Oral pharmaceutical composition, medicament for treatment of androgenetic alopecia, use and method for treatment of androgenetic alopecia

Abstract

The present invention refers to an oral pharmaceutical composition comprising minoxidil having controlled particle size for the treatment of androgenetic alopecia, as well as a medicament, methods for treatment and associated uses.

Description

ORAL PHARMACEUTICAL COMPOSITION, MEDICAMENT FOR TREATMENT OF ANDROGENETIC ALOPECIA, USE AND METHOD FOR TREATMENT OF ANDROGENETIC ALOPECIAField of the invention

[0001] The present invention relates to an oral pharmaceutical composition comprising minoxidil having controlled particle size for the treatment of androgenetic alopecia, as well as related medicaments, uses and methods of treatment.Background of the Invention

[0002] The life cycle of each hair strand is marked by anagen (growth), catagen (transition) and telogen (shedding) phases, which can last from 2 to 10 years. Therefore, hair loss is daily and constant in accordance with this natural process of continuous renewal.

[0003] Baldness is a condition associated with permanent hair loss, which affects men and women, at different ages.

[0004] The two main causes of permanent hair loss are heredity and male hormones. Both promote the atrophy of hair follicles (bulbs) and accelerate permanent hair loss.

[0005] The others are excess oiliness, typical of seborrheic dermatitis, excessive application of chemical products, thyroid disorders, poor diet, vitamin deficiency, certain medicaments, stress, etc.

[0006] In general, this condition has been treated by the use of topical local products (including creams and lotions), use of low-penetration laser, electrostimulation, intradermotherapy, microneedling and even drug microinfusion. As a last resort, it has become increasingly common to seek hair transplantation. Some of these treatments are the subject of constant reports of local pain or discomfort for long periods.

[0007] Drug treatment is also not yet efficient, and is typically carried out with medicaments that cause undesirable side effects, such as decreased libido, breast enlargement, impotence and ejaculation problems, among others.

[0008] Minoxidil is a drug capable of reducing blood pressure by promoting potent and long-lasting vasodilation. Its hypotensive action was described in the patent US3382247 by Upjohn Co, published in 1968, and had a significant impact on the treatment of arterial hypertension, as it works in more aggressive cases of the disease.

[0009] Since it causes hirsutism, its use in the treatment of baldness has also been sought over the years. The most commonly used route of administration is topical, and can be in drops, spray or foam. This means that the product needs to be applied directly to the scalp, on the area affected by hair loss, at least once a day, for an indefinite period of time. This route of application is often the target of complaints from patients, due to the smell, the general appearance of the hair after use or even the daily time spent on the application process.

[0010] Alternatives for oral application have also been developed, generally with some caution, due to the need for adequate adjustment of the dose to be administered.

[0011] The international publication WO2016065426, by Samson Clinical Pty Ltd., discloses the use of minoxidil, in a concentration between 0.1 mg and 20 mg, for oral administration, in tablet form, to treat telogen effluvium.

[0012] The international publication WO2019010535, also from Samson Clinical Pty Ltd., discloses an orodispersible composition of minoxidil for sublingual use.

[0013] However, despite being desirable and efficient in the treatment of baldness, precautions still need to be taken when administering this active ingredient orally. This is because minoxidil is an active ingredient with hypotensive action and high doses can cause unwanted side effects, favoring heart problems.

[0014] Thus, there is still a need for new oral pharmaceutical compositions of minoxidil, which guarantee the desired effect of hypertrichosis with efficacy and safety based on dose regularity and with reduced side effects.Summary of the Invention

[0015] The present invention aims to provide oral pharmaceutical compositions of minoxidil, which present dose regularity, administration safety and control of side effects.

[0016] The pharmaceutical compositions, medicaments, uses and methods of treatment associated with the pharmaceutical composition according to the present invention are also objects of the present invention.Detailed Description of the Invention

[0017] Surprisingly, it was observed that controlling the particle size of minoxidil allows for the production of tablets with lower dosages, which are suitable for the treatment of androgenetic alopecia (baldness), ensuring uniformity of doses throughout the treatment and control of side effects associated with the hypotensive effect of the active ingredient.

[0018] During its development, it was comparatively evident that medicaments with an active pharmaceutical ingredient (API) in an uncontrolled particle size range did not present satisfactory results in terms of content uniformity and, consequently, would affect the efficacy and safety of the treatment.

[0019] The efficacy and safety problem that, for years, prevented providing an efficient oral minoxidil medicament for the treatment of alopecia was solved by controlling the particle size of the API.

[0020] Therefore, according to the present invention, the particle size of minoxidil (d90) should be between a range of about 50 µm and about 250 µm, particularly about 75 µm and about 180 µm, ensuring uniformity of content to the pharmaceutical compositions thus obtained.

[0021] Hence, the pharmaceutical compositions according to the present invention comprise from about 0.25 to about 10 mg of minoxidil, particularly about 2.5 of mg minoxidil, with particle size (d90) ranging from about 50 µm to about 250 µm, particularly about 75 µm to about 180 µm, and pharmaceutically acceptable excipients.

[0022] According to a particular embodiment of the present invention, the pharmaceutical compositions are provided in tablet or capsule form, particularly in tablet form, prepared with excipients from the class of glidants, diluents, disintegrants, colorants and / or lubricants. In a preferred embodiment, the excipients are selected from colloidal silicon dioxide, microcrystalline cellulose, sodium starch glycolate, mannitol, magnesium stearate and / or mixtures thereof.

[0023] In another embodiment, the present invention also relates to the uses and methods of treatment associated with the composition according to the present invention and medicaments prepared therefrom, in the form of tablets or capsules, particularly in the treatment of androgenetic alopecia.Examples

[0024] The examples shown herein are intended to illustrate some of the numerous ways of carrying out the invention, without limiting its scope, and are intended to assist in proving the technical effect, directly and comparatively.

[0025] Example 1 – Pharmaceutical compositions according to the present invention

[0026] [Table 1]. Composition of 0.5% minoxidil.IngredientBy (mg)%Minoxidil0.5000.500Colloidal silicon dioxide1.0001.000Microcrystalline cellulose ph102 fr 10.2500.250Microcrystalline cellulose ph102 fr 20.2500.250Microcrystalline cellulose ph102 fr 30.5000.500Microcrystalline cellulose ph102 fr 42.5002.500Microcrystalline cellulose ph102 fr 54.8404.840Microcrystalline cellulose ph102 fr 65.0005.000Microcrystalline cellulose ph102 fr 75.0005.000Microcrystalline cellulose ph102 fr 85.0005.000Colorant Red iron oxide0.1000.100Sodium starch glycolate2.0002.000Mannitol ezspray dried26.00026.000Mannitol ezspray dried45.06045.060Magnesium stearate from plant2.0002.000

[0027] [Table 2]. Composition of 1% minoxidil.Raw materialsBy (mg)%Minoxidil1.0001.000Colloidal silicon dioxide1.0001.000Microcrystalline cellulose ph102 fr 10.5000.250Microcrystalline cellulose ph102 fr 20.5000.250Microcrystalline cellulose ph102 fr 32.0000.500Microcrystalline cellulose ph102 fr 45.0002.500Microcrystalline cellulose ph102 fr 510.0004.840Microcrystalline cellulose ph102 fr 65.3405.000Colorant Blue fdc 2 lacquer0.1000.100Sodium starch glycolate2.0002.000Mannitol ezspray dried14.50014.500Mannitol ezspray dried40.00040.000Mannitol ezspray dried16.06016.060Magnesium stearate from plant2.0002.000

[0028] [Table 3]. Composition of 2.5% minoxidil.Raw materialsBy (mg)%Minoxidil2.5002.500Colloidal silicon dioxide1.0001.000Microcrystalline cellulose ph102 fr 12.5002.500Microcrystalline cellulose ph102 fr 25.0005.000Microcrystalline cellulose ph102 fr 310.00010.000Microcrystalline cellulose ph102 fr 45.8405.840Sodium starch glycolate2.0002.000Mannitol ezspray dried13.16013.160Mannitol ezspray dried56.00056.000Magnesium stearate from plant2.0002.000

[0029] [Table 4]. Composition of 5.0% Minoxidil.Raw materialsBy (mg)%Minoxidil5.0005.000Colloidal silicon dioxide1.0001.000Microcrystalline cellulose ph102 fr 15.0005.000Microcrystalline cellulose ph102 fr 210.00010.000Microcrystalline cellulose ph102 fr 38.3408.340Sodium starch glycolate2.0002.000Mannitol ezspray dried13.16013.160Mannitol ezspray dried53.50053.500Magnesium stearate from plant2.0002.000

[0030] For the preparation of the compositions of the invention, a bin mixer was used, comprising mixing the ingredients and fractions as defined in the tables above. A person skilled in the art is capable of carrying out the composition of the invention based on common knowledge of the state of the art.

[0031] For descriptive purposes only, the steps for preparing a 0.5 mg Minoxidil composition are exemplified below.1. In a plastic bag, manually mix microcrystalline cellulose PH102 FR 1, microcrystalline cellulose PH102 FR 2 and Minoxidil;2. Add the items obtained in step 1 to the bin mixer and add the microcrystalline cellulose PH102 FR 3 and colloidal silica dioxide, mixing for 10 minutes;3. Add microcrystalline cellulose PH102 FR 4 to the bin and mix it for 10 minutes;4. Sort the items red iron colorant and microcrystalline cellulose PH102 FR 5 into 60 mesh and add them to the bin mixer, mixing for 10 minutes;5. Sort the following items into a smooth 1.0 mm mesh: microcrystalline cellulose PH102 FR 6 and microcrystalline cellulose PH102 FR 7, and add them to the bin mixer and mix for 15 minutes;6. Sort the items sodium starch glycolate and microcrystalline cellulose PH102 FR 8 into a smooth 1.0 mm mesh, adding them to the bin mixer and mixing for 15 minutes;7. Sort the item Mannitol EZ Spray Dried into 1.0 mm smooth mesh, add to the bin mixer and mix for 15 minutes;8. Sort the item Mannitol EZ Spray Dried into 1.0 mm smooth mesh, add to the bin mixer and mix for 15 minutes;9. Sort the magnesium stearate item into 1.0 mm smooth mesh, add to the bin mixer and mix for 3 minutes; and10. Compress the mixture obtained in the previous item.Example 2. Uniformity test

[0032] For the proposed product, in which the unit dose corresponds to less than 25% of the average weight of the product, the content uniformity test is applied.

[0033] The test was carried out by analyzing 10 units individually. This way, the content result of each tablet was determined.

[0034] The individual content results obtained are evaluated for their variability and the acceptance value (VA) is determined, according to calculations described in the pharmacopoeias known in the state of the art.

[0035] The higher the VA value, the greater the variability in content between individual tablets. The maximum permitted limit for VA is 15, which is a parameter for evaluating the production process and, therefore, indicative of the quality of the final product produced.

[0036] As shown in Table 5, with state-of-the-art particle size minoxidil, throughout the entire production process (beginning, middle and end), the final product fails in terms of content uniformity (VA > 15) and, therefore, does not present adequate quality.

[0037] In contrast, batches produced with minoxidil having a particle size according to the present invention are approved (VA < 15) and meet the quality requirements for a final product.

[0038] The results obtained indicate a direct correlation between the API particle size and the test of content uniformity, which is therefore essential for the production of the proposed medicament with adequate quality.

[0039] To ensure that correct doses are administered, each unit in a batch of a pharmaceutical product must contain an amount of the active ingredient close to the declared amount.

[0040] The test of unit dose uniformity makes it possible to evaluate the amount of active component in individual units of the batch and verify whether this amount is uniform in the units tested.

[0041] [Table 5]. Uniformity test with state-of-the-art particle size – 0.5 mg minoxidil – coated tablet.Unit%Start batch%Middle batch%Final batch190.385.988.4298.7121.2108.2393.585.198.6496.285.998.9598.189.1105.0692.8107.186.57100.089.1108.3890.294.993.3987.491.2108.21094.4109.785.1Mean94.295.998.0Standard Deviation4.112.49.3%DPR4.3912.959.47VA143223

[0042] [Table 6] Uniformity test with particle size according to the present invention – 0.5 mg minoxidil – coated tablet.Unit%Start batch%Middle batch%Final batch199.7102.2101.02104.997.3102.8393.698.493.04100.498.094.25100.1105.099.96101.397.7101.3796.596.7102.5898.2100.2100.8999.598.699.01094.099.498.7Mean98.899.499.3Standard Deviation3.42.63.3%DPR3.442.573.32VA868

[0043] The dose uniformity was tested at higher dosages using the particle size of the present invention.

[0044] [Table 7]. Uniformity test with particle size according to the present invention – 2.5 mg minoxidil and 5.0 mg minoxidil – coated tablet.Unit24D0316 (2.5mg)24D0347 (5.0mg)198.0102.7299.7102.53106.9106.4498.6103.75101.7105.86101.5110.47101.598.58103.3104.69104.3103.110101.3105.3Mean101.7104.3DPR%2.63.0VA710

[0045] [Table 8]. Uniformity Test – data calculated for batches 24D0316 (2.5mg) and 24D0347 (5.0mg) according to the previous table.BatchContent (%)UniformityAverageVA24D0316 (2.5mg)102.1101.7724D0347 (5.0mg)102.7104.310Content Specification: Between 90% and 110%

[0046] Uniformity Specification: VA < 15

[0047] As can be seen, satisfactory results are also obtained with higher dosages. Thus, the particle size of the present invention is an indispensable parameter for the production of uniform and commercially viable batches.

[0048] Those skilled in the art will appreciate the knowledge presented herein, which allows the invention to be reproduced in the embodiments presented and in other variants, covered by the scope of the attached claims.

Claims

ORAL PHARMACEUTICAL COMPOSITIONcharacterizedby the fact that it comprises minoxidil with particle size (d90) ranging from 50 µm to 250 µm and pharmaceutically acceptable excipients.ORAL PHARMACEUTICAL COMPOSITION, according to claim 1,characterizedby the fact that it comprises minoxidil with particle size (d90) ranging from 75 µm to 180 µm and pharmaceutically acceptable excipients.PHARMACEUTICAL COMPOSITION, according to claim 1,characterizedby the fact that it comprises pharmaceutically acceptable excipients from the class of glidants, diluents, disintegrants, dyes, lubricants or mixtures thereof.PHARMACEUTICAL COMPOSITION, according to claim 3,characterizedby the fact that the pharmaceutically acceptable excipients are selected from colloidal silicon dioxide, microcrystalline cellulose, sodium starch glycolate, mannitol, magnesium stearate and / or mixtures thereof.PHARMACEUTICAL COMPOSITION, according to any one of claims 1 to 4,characterizedby the fact that it is in the form of tablets or capsules.PHARMACEUTICAL COMPOSITION, according to any one of claims 1 to 5,characterizedby the fact that it comprises from 0.25 to 10 mg of minoxidil.PHARMACEUTICAL COMPOSITION, according to claim 6,characterizedby the fact that it comprises 0.5 mg, 1 mg, 2.5 mg or 5 mg of minoxidil.MEDICAMENT FOR THE TREATMENT OF ANDROGENETIC ALOPECIAcharacterizedby the fact that it comprises the pharmaceutical composition as defined in any one of claims 1 to 7.USE of a pharmaceutical composition as defined in any one of claims 1 to 7,characterizedby the fact that it is in the preparation of a medicament useful in the treatment of androgenetic alopecia.METHOD FOR TREATMENT OF ANDROGENETIC ALOPECIAcharacterizedby the fact that it comprises administering a pharmaceutical composition as defined in any one of claims 1 to 7 to a patient in need thereof.