Timolol maleate gel for topical administration

Abstract

A topical formulation of timolol maleate is disclosed. The formulation contains about 0.4 to about 15 mg / cm. 2 When administered at a dose of 100 mg / day, the steady-state mean timolol blood concentration is maintained below 3 ng / mL in subjects who require it. max,ss / C min,ss The ratio is less than 2.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 18 / 420,370, filed January 23, 2024, the disclosure of which is incorporated herein by reference in its entirety. [Technical Field]

[0002] The present invention provides a topical formulation of timolol maleate for the treatment of infantile hemangiomas and venous stasis leg ulcers, the formulation and administration of which are designed to provide an appropriate pharmacokinetic profile for effective treatment with minimal side effects. [Background technology]

[0003] Infantile hemangiomas (IH) are common benign vascular endothelial cell proliferative tumors. They primarily present on the head and neck of infants, are relatively superficial, and occur in 2.5% to 12% of newborns. Because the lesions often appear in specific locations, they can affect vital organs, and in severe cases, can be life-threatening. They cause significant physiological distress and psychological pressure for patients and their families.

[0004] There are several options 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 the complications they can cause have limited their widespread clinical use.

[0005] In 2008, Le´aute´-Labre`ze et al. first used timolol maleate (TM) for the topical treatment of infantile hemangiomas, achieving remarkable therapeutic effects. Since then, numerous clinical trials of timolol maleate in the treatment of infantile hemangiomas have been conducted, with consistent therapeutic effects. Topical timolol maleate is gradually becoming the most effective treatment for infantile hemangiomas, replacing oral propranolol.

[0006] However, timolol maleate is currently available in only three dosage forms: tablets, eye drops, and ophthalmic gel. Oral timolol has potential cardiotoxic side effects and can cause adverse reactions. Furthermore, infant patients with hemangiomas have low compliance with medication. Eye drops and ointments are less effective due to their liquid nature and the inconvenience of applying them to the skin, and applying them around the eyes can cause a drop in intraocular pressure.

[0007] Effective topical formulations are needed to treat conditions such as infantile hemangiomas and venous stasis leg ulcers, and preferably to overcome the side effects observed with current formulations that reduce patient compliance. Summary of the Invention [Problem to be solved by the invention]

[0008] The formulation disclosed in this patent document addresses that need. By providing an appropriate pharmacokinetic profile, the formulation effectively treats skin disorders with minimal side effects. [Means for solving the problem]

[0009] One aspect of the patent document is a method for determining the mean steady-state timolol blood concentration, C max,ss The present invention provides a method for maintaining the concentration of timolol maleate at about 0.4 to about 15 mg / cm 3 or less. 2 / day, wherein the amount of timolol maleate in the formulation is such that, at steady state, C max,ss / C min,ss is selected so that the ratio is less than 2.

[0010] In some embodiments, the formulation is configured such that the amount of timolol maleate in the formulation is an average C max,ssis selected to be less than 1500 pg / mL, less than 300 pg / mL, or less than 150 pg / mL. In some embodiments, the daily dose is about 0.5 to about 8 mg / cm 2 / day, and the average C max,ss is less than 150 pg / mL.

[0011] In some embodiments, the formulation provides a daily dose of timolol of about 0.4 to about 10 mg / cm 2 / day, or about 0.5 to about 8 mg / cm 2 / day included.

[0012] In some embodiments, the formulation is administered 1 to 5 times per day, 2 to 3 times per day, or twice per day.

[0013] In some embodiments, the subject is 3-12 months of age. In some embodiments, the subject has been diagnosed with infantile hemangioma. In some embodiments, the subject has been diagnosed with venous stasis leg ulcers.

[0014] In some embodiments, the formulation is in the form of a gel. In some embodiments, the formulation does not include a penetration enhancer.

[0015] In some embodiments, the formulation contains propylene glycol in an amount of 5% to 7% by weight, carbomer in an amount of 1.6% to 2.5% by weight, triethanolamine in an amount of 0.6% to 1.0% by weight, and ethylparaben in an amount of 0.05% to 2% by weight. In some embodiments, the formulation contains about 6% by weight propylene glycol, about 1.8% by weight carbomer, about 0.8% by weight triethanolamine, and about 0.1% by weight ethylparaben. In some embodiments, the daily dose is about 0.5 to about 8 mg / cm. 2 / day, and the average C max,ss is less than 150 pg / mL.

[0016] In some embodiments, the formulation is prepared according to the following steps. a. Add the prescribed amount of timolol maleate to water and dissolve by stirring to obtain a clear solution I. b. Add the prescribed amount of carbomer to Solution I and stir to obtain a fully swollen and well-dispersed Solution II. c. Add the prescribed amount of ethyl hydroxybenzoate to the prescribed amount of propylene glycol and stir to dissolve, obtaining a clear solution III. d. Add Solution III to Solution II and stir to mix well to obtain Mixture V. e. Add the prescribed amount of triethanolamine to the mixture V described in step d, add the remaining amount of water and mix well to obtain a pharmaceutical composition of timolol maleate. [Brief explanation of the drawings]

[0017] [Figure 1] 1 shows the mean plasma concentration-time curves following single and multiple topical administration of an exemplary timolol gel formulation in healthy subjects. [Figure 2] A hemangioma after successful treatment in a clinical trial is shown with an example of a timolol gel formulation. DETAILED DESCRIPTION OF THE INVENTION

[0018] In various embodiments, the present disclosure provides a topical formulation of timolol or its pharmaceutically acceptable salt.The formulation provides a therapeutically effective amount of timolol locally and reduces PTF without serious side effects.The formulation is suitable for treating diseases such as hemangiomas and venous stasis leg ulcers.

[0019] The following may refer to or exemplify specific embodiments of pharmaceutical formulations or dosage forms, but are not intended to be limited to the specified scope of pharmaceutical formulations or dosage forms. Considerations of practicality and economy allow those skilled in the art to make various modifications to, for example, the content and administration schedule of active ingredients of dosage forms for the treatment of diseases or disorders.

[0020] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Definitions of various terms are provided below.

[0021] The term "steady state" means that for a given drug, there is substantially no fluctuation in the plasma concentration curve after repeated administration of a dose of the formulation.

[0022] As used herein, the terms "a," "an," or "the" mean "one or more" or "at least one." That is, reference to any element or composition of the present invention by "a," "an," or "the" does not exclude the possibility of multiple elements or compositions being present.

[0023] As used herein, terms such as "about," when used in connection with a numerical variable, generally mean that the value of the variable, and all values ​​of the variable, are within experimental error (e.g., within a 95% confidence interval of the mean), or within ±10%, ±5%, whichever is greater, of the indicated value.

[0024] The term "steady state" means that for a given drug, there is substantially no fluctuation in the plasma concentration curve after repeated administration of a dose of the formulation.

[0025] The term "subject" or "patient" refers to a mammal, which may be an animal or a human.

[0026] Embodiments of the patent document provide formulations for topical administration of a therapeutically effective amount of timolol or a pharmaceutically acceptable salt thereof. Desirably, the formulations contain about 0.4 to about 15 mg / cm. 2 The amount of timolol maleate in the formulation is C max,ss / C min,ss is selected so that the ratio is less than 2.

[0027] In some embodiments, the amount of timolol or a pharmaceutically acceptable salt thereof in the formulation is 0.1%-5%, 0.2%-4%, 0.5%-3%, 0.5%-2.5%, 0.5%-2.0%, 0.5%-1.5%, or 1.0%-2.0% by weight. Non-limiting examples of amounts of timolol or a pharmaceutically acceptable salt thereof in the formulation include 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 foregoing percentages. In some embodiments, the formulation includes timolol maleate.

[0028] The formulation may contain one or more excipients including, for example, solvents, viscosity or rheology control agents, stabilizers, antimicrobial agents, antioxidants, gelling agents, spreadability enhancers, emulsifiers, pH adjusters, and water.

[0029] In some embodiments, the formulation includes excipients including propylene glycol, carbomer, triethanolamine, and ethylparaben. As a solvent, the amount of propylene glycol also affects the release rate of the active ingredient and the degree of skin irritation. In some embodiments, propylene glycol ranges from 4% to 10%, 4% to 8%, or 5% to 7% by weight in the formulation. Non-limiting examples of the amount of propylene glycol 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 percentages.

[0030] In some embodiments, the carbomer is present in the formulation in a 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. Non-limiting examples of amounts of carbomer in the formulation by weight include 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 foregoing percentage values.

[0031] In some embodiments, the amount of triethanolamine present ranges from 0.2% to 2.0%, 0.4% to 1.8%, 0.6% to 1.5%, or 0.8% to 1.0% by weight. Non-limiting examples of amounts of triethanolamine present 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 any range between any two of the foregoing percentages.

[0032] In some embodiments, the ethyl hydroxybenzoate ranges from 0.05% to 2.0%, 0.05% to 1.5%, 0.08% to 1.0%, or 0.1% to 0.5% by weight. Non-limiting examples of amounts of ethyl hydroxybenzoate 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 any range between any two of the foregoing percentage values.

[0033] In some embodiments, the formulation comprises propylene glycol in an amount of about 6% by weight, carbomer in an amount of about 1.8% by weight, triethanolamine in an amount of about 0.8% by weight, and ethyl hydroxybenzoate in an amount of about 0.1% by weight.

[0034] Another aspect of the patent document is a method for determining the mean steady-state timolol blood concentration, C, in a subject in need thereof. max,ssThe method provides a method for reducing the concentration of timolol maleate to less than 3 ng / mL. The method comprises administering a formulation containing timolol maleate at a concentration of about 0.4 to about 15 mg / cm. 2 / day, wherein the formulation comprises: max,ss / C min,ss is selected so that the ratio is less than 3, less than 2.5, less than 2, 1.8 or less, or 1.5 or less. 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 / cm. 2 By way of non-limiting example, daily dosages include about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.8, about 1.0, about 1.5, about 2.0, about 3.0, and about 4.0 mg / cm. 2 / day, and any range between any two of the preceding values.

[0035] In some embodiments, the 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. max,ss 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 any range between any two of the foregoing values.

[0036] The formulations can be administered once, twice, three times, four times, or five times daily. Achieving the desired therapeutic effect while minimizing skin irritation requires consideration of various factors, including formulation composition, amounts of active ingredient and excipients, and frequency of administration. In some embodiments, the daily dose is about 0.5 to about 8 mg / cm. 2 / day, and the average C max,ssis less than 150 pg / mL. In some embodiments, the formulation comprises propylene glycol in an amount ranging from 5-7% by weight, carbomer in an amount ranging from 1.6-2.5% by weight, triethanolamine in an amount ranging from 0.6-1.0% by weight, and ethyl hydroxybenzoate in an amount ranging from 0.05-2% by weight. In some embodiments, the formulation comprises propylene glycol in an amount of about 6% by weight, carbomer in an amount of about 1.8% by weight, triethanolamine in an amount of about 0.8% by weight, and ethyl hydroxybenzoate in an amount of about 0.1% by weight.

[0037] In some embodiments, the formulation is administered twice daily. In some embodiments, the formulation does not contain a penetration enhancer to reduce skin irritation.

[0038] The formulation may be in a variety of suitable forms, such as a gel, an ointment, a cream, etc. In some embodiments, the formulation is a gel.

[0039] In some embodiments, the subject has been diagnosed with infantile hemangioma, hi some embodiments, the subject has been diagnosed with venous stasis leg ulcers.

[0040] In another embodiment, the method comprises administering to a patient in need thereof a formulation comprising timolol maleate as a topical formulation, wherein the topical dosage of timolol is 0.4-15 mg / cm. 2 / day, timolol administration frequency was 1-5 times / day, and after topical administration of timolol maleate to the lesion, the patient's timolol plasma concentration was less than 3ng / mL at steady state. max / C min The ratio is less than 2. The dosage, administration schedule, and other pharmacokinetic parameters can be as described above.

[0041] In some embodiments, the dosage of timolol administered to a patient via topical administration is 0.4 to 10 mg / cm 2 In some embodiments, the range is 0.5 to 8 mg / cm 2In some embodiments, the range is 1.2 to 5 mg / cm. 2 / day range.

[0042] In some embodiments, the frequency of administration of timolol to patients in need of topical administration is 1 to 4 times per day, 2 to 3 times per day, or 2 times per day.

[0043] In some embodiments, the duration of topical administration to a patient in need of timolol treatment ranges from 3 to 12 months.

[0044] The present invention also provides a pharmaceutical composition of timolol maleate, comprising timolol maleate, pharmaceutical excipients, and water. The pharmaceutical excipients comprise, by weight, 1.6-2.5% carbomer, 0.6-1.0% triethanolamine, 5-7% propylene glycol, 0.05-2% ethylparaben, and the remainder water. The pharmaceutical composition is preferably a gel. [Example]

[0045] Example 1 To prepare a formulation suitable for topical administration, various factors must be considered, such as controlled release of the active ingredient, skin irritation, solubility of the excipient, etc. In this experiment, several formulations were prepared and examined. The amount of propylene glycol as a solvent is important.

[0046] When propylene glycol is used at a low level (1% to 4%), skin irritation is reduced, but the solubility of ethyl hydroxybenzoate is reduced, resulting in the precipitation of some of the ethyl hydroxybenzoate as aggregates when gel formulations are prepared using conventional addition methods. As exemplified in the manufacturing process below, diluting the ethyl hydroxybenzoate in propylene glycol solution with water before adding it to the bulk blending solution improved the formulation profile. It was observed that an appropriate amount of propylene glycol not only dissolves excipients such as ethyl hydroxybenzoate, but also provides moisturizing properties and enhances the antibacterial effect of ethyl hydroxybenzoate.

[0047] In the following example formulation, the amount of propylene glycol was increased to 5-7%. In addition, the carbomer was 1.6-2.5%. The high viscosity of the gel slowed the drug release rate, while the active ingredient C max The composition of the new formulation is shown in Tables 1 and 2.

[0048] (Table 1) JPEG2026505932000002.jpg36110

[0049] (Table 2) JPEG2026505932000003.jpg37110

[0050] The gel preparation process includes the following steps: 1) Add a predetermined amount of timolol maleate to water and dissolve by stirring to obtain a clear solution I. 2) A predetermined amount of carbomer is added to Solution I and stirred to completely swell it, to obtain a well-dispersed Solution II. 3) Add a predetermined amount of ethyl hydroxybenzoate to the prescribed dose or a predetermined amount of propylene glycol and stir to dissolve, obtaining a clear solution III. 4) Add Solution III to Solution II and mix well to obtain Mixture V. 5) Add a predetermined amount of triethanolamine to the mixture V described in step 4), add the remaining amount of water, and mix well to obtain a pharmaceutical composition of timolol maleate.

[0051] Example 2 In this experiment, the skin irritation of the prepared formulations was investigated. The irritation of guinea pig skin caused by gels prepared with different formulations (Table 3) was compared with that of formulation 6.

[0052] (Table 3) JPEG2026505932000004.jpg3275Note: Formulation 9 is a gel containing a percutaneous penetration enhancer, and formulation 10 is a gel without a percutaneous penetration enhancer. Both formulations contain 15% propylene glycol.

[0053] A skin irritation test was conducted on 12 guinea pigs using each of the gels prepared using formulations 6, 9, and 10. As shown in Table 4, skin irritation was observed in two of the 12 guinea pigs in the formulation 9 group, skin irritation was observed in one guinea pig in the formulation 10 group, and no skin irritation reactions were observed in the formulation 6 group. This experiment demonstrated that 6% propylene glycol in the gel formulation provides a good safety profile.

[0054] Table 4: Incidence and severity of skin irritation after percutaneous administration JPEG2026505932000005.jpg49131Note: If at least one animal has a skin score of 2 at the administered site and a skin score of less than -2 (no skin irritation) at the non-administered site, the gel formulation is considered to be potentially dermatologically toxic.

[0055] A long-term toxicity study was conducted on minipigs in which gels prepared using formulations 6, 9, and 10 were administered topically to the skin at a dose of 10 mg / kg for 6 hours each morning and evening for 26 weeks. Blood drug concentrations measured after 26 weeks were 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 in the skin of the minipigs. This suggests that the percutaneous penetration enhancer and high concentration of propylene glycol increase timolol plasma concentrations in pediatric patients in clinical use, increasing the risk of systemic side effects.

[0056] Example 3 The plasma concentration of the active ingredient at different daily doses was investigated. 2 Approximately 8 g of Timolol (TM) gel (timolol content: 40 mg (0.5% TM gel)) was applied to a 20 x 10 cm (20 x 10 cm) in the morning (around 8:00 AM) on Day 1. After a two-day washout period, subjects were administered once daily (Group 1), twice daily (Group 2), or three times daily (Group 3) for nine consecutive days. The study demonstrated good safety and tolerability. All drug-related adverse events in this study were mild, with most being skin reactions and primary complaints after administration.

[0057] The mean plasma concentration-time curves (linear) for single and repeated administration of TM Gel are shown in Figure 1. The mean steady-state concentration (C avg,ss ) were 59.9 ± 49.7 pg / mL, 106.8 ± 62.6 pg / mL, and 106.8 ± 86.8 pg / mL, respectively. max,ss ) were 68.5 ± 56.3 pg / mL, 121.3 ± 69.9 pg / mL, and 121.2 ± 98.9 pg / mL, respectively. min,ss) were 48.0±41.0pg / mL, 91.1±56.2pg / mL, and 93.8±75.3pg / mL, respectively. Steady-state plasma concentrations were compared. It is surprising that the steady-state plasma concentrations in Groups 2 and 3 were higher than in Group 1, and there was no difference between Groups 2 and 3. These results suggest that topical administration of TM Gel more than twice (0.4mg / cm) 2 / day) indicates that absorption into the skin is saturated. Because infantile hemangiomas are localized diseases, treatment depends on the drug concentration in the skin. 2 / day) is insufficient, and twice-daily administration (0.4 mg / cm 2 / day) and 3 times daily (0.6 mg / cm 2 / day) may have the same effect because the drug concentration in the skin is the same.

[0058] Example 4 The clinical efficacy of a timolol gel formulation was investigated. 168 infants aged 35 to 150 days with superficial hemangiomas were enrolled in a clinical trial. After obtaining family consent, the patients were randomly assigned to three groups, with 56 patients in each group. Pediatric patients received either timolol gel (formulation 7) applied twice daily, three times daily, or placebo gel for six months. Secondary endpoints for evaluating the efficacy of the treatment included the success rate of nevus treatment after 24 weeks of treatment, visual analog scores, and clinical changes in tumor color during treatment.

[0059] During 24 weeks of IH treatment, a total of 21 subjects in the three-times-daily treatment group achieved complete or near-complete regression, with a success rate of 42.0% (21 / 50) and a 95% confidence interval (CI) of 28.19% to 56.79%. In the twice-daily treatment group, 29 subjects achieved complete / near-complete regression, with a success rate of 55.8% (29 / 52) and a 95% CI of 41.33% to 69.53%. In the placebo group, eight subjects achieved complete / near-complete regression, with a success rate of 15.1% (8 / 53) and a 95% CI of 6.75% to 27.59%. Photographs of successful treatments are shown in Figure 2. Other secondary endpoints were consistent with the results of the primary endpoint analysis.

[0060] All doses in clinical trials were ≥ 0.4 mg / cm² / d, ranging from 0.5 to 15 mg / cm² / d. Subjects were randomly assigned to receive the daily dose / cm² in each group. 2 The IH treatment success rate over 24 weeks of treatment was summarized in Table 5. As a result, the daily dose / cm2 of each group over 24 weeks of treatment was 2 It was shown that acetaminophen does not significantly affect the success rate of IH treatment, which is consistent with the results of a phase 1 study in healthy subjects, which showed that doses above 0.4 mg / cm² / day saturated the skin and were similarly effective.

[0061] Table 5. Summary of IH treatment success rates stratified by daily dose / cm2 over 24 weeks of treatment. JPEG2026505932000006.jpg36111Note: Daily dose / cm 2 is calculated based on active ingredients.

[0062] In the placebo group, the IH treatment success rate after 24 weeks of treatment was 15.1% (8 / 53) (central independent assessment). Safety analysis showed good systemic and local safety when applied to the treatment of superficial nevus in the proliferative phase. Pharmacokinetic (PK) analysis showed that systemic exposure to timolol after application of timolol gel (Formulation 7) was low; at steady state, timolol plasma concentrations in all patients were less than 3 ng / mL, with a median of approximately 100 pg / mL. This is significantly lower than the exposure of commercially available timolol eye drops in pediatric patients (3.5-35 ng / mL).

[0063] The above embodiments represent only some embodiments of the present invention and are described more specifically and in detail. However, they cannot be interpreted as limiting the patent scope of the present invention. It should be noted that those skilled in the art can make variations and modifications without departing from the idea of ​​the present invention, and they all fall within the scope of patent protection of the present invention. Therefore, the scope of protection of the present patent is subject to the appended claims.

Claims

1. In subjects requiring it, mean timolol blood C at steady state max,ss How to maintain blood glucose levels below 3 ng / mL. The method involves administering a formulation containing timolol maleate at a concentration of about 0.4 to about 15 mg / cm. 2 The formulation and content of the preparation are determined by the C max,SS / C min,SS is selected so that the ratio is less than 2.

2. average C max,ss The method of claim 1, wherein the IL-10 level is less than 1500 pg / mL.

3. average C max,ss The method of claim 1, wherein the IL-10 level is less than 300 pg / mL.

4. 10. The method of claim 1, wherein the timolol maleate is present in the formulation in an amount of from about 0.5% to about 2.0% by weight.

5. Daily dose is about 0.4 to about 10 mg / cm 2 10. The method of claim 1, wherein the daily dose is 100 mg / day.

6. Daily dose is about 0.5 to about 8 mg / cm 2 10. The method of claim 1, wherein the daily dose is 100 mg / day.

7. average C max,ss The method of claim 6, wherein the IL-10 level is less than 150 pg / mL.

8. 10. The method of claim 1, wherein the formulation is administered 1 to 5 times daily.

9. 10. The method of claim 1, wherein the formulation is administered two to three times daily.

10. 10. The method of claim 1, wherein the formulation is administered twice daily.

11. Daily dose is about 0.5 to about 8 mg / cm 2 / day, and the average C max,ss The method of claim 10, wherein the IL-10 level is less than 150 pg / mL.

12. 10. The method of claim 1, wherein the subject is 3 to 12 months old.

13. 10. The method of claim 1, wherein the subject has been diagnosed with infantile hemangioma.

14. 10. The method of claim 1, wherein the formulation is in the form of a gel.

15. The method of claim 1 , wherein the formulation does not contain a permeation enhancer.

16. 10. The method of claim 1, wherein the formulation comprises propylene glycol in an amount of 5% to 7% by weight, carbomer in an amount of 1.6% to 2.5% by weight, triethanolamine in an amount of 0.6% to 1.0% by weight, and ethylparaben in an amount of 0.05% to 2% by weight.

17. 10. The method of claim 1, wherein the formulation comprises propylene glycol in an amount of about 6% by weight, carbomer in an amount of about 1.8% by weight, triethanolamine in an amount of about 0.8% by weight, and ethylparaben in an amount of about 0.1% by weight.

18. Daily dose is about 0.5 to about 8 mg / cm 2 / day, and the average C max,ss The method of claim 17, wherein the IL-10 level is less than 150 pg / mL.

19. 18. The method of claim 17, wherein the topical formulation is prepared by the steps of: a. Add the prescribed amount of timolol maleate to water and dissolve by stirring to obtain a clear solution I. b. Add the prescribed amount of carbomer to Solution I and stir to obtain a fully swollen and well-dispersed Solution II. c. Add the prescribed amount of ethyl hydroxybenzoate to the prescribed amount of propylene glycol and stir to dissolve, obtaining a clear solution III. d. Add Solution III to Solution II and mix well to obtain Mixture V. e. Add the prescribed amount of triethanolamine to the mixture V described in step d, add the remaining amount of water and mix well to obtain a pharmaceutical composition of timolol maleate.

20. 10. The method of claim 1, wherein the subject has been diagnosed with a venous stasis leg ulcer.

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