Novel long-acting injectable composition comprising finasteride for prevention or treatment of androgenetic alopecia

Abstract

The present invention relates to a novel long-acting injectable composition comprising finasteride for the prevention or treatment of androgenetic alopecia. The composition inhibits type II 5α-reductase with a single injection lasting over one month, thereby suppressing the conversion of testosterone to DHT and reducing androgen-mediated follicular miniaturization. In addition, after injection into the body, the average elimination half-life (T1 / 2el) of finasteride can be increased to enhance stability and provide more predictable and uniform therapeutic effects compared to oral formulations.

Description

Novel long-acting injectable composition comprising finasteride for the prevention or treatment of androgenetic alopecia

[0001] The present invention relates to a novel long-acting injectable composition comprising finasteride for the prevention or treatment of androgenetic alopecia.

[0002] In androgenetic alopecia, healthy hair gradually becomes thinner, shorter, and weaker, becoming brittle and easily broken—a phenomenon known as miniaturization. Miniaturized hair follicles eventually become thinner, less visible, and develop short, fine hairs, leading to hair loss. Accordingly, numerous studies have recently been published on the prevention and treatment of hair loss through the suppression of androgen activity.

[0003] Testosterone is converted into the active male hormone dihydrotestosterone (DHT) by 5α-reductase, and the activated dihydrotestosterone binds to the androgen receptor, delaying protein synthesis in hair follicle cells, shortening the growth phase of the hair follicle and causing atrophy of the hair follicle, resulting in hair loss.

[0004] Additionally, androgenetic alopecia can cause excessive sebum production, which can result in hair loss accompanied by inflammation on the scalp (Dennis A. Holt, et. al,. 1990).

[0005] Finasteride (Fi) and dutasteride, which are 5α-reductase inhibitors, are known to be effective in treating hair loss by inhibiting the conversion of testosterone into its active metabolite, dihydrotestosterone (DHT), by 5α-reductase.

[0006] Finasteride, a commercially available 5-alpha reductase inhibitor, is sold as an oral medication that must be taken daily. Therefore, daily use is essential to prevent finasteride-induced hair loss. If you stop taking it, the 5-alpha reductase inhibitor effect will cease, and hair loss symptoms may reappear.

[0007] To solve the above problems, it is necessary to develop a long-lasting formulation that can prevent and treat hair loss for more than one month with a single dose.

[0008] [Prior Art Literature]

[0009] [Patent Document]

[0010] KR 10-2021-0129565 A1

[0011] An object of the present invention is to provide a novel long-acting injectable composition comprising finasteride for the prevention or treatment of androgenetic alopecia.

[0012] Another object of the present invention is to provide a novel long-acting injectable composition comprising finasteride for the prevention or treatment of androgenetic alopecia, which inhibits type II 5α-reductase for more than one month with a single injection, thereby converting testosterone to DHT, and which can reduce androgen-mediated hair follicle miniaturization.

[0013] Another object of the present invention is to determine the average half-life (t) of finasteride after intravenous injection. 1 / 2el ) to provide a novel long-acting injectable composition comprising finasteride for the prevention or treatment of androgenetic alopecia, which can increase stability and exhibit more predictable and uniform therapeutic effects compared to oral formulations.

[0014] In order to achieve the above-described purpose, the present invention can be a novel long-lasting injectable composition for the prevention or treatment of androgenetic alopecia, which has a dosage of finasteride of 10 mg to 40 mg and suppresses androgen-mediated hair follicle miniaturization by finasteride for more than one month.

[0015] Additionally, the above injectable composition may be a subcutaneous injection (SC) formulation.

[0016] In addition, the average half-life (t) of finasteride in the body according to administration of the above injection composition 1 / 2el ) can be 100 to 160 hours.

[0017] In addition, the first-order absorption rate constant (Ka, h) of finasteride by the above injection composition -1 ) can be 0.0005 to 0.0015.

[0018] Additionally, the distribution volume (tvV, L) of finasteride in the central compartment of the above injection composition may be 500 to 1500.

[0019] Additionally, the volume of distribution (tvV2, L) of finasteride to the peripheral compartment by the above injection composition may be 0.1 to 0.5.

[0020] Additionally, the clearance rate (tvCL, L / h) of finasteride from the central compartment by the above injection composition may be 5 to 15.

[0021] Additionally, the clearance rate (tvCL2, L / h) between the central compartment and the peripheral compartment of finasteride by the above injection composition may be 0.005 to 0.015.

[0022] In addition, the maximum blood concentration (C) of finasteride by the above injection composition max , pg / mL) can be 500 to 3,000.

[0023] In addition, the average concentration (C) of finasteride at steady state by the above injection composition ss,avg, pg / mL) can be from 1,000 to 6,000.

[0024] In addition, the AUC (ACU) of finasteride from 0 to 672 hours by the above injection composition 0-672h , hr*pg / mL) can be 500,000 to 2,000,000.

[0025] Additionally, the AUC (AUCss, hr*pg / mL) of finasteride at steady state by the above injection composition may be 1,000,000 to 4,000,000.

[0026] The present invention proposes that testosterone is converted to DHT by inhibiting type II 5α-reductase for more than one month with a single injection, thereby reducing androgen-mediated hair follicle miniaturization.

[0027] Additionally, after intravenous injection, the average half-life of finasteride (t 1 / 2el ) can increase stability and exhibit more predictable and uniform therapeutic effects compared to oral formulations.

[0028] Figure 1 is a flowchart for selecting and assigning test participants according to one embodiment of the present invention.

[0029] FIG. 2 is a schematic diagram showing a test design according to one embodiment of the present invention.

[0030] FIG. 3 is an average blood concentration-time curve of IVL3001 and oral finasteride formulations according to one embodiment of the present invention.

[0031] [Revised 27.02.2025 under Rule 91] Figure 4 relates to estimated pharmacokinetic parameters according to a black model according to one embodiment of the present invention.

[0032] [Correction pursuant to Rule 91 dated February 27, 2025]

[0033] Figure 5 shows the baseline corrected DHT intermediate pharmacodynamic measurement results according to one embodiment of the present invention.

[0034] FIG. 6 relates to observed and predicted plasma DHT concentrations after a single administration of IVL3001 and oral finasteride formulations according to one embodiment of the present invention.

[0035] The present invention relates to a novel long-lasting injectable composition for the prevention or treatment of androgenetic alopecia, which comprises a dosage of finasteride of 10 mg to 40 mg and inhibits androgen-mediated hair follicle miniaturization by finasteride for more than one month.

[0036] Hereinafter, embodiments of the present invention will be described in detail so that those skilled in the art can easily implement them. However, the present invention may be implemented in various different forms and is not limited to the embodiments described herein.

[0037] Androgenetic alopecia (AGA), or male pattern hair loss (MPHL), is a genetic condition that affects approximately 50% of men over 50 years of age and a smaller percentage of women, but it remains an important genetic condition in women.

[0038] AGA is a common form of hair loss in adults of both men and women. Patients typically experience progressive thinning and shortening of the hair in the affected area. In men, this is typically characterized by patterned hair loss, with a receding hairline and baldness at the crown. However, in women, it is characterized by generalized hair thinning. This can be a source of psychological distress for both men and women, and is likely to be even more distressing for women.

[0039] Furthermore, the prognosis of AGA can significantly impair the quality of life of affected individuals. AGA is a condition caused by a combination of genetic predisposition and androgen effects on scalp hair follicles.

[0040] Currently, there are two medications approved by the U.S. Food and Drug Administration (FDA) for the treatment of AGA, one of which is finasteride. Men at risk for AGA have a high rate of testosterone conversion to dihydrotestosterone (DHT) within their hair follicles, a process involving type II 5a-reductase.

[0041] Finasteride, a synthetic antiandrogen, inhibits type II 5a-reductase, thereby limiting the conversion of testosterone to DHT and reducing androgen-mediated hair follicle miniaturization, which may have a positive effect on AGA patients. Given its short terminal half-life of 4 to 8 hours, finasteride has been tested in various doses. Previous reports have recommended a daily dose of 1 mg as the most effective for treating men with AGA.

[0042] Previous clinical studies using 1mg finasteride tablets showed a bioavailability of approximately 65%. Furthermore, finasteride's short half-life impacts its long-term effects, necessitating daily dosing to maintain the required therapeutic drug concentration. Therefore, the inconvenience of daily dosing is a significant drawback of existing finasteride dosage forms.

[0043] Long-acting injectables (LAIs) may offer advantages over oral administration in various medical contexts. Therefore, to overcome the shortcomings of oral finasteride, we developed a LAI formulation of microparticles containing finasteride, which can be administered subcutaneously (SC) to deliver finasteride into the body. The injectable composition of the present invention, administered SC, demonstrated efficacy in preventing testosterone-induced hair loss in an animal model, compared to daily oral finasteride administration. Specifically, finasteride-loaded microspheres enhanced the activity of phosphoinositide 3-kinase / protein kinase B and Wnt / β-catenin, stimulating hair follicle cell growth signaling in mouse skin. Furthermore, they downregulated the expression of transforming growth factor-β2 and caspase-3, thereby inhibiting hair follicle cell apoptosis.

[0044] However, in the above animal experiment results, it was not possible to confirm the appropriate administration dosage to maintain the efficacy of preventing hair loss caused by testosterone for more than one month, and it was also not possible to confirm the maximum blood concentration of finasteride when administered to humans, not animal models.

[0045] The present invention relates to a dosage form capable of exhibiting a sustained release effect of finasteride for more than one month, and to specific characteristics compared to existing oral formulations when administered within the dosage range.

[0046] Specifically, the dosage of finasteride is 10 mg to 40 mg, and can suppress androgen-mediated hair follicle miniaturization by finasteride for more than one month. Specifically, the dosage of finasteride to maintain the preventive and therapeutic effect of testosterone-induced hair loss by finasteride for more than one month is 10 mg to 40 mg, 11 mg to 39 mg, 12 mg to 38 mg, and may be 12 mg, 24 mg, or 38 mg, but is not limited to the above dosages, and any dosage that does not cause initial over-release, can slow down the absorption rate in the body, can increase the half-life of finasteride, can be more efficiently distributed throughout the body after being absorbed in the body, and can slow down the rate of elimination from the body may be used without limitation.

[0047] Pharmacokinetic parameters related to absorption are k a And F. When a drug is swallowed with water, it enters the stomach and goes down to the small intestine, where it undergoes an absorption process. The first step in absorption is when the drug in the form of a tablet or capsule breaks down and dissolves in the digestive fluid, and the drug molecules dissolved in it pass through the intestinal epithelial cells. The first absorption rate constant, k, is related to how quickly the disintegration and dissolution process in the digestive tract occurs. a The faster the drug dissolves and penetrates the intestinal epithelial cells into the bloodstream, the more k a is big.

[0048] The injection composition of the present invention has a first-order absorption rate constant (Ka, h) of finasteride by the injection composition -1) is 0.0005 to 0.0015, 0.0006 to 0.0014, 0.0007 to 0.0013, 0.0008 to 0.0012, 0.0009 to 0.0011, and may be 0.001, but is not limited to the above examples. When finasteride is administered into the body using the injection composition of the present invention, the value of the primary absorption rate constant is absolutely smaller than that of the conventional oral formulation, and as it is absorbed slowly, it can be said that an effect can be exhibited for more than one month with a single injection.

[0049] In the early 20th century, with the advent of technologies for measuring plasma drug concentrations, it was discovered that drug concentrations measured after intravenous infusion show a concave curve that initially decreases rapidly over time and then gradually decreases. When plotted in logarithmic concentration units, the concentration curve becomes a straight line, so it can be expressed as an equation such as ln(C) = ln(C(0))-kt. Here, C(0) is the concentration at time 0, and it is a straight line with a slope of -k according to the time t indicated on the x-axis. To eliminate the logarithmic unit, exponentiating both sides of this equation and transforming it into a differential equation gives an equation such as dC / dt = -kC. This simple form of differential equation means that the rate of change in concentration over time (dC / dt) at each moment is the power of the concentration (C=C). 1 ) is proportional to (-kC). Since the direction of change decreases as time passes, the proportionality constant k is given a -. The phenomenon in which the rate of change of a value is proportional to the value itself (to the power of 1) is said to follow first-order kinetics. Drugs that are eliminated according to the first-order kinetics are characterized by a 'half-life' (t 1 / 2 ) has a half-life. The half-life is the time it takes for the plasma drug concentration to decrease by half, and for drugs that are eliminated according to the first-order equation, each drug has a constant half-life (t 1 / 2 ) has.

[0050] In the case of finasteride, which is usually provided as an oral formulation, the average half-life in the body is only about 6.4 hours, but the average half-life (t) of finasteride in the body according to the administration of the injection composition of the present invention 1 / 2el ) showed a significant difference of 100 to 160 hours. Due to the difference in half-life as described above, when provided in a formulation such as the present invention compared to an oral formulation, stability is increased, and a uniform therapeutic effect can be exhibited through continuous and controlled release.

[0051] When the injectable composition of the present invention is administered into the human body, it is distributed along the blood vessels to the liver, pancreas, and the rest of the body. More specifically, the central compartment includes the blood vessels (plasma) and organs with high blood flow and easy drug distribution, such as the liver and kidneys. This compartment is called the central compartment. The remaining body parts, where the drug is distributed more slowly, are called the peripheral compartment. The period immediately after injection in which the plasma drug concentration drops sharply is called the distribution phase. After a certain degree of equilibrium is achieved between the two compartments, the subsequent period in which the concentration decreases gradually is called the elimination phase. This is because the plasma drug concentration decreases primarily due to the phenomenon of the drug being eliminated from the body. Although the mechanism by which the drug is eliminated from the body operates during the distribution phase, the mechanism by which the drug moves (diffusion) to the peripheral compartment is considered to have a more prominent effect than the mechanism by which the drug is eliminated from the body.

[0052] As a result of confirming the distribution volume (tvV, L) for the central compartment according to the administration of the injection composition of the present invention, it can be 500 to 1500, 600 to 1400, 700 to 1300, 800 to 1200, and 900 to 1100. A large value of the distribution volume for the central compartment means that even if the same amount of finasteride is administered, it is distributed more in the tissue than in the plasma, which means that the amount of finasteride that can bind to the tissue surface or penetrate the cell membrane is greater when the injection composition of the present invention is used compared to the oral formulation.

[0053] On the other hand, the distribution volume (tvV2, L) of finasteride in the peripheral compartment by the injection composition of the present invention is 0.1 to 0.5, 0.11 to 0.4, 0.12 to 0.3, 0.14 to 0.3, 0.15 to 0.3, 0.16 to 0.3, 0.17 to 0.3, 0.18 to 0.3, 0.19 to 0.3, 0.20 to 0.3, 0.20 to 0.29, 0.20 to 0.28, 0.20 to 0.27, 0.20 to 0.26, 0.20 to 0.25, 0.20 to 0.24, 0.20 to 0.23, It is 0.20 to 0.22, and can be 0.21 to 0.22. As shown above, the distribution volume value for the central compartment is large, and the distribution volume for the peripheral compartment is small, so it can be confirmed that it is easily distributed around the area where blood flow is abundant.

[0054] In addition, the clearance rate (tvCL, L / h) of finasteride in the central compartment by the injectable composition may be 5 to 15, 6 to 14, 7 to 13, 8 to 12, or 9 to 11, and the clearance rate (tvCL2, L / h) of finasteride between the central compartment and the peripheral compartment by the injectable composition may be 0.005 to 0.015, 0.006 to 0.014, 0.007 to 0.013, 0.008 to 0.012, or 0.009 to 0.011. This is a reduced value compared to the oral formulation, which means that finasteride administered in the body can remain for a long time and exert its effect.

[0055] Maximum blood concentration (C) of finasteride by the above injection composition max , pg / mL) may be 500 to 3,000, 600 to 2,900, 700 to 2,800, 800 to 2,800, and 900 to 2,800. The maximum blood concentration varies depending on the administration dose of finasteride included in the injection composition of the present invention. When the administration dose is 12 mg / every 4 weeks, the maximum blood concentration (C max , pg / mL) may be 500 to 1,300, 600 to 1,200, 700 to 1,100, and 800 to 1,000, and the dose is 24 mg / every 4 weeks, the maximum blood concentration (C max , pg / mL) is 1,500 to 2,100, 1,600 to 2,000, and 1,700 to 1,900, and when the dose is 36 mg / every 4 weeks, the maximum blood concentration (C max, pg / mL) may be 2,400 to 3,100, 2,500 to 3,000, 2,600 to 2,900, and 2,700 to 2,800. In the case of oral formulations, the maximum blood concentration is shown immediately after administration, and the pattern is that the blood concentration decreases rapidly, whereas in the case of the injection composition of the present invention, although the value of the maximum blood concentration changes depending on the administered dose, the blood concentration gradually increases after administration so as to show the maximum blood concentration between 500 hours and 700 hours, and after reaching the maximum blood concentration, it decreases steadily, so that the blood concentration of finasteride does not show a large difference between the highest and lowest levels.

[0056] The average concentration (C) of finasteride at steady state by the above injection composition ss,avg , pg / mL) is 1,000 to 6,000, 1,100 to 5,900, 1,200 to 5,800, 1,300 to 5,700, 1,400 to 5,600, 1,500 to 5,500, 1,600 to 5,400, and 1,700 to 5,300. The average concentration in the steady state also varies depending on the administered dose, and specifically, when the administered dose is 12 mg / every 4 weeks, C ss,avg The pH can be 1,400 to 2,100, 1,500 to 2,000, 1,600 to 1,900, and 1,700 to 1,800, and when the administration dose is 24 mg / every 4 weeks, it can be 3,200 to 3,800, 3,300 to 3,700, and 3,400 to 3,600, and when the administration dose is 36 mg / every 4 weeks, it can be 4,900 to 5,600, 5,000 to 5,500, 5,100 to 5,400, and 5,200 to 5,300. It was confirmed that excellent drug concentration in a steady state can be exhibited through values ​​within the above ranges.

[0057] AUC is determined by the dose and clearance rate as follows:

[0058] AUC = dose / clearance

[0059] The above clearance rate (CLs) is a model-independent parameter, but has the following mathematical relationship with the dissipation rate constant (K) and distribution volume (V).

[0060] CLs = V x K

[0061] As can be seen from this relationship, the clearance rate and volume of distribution determine the rate of drug elimination.

[0062] When clearance is constant, AUC is proportional to dose, so doubling the drug dose doubles AUC. This concept also implies that clearance can be calculated from AUC and dose.

[0063] Since the blood concentration according to the usual dose and time is known, the AUC can be calculated, and thus the clearance rate can be calculated using the following equation.

[0064] Drug clearance = dose / AUC

[0065] Assuming a one-compartment model and administering a fixed dose of drug, AUC can be easily calculated as follows.

[0066] AUC = initial concentration (Co) / elimination rate constant (K)

[0067] However, if the drug is one in which the natural logarithm of the drug concentration over time decreases linearly or nonlinearly, the AUC can be calculated using a method called the "trapezoidal rule."

[0068] The trapezoidal rule views the blood concentration curve against time as a series of connected ladders, with each adjacent measured blood concentration being connected by a straight line.

[0069] Although the upper part of the trapezoid is curved, if the time interval (the height of the trapezoid) is small, the curve can be assumed to be a straight line, and the resulting error is very small and can be ignored. In this way, the area of ​​each trapezoid is easily calculated, and the sum of all trapezoid areas becomes the total area under the concentration curve. When calculating the AUC using the trapezoidal rule, the blood concentration is not converted to a natural logarithm value. The AUC from time 0 to infinity must be used to calculate the clearance. The AUC from time 0 to infinity is also calculated using the trapezoidal rule, which adds the calculated area from the last measurement time to infinity to the AUC from time 0 to the time of the last concentration measurement. A large AUC value indicates a relatively high bioavailability, which can be considered an indicator of the amount of absorption, indicating how much is absorbed in the body.

[0070] The AUC (ACU) of 0 to 672 hours by the injection composition of the present invention 0-672h, hr*pg / mL) may be 500,000 to 2,000,000, 510,000 to 1,900,000, 511,000 to 1,800,000, 512,000 to 1,700,000, 513,000 to 1,600,000, 514,000 to 1,600,000, and 515,000 to 1,600,000. The above AUC also varies depending on the administered dose, and specifically, when the administered dose is 12 mg / every 4 weeks, the AUC may be 500,000 to 525,000, 510,000 to 524,000, 510,000 to 523,000, 510,000 to 522,000, 510,000 to 521,000, and 510,000 to 520,000, and when the administered dose is 24 mg / every 4 weeks, the AUC may be 1,000,000 to 1,300,000, 1,010,000 to 1,200,000, 1,020,000 to 1,100,000, and 1,030,000 to It can be 1,100,000, and if the dosage is 36 mg / every 4 weeks, it can be 1,100,000 to 1,800,000, 1,200,000 to 1,700,000, 1,300,000 to 1,600,000, 1,400,000 to 1,600,000, and 1,500,000 to 1,600,000.

[0071] The AUC (AUCss, hr*pg / mL) of finasteride in the steady state by the above injection composition may be 1,000,000 to 4,000,000, 1,100,000 to 3,900,000, 1,100,000 to 3,800,000, 1,100,000 to 3,700,000, and 1,100,000 to 3,600,000. The AUC at steady state also varies depending on the administered dose. Specifically, when the administered dose is 12 mg / every 4 weeks, the AUC at steady state is 1,000,000 to 1,300,000, and may be 1,100,000 to 1,200,000. When the administered dose is 24 mg / every 4 weeks, the AUC at steady state is 2,000,000 to 2,600,000, and may be 2,100,000 to 2,500,000, and may be 2,200,000 to 2,400,000. When the administered dose is 36 mg / every 4 weeks, the AUC at steady state is 3,100,000 to 3,800,000, and may be 3,200,000 to It can be 3,700,000, 3,300,000 to 3,600,000, and 3,400,000 to 3,600,000. It was confirmed that excellent bioavailability was exhibited within the above range.

[0072] The injection composition of the present invention comprises microparticles containing finasteride, wherein the microparticles contain finasteride and a biodegradable polymer, are spherical in shape and uniformly contain finasteride and a biodegradable polymer, and have an average diameter of 30 to 50 μm.

[0073] The above particles include a biodegradable polymer and finasteride, and at this time, rather than being in a capsule form, the composition in which the biodegradable polymer and finasteride are uniformly mixed is manufactured into a completely spherical particle, and finasteride is characterized in that it is uniformly distributed within the particle.

[0074] The average diameter of the above particles is 30 to 50 μm, and the standard deviation for the average diameter is 3.0 to 5.5.

[0075] The present invention is a particle manufactured by a method for manufacturing microparticles to be described later, and is characterized in that, as described above, a biodegradable polymer and finasteride are evenly distributed, and the manufactured particle has an average diameter of 30 to 50 ㎛ and a standard deviation for the average diameter is distributed as 3.0 to 5.5.

[0076] That is, even though micro-sized particles are manufactured, the standard deviation is only 3.0 to 5.5, so particles of almost the same size can be manufactured.

[0077] The injectable composition comprising microparticles containing finasteride of the present invention can continuously release finasteride for at least one month, one to two months, or one to three months upon intravenous injection. More specifically, as described above, the microparticles of the present invention comprise a biodegradable polymer, and finasteride can be released within the body as the biodegradable polymer decomposes within the body.

[0078] The production of microparticles containing finasteride of the present invention is carried out in the following order: 1) a step of producing a first mixture (S100); 2) a step of producing a second mixture (S200); 3) a step of injecting the first mixture into a linear microchannel (S300); 4) a step of injecting the second mixture into a microchannel on both sides or one side (S400); 5) a step of collecting microparticles (S500); 6) a step of stirring the collected microparticles (S600); and 7) a step of washing and drying the microparticles (S700).

[0079] More specifically, a method for manufacturing microparticles containing finasteride according to one embodiment of the present invention is described as follows.

[0080] 1) Step (S100) is a step for preparing a first mixture, wherein the first mixture is prepared by dissolving a biodegradable polymer and finasteride in an organic solvent, wherein the biodegradable polymer is selected from the group consisting of polylactic acid, polylactide, polylactic-co-glycolic acid, polylactide-co-glycolide (PLGA), polyphosphazine, polyiminocarbonate, polyphosphoester, polyanhydride, polyorthoester, polycaprolactone, polyhydroxyvalerate, polyhydroxybutyrate, polyamino acid, and combinations thereof, and is preferably polylactide-co-glycolide (PLGA), but is not limited to the above examples.

[0081] In addition, the organic solvent is one that does not mix with water, for example, at least one selected from the group consisting of chloroform, chloroethane, dichloroethane, trichloroethane, and mixtures thereof, preferably dichloromethane, but is not limited to the example, and any organic solvent that can dissolve the biodegradable polymer and finasteride, and is not limited to the example, and any organic solvent that can be easily selected by a person skilled in the art can be used.

[0082] The above step 1) (S100) prepares a first mixture in which a biodegradable polymer and finasteride are dissolved. As described above, an organic solvent is used as the solvent. This utilizes the dissolution properties of finasteride and the biodegradable polymer to completely dissolve them using the organic solvent. After complete dissolution, the first mixture contains the biodegradable polymer and finasteride in a weight ratio of 2:1 to 15:1.

[0083] When the weight ratio of the biodegradable polymer and finasteride is less than 2:1, that is, when the biodegradable polymer is included in an amount less than the above weight ratio, the weight ratio of the biodegradable polymer is small compared to the weight of finasteride, and thus it is difficult to manufacture microparticles in which finasteride is evenly distributed and included in spherical biodegradable polymer particles. In addition, when the weight ratio of the biodegradable polymer and finasteride exceeds 15:1, that is, when the biodegradable polymer is included in an amount greater than the above weight ratio, the content of finasteride in the microparticles is small, and thus a problem may arise that a large amount of microparticles must be administered to administer the drug at a desired concentration.

[0084] More specifically, the biodegradable polymer in the first mixture is comprised in an amount of 10 to 20 wt%, preferably 12.5 to 15 wt%, but is not limited to the above example.

[0085] The above step 2) (S200) is a step for preparing a second mixture, and the second mixture is prepared by dissolving a surfactant in water. The surfactant may be used without limitation as long as it can help the biodegradable polymer solution form a stable emulsion. Specifically, it is at least one selected from the group consisting of nonionic surfactants, anionic surfactants, cationic surfactants, and mixtures thereof, and more specifically, it is at least one selected from the group consisting of methylcellulose, polyvinylpyrrolidone, lecithin, gelatin, polyvinyl alcohol, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil derivatives, sodium lauryl sulfate, sodium stearate, ester amines, linear diamines, patty amines, and mixtures thereof, and is preferably polyvinyl alcohol, but is not limited thereto.

[0086] The above steps 3) (S300) and 4) (S400) are steps for injecting the first mixture and the second mixture into the microchannel formed on the wafer and causing them to flow.

[0087] More specifically, the microchannel can be formed in a material selected from the group consisting of a silicon wafer or a polymer film, but examples of the material are not limited to the examples above, and any material capable of forming a microchannel can be used.

[0088] The polymer film may be selected from the group consisting of polyimide, polyethylene, fluorinated ethylene propylene, polypropylene, polyethylene terephthalate, polyethylene naphthalate, polysulfone, and mixtures thereof, but is not limited to the above examples.

[0089] As an example, aluminum is deposited on a silicon wafer using an e-beam evaporator, and photoresist is patterned on the aluminum using photolithography. The aluminum is then etched using the photoresist as a mask, the photoresist is removed, and the silicon is etched using DRIE (deep ion reactive etching) using the aluminum as a mask. After the aluminum is removed, glass is anodic bonded to the wafer to seal it, thereby fabricating the microchannels described above.

[0090] The above microchannel had a horizontal width of 100 μm and a vertical depth of 80 μm, and in order to control the fluctuation of the injection amount (speed) of the oily solution, a resistance channel was positioned at the front of the microchannel so that the oily solution could pass through the resistance channel and be injected into the microchannel at a constant injection amount (speed). The horizontal width of the microchannel may be 20 μm, and the vertical depth may be 100 μm. The average diameter of the microparticles is 30 to 50 μm, preferably 40 μm, but is not limited to the example. When the average diameter of the microchannel is 35 μm or less, there is a possibility that the microparticles produced will have a diameter of 20 μm or less, which increases the possibility of being phagocytosed by macrophages after injection into the human body, and this may affect the release and in vivo absorption of the effective drug. In addition, if the size of the manufactured microparticles exceeds 55㎛, foreign body sensation and pain may increase when administered as an injection, and the particle size distribution of the manufactured particles becomes large, making it difficult to manufacture microparticles with a uniform particle size.

[0091] However, the average diameter of the microchannel can be changed depending on the range of injection pressure. For example, if the diameter of the channel is 100 μm, the second mixture should be injected at a pressure of 1,000 to 2,000 mbar, and the first mixture can be injected at a pressure of 500 to 1,000 mbar.

[0092] The average diameter of the above microchannel is closely related to the average diameter of the particles, but is also closely related to the injection pressures of the first mixture and the second mixture, and is not limited to the above example, and may be changed depending on the average diameter of the particles being manufactured or the pressure conditions during injection.

[0093] In addition, the cross-sectional width (w) and the cross-sectional height (d) of the microchannel are closely related to the average diameter (d') of the microparticles being manufactured. The width (w) of the cross-sectional microchannel is in the ratio range of 0.3 to 0.5 with respect to the average diameter (d') of the microparticles, and the height (d) of the cross-sectional microchannel is in the ratio range of 0.3 to 0.8 with respect to the average diameter (d') of the microparticles.

[0094] The above 3) step (S300) is to inject the first mixture into a straight microchannel and cause it to flow, and the above 4) step (S400) is to inject the second mixture into a microchannel on both sides or one side formed to form an intersection with the straight microchannel and cause it to flow.

[0095] That is, the first mixture flows along a straight microchannel, and the second mixture flows along a microchannel that forms an intersection with the straight microchannel on both sides or one side based on the straight microchannel, and meets the flow of the first mixture.

[0096] At this time, when the first mixture is injected into a straight microchannel, it is injected under a constant pressure condition and flows at a constant flow rate. The pressure condition at this time is 500 to 1500 mbar, preferably 750 to 1,100 mbar, but is not limited to the example.

[0097] In addition, when the second mixture is injected into the microchannels on both sides or one side, it is injected under constant pressure conditions and flows at a constant flow rate. The pressure conditions at this time are 1000 to 2500 mbar, preferably 1,400 to 2,300 bar, but are not limited to examples.

[0098] That is, in order to cause the flow of the second mixture forming an intersection with the flow of the first mixture to flow at a faster flow rate than the flow of the first mixture injected into the straight microchannel, the second mixture is caused to flow under higher pressure conditions.

[0099] As described above, by making the flow rates of the first mixture and the second mixture different and making the flow rate of the second mixture faster than that of the first mixture, the second mixture having a relatively faster flow rate compresses the first mixture at the point where the flow of the first mixture and the flow of the second mixture meet, and at this time, due to the repulsive force of the first mixture and the second mixture, the biodegradable polymer and finasteride in the first mixture form spherical microparticles, and more specifically, microparticles in which finasteride is evenly distributed in the spherical biodegradable polymer are formed.

[0100] The above step 5) (S500) is a step for collecting microparticles, which collects microparticles in a tank containing a second mixture, thereby preventing aggregation between initially generated microparticles.

[0101] The above 5) step (S500) uses the second mixture prepared in the above 2) step (S200), i.e., a mixed solution of a surfactant and water. After the second mixture is prepared in the above 2) step (S200), some of it is injected into the microchannel, and the other part is moved to the tank of the 5) step (S500), thereby preventing the phenomenon of clumping between the collected microparticles.

[0102] The above step 6) (S600) is a step of stirring the microparticles collected in the tank, and the microparticles are stirred under constant temperature conditions and stirring speed to evaporate and remove the organic solvent present on the surface of the microparticles. At this time, the stirring conditions are a first step of stirring at a speed of 100 to 500 rpm while increasing the temperature from 15 to 20°C to 35 to 45°C for 0.5 to 3 hours; and after the first stirring step, a second step of stirring at a speed of 100 to 500 rpm for 4.0 to 24 hours at 35 to 45°C; and after the second stirring step, a third step of stirring at a speed of 100 to 500 rpm for 0.5 to 1.5 hours while adjusting the temperature to 15 to 25°C and cooling.

[0103] In addition to the stirring speed, the temperature condition is also characterized by raising the temperature in the second stirring process compared to the first stirring process, and by gradually increasing the temperature, the evaporation rate of the organic solvent present on the surface of the microparticles can be controlled. In other words, by gradually evaporating the organic solvent present on the surface of the microparticles, microparticles with a smooth surface can be manufactured.

[0104] The temperature at which the first mixture and the second mixture flow through the microchannel is also 15 to 20°C, and preferably 17°C. That is, after flowing through the microchannel and forming an intersection to generate microparticles, the temperature is maintained at a constant low temperature of 15 to 20°C until the collected microparticles are stirred for the first time. Only when a low temperature is maintained during the process of manufacturing microparticles can spherical particles be manufactured and maintained. In other words, if the temperature is not low, it is difficult to manufacture particles with a consistent spherical shape.

[0105] Lastly, the above step 7) (S700) is a step for washing and drying microparticles. The microparticles, which have had all organic solvents on their surface removed by stirring, are washed several times with sterilized, filtered purified water to remove surfactants remaining in the microparticles, and then vacuum dried or freeze-dried.

[0106] The microparticles finally produced are in the form of spherical biodegradable polymer microparticles in which the drug finasteride is evenly distributed, and contain the biodegradable polymer and finasteride in a weight ratio of 2:1 to 15:1.

[0107] The weight ratio of the biodegradable polymer and finasteride contained in the microparticles is the same as the weight ratio in the first mixture, which means that by manufacturing the microparticles and removing all organic solvents by evaporation, microparticles containing the biodegradable polymer and finasteride in the same weight ratio as in the first mixture can be manufactured.

[0108] A novel long-acting injectable composition for preventing or treating androgenetic alopecia according to another embodiment of the present invention may include microparticles comprising finasteride; and a suspending agent.

[0109] The above injection composition is in a form in which microparticles are uniformly contained in a suspension solvent, and when the injection composition is administered, the microparticles themselves are injected into the body, thereby exhibiting the long-term administration effect of finasteride.

[0110] More specifically, when microparticles are injected into the body, the effect of releasing finasteride by decomposition of the biodegradable polymer is exhibited. At this time, since the microparticles of the present invention are in a form in which the biodegradable polymer and finasteride are uniformly mixed, they can exhibit the effect of administering a constant concentration of finasteride for a long period of time.

[0111] That is, when the injectable composition of the present invention is injected once, finasteride is continuously released in the body for more than one month, one to two months, or one to three months, thereby solving the problem of having to take it every day, thereby increasing user convenience.

[0112] The above suspension solvent includes an isotonic agent, a suspending agent and a solvent.

[0113] More specifically, the isotonic agent may be selected from the group consisting of D-Mannitol, Maltitol, Sorbitol, Lactitol, Xylitol, Sodium chloride and mixtures thereof, preferably D-Mannitol, but is not limited to the above examples.

[0114] The above suspending agent is composed of sodium carboxymethylcellulose, polysorbate 80, starch, starch derivatives, polyhydric alcohols, chitosan, chitosan derivatives, cellulose, cellulose derivatives, collagen, gelatin, hyaluronic acid (HA), alginic acid, algin, pectin, carrageenan, chondroitin, chondroitin sulfate, dextran, dextran sulfate, polylysine, titin, fibrin, agarose, fluran, xanthan gum, and mixtures thereof. Selected from the group, preferably sodium carboxymethylcellulose and polysorbate 80, but not limited to the above examples.

[0115] The above solvent can be used as injection water, and any solvent that can be used as injection water can be used without limitation.

[0116] Preparation of microparticles containing finasteride

[0117] 1. Manufacturing of sustained-release particles (main drug) containing finasteride

[0118] (1) A first mixture was prepared by dissolving polylactide-co-glycolide (PLGA) and finasteride in dichloromethane, and then filtered to remove bacteria.

[0119] At this time, polylactide-co-glycolide in the first mixture is included in a proportion of 12.5 wt%, and the weight ratio of polylactide-co-glycolide and finasteride is 2:1.

[0120] (2) A second mixture containing 0.25 wt% of polyvinyl alcohol was prepared by mixing polyvinyl alcohol, a surfactant, with water and subjected to sterilization filtration.

[0121] (3) The first mixture and the second mixture were injected into a microchannel formed on a silicon wafer and allowed to flow. At this time, in order to flow the first mixture and the second mixture at a constant flow rate, the first mixture was allowed to flow under a pressure condition of 750 mbar, and the second mixture was allowed to flow under a pressure condition of 1,400 mbar. The temperature condition was maintained at 17°C.

[0122] (4) The sustained-release particles generated at the intersection where the flow of the first mixture and the flow of the second mixture meet were collected in a tank containing the second mixture. The sustained-release particles collected in the tank were stirred at a speed of 150 rpm for 2 hours while increasing the temperature in the tank to 42°C, and then stirred at a speed of 150 rpm for 10 hours while maintaining 42°C.

[0123] (5) After this, the set temperature was adjusted to 17℃.

[0124] (6) The sustained-release particles that had been stirred were washed several times with sterilized, filtered purified water, and the residual water was removed. Then, the sustained-release particles were dried for 24 hours while maintaining the vacuum inside the tank at 50 mbar or less.

[0125] Preparation of a composition for subcutaneous injection

[0126] (1) The sustained-release particles (main drug) manufactured in the above 1 were uniformly suspended by adding 2.0 ml of an attached solvent per vial to manufacture a composition for subcutaneous injection.

[0127] (2) The above attached solvent was composed as follows.

[0128] - Content standard: 2.0 mL

[0129] - D-Mannitol: 100.0 mg

[0130] - Suspension agent Sodium Carboxymethylcellulose: 10.0 mg

[0131] - Suspension agent Polysorbate 80: 2.0 mg

[0132] - Injection water: remainder

[0133]

[0134] Test method

[0135] participant

[0136] The present study was conducted in accordance with the guidelines of the Therapeutic Goods Administration and the Human Research Ethics Committee. The trial was conducted at the Phase 1 unit of Nucleus Network Pty Ltd in Brisbane, Australia, from October 2021 to March 2022. The entire study was conducted in accordance with the provisions of the Declaration of Helsinki and Good Clinical Practice, and the protocol was registered at www.clinicaltrials.gov (NCT04945226; registration date 2021-06-30). Healthy males aged 18-55 years with a body mass index (BMI) of 18-32 kg / m2 participated in this study. Potential volunteers completed a signed informed consent form and underwent screening prior to the study. A total of 40 healthy, non-smoking adult males across three cohorts were included in this study (Figure 1).

[0137] This trial was approved by the Alfred Hospital Ethics Committee. The ethics committee reference number is Project 364 / 20. Informed consent was obtained from all study participants.

[0138] All participants underwent regular checkups, which included measurements of vital signs (blood pressure, heart rate, body temperature), 12-lead electrocardiogram (ECG), serological tests (hepatitis B surface antigen, hepatitis C virus antibodies, HIV antigen / antibody), health status, and routine laboratory tests (CBC, biochemistry, urinalysis).

[0139] Key inclusion criteria include:

[0140] (1) Healthy males aged 18 to 55 years or older at the time of screening test, non-smokers or moderate or occasional smokers (less than 10 cigarettes or nicotine equivalent per day) who agree to quit smoking 48 hours before the first IP administration;

[0141] (2) The subject meets the screening test criteria and is considered to be in excellent health by the investigator;

[0142] (3) BMI ≥ 18 kg / m 2 At ≤ 32kg / m 2 Subjects whose minimum body weight at the time of screening test was ≥ 50 kg and ≤ 100 kg;

[0143] (4) Ability and willingness to report to the clinical research unit facility and stay overnight whenever necessary;

[0144] (5) Subjects who voluntarily participated in the study, received a detailed explanation of the study, fully understood it, and gave written consent to follow the instructions.

[0145] The main exclusion criteria are as follows:

[0146] (1) any past or current medical condition, medical history, physical examination result, or screening test abnormality that, in the opinion of the researcher, may adversely affect the safety of the participant;

[0147] (2) Presence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, or neurological conditions;

[0148] (3) Subjects with mild depression and anxiety;

[0149] (4) Subjects with known allergy or hypersensitivity to finasteride or a history of drug abuse;

[0150] (5) Age-adjusted prostate-specific pathogens at screening: 0–2.5 ng / mL for subjects under 50 years of age, 0–4 ng / mL for subjects over 50 years of age (unless the investigator determines it is not clinically important);

[0151] (6) Individuals who participated in another human study within 2 months of the start of the study;

[0152] (7) Alcohol abuse or dependence within the past 3 months;

[0153] (8) Hypersensitivity to the drug finasteride or any excipient of IP; however, past use of finasteride was permitted,

[0154] (9) People who were deemed unsuitable for participation in this clinical trial for other reasons defined by the investigator.

[0155] Study design

[0156] A total of 40 healthy, non-smoking adult males were recruited for this study. Participants who passed the screening process and were deemed eligible for the study were assigned to three groups. Group 1 received a single subcutaneous injection of 12 mg IVL3001, and Group 3 received a single subcutaneous injection of 36 mg IVL3001. Each participant was followed for up to 43 days. In contrast, Group 2 was divided into two groups. Group 1 received 1 mg of oral finasteride (Propecia®) once daily for 28 days and was followed for up to 35 days, and Group 2 received a single subcutaneous injection of 24 mg IVL3001 and was followed for up to 43 days. On the morning of Day 1, subjects in each of the three groups received either a single subcutaneous injection of IVL3001 or daily oral finasteride. They were discharged on Day 3 and returned to the hospital according to a predetermined schedule for 43 or 35 days, respectively, to assess tolerability, PK, and PD. This study compared a sustained-release formulation of IVL3001 administered once a month with daily oral finasteride. The study analyzed drug concentrations on Day 28 to investigate comparative efficacy. A schematic diagram illustrating the experimental design is shown in Figure 2.

[0157] Group 1 received a single SC injection of 12 mg IVL3001 and was followed up (f / u) until day 43. Group 2 was divided into two groups, and group 1 of group 2 received 1 mg finasteride orally once daily for 28 days, f / u until day 35, and group 2 of group 2 received a single SC injection of 24 mg IVL3001, f / u until day 43. Similarly, group 3 received a single SC injection of 36 mg IVL3001, f / u until day 43.

[0158] Measurement of plasma finasteride, DHT, and testosterone levels

[0159] Plasma finasteride, dihydrotestosterone (DHT), and testosterone levels were measured using liquid chromatography-tandem mass spectrometry (LC-MS). Calibration standards and test samples for testosterone and DHT LC-MS / MS were prepared using liquid / liquid extraction. Testosterone and DHT analyses were performed using LC-MS / MS (Sciex, USA). After plasma extraction, the analytes were eluted through an ACE Excel 2 C18 column using a gradient profile at a flow rate of 0.5 mL / min. After optimization using electrospray ionization in positive mode, the respective parent / product ion pairs for finasteride, testosterone, and DHT were used for analysis. Finally, the steroid-spiked samples were recovered. The lower limit of quantitation for testosterone D5 was 100 pg / mL, and 50 pg / mL was used as the internal standard for DHT measurement.

[0160] End point

[0161] Primary endpoint

[0162] The primary endpoint of this trial was safety. This was assessed by measuring vital signs, 12-lead ECG, serological tests, and other blood and biochemical tests. Injection site reactions were assessed at 0.5, 1, 12, and 48 hours using a global severity assessment. Severity was assessed on a 4-point scale, ranging from 0 to 3, with 0 representing no reaction, 1 representing mild pain, 2 representing pain distribution, and 3 representing intolerable pain. Injection site reactions were assessed at all outpatient visits after discharge. In addition, PK parameters were derived using a noncompartmental analysis approach based on venous blood samples obtained on days 1, 2, 3, 5, 8, 10, 15, 22, 29, 35, and 43 in the IVL3001 group and on days 2, 3, 8, 15, 22, 28, 29, 30, and 35 in the finasteride group. Whole blood was collected and centrifuged to obtain plasma. Blood finasteride concentrations were measured using a validated LC-MS method. The maximum blood concentration (Cmax), time to Cmax (Tmax), and area under the curve (AUC) at 24 and 672 hours after administration were measured. 0-24 , AUC 0-672 ), the area under the curve from time 0 to the last quantified concentration and to infinity (AUC 0-t , AUC 0-inf ), total plasma clearance, apparent total volume of distribution based on steady state or terminal phase, and elimination half-life were evaluated.

[0163] Secondary endpoint

[0164] Measurements of DHT and testosterone were secondary endpoints. DHT and testosterone were measured as pharmacodynamic markers and were assessed at the same time points as the PK sampling. Additionally, the study assessed and compared changes in DHT levels and testosterone levels during and at the end of treatment in subjects receiving IVL3001 or finasteride 1 mg tablets. Plasma DHT and testosterone concentrations were measured using a validated LC-MS method. All biochemical and chromatographic analyses, including LC-MS, were performed by Syneos Health Clinique Inc. in Quebec, Canada, and Sydpath Clinical Trials in New South Wales, Australia.

[0165] Modeling and Simulation

[0166] PK and PD modeling were performed to determine the therapeutic dose in AGA. A two-compartment PK model was adopted using observed clinical study data. To predict and compare the efficacy of the test drug (IVL3001) and the reference drug (finasteride 1 mg tablets), the Emax model was directly applied to individual plasma DHT concentrations to predict the efficacy of finasteride for both the test and reference drugs, which were then incorporated into the PK model. The effective dose for additional clinical studies was estimated using the established PK / PD model. All PK / PD modeling and simulations were performed using Phoenix WinNonlin, v. 8.3. DHT and testosterone levels (unadjusted and % baseline-corrected) were listed and summarized by nominal sampling time and treatment. The mean ± SD profiles of individual subject and PD data were graphed by treatment using actual and nominal times, respectively.

[0167] Safety measures

[0168] To investigate adverse events, the clinical status and vital signs of the subjects were assessed before and after study participation. Hematological parameters such as white blood cell count, red blood cell count, hemoglobin, hematocrit, and platelet count were analyzed. Adverse events (AEs) were recorded in terms of symptoms and signs, duration, intensity, relationship to study drug, actions taken, outcome, and severity. All biochemical analyses were performed in the clinical laboratory at Mater Hospital in Brisbane, Australia.

[0169] Statistical analysis

[0170] Statistical analyses were performed using SAS v. 9.4 (SAS Institute, Cary, NC, USA). All safety-related information was summarized using descriptive statistics. AEs were classified using the Medical Dictionary for Regulatory Activities (MedDRA) version 24.0 (MedDRA MSSO, McLean, VA, USA) and summarized by system organ class, preferred term, severity, and relationship to IVL3001 or finasteride. PK analyses were based on a noncompartmental approach and performed in the PK population (patients who received at least one dose and had evaluable PK data). PK parameters were calculated using plasma concentrations and actual blood sampling times using Phoenix WinNonlin v. 8.3 (Certara, Princeton, NJ, USA) and summarized.

[0171] result

[0172] Demographic characteristics of participants

[0173] A total of 42 male participants were enrolled, and 41 met the eligibility criteria for study drug administration. Of these, 38 subjects completed the study, 1 did not receive the full dose, and 2 withdrew consent for reasons unrelated to adverse effects. Most participants were of European descent (93.3%), and the mean age was 32.4 ± 9.6 years. The selection process for study participants is shown in Figure 2. General demographic characteristics of the participants are presented in Table 1. There were no statistically significant differences in age, height, weight, or BMI.

[0174] IVL3001 12mg SC(N=11)IVL3001 24mg SC(N=10)IVL3001 36mg SC(N=11)Finasteride 1mg (QD)(N=10)Overall(N=42)Age (Age), mean(SD), y33.5(9.1)33.7(13.0)29.2(9.4)33.4(6.8)32.4(9.6)Sex, n (%)Male11 (100)10 (100)11 (100)10 (100)42 (100)Race, n (%)European descentAfrican-AmericanS-E AsianOther6 (54.5)1 (9.1)4 (36.4)010 (100)0007 (63.6)1 (9.1)2 (18.2)1 (9.1)7 (70.0)01 (10.0)2(20.0)30 (71.4)2 (4.8)7 (16.7)3(10.0)Height, mean(SD), cm179.5(7.6)180.0 (6.3)177.6 (9.2)176.9 (4.7)178.5 (7.0)Weight, mean(SD), kg79.7(10.8)77.8(9.3)77.8(8.8)82.0(13.2)79.3(10.4)BMI, mean(SD) kg / m²24.8(2.9)24.3(3.5)24.8(2.7)26.3(4.7)25.0(3.4)

[0175] Safety

[0176] Forty treatment-emergent adverse events (TEAEs) were identified in 23 of 41 patients (56.1%) who received IVL3001 or finasteride. Thirty-seven TEAEs were reported in 20 of 31 subjects (64.5%) who received a single SC dose of IVL3001, compared with three TEAEs in 3 of 10 subjects (30.0%) who received 1 mg finasteride tablets. A dose-dependent trend in the number of reported TEAEs was observed in the IVL3001 treatment group. However, the number and percentage of patients reporting TEAEs were similar across IVL3001 treatment groups. Overall, most of the reported TEAEs (18, 43.9%) were considered study drug-related and resolved without medical intervention by the end of the study. Most injection-site reactions occurred in the study drug group, and, with the exception of injection-site reactions, the incidence was similar to that in the finasteride group. Most injection-site reactions were mild, and the incidence was similar across dose groups (Table 2). No safety concerns were observed. Vital signs and biochemical parameters (hematology, blood chemistry, ECG, physical examination, and urinalysis) were determined to be within reference ranges and were not clinically significant.

[0177] IVL300112mg (SC)(n=10)IVL300124mg (SC)(n=10)IVL300136mg (SC)(n=11)Finasteride1mg (QD)(n=10)Overall(n=41)Participants, n (%)AEs by MedDRA system organ class MedDRA preferred itemsSubjects with at least one TEAE6 (60.0)7 (70.0)7 (63.6)3 (30.0)23 (56.1)General disorders andadministration site condition6 (60.0)4 (40.0)6 (54.5)016 (39.0)Injection site bruising6 (60.0)0006 (14.6)Injection site induration02 (20.0)4(36.4)06 (14.6)Injection site pain01 (10.0)4(36.4)05 (12.2)Injection site Haematoma02 (20.0)1(9.1)3 (7.3)Nervous system disorder1(10.0)1 (10.0)03 (30.0)5 (12.2)Headache01 (10.0)03 (30.0)4 (9.8)Infections and infestations003 (27.3)03 (7.3)COVID-19003 (27.3)03 (7.3)Investigations1 (10.0)2 (20.0)003 (7.3)Blood creatine phosphokinase increased02 (20.0)002 (4.9)

[0178] 약동학 분석

[0179] Plasma concentration profiles following IVL3001 doses (12, 24, and 36 mg) showed a prolonged absorption phase, reaching peak levels between 500 and 700 hours post-dose, in contrast to the rapid peak and decline observed after oral finasteride 1 mg once daily (QD). The main difference in PK observed over the 672-hour period following IVL3001 SC administration was that finasteride plasma concentrations were more consistent and had fewer abrupt peak and trough fluctuations, which is typical of daily oral dosing (Figure 4).

[0180] The average half-life of finasteride (t 1 / 2el ) are 6.4 hours (day 1) and 6.9 hours (day 28). After IVL3001 administration, t 1 / 2el The PK of IVL3001 administered at the highest dose (36 mg) during the first 24 hours was similar to that of the reference oral formulation. However, the PK of 24 mg IVL3001 during the 28-day exposure period was similar to that of oral finasteride 1 mg tablets, with a geometric mean ratio (IVL3001 24 mg / finasteride 1 mg QD) of 1.406 and a corresponding 90% CI of (1.003, 1.973). AUC 0-24 Wow C max was lower than that of the oral finasteride 1 mg tablet group in all IVL3001 groups. Therefore, it was confirmed that there was no initial burst when the IV13001 formulation was administered. AUC of IVL3001 0-672 , AU C0-inf , C max The values ​​met the proportionality criterion (Fig. 4).

[0181] Pharmacodynamic analysis

[0182] The % of baseline-corrected median DHT values ​​at all time points ranged from -64.35 to 5.99%, -68.93 to 0.96%, and -70.36 to -1.25% for the 12 mg, 24 mg, and 36 mg doses of IVL3001, respectively. Similarly, the % of baseline-corrected median DHT values ​​at all time points ranged from -74.04 to 3.58% for oral finasteride 1 mg tablets. An inhibitory effect on DHT was observed at all concentrations of IVL3001 and oral finasteride 1 mg tablets, with baseline-corrected median testosterone levels initially decreasing and then increasing significantly over time (Figure 5).

[0183] simulation

[0184] A two-compartment PK model for IVL3001 and oral finasteride 1 mg tablets was successfully developed using plasma finasteride concentration-time profiles obtained from a clinical study of single doses of IVL3001 (12, 24, and 36 mg) and repeated doses of oral finasteride 1 mg tablets (1 mg QD for 28 days).

[0185] Simulation results showed that IVL3001 had a significantly lower absorption rate constant and clearance profile compared to oral finasteride 1 mg tablets, and a higher distribution profile in the central compartment (Table 3).

[0186] ParametersEstimatesFinasteride (1 mg)IVL3001tvKa (h -1 )0.4850.001tvV (L)81.61000.9tvV2 (L)373.20.217tvCL (L / h)18.410.0tvCL2 (L / h)18.90.01

[0187] Where, tvKa: first-order absorption rate constant, tvV: volume of distribution (central compartment), tvV2: volume of distribution (peripheral compartment), tvCL: total elimination clearance of the central compartment, tvCL2: distribution clearance between the central and peripheral compartments; Finasteride 1 mg: (Propecia®).

[0188]

[0189] The PK profile was simulated using an established PK model after repeated administration of IVL3001 or oral finasteride 1 mg tablets. The PK profile of oral finasteride 1 mg tablets after administration of 12, 24, and 36 mg of IVL3001 for 4 weeks was C in the oral finasteride 1 mg tablet group. ss, min and C ss, max The concentration range was within the range between (Table 4).

[0190] ParametersFinasteride(1 mg QD)IVL300112 mg / Q4W24 mg / Q4W36 mg / Q4WC max (pg / mL)4,672.9928.81,857.52,786C ss,avg (pg / mL)2,244.51,751.63,503.35,252.7AUC 0-672h (hr*pg / mL)1,463,862519,096.51,038,1931,557,070.1AUC ss (hr*pg / mL)1,508,3211,177,0982,354,1953,529,788.7

[0191] These trial results suggest that IVL3001 has no safety concerns after administration at doses of 12, 24, and 36 mg. Plasma DHT concentrations determined in clinical studies were used to develop a PD model. The direct Emax model, which has ke (the elimination rate constant at the effect compartment), EC50 (the half-maximal effect concentration), and E0 (the reference level), was used as the core structure of the PD model for DHT. Based on the DHT concentration profile, it was predicted that administering 12 to 36 mg of IVL3001 every 4 weeks would achieve plasma concentrations similar to those of oral finasteride 1 mg tablets and result in similar DHT reductions (Figure 6).

[0192] A major obstacle to managing hair loss in AGA patients is poor adherence to prescribed oral medications. A major problem with AGA treatment is partial noncompliance, which can lead to the loss of benefits gained from oral medications over many years. This problem has been partially alleviated by the increasing use of long-acting injectables (LAIs), particularly in managing patients prone to treatment noncompliance. However, the recent development of second-generation LAIs has led clinicians to consider their use in the early stages of the disease, particularly in the treatment of schizophrenia.

[0193] The above LAI offers several advantages over oral administration. It can alleviate withdrawal symptoms associated with non-compliance and maximize the pharmacodynamic range. Similarly, first-pass metabolism does not affect LAI, reducing the potential for drug-drug interactions.

[0194] In this study, the highest dose (36 mg IVL3001) SC formulation was very similar to the oral formulation on a 24-hour basis, but over the 28-day exposure period, 24 mg IVL3001 appeared most similar to Propecia 1 mg tablets when administered daily for 28 days. This finding is particularly relevant in cases where patients are non-compliant with their prescribed oral medication, suggesting a potential important role for LAI in the treatment of AGA.

[0195] Next, the importance of PK / PD analysis lies in understanding the correlation between drug concentration (PK) and pharmacological effect (PD). As observed in the above study, a single dose of IVL3001 achieved and maintained effective blood concentrations for more than 28 days without an initial burst effect. The sustained and rapid blood concentration observed within 30 minutes of administration suggests that IVL3001 may provide more convenient and longer-lasting therapeutic effects than daily oral dosage forms.

[0196] Specifically, administration of IVL3001 of the present invention resulted in peak concentrations observed between 500 and 700 hours after dosing, in contrast to the rapid increases and decreases observed after oral administration of Propecia 1 mg QD. Here, SC IVL3001 finasteride plasma concentrations appeared to remain consistent up to 672 hours, whereas typical trough levels were observed with daily oral finasteride administration.

[0197] As expected, the IVL3001 of the present invention showed Cmax measured at various doses consistent with the adopted concentration. In addition, C ss,avgThe results showed excellent drug concentrations at steady state. Furthermore, pharmacodynamic analysis revealed that IVL3001 exhibited significantly superior initial absorption, volume of distribution, and reduced clearance parameters compared to finasteride. Furthermore, pharmacodynamic analysis revealed that the efficacy of IVL3001 was similar to that of finasteride 1 mg QD when administered at doses higher than 24 mg Q4W, confirming the efficacy of IVL3001 SC injection. Furthermore, the t½ of IVL3001 was longer after SC injection than finasteride, which is consistent with previous reports of similar studies using other drugs. The remarkable bioavailability and blood-brain barrier penetration ability of finasteride with IVL3001 SC injection may explain these superior results.

[0198] Therefore, despite similar clearance (CL / F), the elimination half-life (t) of the same drug when administered via different routes 1 / 2el ) there is a significant difference, and in this trial, the mean elimination half-life for oral finasteride was 6.4 hours on day 1 and 6.9 hours on day 28. However, after IVL3001 administration, t 1 / 2el The elimination half-life ranges from 100 to 160 hours. Extensive hepatic metabolism converts finasteride primarily to inactive metabolites, which can then be eliminated via the biliary and urinary tracts. Subcutaneous administration bypasses the hepatic preferential passage effect, allowing a higher proportion of the administered dose to reach the systemic circulation. This may explain the longer elimination half-life, as the drug enters the systemic circulation without undergoing significant hepatic metabolism, as is the case with orally administered finasteride. Therefore, the increased stability of subcutaneously administered IVL3001 could result in a sustained and controlled release of the drug, potentially leading to a more predictable and uniform therapeutic effect than oral formulations.

[0199] Although the preferred embodiments of the present invention have been described in detail above, the scope of the present invention is not limited thereto, and various modifications and improvements made by those skilled in the art using the basic concept of the present invention defined in the following claims also fall within the scope of the present invention.

[0200] The present invention relates to a novel long-acting injectable composition comprising finasteride for the prevention or treatment of androgenetic alopecia.

Claims

1. The dosage of finasteride is 10 mg to 40 mg. Inhibition of androgen-mediated hair follicle miniaturization by finasteride for more than 1 month A novel long-acting injectable composition for the prevention or treatment of androgenetic alopecia.

2. In paragraph 1, The above injection composition is a subcutaneous injection (SC) formulation. A novel long-acting injectable composition for the prevention or treatment of androgenetic alopecia.

3. In paragraph 1, The average half-life (t) of finasteride in the body following administration of the above injection composition 1 / 2el ) is 100 to 160 hours. A novel long-acting injectable composition for the prevention or treatment of androgenetic alopecia.

4. In paragraph 1, The first-order absorption rate constant (Ka, h) of finasteride by the above injection composition -1 ) is 0.0005 to 0.0015 A novel long-acting injectable composition for the prevention or treatment of androgenetic alopecia.

5. In paragraph 1, The distribution volume (tvV, L) of finasteride in the central compartment of the above injection composition is 500 to 1500 A novel long-acting injectable composition for the prevention or treatment of androgenetic alopecia.

6. In paragraph 1, The distribution volume (tvV2, L) of finasteride to the peripheral compartment by the above injection composition is 0.1 to 0.

5. A novel long-acting injectable composition for the prevention or treatment of androgenetic alopecia.

7. In paragraph 1, The clearance rate (tvCL, L / h) of finasteride in the central compartment by the above injection composition is 5 to 15. A novel long-acting injectable composition for the prevention or treatment of androgenetic alopecia.

8. In paragraph 1, The clearance rate (tvCL2, L / h) between the central and peripheral compartments of finasteride by the above injection composition is 0.005 to 0.

015. A novel long-acting injectable composition for the prevention or treatment of androgenetic alopecia.

9. In paragraph 1, The maximum blood concentration (C) of finasteride by the above injection composition max , pg / mL) is 500 to 3,000 A novel long-acting injectable composition for the prevention or treatment of androgenetic alopecia.

10. In paragraph 1, The average concentration (C) of finasteride at steady state by the above injection composition ss,avg , pg / mL) is 1,000 to 6,000 A novel long-acting injectable composition for the prevention or treatment of androgenetic alopecia.

11. In paragraph 1, AUC (ACU) of finasteride from 0 to 672 hours by the above injection composition 0-672h , hr*pg / mL) is 500,000 to 2,000,000 A novel long-acting injectable composition for the prevention or treatment of androgenetic alopecia.

12. In paragraph 1, The AUC (AUCss, hr*pg / mL) of finasteride in the steady state by the above injection composition is 1,000,000 to 4,000,000. A novel long-acting injectable composition for the prevention or treatment of androgenetic alopecia.

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