject suffers from simple epidermal bullous disease, conjugated epidermal bullous disease, overt atrophic epidermal bullous disease, latent atrophic epidermal bullous disease, Kindle syndrome, or acquired epidermal bullous disease.

[0018] In at least one embodiment of this disclosure, application of the pharmaceutical composition reduces the size of wounds associated with epidermal blistering. In some embodiments, application of the pharmaceutical composition shortens the time required for the wound to close.

[0019] In at least one embodiment of this disclosure, wounds associated with epidermal blistering can include at least one of chronic and acute wounds. In some embodiments, wounds associated with epidermal blistering can be selected from blisters and tears of the skin and mucous membranes.

[0020] In at least one specific embodiment of this disclosure, the pharmaceutical composition can be applied to a wound associated with epidermal blistering in an effective amount of adenine or a salt thereof, said effective amount being between 0.001 mg / cm². 2 and 100 mg / cm 2 Between. In some specific embodiments, the effective amount of adenine or its salt applied to the wound is selected from 0.001 mg / cm². 2 0.005 mg / cm 2 0.01 mg / cm 2 0.02 mg / cm 2 0.05 mg / cm 2 0.1 mg / cm 2 0.3 mg / cm2 0.5 mg / cm 2 1 mg / cm 2 3 mg / cm 2 5 mg / cm 2 10 mg / cm 2 15 mg / cm 2 20 mg / cm 2 25 mg / cm 2 and 30 mg / cm 2 The lower limit, and selected from 100 mg / cm 2 90 mg / cm 2 80 mg / cm 2 70 mg / cm 2 60 mg / cm 2 50 mg / cm 2 and 40 mg / cm 2 The upper limit. In some specific embodiments, the adenine or its salt is at 0.01 mg / cm³. 2 Up to 50 mg / cm 2 Apply the effective amount to the wound.

[0021] In at least one embodiment of this disclosure, the pharmaceutical composition is administered to the subject for a treatment duration. In some embodiments, the treatment duration is at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, at least six weeks, at least seven weeks, at least eight weeks, at least three months, at least four months, at least five months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least eleven months, or at least twelve months. In some embodiments, the treatment duration is lifelong.

[0022] In at least one embodiment of this disclosure, during the duration of treatment, for example, within one week, the application of the pharmaceutical composition reduces the size of the wound by at least about 50%. In some embodiments, the application of the pharmaceutical composition reduces the size of the wound by at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95% during the duration of treatment. In some embodiments, the application of the pharmaceutical composition reduces the size of the wound by at least about 90% within three weeks.

[0023] In some specific embodiments, the method of this disclosure may further include applying a dressing to a skin area affected by a wound associated with epidermal blistering. Examples of the dressing in some specific embodiments include, but are not limited to, bandages, gauze, mesh fabrics, tubular bandages, adhesive bandages, soft silicone bandages, hydrogel-impregnated gauze, biosynthetic cellulose, and edging dressings.

[0024] In at least one embodiment of this disclosure, a pharmaceutical composition is provided for treating epidermal blistering in subjects in need. In some embodiments, the pharmaceutical composition comprises adenine or a salt thereof and at least one pharmaceutically acceptable excipient.

[0025] In at least one embodiment of this disclosure, the use of a pharmaceutical composition in the preparation of a medicament for treating epidermal blistering in subjects in need is provided. In some embodiments, the pharmaceutical composition comprises adenine or a salt thereof and at least one pharmaceutically acceptable excipient thereof. In some embodiments, the use of adenine or a salt thereof in the preparation of a medicament for treating epidermal blistering is also provided. Attached Figure Description

[0026] This disclosure can be more fully understood by reading the following detailed description of specific embodiments and referring to the accompanying drawings.

[0027] Figures 1A to 1E A series of images were taken to show the effect of adenine on wound closure over the duration of treatment compared to carrier-treated wounds in five subjects with epidermal blistering disease.

[0028] Figure 2 The effect of adenine on reducing wound surface area (BSA) during the duration of treatment was demonstrated in subjects with epidermal blistering. Detailed Implementation

[0029] This specification discloses in detail some specific embodiments, enabling those skilled in the art to utilize these embodiments based on this disclosure. Not all steps or features of the described embodiments are discussed in detail, as many steps or features will be obvious to those skilled in the art based on this disclosure.

[0030] It should also be noted that, as used in this disclosure, the singular forms “a” and “the” include multiple indicators unless explicitly and unequivocally limited to one. Unless the context clearly indicates otherwise, the term “or” may be used interchangeably with the term “and / or”.

[0031] As used herein, the term "about" generally means within 10%, 5%, 1%, or 0.5% of a given value or range. Alternatively, the term "about" means within an acceptable standard error of the average value as would be considered by a person skilled in the art. Unless otherwise expressly specified, all numerical ranges, quantities, values, and percentages disclosed herein, such as those for material quantities, durations, temperatures, operating conditions, quantity ratios, etc., should be understood to be modified by the term "about" in all cases.

[0032] This disclosure provides a method for treating epidermal blistering in a subject who requires treatment. In some specific embodiments of this disclosure, the method includes administering an effective amount of a pharmaceutical composition to the subject, wherein the pharmaceutical composition comprises adenine or a salt thereof and pharmaceutically acceptable excipients thereof.

[0033] As used herein, the terms “comprising” or “including” are used to refer to compositions, methods and their respective components included in this disclosure, but are open to including unspecified elements.

[0034] As used herein, the term "treatment" ("treat", "treating", or "treatment") encompasses the partial or complete prevention, improvement, reduction, and / or control of symptoms, conditions, or states associated with a disease, such as epidermal blistering disease. As used herein, "treatment" ("treat", "treating", or "treatment") means the administration or delivery of one or more therapeutic agents or procedures to a subject exhibiting symptoms, conditions, or states associated with a disease, with the aim of achieving partial or complete relief, improvement, alleviation, delay of onset, inhibition of progression, reduction of severity, and / or reduction of incidence of one or more symptoms, conditions, or states associated with the disease. Such treatment may be administered to subjects exhibiting only early signs of such symptoms, conditions, and / or states to reduce the risk of developing disease-related symptoms, conditions, and / or states.

[0035] As used herein, the terms “patient,” “individual,” and “subject” are used interchangeably. The term “subject” means human or animal. Examples of subjects include, but are not limited to, rodents, rats, monkeys, guinea pigs, dogs, cats, cattle, sheep, pigs, horses, rabbits, and humans. In some specific embodiments of this disclosure, the subject is a mammal, such as a primate, like a human.

[0036] As used herein, the phrase “effective dose” means the amount of active ingredient (e.g., adenine) required to impart the desired effect (e.g., reduction of wound size) to a treated subject. As those skilled in the art will recognize, the effective dose will vary depending on the route of administration, the excipients used, the possibility of co-administration with other therapies, and the condition to be treated.

[0037] In at least one embodiment of this disclosure, the pharmaceutical composition may be applied topically to a wound in the subject. In some embodiments, the pharmaceutical composition is administered at a concentration between about 0.001 mg / cm³. 2 and approximately 100 mg / cm 2 An effective amount of adenine or its salts is applied topically to the wound.

[0038] In at least one embodiment of this disclosure, the pharmaceutical composition is applied topically in an effective amount of adenine or a salt thereof, said effective amount being from about 0.001 mg / kg to about 100 mg / kg (based on the weight of each subject). In several cases, the effective amount of adenine or a salt thereof to be applied may be from about 0.001 mg / kg to about 80 mg / kg, from about 0.002 mg / kg to about 70 mg / kg, from about 0.005 mg / kg to about 60 mg / kg, from about 0.01 mg / kg to about 60 mg / kg, from about 0.05 mg / kg to about 80 mg / kg, from about 0.05 mg / kg to about 50 mg / kg, from about 0.1 mg / kg to about 70 mg / kg, from about 0.1 mg / kg to about 30 mg / kg, from about 0.5 mg / kg to about 60 mg / kg, from about 0.5 mg / kg to about 20 mg / kg, from about 1 mg / kg to about 10 mg / kg, or from about 1 mg / kg to about 5 mg / kg.

[0039] As used herein, the terms “application” or “administration” mean the placement of an active ingredient into a subject’s body by means of a method or route that at least partially positions an active ingredient (such as adenine) at a desired site to produce a desired effect.

[0040] In at least one specific embodiment of this disclosure, the pharmaceutical composition may be administered to the subject 1 to 4 times daily or 1 to 14 times weekly during the duration of treatment. For example, the pharmaceutical composition may be administered to the subject once daily, twice daily, three times daily, four times daily, once every two days, twice every two days, once every three days, twice every three days, three times every three days, once weekly, twice weekly, three times weekly, four times weekly, five times weekly, six times weekly, seven times weekly, eight times weekly, nine times weekly, ten times weekly, eleven times weekly, twelve times weekly, thirteen times weekly, or fourteen times weekly.

[0041] The compositions disclosed herein may include adenine or a salt thereof as the sole active ingredient for treating epidermal blistering. That is, the adenine or a salt thereof is the sole active ingredient in the pharmaceutical composition for treating epidermal blistering. In this specific embodiment, the present disclosure provides a safe and effective therapy for treating epidermal blistering by administering adenine or a salt thereof, as the sole active ingredient.

[0042] As used herein, the term "medically acceptable excipient" means a pharmaceutically acceptable material, composition, or medium, such as a disintegrant, binder, lubricant, or surfactant, that does not eliminate the biological activity or properties of the active ingredient and is relatively non-toxic; that is, the material can be administered to a subject without causing undesirable biological effects or interacting with any component of the composition in a harmful manner.

[0043] This disclosure will use various embodiments for illustration, and the following embodiments should not be regarded as limiting the scope of this disclosure.

[0044] Example

[0045] Example 1: Effects of adenine on patients with epidermal vesicular ecchymosis

[0046] In this embodiment, a clinical study was conducted at a relevant institution, in which five subjects with anatrophic epidermal blistering (DEB) were recruited. The wound size of the subjects ranged from 2 cm. 2 Up to 20 cm 2 Treatment was administered daily with either adenine cream or a vehicle, once a day, in a single-blind manner for one month. The adenine cream used in this study contained 0.02% adenine and excipients including beeswax, glyceryl monostearate, sorbitan palmitate, sorbitan stearate, cetyl hexanoate, stearic acid, sorbitan monooleate, phenoxyethanol, propylene glycol, paraffin oil, sodium chloride, methylparaben, propylparaben, cetearyl alcohol, and cetyl palmitate. The primary endpoint was the percentage of unclosed wound area on day 14 (compared to day 1). Secondary outcome measures included: (1) The time required for the target wound of epidermal vesicular lesions to achieve 100% closure for the first time; (2) The time required for the target wound of epidermal vesicular lesions to achieve 75% closure for the first time; and (3) The proportion of target wounds of epidermal catarrhal bullous disease that are completely closed for the first time within 3 weeks of treatment.

[0047] In this preclinical trial, a total of 23 wounds in 5 subjects were evaluated weekly (14 wounds in the adenine treatment group and 9 wounds in the carrier treatment group).

[0048] In addition, following the initial study, three of the five subjects (P1, P2, and P3) continued to receive adenine cream according to the same administration regimen. A total of 22 wounds (13 in the adenine treatment group and 9 in the carrier treatment group) were assessed daily for one month. The benefit of daily wound recording was that it clearly demonstrated the efficacy of adenine in promoting wound healing in patients with epidermal vesicular lesions. Tables 1 and 2 list the data from the daily assessments of these three subjects.

[0049] Table 1. Effect of adenine on the area of ​​unclosed wounds

[0050] As shown in Table 1, among the wounds treated with adenine, 5 out of 10 wounds had an unclosed wound area percentage of zero (i.e., completely closed) on day 14, while the remaining 5 wounds had unclosed wound area percentages of 1%, 2%, 2%, 15%, and 30%, respectively. In contrast, for the 5 wounds treated with the carrier, the unclosed wound area percentages on day 14 were 16%, 22%, 37%, 51%, and 54%, respectively.

[0051] Regarding secondary endpoints, multiple wounds were treated for each patient, and another patient was included in the analysis. The time required to achieve 100% and 75% closure of target wounds for epidermal bullous lesions is summarized in Table 2 below. Adenine-treated wounds achieved 100% closure in 16.7 ± 6.18 days, while carrier-treated wounds required 24.0 ± 3.32 days (P = 0.0037). Similarly, the mean time to achieve 75% closure for adenine-treated wounds was 10.4 ± 3.50 days, while for carrier-treated wounds it was 15.6 ± 3.74 days (P = 0.0117).

[0052] Table 2. Time required to achieve 100% and 75% closure of the target wound in epidermal vesicatoria.

[0053] The results showed that, compared with the carrier, adenine treatment achieved a significantly higher rate of complete wound closure (100%) and partial wound closure (>75%). This indicates that wounds treated with adenine achieve complete healing earlier than those treated with the carrier. Therefore, given the lack of any effective treatment to date, adenine can accelerate wound healing and thus has the potential to alleviate pain and improve the quality of life for patients with epidermal blistering disease.

[0054] Furthermore, according to patient feedback and questionnaire results, wounds treated with adenine are less likely to recur, which means that adenine can also delay wound recurrence.

[0055] Furthermore, the results of the secondary endpoint, namely the proportion of target wounds for epidermal bullous lesions that achieved complete closure for the first time within 3 weeks of treatment, are shown in Table 3. Among wounds treated with adenine, 22 out of 27 wounds (81%) achieved complete closure, compared to 5 out of 18 wounds treated with the carrier (28%) (P = 0.0003). These results indicate that the proportion of epidermal bullous lesions achieving complete closure for the first time was significantly higher in the adenine-treated group than in the carrier-treated group, demonstrating the superior efficacy of adenine in promoting wound healing in epidermal bullous lesions.

[0056] Table 3. Percentage of target wounds for epidermal vesicle decomposition vesicle disease that achieved complete closure for the first time within 3 weeks of treatment.

[0057] In addition to the data mentioned above, Figures 1A to 1E Images of a series of patients with epidermal blistering disease were presented, along with quantitative data, to demonstrate the effect of adenine on wound closure compared to wounds treated with a carrier. Additionally, the mean percentage of wound surface area (BSA) was calculated for three subjects (P1, P2, and P3) and displayed. Figure 2 A total of 22 wounds were evaluated (13 wounds in the adenine treatment group and 9 wounds in the carrier treatment group).

[0058] In summary, both in vitro data and the effect of adenine cream on wound closure in patients with epidermal bullous lesions confirm that adenine has potential effectiveness in treating epidermal bullous lesions.

[0059] Example 2: Comparison of adenine, betulinum triterpenoids (Filsuvez), LEAES, and B-VEC in the treatment of epidermal blistering syndrome

[0060] In June 2022, the European Commission approved the topical gel Filsuvez (AmrytPharma) for the treatment of partial-thickness wounds associated with anatrophic epidermolysis bullosa and conjugated epidermolysis bullosa in patients aged 6 months and older.

[0061] In addition, for the first gene therapy trial of retinal dystrophic epidermal blistering disease (RDEB), autologous gene-corrected keratinocytes expressing full-length collagen VII (C7) using a retroviral vector were developed for the treatment of chronic open wounds in patients with severe RDEB. The skin grafts, LZRSE-COL7A1 engineered autologous epidermal sheets (LEAES), are derived from the patient's own skin cells, which are genetically engineered to express the missing protein (i.e., C7), and the corrected cells are transplanted back into the patient.

[0062] Furthermore, Beremagene geperpavec (B-VEC) is a gene therapy based on specialized research on herpes simplex virus type 1 (HSV-1), which aims to restore the C7 protein by delivering COL7A1. It has been approved by the United States Food and Drug Administration (FDA) for the treatment of anatrophic epidermal lesions (DEB).

[0063] In this embodiment, the adenine cream of this disclosure was compared with conventional therapies (i.e., Filsuvez, LEAES, and B-VEC) in terms of clinical efficacy, and the results are shown in Table 4. Furthermore, comparisons of Filsuvez and the adenine cream of this disclosure in terms of trial design, closure rate, and time required for initial complete closure are shown in Tables 5 to 7, respectively.

[0064] Table 4. Comparison of conventional therapies and the method disclosed herein for the treatment of epidermal vesicular lesions.

[0065] NA: Not applicable; MOA: Mechanism of action; AF: Anchoring fiber.

[0066] Table 5. Comparison of experimental designs for Filsuvez and adenine cream

[0067] Table 6. Comparison of the proportion of patients with first complete closure using adenine cream and Filsuvez. Consider the Independent Data Monitoring Committee (IDMC) mid-term sample size reestimation and make pre-specified adjustments. CI: Confidence interval.

[0068] Table 7. Comparison of time required for first complete closure between adenine cream and Filsuvez.

[0069] These results indicate that after 12 months of LEAES treatment, over 50% of subjects lost molecular correction, and over 30% had a healing rate below 50%, suggesting insufficient effectiveness of skin grafting. The adenine cream disclosed herein exhibits efficacy comparable to B-VEC gene therapy. However, the safety of gene therapy remains to be observed.

[0070] Furthermore, compared to Filsuvez, the adenine cream of this disclosure takes effect earlier than 45 days, indicating that wounds treated with adenine close faster. In addition, the adenine cream is effective for both chronic and acute wounds, while Filsuvez is only effective for wounds ≥21 days and <9 months old.

[0071] Furthermore, there was no statistically significant difference in wound healing time within 90 days between the Filsuvez group and the control group (P = 0.302), while with adenine treatment, the time to first complete closure was only 16.7 days, significantly different from the 24 days in the control group (P = 0.0037). Similarly, there was no statistically significant intra-individual difference in the median percentage of wound epithelialization between the Filsuvez group and the control group (P = 0.21 and 0.33, respectively). With adenine treatment, the healing rate of the target wound reached 94.0% by day 14, significantly different from the 64.4% in the control group (P = 0.01).

[0072] As can be clearly understood from the foregoing, the pharmaceutical composition provided in this disclosure includes adenine or its salts, which can effectively relieve the symptoms of epidermal bullous eczema, including shortening wound healing time and delaying wound recurrence. Furthermore, compared with conventional therapies, the pharmaceutical composition of this disclosure exhibits superior therapeutic effects. Therefore, the method of this disclosure can be used to improve the treatment of epidermal bullous eczema, demonstrating safety and efficacy in reducing the risk of complications such as infection and squamous cell carcinoma, and improving the quality of life of patients with epidermal bullous eczema.

[0073] It will be apparent to those skilled in the art that the basic concept can be implemented in various ways as technology advances. Therefore, specific embodiments are not limited to the embodiments described above; rather, variations are possible within the scope of the claims.

[0074] The specific embodiments described above can be used in any combination with each other, and several specific embodiments can be combined together to form other specific embodiments. The compounds, compositions, or methods disclosed herein may include at least one specific embodiment described above. It should be understood that the above benefits and advantages may relate to one specific embodiment or several specific embodiments. The specific embodiments are not limited to solving any or all of the described problems, nor are they limited to having any or all of the described benefits and advantages.

Claims

1. The use of a pharmaceutical composition in the preparation of a medicament for treating epidermal blistering in subjects in need, characterized in that, The pharmaceutical composition comprises adenine or a salt thereof and a pharmaceutically acceptable excipient thereof, for reducing the size of wounds associated with epidermal blistering in the subject.

2. The use according to claim 1, characterized in that, The epidermal bullous disease is classified as simple epidermal bullous disease, conjugated epidermal bullous disease, overt atrophic epidermal bullous disease, latent atrophic epidermal bullous disease, Kindle syndrome, or acquired epidermal bullous disease.

3. The use according to claim 1, characterized in that, The wounds associated with epidermal blistering include at least one of chronic and acute wounds.

4. The use according to claim 1, characterized in that, The wounds associated with epidermal blistering are selected from blisters and tears of the skin and mucous membranes.

5. The use according to claim 1, characterized in that, The pharmaceutical composition is used for topical application to the subject.

6. The use according to claim 5, characterized in that, The pharmaceutical composition is used to administer an effective amount of the adenine or its salt to the wound associated with epidermal blistering, wherein the effective amount is between 0.001 mg / cm². 2 and 100 mg / cm 2 between.

7. The use according to claim 6, characterized in that, The pharmaceutical composition is used to administer an effective amount of the adenine or its salt to the wound associated with epidermal blistering, wherein the effective amount is between 0.01 mg / cm². 2 and 50 mg / cm 2 between.

8. The use according to claim 1, characterized in that, The adenine or its salt is present in the pharmaceutical composition at a concentration of about 0.001% by weight to about 80% by weight.

9. The use according to claim 8, characterized in that, The adenine or its salt is present in the pharmaceutical composition at a concentration of about 0.01% by weight to about 50% by weight.

10. The use according to claim 1, characterized in that, The adenine or its salt is the sole active ingredient in the pharmaceutical composition for the treatment of epidermal blistering.

11. The use according to claim 1, characterized in that, The pharmaceutical composition is intended to be administered to the subject for a treatment duration of at least one week.

12. The use according to claim 11, characterized in that, The pharmaceutical composition reduces the size of the wound by at least about 50% during the duration of the treatment.

13. The use according to claim 11, characterized in that, The treatment lasts for at least three weeks.

14. The use according to claim 13, characterized in that, The pharmaceutical composition reduces the size of the wound by at least about 90% during the duration of the treatment.

15. The use according to claim 11, characterized in that, The pharmaceutical composition is to be administered to the subject 1 to 4 times daily or 1 to 14 times weekly during the duration of treatment.

16. The use according to claim 1, characterized in that, The pharmaceutical composition further reduces the time required for the wound to close.

17. The use according to claim 1, characterized in that, The pharmaceutical composition is in the form of a group selected from solutions, liniments, lotions, sprays, ointments, foams or foamable preparations, emulsions, creams, gels, pastes, patches, adhesives, films, powders, granules and wound dressings.

18. The use according to claim 1, characterized in that, The pharmaceutically acceptable excipients are selected from the group consisting of fillers, binders, preservatives, disintegrants, lubricants, suspending agents, wetting agents, solvents, surfactants, acids, flavoring agents, polyethylene glycol, alkyl glycols, sebacic acid, dimethyl sulfoxide, alcohols, calcium stearate, microcrystalline cellulose, silica, gelatin, fats, glycerol, dietary fiber, alginate, pectin, carrageenan, amidated pectin, xanthan gum, galvanic gum, ebony gum, rhamnose gum, vetiver gum, gum arabic, gum arabic, and any combination thereof.

Images