Timolol maleate gel for topical administration

Abstract

A formulation of timolol maleate for topical administration is disclosed. When administered to subjects requiring this at a dose of about 0.4 to about 15 mg / cm2 / day, this formulation maintains the average blood Cmax,SS of timolol at less than 3 ng / mL, and the ratio of Cmax,SS to Cmin,SS in steady state is less than 2. Additionally, the present specification discloses a method for treating skin diseases such as infantile hemangiomas and chronic venous ulcers of the lower extremities.

Description

Technology Field

[0001] This application claims priority to U.S. Patent Application No. 18 / 420,370 filed January 23, 2024. The entire disclosure of this application is incorporated herein by reference. This patent document relates to a timolol maleate formulation for topical administration to treat infantile hemangiomas and chronic venous ulcers of the lower extremities. The formulation and the method of administration are designed to provide appropriate pharmacokinetic characteristics for effective treatment while minimizing side effects. Background Technology

[0002] Infantile hemangioma (IH) is a common benign vascular endothelial proliferative tumor. This lesion primarily appears on the head and neck of infants and is relatively superficial, with an incidence rate of 2.5% to 12% in newborns. Major organs are frequently affected due to the specific location of the lesion, and in severe cases, it threatens the patient's life, causing extreme physical pain and psychological burden to the patient and their family.

[0003] There are various methods for treating infantile hemangiomas, and traditionally, systemic drug therapy has been the first choice. Corticosteroids, interferon, and vincristine have been used to treat infantile hemangiomas, but their widespread use in clinical practice has been limited due to the complications these drugs can cause.

[0004] Timolol maleate™ was first used topically for the treatment of infantile hemangiomas by Le'aute'-Labre'ze et al. in 2008 and demonstrated significant therapeutic effects. Since then, numerous clinical trials have been conducted on the treatment of infantile hemangiomas using timolol maleate, achieving consistent therapeutic efficacy. Topical timolol maleate is gradually establishing itself as the most effective drug to replace oral propranolol in the treatment of infantile hemangiomas.

[0005] However, timolol maleate is currently available in only three formulations: tablets, eye drops, and eye gel. Oral timolol carries the potential to cause cardiotoxic side effects, and medication adherence is low, particularly among pediatric patients with hemangiomas. Since the eye drops and gel are in liquid form, they are inconvenient to apply to the skin, resulting in reduced efficacy; furthermore, applying them around the eyes may potentially lower intraocular pressure.

[0006] There is a need for a local administration formulation effective for the treatment of conditions such as infantile hemangiomas and chronic venous ulcers of the lower extremities. Preferably, this formulation should be able to overcome the side effects observed in existing formulations that impede patient compliance. The problem to be solved

[0007] The formulation disclosed in this patent document satisfies the following requirements. By providing appropriate pharmacokinetic properties, this formulation effectively treats skin diseases while minimizing side effects. means of solving the problem

[0008] One aspect of the present patent document is that the steady-state mean blood C of timolol in subjects requiring timolol. max,SS The present invention provides a method for maintaining [the value] below 3 ng / mL. The method involves administering a preparation containing timolol maleate to a subject at a dose of about 0.4 to about 15 mg / cm² per day. 2 It includes a step of local administration at a daily dosage. Here, the preparation is C in a steady state. max,SS / C min,SS It is configured so that the ratio is less than 2, and the content of timolol maleate in the above formulation is selected accordingly.

[0009] In some embodiments, the formulation is average C max,SS It is formulated to be less than 1500 pg / mL, less than 300 pg / mL, or less than 150 pg / mL, and the content of timolol maleate in the formulation is selected accordingly. In some embodiments, the daily dose is about 0.5 to 8 mg / cm² 2 / day range, average C max,SS It is less than 150 pg / mL.

[0010] In some embodiments, the formulation contains about 0.4 to about 10 mg / cm² of timolol per day. 2 / day or about 0.5 to about 8 mg / cm² 2 Includes as a daily dosage.

[0011] In some embodiments, the preparation is administered 1 to 5 times a day, 2 to 3 times a day, or 2 times a day.

[0012] In some embodiments, the age of the subject is 3 to 12 months. In some embodiments, the subject is diagnosed with infantile hemangioma. In some embodiments, the subject is diagnosed with chronic venous lower extremity ulcers.

[0013] In some embodiments, the formulation is in the form of a gel. In some embodiments, the formulation does not contain a penetration enhancer.

[0014] In some embodiments, the formulation comprises propylene glycol in the range of 5% to 7% by weight, carbomer in the range of 1.6% to 2.5% by weight, triethanolamine in the range of 0.6% to 1.0% by weight, and ethyl hydroxybenzoate in the range of 0.05% to 2% by weight. In some embodiments, the formulation comprises about 6% by weight of propylene glycol, about 1.8% by weight of carbomer, about 0.8% by weight of triethanolamine, and about 0.1% by weight of ethyl hydroxybenzoate. In some embodiments, the daily dose is about 0.5 to 8 mg / cm² 2 / day range, average C max,SS It is less than 150 pg / mL.

[0015] In some embodiments, the formulation is prepared according to the following steps.

[0016] a. A step of adding a prescribed amount of timolol maleate to water and stirring to dissolve it, thereby obtaining a clear solution I;

[0017] b. A step of adding a prescribed amount of carbomer to solution I and stirring until completely swollen to obtain a well-dispersed solution II;

[0018] c. A step of adding a prescribed amount of ethyl hydroxybenzoate to a formulation amount of propylene glycol and stirring to dissolve it to obtain a clear solution III;

[0019] d. A step of adding Solution III to Solution II, stirring, and mixing well to obtain Mixture V;

[0020] e. A step of adding a prescribed amount of triethanolamine to the mixture V described in step d, adding the remaining amount of water, and mixing well to obtain a pharmaceutical composition of timolol maleate. Effects of the invention

[0021] Various embodiments disclosed herein disclose formulations of timolol for topical administration or pharmaceutically acceptable salts thereof. Such formulations provide a therapeutically effective amount of timolol topically and reduce PTF without serious side effects. Such formulations are suitable for treating conditions including hemangiomas and chronic venous ulcers of the lower extremities. Brief explanation of the drawing

[0022] Figure 1 shows the average plasma concentration-time curve when a timolol gel formulation was administered topically once and multiple times to healthy subjects. Figure 2 is a figure showing a hemangioma successfully treated in a clinical trial using an exemplary timolol gel formulation. Specific details for implementing the invention

[0023] The following description may mention or exemplify specific examples of pharmaceutical formulations or dosage forms, but is not limited to the specified scope of such pharmaceutical formulations or dosage forms. With consideration of practicality and economics, those skilled in the art may make various modifications regarding the content of the active ingredient and the method of administration, etc., to treat diseases or disorders.

[0024] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as generally understood by a person skilled in the art to which the present invention pertains. Definitions of various terms are as follows.

[0025] The term "steady state" refers to a state in which the plasma concentration curve of a specific drug does not substantially change even after repeated administration of the formulation.

[0026] As used herein, the terms "one" or "one" mean "one or more" or "at least one." That is, referring to any component or composition of the present invention as "one" or "one" does not exclude the possibility that such component and composition may be plural.

[0027] When terms such as “about” used in this specification are used in relation to numerical variables, they generally mean that the value of the variable and all values ​​of the variable are within the experimental error range (e.g., within a 95% confidence interval for the mean) or within ±10% or ±5% of the indicated value, whichever is greater.

[0028] The term "steady state" refers to a state in which the plasma concentration curve of a specific drug does not substantially change even after repeated administration of the formulation.

[0029] The terms "subject" or "patient" refer to mammals and can be animals or humans.

[0030] One aspect of the present patent document provides a formulation for topical administration of a therapeutically effective amount of timolol or a pharmaceutically acceptable salt thereof. Preferably, said formulation is about 0.4 to about 15 mg / cm² per day. 2 It is configured to be administered at a daily dosage, and the timolol maleate content in the preparation is C under normal conditions. max,SS / C min,SSIt is selected so that the ratio is less than 2.

[0031] In some embodiments, the amount of timolol or a pharmaceutically acceptable salt thereof is in the range of 0.1% to 5%, 0.2% to 4%, 0.5% to 3%, 0.5% to 2.5%, 0.5% to 2.0%, 0.5% to 1.5%, or 1.0% to 2.0% by weight in the formulation. Non-limiting examples of timolol or pharmaceutically acceptable salts thereof in the above formulation include, by weight, about 0.2%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 1.0%, about 1.2%, about 1.4%, about 1.6%, about 1.8%, about 2.0%, about 2.2%, about 2.4%, about 2.6%, about 2.8%, about 3.0%, and any range between any two of the aforementioned percentage values. In some embodiments, the formulation comprises timolol maleate.

[0032] The above formulation may include one or more excipients such as a solvent, a viscosity or flow control agent, a stabilizer, an antimicrobial agent, an antioxidant, a gelling agent, a coating improver, an emulsifier, a pH adjuster, and water.

[0033] In some embodiments, the formulation comprises an excipient containing propylene glycol, a carbomer, triethanolamine, and ethyl hydroxybenzoate. The amount of propylene glycol as a solvent also affects the release rate of the active ingredient and the degree of skin irritation. In some embodiments, the propylene glycol in the formulation has a range of 4% to 10%, 4% to 8%, or 5% to 7% by weight. Non-limiting examples of the propylene glycol content in the formulation include about 3%, about 4%, about 5%, about 6%, about 7%, about 8% by weight, and any range between any two of the aforementioned percentage values.

[0034] In some embodiments, the carbomer is in the range of 1.0% to 4.5%, 1.5% to 3.5%, 1.6% to 2.5%, or 2.0% to 2.5% by weight in the formulation. Non-limiting examples of the carbomer content in the formulation include, by weight, about 1.0%, about 1.2%, about 1.4%, about 1.6%, about 1.8%, about 2.0%, about 2.2%, about 2.4%, about 2.6%, about 2.8%, about 3.0%, and all ranges between any two of the aforementioned percentage values.

[0035] In some embodiments, triethanolamine has a range of 0.2% to 2.0%, 0.4% to 1.8%, 0.6% to 1.5%, or 0.8% to 1.0% by weight in the formulation. Non-limiting examples of triethanolamine content in the formulation include about 0.2%, about 0.4%, about 0.6%, about 0.8%, about 1.0%, about 1.2%, about 1.4%, about 1.6%, about 1.8%, about 2.0% by weight, and all ranges between any two of the aforementioned percentage values.

[0036] In some embodiments, ethyl hydroxybenzoate has a range of 0.05% to 2.0%, 0.05% to 1.5%, 0.08% to 1.0%, or 0.1% to 0.5% by weight in the formulation. Non-limiting examples of the ethyl hydroxybenzoate content in the formulation include about 0.03%, about 0.05%, about 0.08%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 1.0%, about 2.0% by weight, and all ranges between any two of the aforementioned percentage values.

[0037] In some embodiments, the formulation comprises about 6 weight% propylene glycol, about 1.8 weight% carbomer, about 0.8 weight% triethanolamine, and about 0.1 weight% ethyl hydroxybenzoate.

[0038] Another aspect of this patent document concerns the steady-state mean blood C of timolol in subjects requiring timolol. max,SS The present invention provides a method for maintaining [the value] below 3 ng / mL. The method involves administering a preparation containing timolol maleate to a subject at a daily timolol dosage of approximately 0.4 to approximately 15 mg / cm². 2 It includes a step of administering locally within a range of / days. Here, the preparation is C in a normal state. max,SS / C min,SS The ratio is configured to be less than 3, less than 2.5, less than 2, less than 1.8, or less than 1.5, and the amount of timolol maleate in the formulation is selected accordingly. In some embodiments, the daily dose is about 0.2 to about 15, about 0.4 to about 10, about 0.4 to about 5, about 0.4 to about 2, about 0.4 to about 1, or about 0.4 to about 0.8 mg / cm² 2 The range is per day. Non-limiting examples of daily doses include approx. 0.2, approx. 0.3, approx. 0.4, approx. 0.5, approx. 0.6, approx. 0.8, approx. 1.0, approx. 1.5, approx. 2.0, approx. 3.0, and approx. 4.0 mg / cm². 2 / day, and all ranges between any two of the previously mentioned values ​​are included.

[0039] In some embodiments, average C max,SS is less than 2500, less than 2000, less than 1500, less than 1000, less than 500, less than 300, less than 200, less than 150, or less than 100 pg / mL. Mean C max,SS Non-limiting examples include about 80 pg / mL, about 100 pg / mL, about 120 pg / mL, about 150 pg / mL, about 200 pg / mL, about 250 pg / mL, about 300 pg / mL, about 500 pg / mL, about 1000 pg / mL, about 1500 pg / mL, about 2000 pg / mL, about 2500 pg / mL, about 3000 pg / mL, and all ranges between any two of the previously mentioned values.

[0040] The above formulation may be administered 1, 2, 3, 4, or 5 times per day. To achieve a desirable therapeutic effect while minimizing skin irritation, various factors such as the composition of the formulation, the amounts of active ingredients and excipients, and the frequency of administration must be considered. In some embodiments, the daily dose is about 0.5 to about 8 mg / cm² 2 / is a daily range, and the average C max,SS is less than 150 pg / mL. In some embodiments, the formulation comprises 5% to 7% by weight of propylene glycol, 1.6% to 2.5% by weight of carbomer, 0.6% to 1.0% by weight of triethanolamine, and 0.05% to 2% by weight of ethyl hydroxybenzoate. In some embodiments, the formulation comprises about 6% by weight of propylene glycol, about 1.8% by weight of carbomer, about 0.8% by weight of triethanolamine, and about 0.1% by weight of ethyl hydroxybenzoate.

[0041] In some embodiments, the formulation is administered twice a day. In some embodiments, the formulation does not contain a penetration enhancer to reduce skin irritation.

[0042] The above formulation may be in various suitable forms, such as gels, ointments, and creams. In some embodiments, the formulation is a gel.

[0043] In some embodiments, the subject is diagnosed with an infantile hemangioma. In some embodiments, the subject is diagnosed with a chronic venous ulcer of the lower extremities.

[0044] Another aspect provides a method for treating infantile hemangiomas comprising the step of locally administering a topical formulation to a patient requiring treatment. The topical formulation contains a timolol dose of 0.4 to 15 mg / cm² when administered locally. 2It contains timolol maleate in the range of / day, and the frequency of timolol administration is in the range of 1 to 5 times / day. Here, after local administration of timolol maleate to the diseased lesion, the patient's timolol plasma concentration at steady state is less than 3 ng / mL, and C max / C min The ratio is less than 2. The dosage, administration schedule, and other PK parameters may be the same as described above.

[0045] In some embodiments, the amount of timolol administered topically to patients requiring timolol is 0.4 to 10 mg / cm² 2 The range is / day, and in some examples, 0.5 to 8 mg / cm² 2 The range is / day, and in some examples, 1.2 to 5 mg / cm² 2 / is a range of days.

[0046] In some embodiments, the frequency of administration of timolol administered topically to patients requiring timolol is in the range of 1 to 4 times / day; in some embodiments, it is in the range of 2 to 3 times / day; and in some embodiments, it is 2 times / day.

[0047] In some embodiments, the duration of administration of timolol to patients requiring timolol treatment is in the range of 3 to 12 months.

[0048] The present invention also provides a pharmaceutical composition of timolol maleate comprising timolol maleate, a pharmaceutical excipient, and water. The pharmaceutical excipient comprises 1.6 to 2.5 wt% of carbomer, 0.6 to 1.0 wt% of triethanolamine, 5 to 7 wt% of propylene glycol, and 0.05 to 2 wt% of ethyl hydroxybenzoate, with the remainder being water. The pharmaceutical composition is preferably a gel.

[0049] [Example 1]

[0050] To manufacture formulations suitable for topical administration, various factors including the control of active ingredient release, skin irritation, and the solubility of excipients must be considered. In this experiment, various formulations were prepared and investigated.

[0051] The amount of propylene glycol as a solvent is important.

[0052] When the amount of propylene glycol in the above formulation is low (1%-4%), it helps reduce skin irritation; however, at the same time, the solubility of ethyl hydroxybenzoate in the formulation decreases, and a phenomenon was observed in which some of the ethyl hydroxybenzoate precipitates in the form of aggregates in gel formulations prepared by the conventional method of adding ethyl hydroxybenzoate. As exemplified in the manufacturing process below, it was found that the properties of the formulation improved when ethyl hydroxybenzoate dissolved in a propylene glycol solution was first diluted with water and then added to and mixed with a bulk solution. It was observed that an appropriate amount of propylene glycol not only dissolves excipients such as ethyl hydroxybenzoate but also provides a certain degree of moisturizing function while enhancing the antibacterial effect of ethyl hydroxybenzoate.

[0053] In the formulations exemplified below, the propylene glycol content was increased to 5%–7%. Additionally, the carbomer content was 1.6–2.5%. Due to the high gel viscosity, the drug release rate was slowed, and at the same time, the C of the active ingredient max ...decreased. The composition of the new formulation is shown in Tables 1 and 2.

[0054]

[0055]

[0056] The gel manufacturing process includes the following steps.

[0057] (1) A step of adding a predetermined amount of timolol maleate to water and stirring to dissolve it to obtain a clear solution I;

[0058] (2) A step of adding a predetermined amount of carbomer to solution I and stirring until completely swollen to obtain a well-dispersed solution II;

[0059] (3) A step of adding a predetermined amount of ethyl hydroxybenzoate to a formulation dose or a predetermined amount of propylene glycol, stirring to dissolve it, and obtaining a clear solution III;

[0060] (4) Adding solution III to solution II, stirring and mixing well to obtain mixture V;

[0061] (5) A step of adding a predetermined amount of triethanolamine to the mixture V described in step (4), adding the remaining amount of water, and mixing well to obtain a pharmaceutical composition of timolol maleate.

[0062] [Example 2]

[0063] In this experiment, the skin irritation of the prepared formulations was investigated. The results of comparing the irritation to guinea pig skin caused by gels prepared with various formulations (Table 3) with formulation 6 are as follows.

[0064]

[0065] Note: Formulation 9 is a gel containing a transdermal penetration enhancer, and Formulation 10 is a gel without a transdermal penetration enhancer. Both formulations have a high propylene glycol content (15%).

[0066] Skin irritation tests were conducted on 12 guinea pigs each for the gels prepared with formulations 6, 9, and 10. As shown in Table 4, skin irritation occurred in 2 of the 12 guinea pigs in the formulation 9 group, in 1 of the formulation 10 group, and no skin irritation reaction was observed in the formulation 6 group. The results of this experiment showed that the stability was excellent when the gel formulation contained 6% propylene glycol.

[0067] Incidence and severity of skin irritation after transdermal administration of drugs

[0068]

[0069] A long-term toxicity study was conducted on minipigs for 26 weeks by topically applying gels prepared as formulations 6, 9, and 10 to the skin at a dose of 10 mg / kg for 6 hours in the morning and evening, respectively. After 26 weeks, blood drug concentrations in the minipigs were detected at 4.35–11.4 ng / mL, 72.4–193.5 ng / mL, and 22.1–65.7 ng / mL, respectively, and no allergic reactions were observed on the skin of the minipigs. This indicates that when transdermal injection promoters and high concentrations of propylene glycol are used clinically, they may increase plasma concentrations of timolol in infant patients, thereby increasing the risk of systemic side effects.

[0070] [Example 3]

[0071] Plasma concentrations of the active ingredient were investigated according to various daily doses. Timolol™ gel was administered to healthy subjects on the dorsal side (area: 200 cm²) on the morning of Day 1 (around 8:00 AM). 2 Approximately 8 g (timolol content: 40 mg (0.5% TM gel)) was applied to a 20×10 cm area, followed by a 2-day break. Subsequently, the gel was applied once daily (Group 1), twice daily (Group 2), or three times daily (Group 3) for 9 days, respectively. The results demonstrated excellent safety and tolerability. In this study, all drug-related adverse events (AEs) were mild, and most adverse events were skin reactions and major symptoms reported by the subjects after administration.

[0072] The mean plasma concentration-time curves (linear) for single and multiple administrations of TM Gel are shown in Fig. 1. The mean steady-state concentrations (C) of the three groups avg,SS The values ​​were 59.9±49.7 pg / mL, 106.8±62.6 pg / mL, and 106.8±86.8 pg / mL, respectively. The maximum concentration observed under steady conditions (C max,SS The values ​​were 68.5±56.3 pg / mL, 121.3±69.9 pg / mL, and 121.2±98.9 pg / mL, respectively. The lowest concentration under steady conditions (Cmin,SS The values ​​were 48.0±41.0 pg / mL, 91.1±56.2 pg / mL, and 93.8±75.3 pg / mL, respectively. Steady-state plasma concentrations were compared. Surprisingly, the steady-state plasma concentrations of Group 2 and Group 3 were higher than those of Group 1, and there was no difference between Group 2 and Group 3. This is due to topical administration of TM Gel two or more times (0.4 mg / cm²). 2 This indicates that intradermal drug absorption has reached saturation after administration ( / day). Since infantile hemangioma is a localized disease, the therapeutic effect is determined by the intradermal drug concentration, and once daily administration (0.2 mg / cm²) 2 / day) may not be sufficient, and twice a day (0.4 mg / cm²) 2 / day) or administer 3 times a day (0.6 mg / cm² 2 Since the saturated drug concentration in the skin is the same (per day), the therapeutic effect may be the same.

[0073] [Example 4]

[0074] The clinical efficacy of the formulated timolol gel was investigated. A total of 168 infant patients aged 35 to 150 days with superficial hemangiomas were enrolled in this study. After obtaining family consent, patients were randomly assigned to three groups of 56 patients each. A clinical trial was conducted in infant patients administering timolol gel (Formulation 7) twice daily, three times daily, and placebo gel for 6 months. To evaluate the therapeutic effect, secondary endpoints recorded after 24 weeks of treatment included the success rate of IH treatment, Visual Analog Scale (VAS) scores, and clinical changes in tumor color during the treatment period.

[0075] In the 24-week IH treatment, a total of 21 subjects in the group administered three times daily achieved complete / nearly complete regression, with a success rate of 42.0% (21 / 50) and a 95% confidence interval of 28.19%–56.79%; in the group administered twice daily, 29 subjects achieved complete / nearly complete regression, with a success rate of 55.8% (29 / 52) and a 95% confidence interval of 41.33%–69.53%; and in the placebo group, 8 subjects achieved complete / nearly complete regression, with a success rate of 15.1% (8 / 53) and a 95% confidence interval of 6.75%–27.59%. Photographs of successful treatment cases are shown in Figure 2. Other secondary endpoints were consistent with the results of the primary efficacy analysis.

[0076] All doses used in clinical studies were 0.4 mg / cm² 2 It was higher than / day, and the range was 0.5–15 mg / cm² 2 It was / day. The subjects in each group received a daily dose / cm² 2 (Active ingredient standard: ≥0.5, < 2.0 mg / cm² 2 / day, ≥2.0, < 4.0 mg / cm² 2 / day and ≥4.0 mg / cm² 2 They were classified according to ( / day), and the IH treatment success rates after 24 weeks of treatment are summarized in Table 3. According to the results, the daily dosage / cm² in each group 2 It was found that there was no significant effect on the success rate of IH treatment during this 24-week treatment period. This was consistent with the results of a Phase 1 study in healthy subjects, where the dose was 0.4 mg / cm² 2 If the duration exceeds one day, the skin reaches a saturation state, and the efficacy was found to be similar.

[0077]

[0078] According to a centralized independent evaluation, the success rate of IH treatment in the placebo group after 24 weeks of treatment was 15.1% (8 / 53).

[0079] Safety analysis results showed that timolol gel exhibited excellent systemic and local safety when used to treat proliferative superficial IH. PK analysis revealed that after the application of timolol gel (Formulation 7), systemic exposure to timolol was low; under steady conditions, plasma timolol concentrations in all patients were less than 3 ng / mL, with a median concentration of approximately 100 pg / mL. This was significantly lower than the exposure levels of commercial timolol eye drops (3.5–35 ng / mL) in pediatric patients.

[0080] The above embodiments merely represent some embodiments of the present invention and have been described more specifically and in detail. However, this should not be interpreted as limiting the scope of the patent of the present invention. Those skilled in the art should note that various modifications and variations are possible within the scope of the spirit of the present invention, and all such variations and modifications are included within the scope of patent protection of the present invention. Accordingly, the scope of patent protection of the present invention is defined by the appended claims.

Claims

Claim 1 Contains timolol maleate, and C in normal state max,SS / C min,SS A formulation configured such that the ratio is less than 2 and the timolol maleate content is selected, with a daily dose of timolol of about 0.4 to about 15 mg / cm² 2 A steady-state mean timolol blood C of less than 3 ng / mL in the necessary subjects, comprising the step of local administration to the subject such that / day max,SS How to maintain. Claim 2 In paragraph 1, average C max,SS Maintenance method with a value of less than 1500 pg / mL. Claim 3 In paragraph 1, average C max,SS Maintenance method with a value of less than 300 pg / mL. Claim 4 A maintenance method according to claim 1, wherein the amount of timolol maleate is about 0.5% to about 2.0% by weight of the formulation. Claim 5 In claim 1, the daily dose is about 0.4 to about 10 mg / cm² 2 / Method for maintaining one person. Claim 6 In claim 1, the daily dose is about 0.5 to about 8 mg / cm² 2 / Method for maintaining one person. Claim 7 In Paragraph 6, average C max,SS Maintenance method with a g of less than 150 pg / mL. Claim 8 A maintenance method according to claim 1, wherein the above preparation is administered 1 to 5 times a day. Claim 9 A maintenance method according to claim 1, wherein the above preparation is administered 2 to 3 times a day. Claim 10 A maintenance method according to claim 1, wherein the above preparation is administered twice a day. Claim 11 In item 10, the daily dose is about 0.5 to about 8 mg / cm² 2 / work and average C max,SS Maintenance method with a g of less than 150 pg / mL. Claim 12 In claim 1, the maintenance method in which the subject is 3 to 12 months old. Claim 13 In claim 1, a method of maintaining the above subject being diagnosed with an infantile hemangioma. Claim 14 A method of maintenance in which the above preparation is in the form of a gel, in claim 1. Claim 15 A maintenance method according to claim 1, wherein the above formulation does not include a penetration enhancer. Claim 16 A method of maintenance according to claim 1, wherein the preparation comprises 5% to 7% by weight of propylene glycol, 1.6% to 2.5% by weight of carbomer, 0.6% to 1.0% by weight of triethanolamine, and 0.05% to 2% by weight of ethyl hydroxybenzoate. Claim 17 A method of maintenance according to claim 1, wherein the preparation comprises about 6% by weight of propylene glycol, about 1.8% by weight of carbomer, about 0.8% by weight of triethanolamine, and about 0.1% by weight of ethyl hydroxybenzoate. Claim 18 In paragraph 17, the daily dose is about 0.5 to about 8 mg / cm² 2 / day and average C max,SS Maintenance method with a g of less than 150 pg / mL. Claim 19 In claim 17, a method for preparing the topical formulation from the following steps: a. adding a prescribed amount of timolol maleate to water and stirring to dissolve it to obtain a clear solution I; b. adding a prescribed amount of carbomer to solution I and stirring until completely swollen to obtain a well-dispersed solution II; c. adding a prescribed amount of ethyl hydroxybenzoate to a formulation amount of propylene glycol and stirring to dissolve it to obtain a clear solution III; d. adding solution III to solution II and stirring to mix well to obtain mixture V; e. adding a prescribed amount of triethanolamine to mixture V described in step d, adding the remaining amount of water and mixing well to obtain a pharmaceutical composition of timolol maleate. Claim 20 A maintenance method according to claim 1, wherein the subject is diagnosed with chronic venous lower extremity ulcers.

Images