Treatment for hemangiomas

Abstract

The present invention relates to a medicament or a method for the topical treatment of hemangiomas comprising or administering propranolol and fosinopril in a molar ratio of 2 to 0.9-1.3, respectively. The present invention also relates to the use of propranolol and fosinopril in the manufacture of a medicament for the topical administration to a human patient for the treatment of hemangiomas, wherein the molar ratio of propranolol and fosinopril is 2 to 0.9-1.3.

Description

Technical Field

[0001] This invention relates to the treatment of hemangiomas, including but not limited to infantile hemangiomas, using a specific ratio of fosinopril and propranolol. Background Technology

[0002] Hemangiomas are complex growths that form from the proliferation of endothelial cells surrounding a blood-filled lumen. They can occur anywhere on the body, but are most common on the face, scalp, chest, or back. Hemangiomas usually regress over time, and most do not require treatment. However, they can affect appearance, cause psychological distress, and lead to functional disabilities depending on the location of the lesion. For example, if the tissue around the eye is affected, they can cause blindness. In particular, infantile hemangiomas affect up to 10% of children. This is the most common type of hemangioma, characterized by an initial period of rapid proliferation followed by a slow, spontaneous regression over 5 to 10 years, which may result in fibrofatty residue (Itinteang et al., Plast. Reconstr. Surg. 2011; 128, 499-507.).

[0003] Patent publication WO 2021 / 154102 (Davis, MacKay, Patterson, Tan, and Tan, 5 Aug 2021.) discloses the use of certain ACE inhibitors (ACEi) and beta-blockers for the treatment of infantile hemangiomas. In the WO document, the inventors are concerned with cases where the molar ratio of ACEi is significantly higher than that of beta-blockers. The document does not provide specific ratios, dosages, or application rate data for fosinopril + propranolol or fosinopril alone.

[0004] The inventors of this invention have discovered that, for the combination of ACEi and propranolol used to treat hemangiomas, the ACEi should be present in a much lower molar amount than propranolol. This was unexpected and makes it possible to formulate treatments using relatively low amounts of ACEi, thus helping to reduce the risk of undesirable systemic absorption.

[0005] definition

[0006] The terms “comprising” or “having”, when used in connection with one or more features in this document, should not be considered as excluding the selection of additional, unmentioned features. The same applies to derived terms such as “comprising” and “having”.

[0007] When referring to propranolol and fosinopril, the molecules themselves and all their pharmaceutically acceptable salts should be included. If the weights of propranolol and fosinopril are given, the weights cited should be considered proportionally increased to account for the additional mass of the salt component, i.e., the same amount of base should be given.

[0008] For example, 1 mol of propranolol weighs 259.3 g and can be considered substantially equivalent to 1 mol of propranolol hydrochloride weighing 295.8 g. Therefore, claims concerning 1% wt of "propranolol" should be considered sufficiently broad to cover 1.14% wt of propranolol hydrochloride, etc.

[0009] As another example, 1 mol of fosinopril weighs 563.7 g and can be considered substantially equivalent to 1 mol of fosinopril sodium, which weighs 585.6 g. Therefore, the claims concerning 1% wt of "fosinopril" should be considered broad enough to cover 1.04% wt of fosinopril sodium, etc.

[0010] Unless the context otherwise requires, the term hemangioma as used in this specification refers to all forms of the condition. This term includes, but is not limited to, infantile hemangioma, cutaneous hemangioma, capillary hemangioma, lobular capillary hemangioma, pyogenic granuloma, cavernous hemangioma, retinal hemangioma (including, for example, retinal cavernous hemangioma, retinal capillary hemangioma, choroidal hemangioma, orbital cavernous hemangioma), and / or periorbital hemangioma.

[0011] The term "topical treatment" as used herein preferably means application to the skin, but may also optionally mean application to the eyes, such as as an ointment or eye drops.

[0012] When the term “about” or “approximately” is used to define a numerical value in the “Summary of the Invention” or “Claims”, it means ± 0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% of the stated value. Summary of the Invention

[0013] The first aspect – medicine

[0014] According to a first aspect of the invention, a medicament for the local treatment of hemangiomas is provided, comprising propranolol and fosinopril in a molar ratio of 2:0.9-1.3.

[0015] Optionally, the molar ratio of propranol to fosinopril is 2 to 1 to 1.2.

[0016] Optionally, the molar ratio of propranol to forosine is 2 to approximately 1.

[0017] Optionally, the molar ratio of propranol to forosine is 2 to 1.

[0018] Optionally, the drug comprises about 0.1% to about 5% by weight of propranolol and about 0.1% to about 5% by weight of fosinopril.

[0019] Optionally, the drug comprises about 0.5% to about 5% by weight of propranolol and about 0.5% to about 5% by weight of fosinopril.

[0020] Optionally, the drug comprises about 1% to about 5% by weight propranolol and about 1% to about 5% by weight fosinopril.

[0021] Optionally, the drug comprises about 1% propranolol by weight and about 1.1% fosinopril by weight.

[0022] Optionally, the drug comprises about 1.5% to about 4.5% by weight of propranolol and about 1.5% to about 4.5% by weight of fosinopril.

[0023] Optionally, the drug comprises about 2% to about 4% by weight propranolol and about 2% to about 4% by weight fosinopril.

[0024] Optionally, the drug comprises about 2.5% to about 3.5% by weight of propranolol and about 2.5% to about 3.5% by weight of fosinopril.

[0025] Optionally, the drug comprises approximately 3% by weight propranolol and approximately 3% by weight fosinopril.

[0026] Optionally, the drug comprises about 0.9% by weight propranolol and about 1% by weight fosinopril.

[0027] Optionally, the drug comprises about 1% by weight propranolol hydrochloride and about 1% by weight fosinopril sodium.

[0028] Optionally, the drug is in the form of a topical wash, cream, ointment, or gel.

[0029] Optionally, the drug comprises a carrier, an emulsifier, and a preservative.

[0030] Optionally, the drug comprises a cream having the following components:

[0031] a) Propranolol hydrochloride;

[0032] b) Fosinopril sodium;

[0033] c) Moisturizer;

[0034] d) Emulsifiers;

[0035] e) Buffer;

[0036] f) Moisturizer;

[0037] g) Preservatives;

[0038] h) chelating agents; and

[0039] i) Water.

[0040] Optionally, the drug comprises a cream having the following components:

[0041] a) Propranolol hydrochloride

[0042] b) Fosinopril sodium

[0043] c) Liquid paraffin

[0044] d) Cetyl alcohol

[0045] e) Isopropyl myristate

[0046] f) Sorbitol (70%)

[0047] g) Glyceryl stearate

[0048] h) PEG-40 stearate

[0049] i) Citric acid

[0050] j) Potassium sorbate

[0051] k) Sodium hydroxide

[0052] l) Disodium EDTA

[0053] m) water

[0054] Optionally, the drug comprises a cream having the following ingredients and amounts—

[0055]

[0056] Optionally, the drug comprises the following components:

[0057] a) Propranolol hydrochloride;

[0058] b) Fosinopril sodium;

[0059] c) Vitamin E;

[0060] d) Isopropyl palmitate;

[0061] e) Liquid paraffin;

[0062] f) White beeswax;

[0063] g) White petrolatum;

[0064] Optionally, the drug comprises any one of the following three components:

[0065]

[0066] Optionally, the drug is not essential for local treatment and / or for treating hemangiomas.

[0067] The options in the first aspect above can be implemented individually or in any combination thereof.

[0068] The second aspect – its use in manufacturing

[0069] According to a second aspect, the present invention includes the use of propranolol and fosinopril in the preparation of a medicament according to any one of the pharmaceutical descriptions of the first aspect above, said medicament being used for topical application to a human patient to treat hemangioma.

[0070] Optionally, the hemangioma includes infantile hemangioma.

[0071] Optionally, the drug is applied to hemangiomas at a ratio of 150 mg to 1,500 mg of propranolol and 150 mg to 1,500 mg of fosinopril per dosing event.

[0072] Optionally, the drug is applied to the hemangioma at one or more of the following rates, or at rates equivalent to one or more of the following:

[0073] a) 1 FTU for face and neck;

[0074] b) 1 FTU for use in the arm and hand;

[0075] c) 1.5 FTU for legs and feet;

[0076] d) 1 FTU for use in the chest and stomach; and

[0077] e) 1.5 FTU for back and hips.

[0078] The options in the second aspect above can be implemented individually or in any combination thereof.

[0079] The third aspect – treatment methods

[0080] According to a third aspect, the present invention is a method for treating hemangiomas in human subjects, comprising applying locally to the hemangioma a drug as described in any of the drugs in the first aspect above.

[0081] Optionally, the hemangioma includes infantile hemangioma.

[0082] Optionally, the drug is applied to hemangiomas at a ratio of 150 mg to 1,500 mg of propranolol and 150 mg to 1,500 mg of fosinopril per dosing event.

[0083] Optionally, the drug is applied to the hemangioma at one or more of the following rates, or at rates equivalent to one or more of the following:

[0084] a) 1 FTU for face and neck;

[0085] b) 1 FTU for use in the arm and hand;

[0086] c) 1.5 FTU for legs and feet;

[0087] d) 1 FTU for use in the chest and stomach; and

[0088] e) 1.5 FTU for back and hips.

[0089] The options in the first aspect above can be implemented individually or in any combination thereof.

[0090] Fourth aspect

[0091] According to a fourth aspect, the present invention is a pharmaceutical composition for topical use comprising propranolol and fosinopril in molar ratios or by weights as described in the first aspect. Attached Figure Description

[0092] Some preferred embodiments of the invention will now be described by way of examples and with reference to the accompanying drawings / figures, wherein—

[0093] Figure 1 This is a graphic representation of the efficacy and cytotoxicity test results of various ACEis used on infantile hemangioma cell lines;

[0094] Figure 2 This is a graphic representation of the efficacy test results of various ACEi at high concentrations when used against infantile hemangioma cell lines;

[0095] Figure 3 This is a graphic representation of the efficacy test results of propranolol against hemangioma cell lines when used in a 2:1 molar ratio with ACEi fosinopril, and a comparison of this combination with the two active agents alone;

[0096] Figure 4 This is a diagram illustrating the efficacy results of propranolol + fosinopril at various ratios against infantile hemangioma cell lines;

[0097] Figure 5This is a graph showing the results of a skin penetration test, displaying the percentage of fosinopril in a formulation containing salts of fosinopril and propranolol.

[0098] Figure 6 This is a diagram of the skin penetration test results, showing the weight of fosinopril in a formulation containing salts of fosinopril and propranolol.

[0099] Figure 7 This is a diagram of the skin penetration test results, showing the percentage of propranolol in formulations containing salts of fosinopril and propranolol.

[0100] Figure 8 This is a diagram of the skin penetration test results, showing the weight of propranolol in a formulation containing salts of fosinopril and propranolol. Detailed Implementation

[0101] Comparison of fosinopril with other ACE inhibitors

[0102] A series of studies have been conducted to develop drug combinations for the local treatment of hemangiomas in human subjects, such as infantile hemangiomas. These studies involved evaluating both inhibitory effects on cell proliferation and cytotoxicity using the MTS cell proliferation assay model with patient-derived primary hemangioma cell lines.

[0103] These studies were conducted in vitro using primary hemangioma cell lines derived from excised human patient tissue (n=14). All tissues were obtained during the proliferative phase of infantile hemangiomas as assessed by pathologists, and each cell line was evaluated / characterized to confirm its hemangioma phenotype, as indicated by the expression of surface CD31 (a marker of endothelial cells).

[0104] The tests also involved growth cells isolated from patients with infantile hemangiomas. These cells were passaged up to six times in vitro. To test drug efficacy, cells were grown in Biolamin 521-coated tissue culture flasks and then placed in Biolamin-coated 96-well plates. The assays were performed by adding one dose of the drug at the start of the culture process, or by administering the drug daily for up to three days, and cell growth rate was measured using MTS on day 3. Inhibition of cell growth in the culture (measured by metabolic output) was compared to growth in wells without the drug or with the active drug component.

[0105] The assay initially tested the effectiveness of the following drugs:

[0106] a) Captopril;

[0107] b) Remipril;

[0108] c) Lisinopril;

[0109] d) Group Doppler;

[0110] e) Quinapril;

[0111] f) Fossipry; and

[0112] g) Captopril.

[0113] refer to Figure 1 and 2 Besides lisinopril, all ACE inhibitors were found to inhibit hemangioma cell growth. However, fosinopril was found to be surprisingly more effective than other drugs, with negligible cytotoxicity, producing near-100% inhibition even at significantly lower concentrations than other ACE inhibitors. Fosinopril also showed surprising efficacy compared to propranolol (often considered the "standard of care" for this disease). Further evaluation of MTT data, such as... Figure 2 As shown, even at high concentrations, the performance of ACEi ramipril, lisinopril, quinapril, and quinapril is not as good as that of fosinopril at low concentrations.

[0114] The optimal ratio of propranolol + ACEI

[0115] The inventors also used MTS (a measurement similar to MTT, but without dissolving the crystal before readout) data to investigate the efficacy of various dose / ratio combinations of propranolol and ACE inhibitors. In this regard, 0-150 µM propranolol and 0-600 µM ACE inhibitors selected from fosinopril, trandopril, ramipril, or quinapril were administered to primary hemangioma cell lines. The results showed that the following ratios were optimal for each pair, with substantially similar efficacy.

[0116]

[0117] As mentioned above, surprisingly, fosinopril yielded the best results when the ACEi was significantly less than propranolol compared to other ACEi. For other ACEi, the ratio relationship was the opposite.

[0118] While not wishing to be bound by theory, it is hypothesized that the superior results of the combination of fosinopril and propranolol are related to the presence of a phosphate group in fosinopril. It is noteworthy that the other tested ACEis do not possess a phosphate group.

[0119] 2:1 Propranolol + Fosinopril

[0120] refer to Figure 3Using the MTS assay, the same infantile hemangioma cell lines derived from 14 individual patients were used to further test the 2:1 ratio of propranolol to fosinopril, comparing the 2:1 molar combination of propranolol and fosinopril with the individual active ingredients.

[0121] As mentioned above, propranolol at a 2:1 molar ratio is significantly more effective than fosinopril at an equivalent dose, and even more effective than propranolol at an equivalent dose.

[0122] This indicates that, compared to at least one ACE inhibitor, the use of a 2:1 propranolol-fosinopril combination results in a lower risk of systemic and cytotoxic adverse events due to the need for only a smaller amount of ACE inhibitor. The lower amount of ACE inhibitor also benefits manufacturing in terms of handling and cost. Furthermore, the ability to use fewer ACE inhibitors helps reduce the likelihood of adverse events related to cytotoxicity and cardiovascular health in patients.

[0123] Other ratios of propranolol + fosinopril

[0124] For comparison, the inventors conducted further MTS tests to investigate the substitution molar ratio of propranolol + fosinopril. The results are as follows... Figure 4 As shown, it illustrates the region of maximum synergy between propranolol and fosinopril and the boundary where the synergistic effect decreases.

[0125] As shown in the figure, the optimal molar ratio range was found to be 3.3:1 to 2:1 for propranolol:fosinopril. More preferably, the optimal molar ratio range for propranolol to fosinopril was found to be approximately 2.5:1 to approximately 2:1.

[0126] formulation excipients

[0127] In a preferred embodiment of the invention, the drug is in the form of a lotion, cream, ointment or gel for topical application to human skin affected by hemangioma, and the drug contains propranolol and fosinopril in the same formulation.

[0128] The drug may include one or more of water and liquid paraffin as a solvent or carrier.

[0129] The drug may include one or more of liquid paraffin and isopropyl myristate as a skin conditioning agent or emollient.

[0130] The drug may include one or more of cetyl alcohol, glyceryl stearate, PEG 100 stearate and PEG 40 stearate as emulsifiers.

[0131] The drug may include potassium sorbate as a preservative.

[0132] The drug may include sorbitol as a moisturizer.

[0133] The drug may include one or more of citric acid and sodium hydroxide as a buffer.

[0134] The drug may include disodium EDTA as a chelating agent.

[0135] It is not necessary to use all of the above-mentioned excipients; the excipients used can be combined in any way. Preferably, all the excipients used and the resulting formulation are suitable for pediatric use.

[0136] A preferred embodiment of the present invention comprises the following topical formulation—

[0137]

[0138] For the above formulations, in order to obtain the best results, the active ingredient should be mixed into the oil-based component before adding water.

[0139] While propranolol and fosinopril are preferably in the same lotion, cream, or gel, in other embodiments, the drugs may be formulated as separate lotions, creams, or gels, for example, in the same package.

[0140] Application rate

[0141] Optionally, the drug comprises about 0.1% to about 5% by weight of propranolol and about 0.1% to about 5% by weight of fosinopril, provided that the molar ratio is about 2 propranolol to 0.9-1.3 fosinopril.

[0142] Preferably, the drug is applied to the hemangioma at a ratio of 150 mg to 1,500 mg of propranolol and 150 mg to 1,500 mg of fosinopril per dosing event.

[0143] Optionally, the drug is applied to the hemangioma at one or more of the following rates, or at rates equivalent to one or more of the following rates, especially in the case of infants / children:

[0144] a) 1 FTU for face and neck;

[0145] b) 1 FTU for use in the arm and hand;

[0146] c) 1.5 FTU for legs and feet;

[0147] d) 1 FTU for use in the chest and stomach; and

[0148] e) 1.5 FTU for back and hips.

[0149] The term "FTU" stands for "fingertip unit," or in other words, the amount of medication that an adult fingertip typically carries when fully loaded with the medication. One FTU contains approximately 450 mg to 550 mg of medication, and preferably approximately 500 mg of medication.

[0150] Skin penetration test

[0151] The following formulations were prepared for in vitro skin permeability testing.

[0152]

[0153] The viscosity of each formulation at room temperature and the particle size distribution of the two surfactant combinations under each condition are as follows:

[0154]

[0155] Skin samples were obtained from a 69-year-old Black male donor and, in accordance with ICH guidelines, permeation tests were performed using the LOGAN Dry Heating Transdermal Diffusion System, based on the following parameters.

[0156]

[0157] These tests are conducted to determine the ability of these formulations to deposit and retain the active ingredients in the skin, which is precisely where these active ingredients are located for optimal treatment of hemangiomas—meaning that excessive amounts of the active ingredients should not penetrate the skin and enter the bloodstream. Understandably, it is generally undesirable for ACE inhibitors (such as fosinopril) or beta-blockers (such as propranolol) to enter the bloodstream to the extent that they could adversely affect the heart or other bodily functions.

[0158] refer to Figure 5 and 6 These figures show the percentage and weight of fosinopril that can penetrate the skin and remain in each layer of the skin in each formulation. Figure 7 and 8 Similar data on propranolol were provided in a similar manner. For optimal treatment of hemangiomas, the preferred active agent is located within the epidermis and dermis (the key layers).

[0159] like Figure 5 and 6As shown, compared to the higher concentrations of formulations B and C (2.5% and 5%), formulations A and D (1%) at lower concentrations were found to deliver a higher proportion of fosinopril to the critical layer of the skin. For example, 1% formulation A delivers approximately 89% of the fosinopril to the critical layer as 2% formulation B, even though the concentration of formulation A is only half that of the latter. Furthermore, 1% formulation A delivers approximately 54% of the fosinopril to the critical layer as 5% formulation C, even though the concentration of formulation A is only one-fifth that of the latter.

[0160] like Figure 7 and 8 As shown, a higher proportion of propranolol was found in the critical layer of the skin for the low-concentration 1% formulation A compared to the higher concentrations of 2.5% and 5% formulations (B and C). For example, 1% formulation A delivered approximately 81% of the propranolol to the critical layer as 2% formulation B, even though the concentration of formulation A was only half that of the latter. Furthermore, 1% formulation A delivered approximately 80% of the propranolol to the critical layer as 5% formulation C, even though the concentration of formulation A was only one-fifth that of the latter.

[0161] The results showed that a 1:1 molar ratio combination can be formulated at lower concentrations without compromising the ability of fosinopril and propranolol to reach the critical layers in sufficient quantities. This helps to avoid the risk of side effects caused by unnecessary large amounts of active agents entering the bloodstream.

[0162] Miscellaneous

[0163] While some forms of the invention have been described by way of example, it should be understood that modifications and improvements may be made without departing from the scope of the appended claims.

[0164] For the purposes of disclosure, this document contemplates and thereby presupposes any feature mentioned herein in combination with itself (e.g., two identical features) or any other feature mentioned herein, even if such combination is not claimed above.

Claims

1. A drug for the local treatment of hemangiomas, comprising propranolol and fosinopril in a molar ratio of 2 to 0.9-1.

3.

2. The drug according to claim 1, wherein the molar ratio of propranolol to fosinopril is 2:1-1.

2.

3. The drug according to claim 1, wherein the molar ratio of propranolol to fosinopril is 2 to approximately 1.

4. The drug according to claim 1, wherein the molar ratio of propranolol to fosinopril is 2 to 1.

5. The medicament according to any one of the preceding claims, comprising about 0.1% to about 5% by weight propranolol and about 0.1% to about 5% by weight fosinopril.

6. The medicament according to any one of the preceding claims, comprising about 0.5% to about 5% by weight propranolol and about 0.5% to about 5% by weight fosinopril.

7. The medicament according to any one of the preceding claims, comprising about 1% to about 5% by weight propranolol and about 1% to about 5% by weight fosinopril.

8. The medicament according to any one of claims 1 to 4, comprising about 1.5% to about 4.5% by weight propranolol and about 1.5% to about 4.5% by weight fosinopril.

9. The medicament according to any one of claims 1 to 4, comprising about 2% to about 4% by weight propranolol and about 2% to about 4% by weight fosinopril.

10. The medicament according to any one of claims 1 to 4, comprising about 2.5% to about 3.5% by weight propranolol and about 2.5% to about 3.5% by weight fosinopril.

11. The medicament according to any one of claims 1 to 4, comprising about 3% propranolol by weight and about 3% fosinopril by weight.

12. The medicament according to any one of claims 1 to 4, comprising about 0.9% by weight propranolol and about 1% by weight fosinopril.

13. The medicament according to any one of claims 1 to 4, comprising about 1% propranolol by weight and about 1.1% fosinopril by weight.

14. The medicament according to any one of claims 1 to 4, comprising about 1% by weight propranolol hydrochloride and about 1% by weight fosinopril sodium.

15. The medicament according to any one of the preceding claims, wherein it is in the form of a topical lotion, cream, ointment or gel.

16. The medicament according to any one of the preceding claims, comprising a carrier, an emulsifier, and a preservative.

17. The medicament according to claim 1, comprising a cream having the following components: a) Propranolol hydrochloride; b) Fosinopril sodium; c) Emollients; d) Emulsifiers; e) Buffer; f) Moisturizer; g) Preservatives; h) chelating agents; and i) Water.

18. The medicament according to claim 1, comprising a cream having the following components: a) Propranolol hydrochloride; b) Fosinopril sodium; c) Liquid paraffin; d) Hexadecyl alcohol; e) Isopropyl myristate; f) Sorbitol (70%); g) Glyceryl stearate; h) PEG-40 stearate; i) Citric acid; j) Potassium sorbate; k) Sodium hydroxide; l) Disodium EDTA; m) water.

19. The medicament according to claim 1, comprising a cream having the following components and amounts:

20. The medicament according to claim 1, comprising the following components: a) Propranolol hydrochloride; b) Fosinopril sodium; c) Vitamin E; d) Isopropyl palmitate; e) Liquid paraffin; f) White beeswax; g) White petrolatum.

21. The medicament according to claim 1, comprising any one of the following three components:

22. Use of propranolol and fosinopril in the preparation of a medicament according to any one of the preceding claims, the medicament being used to treat hemangiomas by topical application.

23. The use according to claim 22, wherein the hemangioma comprises an infantile hemangioma.

24. The use according to claim 22 or 23, wherein the drug is applied to the hemangioma at one or more of the following rates or equivalent to one or more of the following rates: a) 1 FTU for face and neck; b) 1 FTU for use in the arm and hand; c) 1.5 FTU for legs and feet; d) 1 FTU for use in the chest and stomach; and e) 1.5 FTU for back and hips.

25. A method for treating a hemangioma in a human subject, comprising applying topically to the hemangioma the drug according to any one of claims 1 to 21.

26. The method of claim 25, wherein the hemangioma comprises an infantile hemangioma.

27. The method according to claim 25 or 26, wherein the drug is applied to the hemangioma at one or more of the following rates or equivalent to one or more of the following rates: a) 1 FTU for face and neck; b) 1 FTU for use in the arm and hand; c) 1.5 FTU for legs and feet; d) 1 FTU for use in the chest and stomach; and e) 1.5 FTU for back and hips.

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