Modified-release silodosin compositions and their use in methods for male contraception

Abstract

The present disclosure relates to a modified-release silodosin composition comprising at least one pellet comprising a silodosin drug layer and a sustained-release coating. The drug layer may comprise silodosin and a binder. The pellet may further comprise a seal coating. The pellet may further comprise an enteric coating. The present disclosure further relates to the use of the composition in a method for male contraception. The present disclosure further relates to a process for producing the pellets or dosage forms described herein.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 USC § 119(e) of U.S. Provisional Application No. 63 / 427,480, filed November 23, 2022, and the benefit under 35 USC § 119(a) of European Patent Application No. 22208994.8, filed November 23, 2022, the entire disclosures of which are incorporated herein by reference.

[0002] The technology described herein relates to modified-release silodosin compositions comprising silodosin-loaded pellets comprising a silodosin drug layer and an extended-release coating. The technology further relates to the use of such compositions in methods for male contraception. [Background technology]

[0003] Contraceptive methods for female subjects, including contraceptive compositions, can be traced back to the Middle Ages or even antiquity. Safer and more convenient pharmaceuticals for women gradually became available during the 20th century and are now part of everyday life almost everywhere around the world. In contrast, male contraception has historically been less popular, and men's interest in pharmacological contraception has remained fairly limited until modern times. Although state-of-the-art male contraceptive methods, such as condoms or vasectomies, have well-documented drawbacks and limitations, little effort has been made to find alternatives. As a result, men who wish to use oral contraceptives to reduce the emotional burden on their female partners, to assume birth control responsibilities, or to find alternatives to female contraception currently find that very few options are available.

[0004] When significant investments began to be directed into this field of research, the development of male contraceptives proved extremely difficult. By analogy with female contraceptive compositions, much of the early effort was focused on hormonal contraception. However, repeated administration of hormones to men is associated with psychological, behavioral, physiological, and sexual side effects that are generally considered unacceptable by the male subjects themselves. Among these, reported effects include decreased libido, "loss of masculinity" (e.g., erectile dysfunction, breast tenderness and enlargement, shrinkage of the testicles and penis, or loss of muscle mass), depression, possible suicidal thoughts, decreased mental clarity, weight gain, fatigue, and hot flashes. Hormonal compositions also have significant limitations in terms of dosage or injection schedule. Unlike women, men do not have a hormonal cycle, which limits the development of hormonal treatments suitable for both male menopause and male contraception.

[0005] Silodosin is an alpha-1 adrenergic receptor antagonist with high selectivity for the lower urinary tract (prostate, urethra, and bladder neck) (uroselectivity), and is marketed specifically under the trade names RAPAFLO® (USA), SILODYX®, or UROREC® (European Union) for the treatment of signs and symptoms of benign prostatic hyperplasia (BPH). Alpha-1 adrenergic receptors are present in arteries, smooth muscle, and central nervous system tissue. "Alpha-1 adrenergic receptor antagonists" refer to compounds that inhibit these receptors. Administration of alpha-1 adrenergic receptor antagonists to humans prevents the hormone norepinephrine from tightening the muscles in the walls of small arteries and veins, thereby keeping blood vessels open or relaxed. This improves blood flow and lowers blood pressure. Because male urinary tract smooth muscle contains a high density of alpha-1 adrenergic receptors, alpha-1 adrenergic receptor antagonists such as silodosin may be useful in improving urine flow in cases of prostate dysfunction, for example BPH.

[0006] During the treatment of BPH with silodosin, it has been found that silodosin can sometimes have the effect of causing azoospermia, azoospermia, or severe oligospermia, particularly the inability to ejaculate (azoospermia), in male subjects (KOBAYASHI, K. et al., International Journal of Impotence Research, June 2009, Vol. 21, pp. 306-310; SAKATA, K. et al., BMC Urology, 2012, Vol. 12, No. 29). Although these were initially considered side effects of BPH treatment, these results suggested that silodosin could potentially be used as a male contraceptive, leading to further investigation (Bhat, G. et al., Indian Journal of Urology, January 1, 2018, Vol. 34, No. 5, Suppl. 1, p. S7; Bhat, G. et al., World Journal of Urology, May 10, 2019, Vol. 38, pp. 747-751). However, the relevant scientific information provided by Bhat et al. was very limited, particularly due to the experimental setting. Therefore, Bhat et al. did their best to demonstrate that silodosin could potentially be used as an "on-demand" contraceptive method. In this method, oral contraceptives are taken in advance, just before intercourse. This is clearly inconvenient for the subjects involved. More importantly, "on-demand" contraceptives do not provide continuous contraception, let alone safe and reliable continuous contraception.

[0007] Therefore, early silodosin-based contraceptive compositions did not meet the needs of men who require a safe contraceptive method, especially one that guarantees long-lasting contraceptive efficacy. Furthermore, administration of silodosin is known to be associated with many undesirable sexually related side effects, such as discomfort during ejaculation, decreased orgasm quality, decreased erectile function, and decreased libido. Immediate-release (IR) silodosin compositions known in the art, such as those marketed for the treatment of BPH, were not suitable for the purpose of repositioning silodosin as a contraceptive.

[0008] WO 2019 / 180217A1 (LABORATOIRES MAJOR) discloses the use of an extended-release (ER) formulation containing silodosin in a non-hormonal contraceptive method for male subjects. In particular, WO 2019 / 180217A1 discloses ER granules of (R)-silodosin, identified as "Formulation A," having the structure and composition shown in Table 1 below. [Table 1]

[0009] Aquacoat® ECD is an aqueous ethylcellulose dispersion. Guar gum is a polysaccharide commonly used as a stabilizer or thickener. Dibutyl sebacate (DBS) is a dibutyl ester of sebacic acid commonly used as a plasticizer. In WO 2019 / 180217 A1, the ER formulation is administered once daily at approximately the same time each day to induce persistent, reversible azoospermia, azoospermia, or severe oligozoospermia in male subjects. Interestingly, delaying subsequent daily administration after an initial consecutive period of at least two days does not impair contraceptive efficacy. Thus, WO 2019 / 180217 A1 teaches that a male contraceptive method using "Formulation A" as the contraceptive composition provides safe contraception. The method of WO 2019 / 180217 A1 represents a significant improvement over state-of-the-art methods and compositions, particularly the IR silodosin composition used by Bhat et al. Summary of the Invention

[0010] The present disclosure provides further improvements in the physicochemical and / or biological properties of modified-release silodosin formulations for male oral contraceptives, including improvements addressing chemical stability of silodosin, intra-batch uniformity, inter-batch reproducibility, migration of silodosin within modified-release granules, stability of the release profile (e.g., dissolution profile) over time, side effects (especially sex-related effects), and contraceptive reliability with respect to subject compliance. Also provided are compositions that allow for easy determination or adjustment of the optimal dose ("dose range") of silodosin and / or the release rate of silodosin. In particular, the compositions described herein prevent or limit "burst release effect," which is the undesirable, uncontrollable, premature, and rapid release of the active ingredient. Improvements related to manufacturing process aspects also optimize parameters, for example, particularly those related to silodosin degradation and coating yield.

[0011] Further modified-release compositions are described herein, in which the modified-release effect is achieved by at least one pellet comprising an inert core, at least one drug layer applied to the inert core, the drug layer comprising silodosin and at least one binder, and at least one extended-release coating surrounding the drug layer or any seal coating. In certain embodiments, the pellet can further comprise at least one seal coating surrounding the drug layer. In other embodiments, the pellet can further comprise at least one enteric coating comprising at least one polymer selected from acrylate polymers, cellulose polymers, and mixtures thereof. In the technology described herein, the extended-release coating comprises at least one vinyl polymer, which the applicant has surprisingly found to be a highly suitable material for preparing modified-release silodosin compositions. In particular, the use of vinyl polymers unexpectedly overcomes some significant limitations of cellulose-based ER coatings (e.g., ethylcellulose) for silodosin formulations as contraceptives.

[0012] In one aspect, described herein are pellets comprising: (a) an inert core; (b) at least one drug layer applied to the inert core, the drug layer comprising silodosin and at least one binder; and (c) at least one extended release coating, the extended release coating comprising at least one vinyl polymer surrounding the drug layer.

[0013] In one embodiment of this aspect or any other aspect described herein, the pellet further comprises at least one seal coating surrounding the drug layer, wherein the extended release coating surrounds the seal coating.

[0014] In another embodiment of this aspect or any other aspect described herein, the binder comprises a cellulose polymer, hi another embodiment, the cellulose polymer is selected from the group consisting of hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose, methyl cellulose, ethyl cellulose, povidone, polyvinylpyrrolidone, and mixtures thereof.

[0015] In another embodiment of this or any other aspect described herein, the seal coating comprises at least one cellulose polymer. In another embodiment of this or any other aspect described herein, the cellulose polymer is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose, methyl cellulose, ethyl cellulose, and mixtures thereof.

[0016] In another embodiment of this or any other aspect described herein, the inert core comprises a cellulose polymer or a mixture thereof. In another embodiment of this or any other aspect described herein, the inert core comprises microcrystalline cellulose.

[0017] In another embodiment of this aspect or any other aspect described herein, the inert core has a particle size in the range of about 300-500 μm.

[0018] In another embodiment of this aspect or any other aspect described herein, the sustained-release coating comprises at least one polyvinyl ester polymer. In another embodiment of this aspect or any other aspect described herein, the polyvinyl ester polymer is a polyvinyl acetate polymer. In another embodiment of this aspect or any other aspect described herein, the polyvinyl acetate polymer is polyvinyl acetate (PVA). In another embodiment of this aspect or any other aspect described herein, the sustained-release coating further comprises povidone (PVP). In another embodiment of this aspect or any other aspect described herein, the sustained-release coating comprises about 90% w / w polyvinyl acetate (PVA) and about 9% w / w povidone (PVP), by weight of said sustained-release coating.

[0019] In another embodiment of this aspect or any other aspect described herein, the pellets further comprise one or more of at least one antioxidant, at least one anti-blocking agent, and / or anti-static agent, and / or at least one plasticizer. In another embodiment of this aspect or any other aspect described herein, the antioxidant is selected from phenol, vitamin E and its derivatives, vitamin C and its derivatives, propyl gallate, and mixtures thereof. In another embodiment of this aspect or any other aspect described herein, the antioxidant is selected from butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), α-tocopherol, ascorbyl palmitate, propyl gallate, and mixtures thereof. In another embodiment of this aspect or any other aspect described herein, the anti-blocking agent and / or anti-static agent is selected from inorganic carbonates, magnesium silicate, and mixtures thereof. In another embodiment of this aspect or any other aspect described herein, the anti-blocking agent and / or anti-static agent is selected from calcium carbonate (CaCO), talc, and mixtures thereof.

[0013] In another embodiment of this or any other aspect described herein, the plasticizer is a citrate ester.

[0014] In another embodiment of this or any other aspect described herein, the plasticizer is triethyl citrate (TEC).

[0020] In another embodiment of this aspect or any other aspect described herein, the pellet further comprises at least one enteric coating, wherein the enteric coating surrounds or is surrounded by the extended release coating and surrounds the seal coating or drug layer.

[0021] In another embodiment of this or any other aspect described herein, the enteric coating comprises at least one acrylate copolymer. In another embodiment of this or any other aspect described herein, the acrylate copolymer is a methacrylic acid / ethyl acrylate (MAE) copolymer.

[0022] In another embodiment of this aspect or any other aspect described herein, the pellet comprises Pellet A consisting essentially of about 24-95% w / w of an inert core, about 5-76% w / w of a drug layer comprising about 5-25% w / w of silodosin, about 0.1-7.5% w / w of a binder, about 0-20% w / w of at least one antioxidant, and about 0-25% w / w of at least one anti-adhesive and / or anti-static agent, by weight relative to the total weight of Pellet A.

[0023] In another embodiment of this aspect or any other aspect described herein, Pellet A is included in Pellet B, which consists essentially of about 90-100% w / w of Pellet A and about 0-10% w / w of at least one seal coating, by weight relative to the total weight of Pellet B.

[0024] In another embodiment of this aspect or any other aspect described herein, Pellet A or Pellet B is included in Pellet C, which consists essentially of a sustained release coating comprising about 50-98% w / w of Pellet A or Pellet B, about 0.5-47% w / w of at least one sustained release agent, about 0.02-7% w / w of at least one plasticizer, and about 0.3-23% w / w of at least one anti-sticking agent, by weight based on the total weight of Pellet C.

[0025] In another embodiment of this aspect or any other aspect described herein, pellet C is included in pellet D, which consists essentially of an enteric coating comprising about 50-95% w / w of pellet C, about 4-49.5% w / w of at least one enteric agent, and about 0.04-10% w / w of at least one plasticizer, by weight based on the total weight of pellet D.

[0026] In another embodiment of the pellets described herein, (a) a drug layer is applied to the inert core at a weight gain ranging from about 5 to 318%, (b) a seal coating is applied to the drug layer at a weight gain ranging from 0 to about 11%, (c) a sustained release coating is applied to the drug layer or seal coating at a weight gain ranging from about 2 to 100%, and / or (d) an enteric coating is applied to the sustained release coating at a weight gain ranging from 0 to about 100%.

[0027] In another embodiment of this aspect or any other aspect described herein, the pellet comprises: (a) an inert core comprising cellulose microspheres; (b) at least one drug layer applied to the inert core, the drug layer comprising silodosin, hydroxypropyl cellulose (HPC), calcium carbonate (CaCO), and butylhydroxytoluene (BHT); (c) at least one seal coating surrounding the drug layer, the seal coating comprising hydroxypropyl methylcellulose (HPMC); and (d) at least one extended-release coating surrounding the drug layer or any seal coating, the extended-release coating comprising polyvinyl acetate (PVA), polyvinylpyrrolidone (PVP), triethyl citrate (TEC), and talc.

[0028] In another embodiment of this aspect or any other aspect described herein, the pellet further comprises (e) at least one enteric coating surrounding or surrounded by the extended release coating and surrounding any seal coating or drug layer, the enteric coating comprising methacrylic acid / ethyl acrylate copolymer (1:1) (“MAE(1:1)”) and triethyl citrate (TEC).

[0029] In another aspect, described herein is a pharmaceutical composition comprising a plurality of pellets described herein. In one embodiment of this aspect or any other aspect described herein, the plurality of pellets is contained in a capsule. In one embodiment of this aspect or any other aspect described herein, the capsule is a hard-shell capsule. In one embodiment of this aspect or any other aspect described herein, the capsule is a functional capsule. In another embodiment of this aspect or any other aspect described herein, the capsule comprises an enteric-coated capsule.

[0030] In one embodiment of this aspect or any other aspect described herein, the plurality of pellets comprises silodosin in an amount ranging from about 4 to 32 mg. In another embodiment of this aspect or any other aspect described herein, the plurality of pellets comprises silodosin in an amount ranging from about 8 to 28 mg. In another embodiment of this aspect or any other aspect described herein, the plurality of pellets comprises silodosin in an amount ranging from about 12 to 24 mg.

[0031] In another aspect, described herein is a method of contraception for a male subject, comprising administering to the male subject a pharmaceutical composition described herein at approximately the same time each day.

[0032] In another aspect, described herein is a process for producing a plurality of pellets described herein or a pharmaceutical composition described herein, the process comprising: (1-a) preparing a drug solution or a drug suspension comprising the drug solution, the drug solution comprising silodosin, at least one binder, and at least one solvent; (1-b) applying the drug solution or drug suspension to a plurality of inert cores, thereby obtaining a plurality of pellets A; (2-a) applying a seal coating suspension to the plurality of pellets A, thereby obtaining a plurality of pellets B; (3-a) preparing a sustained release coating suspension comprising at least one sustained release coating agent, at least one plasticizer, and at least one anti-adherent agent; and then (3-b) applying the sustained release coating suspension to the plurality of pellets A or the plurality of pellets B, thereby obtaining a plurality of pellets described herein. In one embodiment of this or any other aspect described herein, the step of preparing a seal coating suspension comprising at least one seal coating agent occurs before step (2-a). In another embodiment of this or any other aspect described herein, the drug solution in step (1-a) contains at least one antioxidant. In another embodiment of this aspect or any other aspect described herein, the drug solution of step (1-a) contains at least one anti-adherent and / or anti-static agent.

[0033] In another aspect, described herein is a process for producing a plurality of pellets described herein or a pharmaceutical composition described herein, the process comprising the steps of: (1-a) preparing a drug solution or a drug suspension comprising the drug solution, the drug solution comprising silodosin, at least one binder, and at least one solvent; (1-b) applying the drug solution or drug suspension to a plurality of inert cores, thereby obtaining a plurality of pellets A; (2-a) applying a seal coating suspension to the plurality of pellets A, thereby obtaining a plurality of pellets B; (3-a) preparing a sustained release coating suspension comprising at least one sustained release coating agent, at least one plasticizer, and at least one anti-adherent agent; then (3'-b) applying the sustained release coating suspension to the plurality of pellets A or the plurality of pellets B, thereby obtaining a plurality of pellets C; (4'-a) preparing an enteric coating suspension comprising at least one enteric coating agent and at least one plasticizer; then (4'-b) applying the enteric coating suspension to the plurality of pellets C, thereby obtaining a plurality of pellets described herein. In one embodiment of this aspect or any other aspect described herein, a step of preparing a seal coating suspension comprising at least one seal coating agent occurs before step (2-a). In another embodiment of this aspect or any other aspect described herein, the drug solution of step (1-a) contains at least one antioxidant. In another embodiment of this aspect or any other aspect described herein, the drug solution of step (1-a) contains at least one anti-adherent and / or anti-static agent.

[0034] In another aspect, described herein is a process for producing a plurality of pellets described herein or a pharmaceutical composition described herein, the process comprising the steps of: (1-a) preparing a drug solution or a drug suspension comprising the drug solution, the drug solution comprising silodosin, at least one binder, and at least one solvent; (1-b) applying the drug solution or drug suspension to a plurality of inert cores, thereby obtaining a plurality of pellets A; (2-a) applying a seal coating suspension to the plurality of pellets A, thereby obtaining a plurality of pellets B; (3"-a) preparing an enteric coating suspension comprising at least one enteric coating agent and at least one plasticizer; then (3"-b) applying the enteric coating suspension to the plurality of pellets A or the plurality of pellets B, thereby obtaining a plurality of pellets E; (4"-a) preparing an extended release coating suspension comprising at least one extended release coating agent, at least one plasticizer, and at least one anti-adherent; then (4"-b) applying the extended release coating suspension to the plurality of pellets E, thereby obtaining a plurality of pellets described herein. In one embodiment of this aspect or any other aspect described herein, a step of preparing a seal coating suspension comprising at least one seal coating agent occurs before step (2-a). In another embodiment of this aspect or any other aspect described herein, the process further comprises filling the resulting plurality of pellets into at least one capsule, thereby obtaining a pharmaceutical composition described herein. In another embodiment of this aspect or any other aspect described herein, the drug solution or drug suspension of step (1-a) contains at least one antioxidant. In another embodiment of this aspect or any other aspect described herein, the drug solution or drug suspension of step (1-a) contains at least one anti-adherent and / or anti-static agent.

[0035] The technology described herein relates to pellets comprising: (a) an inert core; (b) at least one drug layer applied to the inert core, the drug layer comprising silodosin and at least one binder; (c) optionally, at least one seal coating surrounding the drug layer; and / or (d) at least one sustained-release coating surrounding the drug layer or any seal coating, the sustained-release coating comprising at least one vinyl polymer.

[0036] According to some embodiments, the binder is selected from cellulose polymers, preferably the binder is selected from hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose, methyl cellulose, ethyl cellulose, povidone, polyvinylpyrrolidone and mixtures thereof.

[0037] According to some embodiments, the optional seal coating comprises at least one cellulose polymer, preferably the cellulose polymer is selected from hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose, methylcellulose, ethylcellulose, and mixtures thereof.

[0038] According to some embodiments, the inert core comprises cellulose polymers and mixtures thereof, preferably the inert core comprises microcrystalline cellulose and / or the inert core has a particle size in the range of about 300-500 μm.

[0039] According to some embodiments, the sustained release coating comprises at least one polyvinyl ester polymer, preferably a polyvinyl acetate polymer, more preferably polyvinyl acetate (PVA).

[0040] According to some embodiments, the pellets further comprise at least one antioxidant, preferably the antioxidant is selected from phenol, vitamin E and its derivatives, vitamin C and its derivatives, propyl gallate and mixtures thereof, more preferably the antioxidant is selected from butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), α-tocopherol, ascorbyl palmitate, propyl gallate and mixtures thereof, at least one anti-blocking and / or anti-static agent, preferably the anti-blocking and / or anti-static agent is selected from inorganic carbonates, magnesium silicate and mixtures thereof, more preferably the anti-blocking and / or anti-static agent is selected from calcium carbonate (CaCO), talc and mixtures thereof, and / or at least one plasticizer, preferably the plasticizer is selected from citrate esters, more preferably the plasticizer is triethyl citrate (TEC).

[0041] According to some embodiments, the pellets further comprise (e) at least one enteric coating surrounding or surrounded by the sustained-release coating and surrounding any seal coating or drug layer. In some embodiments, the enteric coating comprises at least one acrylate copolymer, preferably a methacrylic acid / ethyl acrylate (MAE) copolymer.

[0042] According to some embodiments, the pellets comprise: Pellet A consisting essentially of about 24 to 95% w / w of an inert core, about 5 to 76% w / w of a drug layer containing about 5 to 25% w / w of silodosin, about 0.1 to 7.5% w / w of a binder, about 0 to 20% w / w of at least one antioxidant, and about 0 to 25% w / w of at least one anti-adhesive agent and / or anti-static agent, based on the total weight of pellet A. Including, Pellet A is optionally contained in Pellet B consisting essentially of at least one seal coating surrounding about 90-100% Pellet A and about 0-10% w / w drug layer, based on the total weight of Pellet B; Pellet A or any pellet B is contained in pellet C consisting essentially of a sustained release coating comprising about 50-98% w / w of pellet A or any pellet B, about 0.5-47% w / w of at least one sustained release agent, about 0.02-0.7% w / w of at least one plasticizer, and about 0.3-23% w / w of at least one anti-adherent agent, by weight based on the total weight of pellet C; and Pellets C are optionally contained in pellets D, which consist essentially of an enteric coating comprising about 50-95% w / w of pellets C, about 4-49.5% w / w of at least one enteric agent, and about 0.04-10% w / w of at least one plasticizer, by weight based on the total weight of any pellet D.

[0043] According to some embodiments, (b) the drug layer is applied to the inert core at a weight gain ranging from about 5 to 318%, (c) the optional seal coating is applied to the drug layer at a weight gain ranging from 0 to about 11%, (d) the sustained release coating is applied to the drug layer or the optional seal coating at a weight gain ranging from about 2 to 100%, and / or (e) the optional enteric coating is applied to the sustained release coating at a weight gain ranging from 0 to about 100%.

[0044] The technology described herein further relates to a dosage form comprising a plurality of the pellets described herein. According to some embodiments, the plurality of pellets is contained in a capsule, preferably a hard-shell capsule and / or a functional capsule (e.g., an enteric-coated capsule). According to some embodiments, the plurality of pellets comprises silodosin in an amount ranging from about 4 to 32 mg, preferably from about 8 to 28 mg, and more preferably from about 12 to 24 mg.

[0045] The technology described herein further relates to a method of contraception for a male subject, comprising administering to the male subject a dosage form described herein at approximately the same time each day.

[0046] The technology described herein further provides a process for producing a plurality of pellets described herein or a dosage form described herein, comprising: (1-a) preparing a drug solution or a drug suspension comprising the drug solution, comprising silodosin, at least one binder, at least one solvent, and optionally at least one antioxidant and optionally at least one anti-adherent and / or anti-static agent; then (1-b) applying the drug solution or drug suspension to a plurality of inert cores, thereby obtaining a plurality of pellets A; (2-a) optionally preparing a seal coating suspension comprising at least one seal coating agent; then (2-b) applying the seal coating suspension to the plurality of pellets A, thereby obtaining a plurality of pellets B; (3-a) preparing a sustained release coating suspension comprising at least one sustained release coating agent, at least one plasticizer, and at least one anti-adherent; then (3-b) applying the sustained release coating suspension to the plurality of pellets A or any of a plurality of pellets B, thereby obtaining a plurality of pellets described herein. or (3'-a) preparing a sustained release coating suspension comprising at least one sustained release coating agent, at least one plasticizer, and at least one anti-adherent agent, then (3'-b) applying the sustained release coating suspension to a plurality of pellets A or any plurality of pellets B, thereby obtaining a plurality of pellets C; (4'-a) preparing an enteric coating suspension comprising at least one enteric coating agent and at least one plasticizer, then (4'-b) applying the enteric coating suspension to a plurality of pellets C, thereby obtaining a plurality of pellets described herein; or (3"-a) preparing an enteric coating suspension comprising at least one enteric coating agent and at least one plasticizer, then (3"-b) applying the enteric coating suspension to a plurality of pellets A or any plurality of pellets B, thereby obtaining a plurality of pellets E; (4"-a) preparing a sustained release coating suspension comprising at least one sustained release coating agent, at least one plasticizer, and at least one anti-adherent agent;Then, (4''-b) applying the sustained-release coating suspension to the plurality of pellets E, thereby obtaining the plurality of pellets described herein, and (5) optionally, filling the obtained plurality of pellets into at least one capsule, thereby obtaining the dosage form described herein.

[0047] definition In this disclosure, the following terms have the following meanings unless otherwise specified.

[0048] "About" is used herein to mean "approximately," "roughly," "around," or "in the range of." When the word "about" precedes a number, it means ±10% of the value of said number ("plus or minus 10% of the value" or "10% more or less than the value"). When the word "about" is used in conjunction with a numerical range, it modifies that range by expanding the limits above and below the stated numerical values ​​by 10%.

[0049] "Active ingredient" or "active pharmaceutical ingredient" or "drug" (abbreviated "API") are synonymous and refer collectively to contraceptives, therapeutic agents, and agents that are both contraceptives and therapeutic agents.

[0050] "Administration" or variations thereof (eg, "administering") means providing the active ingredient, alone or as part of a pharmaceutically acceptable composition, to the subject on whom contraception is to be administered.

[0051] "Azoospermia" refers to the inability to produce or ejaculate semen.

[0052] "Azoospermia" refers to the absence of sperm in semen.

[0053] "Binder" refers to a substance that holds or attracts other substances or materials together to form a cohesive body mechanically or chemically, or by adhesion or cohesion.

[0054] "Coating agent" refers to an agent that, when applied to the surface of a substrate and optionally subjected to a final processing step (e.g., curing, setting, polymerizing, or crosslinking), results in a "coating material" (or "coating" for short) that covers the surface of the substrate.

[0055] "Contraception" refers to preventative measures aimed at preventing or at least reducing the risk of pregnancy. In the technology described herein, the purpose of contraception is to prevent fertilization, i.e., avoiding the fusion of gametes (e.g., the union of a human egg and sperm). Individuals in need of contraception are typically subjects of childbearing age who wish to avoid pregnancy regardless of their fertility status. Contraception can be irreversible or reversible, although many subjects prefer reversible. When contraception is achieved by preventing a male subject from becoming pregnant, it is referred to as "male contraception" (or "male subject contraception"). In preferred embodiments, contraception involves inducing persistent azoospermia, azoospermia, or severe oligozoospermia in a male subject. In these embodiments, the contraception is male contraception.

[0056] "Contraceptive" refers to compounds related to birth control for contraceptive use. Specifically, contraceptives may be prescribed to prevent pregnancy. They may also be prescribed to enhance the contraceptive effect of another contraceptive.

[0057] "Contraceptive composition" (abbreviated "contraceptive") refers to a composition related to birth control for contraceptive use. In particular, a contraceptive composition may be formulated to prevent pregnancy. A contraceptive composition may also be formulated to enhance the contraceptive effect of another contraceptive composition.

[0058] "Contraceptive method" refers to a method intended to induce or maintain contraception in a subject. A contraceptive method may include the definition of at least one subject and / or an administration scheme.

[0059] "Delayed release" (abbreviated "DR") refers to the release of an active ingredient (e.g., silodosin) from a composition in which the API is not released immediately after administration to a subject, as opposed to an immediate release (IR) composition containing the same API at the same dosage. A "delayed release composition" is a composition suitable for obtaining a DR release of the API contained therein after its administration to a subject. A "delayed release coating" is a coating that contributes to making the composition "delayed-release" as defined herein. The European Pharmacopoeia defines "delayed release" as follows: "Delayed-release dosage forms are modified-release dosage forms, usually administered orally, that are adapted so that the onset of release of the active substance occurs after a specific time or at a specific location in the gastrointestinal tract." Delayed release is achieved by special formulation design and / or manufacturing methods. Delayed-release dosage forms include enteric-coated formulations that meet the above definition.

[0060] "Enteric coating" refers to a barrier (typically a polymer coating) applied to an oral drug to prevent its dissolution or disintegration in the gastric environment. Enteric coatings serve to protect the drug from stomach acidity, protect the stomach from the drug's harmful effects, or release the drug after the stomach (usually in the upper intestine). Typically, enteric coatings are expected to dissolve at a pH of about 5.5 or higher. In particular, enteric coatings can help avoid or reduce the effect of the stomach's acidic environment on the release rate of the active ingredient. Based on the effects of this last category, enteric coatings can be considered a specific type of "delayed-release" coating. "Enteric" refers to a drug that, when applied to the surface of a substrate and optionally subjected to final processing steps (e.g., curing, setting, polymerization, or crosslinking), results in an "enteric coating" (as defined herein) covering the surface of that substrate.

[0061] "Extended release" (abbreviated "ER") refers to the release of an active ingredient (e.g., silodosin) from a composition in which the active ingredient (API) is released over time after administration to a subject, as opposed to an immediate release (IR) composition containing the same API at the same dosage. A "extended release composition" is a pharmaceutical composition suitable for obtaining ER release of the API contained therein after its administration to a subject. A "extended release coating" is a coating that contributes to making a composition "extended-release," as defined herein. A "extended-release agent" refers to an agent that, when applied to the surface of a substrate and optionally subjected to a final processing step (e.g., curing, setting, polymerization, or crosslinking), results in a "extended-release coating" (defined herein) covering the surface of the substrate.

[0062] "Human" refers to a male or female human subject at any stage of development, including newborns, infants, juveniles, adolescents, and adults. In some preferred embodiments, the human is a male subject. In some preferred embodiments, the human is an adolescent or adult subject.

[0063] "Modified release" (abbreviated "MR") refers to the release of an active ingredient (e.g., silodosin) from a composition that comprises at least one modification of the release of the active ingredient (API) after administration to a subject, when compared to an immediate release (IR) composition containing the same API at the same dosage. According to some embodiments, "modified release" refers to "extended release (ER)" with at least one modification of the release of the API. In some embodiments, "modified release" refers to "extended release (ER)" and "delayed release (DR)," i.e., a release that is both extended and delayed (DR+ER). A "modified release composition" is a pharmaceutical composition suitable for obtaining modified release of an API contained therein after its administration to a subject. A "modified release coating" is a coating that contributes to making the composition "modified release" as defined herein.

[0064] "Pellets" or "granules" refer to small compressed masses of hard material. Typically, pellets contain a core surrounded by multiple continuous coatings.

[0065] A "pharmaceutical composition" refers to a composition comprising at least one active ingredient (e.g., silodosin) and at least one pharmaceutically acceptable carrier. Thus, a contraceptive composition may be a "pharmaceutical composition" within the meaning of the present disclosure.

[0066] "Pharmaceutically acceptable" means that the components of the composition are compatible with each other and not harmful to the subject to which they are administered.

[0067] A "pharmaceutically acceptable carrier" refers to an excipient that does not produce adverse, allergic, or other untoward reactions when administered to animals, preferably humans. It includes any and all solvents, i.e., dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. For human administration, formulations must meet sterility, pyrogenicity, general safety, and purity standards required by regulatory authorities, such as the FDA or EMA. Examples of pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, salts or electrolytes such as zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances (e.g., sodium carboxymethylcellulose), polyethylene glycol, polyacrylates, waxes, polyethylene / polyoxypropylene block polymers, polyethylene glycol, and wool fat.

[0068] "Plasticizer" refers to a substance added to a material to make it soft and flexible, increase its plasticity, decrease its viscosity, and / or reduce friction during its handling during manufacturing.

[0069] The term "polymer" following a term referring to a general class of polymer (e.g., "acrylate polymer") refers to any homopolymer, copolymer, and mixtures thereof belonging to the indicated class. For example, reference to "acrylate polymer" encompasses "acrylate homopolymer," "acrylate copolymer," and any mixtures thereof. Copolymers may be block, alternating, and / or random. Copolymers also include monomers that do not belong to the indicated class but are polymerizable by the same pathway.

[0070] "Prodrug" refers to a pharmacologically acceptable derivative of an active ingredient (e.g., silodosin), the in vivo biotransformation product of which is the active ingredient (active drug). Prodrugs are typically characterized by increased bioavailability and are readily metabolized in vivo to active compounds. Non-limiting examples of prodrugs include amide prodrugs and carboxylic acid ester prodrugs.

[0071] "Severe oligozoospermia" refers to semen with a low total sperm count or a low sperm concentration, typically about 5 × 10 per ejaculate 6 less than 1 x 10 per ejaculate, preferably about 1 x 10 6 There are less than 100 pieces.

[0072] A "solvate" refers to a molecular complex containing a compound (e.g., silodosin) and a stoichiometric or substoichiometric amount of one or more pharmaceutically acceptable solvent molecules, such as ethanol. The term "hydrate" refers to when the solvent is water.

[0073] "Subject" refers to an animal, typically a warm-blooded animal, particularly a mammal, more particularly a primate, preferably a human. The subject may also be a "patient." The subject may be referred to as a "male subject" or a "female subject" depending on the subject's respective gender. In a preferred embodiment, the subject is a male subject. In a preferred embodiment, the subject is in need of contraception.

[0074] As used herein, the terms "comprising" or "comprises" are used in reference to compositions, methods and their respective components essential to the invention, which may include unspecified elements, whether essential or not.

[0075] As used herein, the term "consisting essentially of" refers to elements required for a given embodiment. The term permits the presence of additional elements that do not materially affect the basic and novel or functional characteristics of the embodiment of this invention.

[0076] The term "consisting of" refers to compositions, methods, and their respective components described herein, excluding any element not recited in the description of the embodiment.

[0077] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "the method" includes one or more methods, and / or steps of the type described herein and / or that will become apparent to those skilled in the art upon reading this disclosure, and so forth. DETAILED DESCRIPTION OF THE INVENTION

[0078] pellet One objective of the techniques described herein is to (a) an inert core; (b) at least one drug layer applied to the inert core, the drug layer comprising silodosin and at least one binder; (d) at least one sustained release coating, the sustained release coating comprising at least one vinyl polymer surrounding the drug layer; The pellets include:

[0079] According to some embodiments, the pellets have a near-spherical or spherical shape, i.e., the pellets are "spherical" or "spheres." In some embodiments, the spheres are solid spheres (or "spheres").

[0080] Inert Core "Inert core" means that the core is chemically inert (or "neutral"), so that it does not react with the active ingredient. The core may be inert, for example, by the nature of its material or by the presence of an insulating coating.

[0081] According to some embodiments, the inert core has a near-spherical or spherical shape, i.e., the inert core is "spherical" or "spherical." In some embodiments, the sphere is a "hollow" sphere. In some embodiments, the sphere is a "solid" sphere (or "sphere").

[0082] According to some embodiments, the inert core has a particle size in the range of about 106-850 μm (at least 85% of the particles fall within this range). In some embodiments, the inert core has a particle size in the range of about 106-212 μm (at least 85% of the particles fall within this range). In some embodiments, the inert core has a particle size in the range of about 150-300 μm (at least 85% of the particles fall within this range). In some embodiments, the inert core has a particle size in the range of about 300-500 μm (at least 85% of the particles fall within this range). In some embodiments, the inert core has a particle size in the range of about 500-710 μm (at least 85% of the particles fall within this range). In some embodiments, the inert core has a particle size in the range of about 710-850 μm (at least 85% of the particles fall within this range). In some preferred embodiments, the inert core has a particle size in the range of about 300-500 μm (at least 85% of the particles fall within this range).

[0083] According to some embodiments, the inert core has a particle size in the range of about 100-1400 μm (at least 85% of the particles fall within this range). In some embodiments, the inert core has a particle size in the range of about 100-200 μm (at least 85% of the particles fall within this range). In some embodiments, the inert core has a particle size in the range of about 200-355 μm (at least 85% of the particles fall within this range). In some embodiments, the inert core has a particle size in the range of about 350-500 μm (at least 85% of the particles fall within this range). In some embodiments, the inert core has a particle size in the range of about 500-710 μm (at least 85% of the particles fall within this range). In some embodiments, the inert core has a particle size in the range of about 700-1000 μm (at least 85% of the particles fall within this range). In some embodiments, the inert core has a particle size in the range of about 1000-1400 μm (at least 85% of the particles fall within this range).

[0084] "Particle size" refers to particle width as measured by sieve analysis. A sieve stack consists of several sieves with gradually increasing openings. A sample is placed on the top sieve and the stack is shaken. As a result, particles are distributed among the sieves in the stack according to their size.

[0085] The present applicant unexpectedly found that, in producing a silodosin composition, the yield of the step of applying a drug layer (silodosin) to an inert core is high enough for industrial needs. The present applicant surprisingly discovered that the use of inert cores having an average particle size in the range of about 300 to 500 μm can significantly improve the coating performance of the drug layer on the inert core (up to 95%).

[0086] According to some embodiments, the inert core comprises cellulose polymers and mixtures thereof. In some specific embodiments, the inert core comprises microcrystalline cellulose (MCC). In some preferred embodiments, the microcrystalline cellulose is Celphere™ (Asahi Kasei, Japan).

[0087] Silodosin "Silodosin" is the compound 1-(3-hydroxypropyl)-5-[2-[[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]amino]propyl]indoline-7-carboxamide (C 25 H 32 F3N3O4, MW 495.53 g / mol).

[0088] According to some preferred embodiments, silodosin is in the form of its (R)-stereoisomer, i.e., "(R)-silodosin." (R)-Silodosin is formally known as (-)-(R)-1-(3-hydroxypropyl)-5-[2-[[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]amino]propyl]indoline-7-carboxamide. (R)-Silodosin has the following formula: [ka] It has.

[0089] (R)-Silodosin is a white or pale yellow / white powder (melting point: approximately 105-109°C). It is very soluble in acetic acid, freely soluble in alcohol, and very slightly soluble in water.

[0090] All references to "silodosin" include references to salts, solvates, multi-component complexes and / or liquid crystals thereof. All references to "silodosin" include references to polymorphs and / or crystal habits thereof. All references to "silodosin" include references to pharmaceutically acceptable prodrugs thereof. All references to "silodosin" include references to isotopically labeled silodosin, including deuterated silodosin.

[0091] Silodosin may be in the form of a pharmaceutically acceptable salt.The pharmaceutically acceptable salt of silodosin includes its acid addition salt and base salt.Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and xinafoate. Suitable base salts are formed from bases which form non-toxic salts, examples of which include the aluminum, arginine, benzathine, calcium, choline, diethylamine, 2-(diethylamino)ethanol, diolamine, ethanolamine, glycine, 4-(2-hydroxyethyl)morpholine, lysine, magnesium, meglumine, morpholine, olamine, potassium, sodium, tromethamine, and zinc salts.

[0092] Silodosin may be polymorphic or amorphous. According to some embodiments, silodosin is polymorphic. According to some embodiments, silodosin is amorphous.

[0093] Silodosin may be in the form of a pharmaceutically acceptable solvate, including a hydrate thereof.

[0094] Binder According to some embodiments, the binder is selected from cellulose polymers. In some embodiments, the binder is selected from hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose, methyl cellulose, ethyl cellulose, povidone, polyvinylpyrrolidone, and mixtures thereof. In some preferred embodiments, the binder is hydroxypropyl cellulose (HPC).

[0095] antioxidants According to some embodiments, the pellet further comprises at least one antioxidant. In some preferred embodiments, the drug layer comprises at least one antioxidant.

[0096] In some embodiments, the antioxidant is selected from phenol, vitamin E and its derivatives, vitamin C and its derivatives (e.g., ascorbic acid), citric acid, propanoic acid (propionic acid), erythorbic acid (or "D-erythro-hex-2-enosono-1,4-lactone"), fumaric acid (or "(2E)-but-2-enedioic acid"), malic acid (or "2-hydroxybutanedioic acid") methionine, potassium metabisulfite, sodium metabisulfite, propyl gallate, sodium ascorbate, sodium thiosulfate, polyethylene glycol succinate (PGS), and mixtures thereof. In some embodiments, the vitamin E derivative is selected from d-alpha tocopherol, dl-alpha tocopherol, d-alpha tocopherol acetate, dl-alpha tocopherol acetate, d-alpha tocopheryl succinate, dl-alpha tocopheryl succinate, beta tocopherol, delta tocopherol, gamma tocopherol, vitamin E polyethylene glycol succinate (tocophersolan) (also known as "vitamin E TPGS"), and mixtures thereof. In some embodiments, the vitamin C derivative is selected from ascorbic acid, ascorbyl palmitate, erythorbic acid, sodium ascorbate, and mixtures thereof.

[0097] In some embodiments, the antioxidant is selected from phenol, vitamin E and its derivatives, vitamin C and its derivatives, propyl gallate, and mixtures thereof. In some embodiments, the antioxidant is selected from butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), α-tocopherol, ascorbyl palmitate, propyl gallate, and mixtures thereof.

[0098] In some embodiments, the antioxidant is selected from phenols. In some embodiments, the antioxidant is selected from butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), and mixtures thereof. In some preferred embodiments, the antioxidant is butylhydroxytoluene (BHT).

[0099] In some embodiments, the antioxidant is selected from vitamin E and its derivatives. In some preferred embodiments, the antioxidant is alpha-tocopherol.

[0100] In some embodiments, the antioxidant is selected from vitamin C and its derivatives. In some embodiments, the antioxidant is ascorbyl palmitate.

[0101] Anti-blocking and / or anti-static agents According to some embodiments, the pellets further comprise at least one anti-adhesive and / or anti-static agent. In some preferred embodiments, the drug layer comprises at least one anti-adhesive and / or anti-static agent. In some preferred embodiments, the sustained-release coating comprises at least one anti-adhesive and / or anti-static agent.

[0102] In some embodiments, the anti-blocking and / or anti-static agent is selected from calcium carbonate (CaCO), talc, calcium phosphate, tribasic calcium silicate, colloidal silicon dioxide, hydrophobic colloidal silica, magnesium oxide, magnesium silicate, magnesium trisilicate, and mixtures thereof.

[0103] In some embodiments, the anti-blocking and / or anti-static agent is selected from inorganic carbonates, magnesium silicate, and mixtures thereof, hi some embodiments, the anti-blocking and / or anti-static agent is selected from calcium carbonate (CaCO), talc, and mixtures thereof.

[0104] In some embodiments, the anti-adhesive and / or anti-static agent is selected from inorganic carbonates. In some embodiments, the anti-adhesive and / or anti-static agent is calcium carbonate (CaCO3). In some preferred embodiments, the drug layer comprises calcium carbonate (CaCO3).

[0105] In some embodiments, the anti-adhesive and / or anti-static agent is selected from magnesium silicate. In some embodiments, the anti-adhesive and / or anti-static agent is talc. In some preferred embodiments, the sustained release coating comprises talc.

[0106] plasticizer According to some embodiments, the pellets further comprise at least one plasticizer. In some preferred embodiments, the sustained-release coating comprises at least one plasticizer. The pellets may further comprise an enteric coating, as described hereinafter, and in some preferred embodiments, this optional enteric coating comprises at least one plasticizer.

[0107] In some embodiments, the plasticizer is selected from citrate esters, hi some preferred embodiments, the plasticizer is triethyl citrate (TEC).

[0108] In some embodiments, the plasticizer is selected from a diol, hi some embodiments, the plasticizer is 1,2-propylene glycol.

[0109] Seal Coating According to some preferred embodiments, the pellet further comprises (c) at least one seal coating surrounding the drug layer, and the sustained-release coating then surrounds any seal coating in place of the drug layer.

[0110] The present applicant has unexpectedly found that in silodosin ER compositions, migration of silodosin into the ER coating is sometimes observed. The present applicant has surprisingly discovered that the inclusion of an optional seal coating can significantly prevent migration of silodosin into the ER coating (particularly when an ethyl cellulose ER coating, such as Aquacoat® ECD, is used). The present applicant has further surprisingly discovered that the inclusion of a seal coating can significantly prevent interaction of silodosin with the ER coating (particularly a vinyl polymer ER coating, such as Kollicoat® SR 30 D).

[0111] In some embodiments, the optional seal coating comprises at least one cellulose polymer, hi some embodiments, the cellulose polymer is selected from hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose, methyl cellulose, ethyl cellulose, and mixtures thereof.

[0112] In some preferred embodiments, the optional seal coating comprises hydroxypropyl methylcellulose (HPMC). In some preferred embodiments, the optional seal coating is obtained by application of the coating agent Opadry® (Colorcon, US).

[0113] Sustained-Release Coating In the pellets described herein, the seal coating (if present) and the sustained release coating are different coatings. In other words, the same coating cannot simultaneously be a "seal coating" and a "sustained release coating" as used in this application.

[0114] According to some embodiments, the sustained release coating comprises at least one polyvinyl ester polymer. In some embodiments, the sustained release coating comprises at least one polyvinyl acetate polymer. In some preferred embodiments, the sustained release coating comprises polyvinyl acetate (PVA), i.e., PVA as a homopolymer. In some preferred embodiments, the sustained release coating comprises polyvinylpyrrolidone (PVP) (also commonly referred to as "polyvidone" or "povidone"). In some embodiments, the sustained release coating comprises a mixture of vinyl polymers. In some preferred embodiments, the sustained release coating comprises polyvinyl acetate (PVA) and polyvinylpyrrolidone (PVP).

[0115] According to some embodiments, the sustained-release coating comprises at least one additive typically found in coatings. In some embodiments, the sustained-release coating comprises at least one dispersing agent and / or at least one surfactant. Typically, the dispersing agent and / or surfactant may be present in the polymer coating, for example, to stabilize the dispersion before the coating is applied during the manufacturing process. In some embodiments, the sustained-release coating comprises at least one dispersing agent. The dispersing agent may comprise, for example, povidone (PVP). In some embodiments, the sustained-release coating comprises at least one surfactant. The surfactant may comprise, for example, sodium lauryl sulfate (SLS).

[0116] In some embodiments, the sustained release coating comprises about 70%-99% w / w of a polyvinyl acetate (PVA) polymer or copolymer by weight of the sustained release coating. In some embodiments, the sustained release coating comprises about 75%-99% w / w, preferably about 80%-98% w / w, and more preferably about 85%-95% w / w of a polyvinyl acetate (PVA) polymer or copolymer by weight of the sustained release coating. In some embodiments, the sustained release coating comprises at least about 70% w / w, at least about 75% w / w, at least about 80% w / w, at least about 85% w / w, or at least about 90% w / w of a polyvinyl acetate (PVA) polymer or copolymer by weight of the sustained release coating. In some preferred embodiments, the sustained release coating comprises about 90% w / w of a polyvinyl acetate (PVA) polymer or copolymer by weight of the sustained release coating.

[0117] In some embodiments, the sustained-release coating comprises about 6% to 15% w / w polyvinylpyrrolidone (PVP) by weight of the sustained-release coating. In some embodiments, the sustained-release coating comprises about 6% to 15% w / w polyvinylpyrrolidone (PVP), preferably about 7% to 13% w / w polyvinylpyrrolidone (PVP), and more preferably about 8% to 11% w / w polyvinylpyrrolidone (PVP), by weight of the sustained-release coating. In some embodiments, the sustained-release coating comprises no more than about 15% w / w polyvinylpyrrolidone (PVP), no more than about 14% w / w polyvinylpyrrolidone (PVP), no more than about 13% w / w polyvinylpyrrolidone (PVP), no more than about 12% w / w polyvinylpyrrolidone (PVP), no more than about 11% w / w polyvinylpyrrolidone (PVP), or no more than about 10% w / w polyvinylpyrrolidone (PVP), by weight of the sustained-release coating. In some preferred embodiments, the sustained-release coating comprises about 9% w / w polyvinylpyrrolidone (PVP), by weight of the sustained-release coating.

[0118] In some preferred embodiments, the sustained-release coating comprises sodium lauryl sulfate (SLS). In some embodiments, the sustained-release coating comprises about 0.6% to 1.5% w / w of sodium lauryl sulfate (SLS) by weight of the sustained-release coating. In some embodiments, the sustained-release coating comprises about 0.6% to 1.5% w / w, preferably about 0.7% to 1.3% w / w, and more preferably about 0.8% to 1.1% w / w of sodium lauryl sulfate (SLS) by weight of the sustained-release coating. In some embodiments, the sustained-release coating comprises about 1.5% w / w or less, about 1.4% w / w or less, about 1.3% w / w or less, about 1.2% w / w or less, about 1.1% w / w or less, or about 1% w / w or less of sodium lauryl sulfate (SLS) by weight of the sustained-release coating. In some preferred embodiments, the sustained-release coating comprises about 1% w / w of sodium lauryl sulfate (SLS) by weight of the sustained-release coating.

[0119] In some preferred embodiments, the sustained-release coating is obtained by applying the coating agent "Kollicoat® SR 30 D" (BASF Pharma, Germany), abbreviated as "KSR." Kollicoat® SR 30 D is an aqueous dispersion containing 30% solids. The dispersion consists of 27% polyvinyl acetate (PVA), approximately 2.7% povidone (PVP), approximately 0.3% sodium lauryl sulfate (SLS), and water.

[0120] The applicant unexpectedly found that the release profile of silodosin in a silodosin composition in which the ER coating is ethyl cellulose (e.g., Aquacoat® ECD, etc.) is unstable. An unstable release pattern can sometimes make the effect of a continuous contraceptive unstable and therefore unreliable. The applicant conducted significant research and tested a wide range of common ER polymers, but none of them provided a suitable and / or sufficiently stable release profile of silodosin. Finally, the applicant surprisingly discovered that the use of a vinyl polymer (e.g., Kollicoat® SR 30 D, etc.) as the ER coating significantly improved the stability of the release profile of silodosin.

[0121] However, the Applicant has also surprisingly discovered that the release profile of the silodosin pellets described herein coated with an ER vinyl polymer (e.g., Kollicoat® SR 30 D) is strongly "pH-dependent," in the sense that the release of silodosin is accelerated by the acidic pH of the environmental medium. In the art, this type of "pH-dependent" composition typically begins to dissolve in the stomach (where the pH is very acidic) under conditions that cannot be adequately controlled and may also depend on the characteristics of the subject, and this property is generally considered to be disadvantageous for therapeutic or contraceptive formulations. Therefore, one skilled in the art would strongly expect that this type of "pH-dependent" composition would cause an uncontrollable "burst release" (or "burst release effect") upon passage through the stomach, thereby limiting or suppressing the ER effect.

[0122] Furthermore, the applicant surprisingly discovered that the silodosin pellets described herein coated with an ER vinyl polymer (e.g., Kollicoat® SR 30 D, etc.) exhibited a "lag time" during in vitro assays, i.e., the release of silodosin did not begin immediately but instead was delayed for some time (e.g., about 1 hour). Thus, these pellets were "delayed-release" compositions within the meaning of the present disclosure. In the art, this property is generally considered to be a disadvantage for contraceptive formulations, since it may be desirable for the contraceptive effect to begin as soon as possible after administration. However, when continuous contraception is required, the present contraceptive compositions are generally taken daily, and therefore a limited delay in silodosin release should not affect the reliability of contraception. Thus, "delayed-release" can be advantageous for contraceptive purposes, as long as the "lag time" remains relatively short compared to the overall duration of the contraceptive effect.

[0123] As explained above, silodosin pellets coated with ER vinyl polymers (such as Kollicoat® SR 30 D) are "pH-dependent," and therefore pose a significant risk of a "burst-release effect" when administered to a subject, so that the ER release of silodosin observed in vitro is not maintained in vivo. However, the applicant surprisingly discovered that no burst-release effect was observed in treated subjects, which was completely unexpected based on the general knowledge in the art. Without being bound by theory, the applicant believes that there may be some correlation between the absence of a "burst-release effect" in vivo and the "lag time" observed in vitro, which may explain the surprising technical effect of the pellets and dosage forms described herein.

[0124] Enteric coating According to some embodiments, the pellets further comprise (e) at least one enteric coating. In some preferred embodiments, the enteric coating surrounds the sustained-release coating. In some other embodiments, the enteric coating is surrounded by the sustained-release coating and surrounds the drug layer or any seal coating. In some preferred embodiments, the drug layer or any seal coating is coated with at least one sustained-release coating, followed by at least one enteric coating. In some other embodiments, the drug layer or any seal coating is coated with at least one enteric coating, followed by at least one sustained-release coating.

[0125] For the pellets described herein, the seal coating (if present) and the enteric coating are different coatings. In other words, the same coating cannot simultaneously be a "seal coating" and an "enteric coating" as used in this application.

[0126] In the pellets described herein, the sustained release coating and the enteric coating are different coatings, in other words, the same coating cannot simultaneously be a "sustained release coating" and an "enteric coating" as used in this application.

[0127] In some embodiments, the enteric coating comprises at least one polymer selected from acrylate polymers, cellulose polymers, and mixtures thereof.

[0128] In some embodiments, the enteric coating comprises at least one acrylate polymer.

[0129] In some preferred embodiments, the enteric coating comprises at least one acrylate copolymer. In some embodiments, the enteric coating comprises at least one methacrylic acid / ethyl acrylate (MAE) copolymer. In some preferred embodiments, the enteric coating comprises methacrylic acid / ethyl acrylate copolymer (1:1) (“MAE(1:1)”).

[0130] In some embodiments, the enteric coating comprises at least one polymethacrylate polymer (eg, Eudragit® NE).

[0131] In some embodiments, the enteric coating comprises about 70%-99% w / w of the acrylate copolymer by weight of the enteric coating, hi some preferred embodiments, the enteric coating comprises about 97% w / w of the acrylate copolymer by weight of the enteric coating.

[0132] In some embodiments, the enteric coating comprises at least one polyethoxylated sorbitan fatty acid ester. In some embodiments, the enteric coating comprises at least one polysorbate. In some preferred embodiments, the enteric coating comprises polyoxyethylene (20) sorbitan monooleate ("polysorbate 80").

[0133] In some embodiments, the enteric coating comprises about 1.5% to 3% w / w of the polyethoxylated sorbitan fatty acid ester by weight of the enteric coating, hi some preferred embodiments, the enteric coating comprises about 2.3% w / w of the polyethoxylated sorbitan fatty acid ester by weight of the enteric coating.

[0134] In some embodiments, the enteric coating comprises a mixture of at least one acrylate polymer and at least one polyethoxylated sorbitan fatty acid ester. In some preferred embodiments, the enteric coating comprises a mixture of methacrylic acid / ethyl acrylate (MAE) copolymer and polysorbate 80.

[0135] In some preferred embodiments, the enteric coating is obtained by applying the coating agent "Kollicoat® MAE 30 DP" (BASF Pharma, Germany), abbreviated as "KMAE." Kollicoat® MAE 30 DP is an aqueous dispersion containing 30% (w / w) solids. Based on the solids, the dispersion consists of 97% (w / w) methacrylic acid / ethyl acrylate copolymer (1:1), about 2.3% (w / w) polysorbate 80, and about 0.7% (w / w) sodium lauryl sulfate.

[0136] In some embodiments, the enteric coating comprises at least one cellulose polymer. In some embodiments, the enteric coating comprises at least one carboxymethylcellulose polymer. In some embodiments, the cellulose polymer is selected from hypromellose acetate succinate (e.g., AQOAT®), cellulose acetate phthalate (CAP), hypromellose phthalate (HPMPC), and mixtures thereof.

[0137] In some embodiments, the enteric coating comprises at least one poly(methyl vinyl ether / maleic anhydride) copolymer (eg, Gantrez™).

[0138] In some embodiments, the enteric coating comprises at least one polyvinyl acetate phthalate (eg, Opadry® Enteric).

[0139] The applicant has surprisingly found that the addition of an enteric coating (such as Kollicoat® MAE 30 DP) makes the pellets more resistant to acidity, e.g., there is no significant release of silodosin in simulated gastric fluid over a 2 hour period.

[0140] concrete pellets According to some embodiments, the drug layer comprises silodosin or a pharmaceutically acceptable salt and / or solvate thereof, at least one binder, at least one antioxidant, and at least one anti-adherent and / or anti-static agent.

[0141] The applicant unexpectedly found that when preparing a drug layer of a silodosin composition on a laboratory scale (small-scale experiments), it is advantageous to include a minimum amount of a binder and a minimum amount of an anti-adhesive agent and / or an anti-static agent to improve coating formation, but their presence is found to be a potential cause of degradation of silodosin. The applicant surprisingly discovered that the inclusion of at least one antioxidant in the drug layer significantly prevents degradation of silodosin during the manufacturing process.

[0142] According to some embodiments, the pellets include a pellet (hereinafter "Pellet A") comprising or consisting essentially of an inert core surrounded by a drug layer. Pellet A is particularly advantageous as an intermediate in the manufacture of other pellets. Pellet A is also particularly useful as an immediate-release (IR) silodosin formulation.

[0143] According to some embodiments, the pellets include a pellet (hereinafter "Pellet B") comprising or consisting essentially of an inert core surrounded by a drug layer surrounded by a seal coat. Pellet B is particularly advantageous as an intermediate in the manufacture of other pellets. Pellet B is also particularly useful as an immediate-release (IR) silodosin formulation.

[0144] According to some embodiments, the pellets include pellets comprising or consisting essentially of an inert core surrounded by a drug layer, the drug layer optionally surrounded by a seal coating, and the drug layer or optional seal coating surrounded by a sustained-release coating (hereinafter "Pellet C"). Pellet C is particularly useful as part of a contraceptive composition.

[0145] According to some embodiments, the pellets include pellets comprising or consisting essentially of an inert core surrounded by a drug layer, the drug layer optionally surrounded by a seal coating, the drug layer or optional seal coating surrounded by a sustained release coating, the sustained release coating surrounded by an enteric coating (hereinafter "Pellet D"). Pellet D is particularly useful as part of a contraceptive composition.

[0146] According to some embodiments, the pellets include pellets comprising or consisting essentially of an inert core surrounded by a drug layer, the drug layer optionally surrounded by a seal coating, and the drug layer or optional seal coating surrounded by an enteric coating (hereinafter "Pellet E"). Pellet E is particularly advantageous as an intermediate in the manufacture of other pellets. Pellet E is also particularly useful as an extended-release and immediate-release silodosin formulation.

[0147] According to some embodiments, the pellets include pellets comprising or consisting essentially of an inert core surrounded by a drug layer, the drug layer optionally surrounded by a seal coating, the drug layer or optional seal coating surrounded by an enteric coating, the enteric coating surrounded by a sustained-release coating (hereinafter "Pellet F"). Pellet F is particularly useful as part of a contraceptive composition.

[0148] Applicant has surprisingly discovered that when silodosin is formulated in the form of Pellet C, Pellet D, or Pellet F described herein, determining or adjusting the optimal dose ("dose range") of silodosin is easier than with other ER compositions.

[0149] The applicant has surprisingly discovered that when silodosin is formulated in the form of pellets C, D, or F described herein, the release rate of silodosin can be determined or adjusted more easily than when other ER compositions are used.

[0150] Specific formulations According to some embodiments, the pellets comprise: (a) one inert core containing cellulose microspheres; (b) at least one drug layer coated on an inert core, the drug layer comprising silodosin, hydroxypropyl cellulose (HPC), calcium carbonate (CaCO3), and butylhydroxytoluene (BHT); (c) at least one seal coating surrounding the drug layer, the seal coating comprising hydroxypropyl methylcellulose (HPMC); and (d) at least one sustained release coating surrounding the drug layer or any seal coating, the sustained release coating comprising polyvinyl acetate (PVA), polyvinylpyrrolidone (PVP), triethyl citrate (TEC), and talc; Includes.

[0151] In some embodiments, the pellet comprises: (e) at least one enteric coating, surrounding or surrounded by the sustained-release coating and surrounding any seal coating or drug layer, the enteric coating comprising methacrylic acid / ethyl acrylate copolymer (1:1) (“MAE(1:1)”) and triethyl citrate (TEC); Further includes:

[0152] Amount of ingredients According to some embodiments, the pellets comprise a weight of Pellet A relative to the total weight of Pellet B. Approximately 24-95% w / w, preferably 43.3-91.5% w / w, more preferably 74-83.5% w / w of an inert core, a drug layer of about 5-76% w / w, preferably 8.5-56.7% w / w, more preferably 16.5-26% w / w, approximately 5-25% w / w, preferably 8-18% w / w, more preferably 11-15% w / w of silodosin, about 0.1 to 7.5% w / w, preferably 0.4 to 3.6% w / w, more preferably 0.88 to 1.8% w / w of a binder, Approximately 0-25% w / w, preferably 0.01-10% w / w, more preferably 0.022-0.09% of at least one antioxidant, and Approximately 0-25% w / w, preferably 2-13.5% w / w, more preferably 4.4-9% w / w of at least one anti-blocking and / or anti-static agent a drug layer comprising The pellet A comprises or consists essentially of:

[0153] According to some embodiments, the pellets may be 0.01g or more, based on the total weight of pellets B. approximately 90-100% w / w, preferably 92.5-97.5% w / w, more preferably 94-96% w / w of pellets A, and Approximately 0-10% w / w, preferably 2.5-7.5% w / w, more preferably 4-6% w / w of at least one seal coating and pellet B, which comprises or consists essentially of:

[0154] According to some embodiments, the pellets comprise a weight of about 100g of pellets C based on the total weight of pellets C. Approximately 50 to 98% w / w, preferably 75 to 96.5% w / w, more preferably 82 to 94% w / w of pellets A or pellets B, and A sustained release coating, about 0.5 to 47% w / w, preferably 1.6 to 19.1% w / w, more preferably 4.7 to 12.25% w / w of at least one sustained release agent, Approximately 0.02 to 0.7% w / w, preferably 0.06 to 1.6% w / w, more preferably 0.19 to 0.75% w / w of at least one plasticizer, and Approximately 0.3 to 23% w / w, preferably 0.3 to 8.6% w / w, more preferably 1.3 to 5.15% w / w of at least one anti-blocking agent a sustained release coating comprising and pellets C comprising or consisting essentially of:

[0155] According to some embodiments, the pellets comprise a weight of about 100g of pellets D relative to the total weight of pellets D. approximately 50-95% w / w, preferably 62-88% w / w, more preferably 70-80% w / w of pellets C, and an enteric coating, about 4-49.5% w / w, preferably 10-36%, more preferably 17.5-27.5% w / w, of at least one enteric agent, and Approximately 0.04 to 10% w / w, preferably 0.5 to 5.5% w / w, more preferably 1.4 to 3.3% w / w of at least one plasticizer an enteric coating comprising and pellet D comprising or consisting essentially of:

[0156] According to some embodiments, the pellets comprise a weight of Pellet A relative to the total weight of Pellet B. Approximately 24-95% w / w, preferably 43.3-91.5% w / w, more preferably 74-83.5% w / w of an inert core, a drug layer of about 5-76% w / w, preferably 8.5-56.7% w / w, more preferably 16.5-26% w / w, approximately 5-25% w / w, preferably 8-18% w / w, more preferably 11-15% w / w of silodosin, about 0.1 to 7.5% w / w, preferably 0.4 to 3.6% w / w, more preferably 0.88 to 1.8% w / w of a binder, Approximately 0-20% w / w, preferably 0.01-10% w / w, more preferably 0.022-0.09% of at least one antioxidant, and Approximately 0-25% w / w, preferably 2-13.5% w / w, more preferably 4.4-9% w / w of at least one anti-blocking and / or anti-static agent a drug layer comprising Pellet A comprising or consisting essentially of Pellet A is arbitrarily divided by the weight of pellet B. approximately 90-100% w / w, preferably 92.5-97.5% w / w, more preferably 94-96% w / w of pellets A, and At least one seal coating of about 0-10% w / w, preferably 2.5-7.5% w / w, more preferably 4-6% w / w, surrounding the drug layer and a pellet B comprising or consisting essentially of: The weight of pellet A or pellet B is the ratio of the total weight of pellet C to the total weight of pellet C. Approximately 50 to 98% w / w, preferably 75 to 96.5% w / w, more preferably 82 to 94% w / w of pellets A or pellets B, and A sustained release coating, about 0.5 to 47% w / w, preferably 1.6 to 19.1% w / w, more preferably 4.7 to 12.25% w / w of at least one sustained release agent, Approximately 0.02 to 0.7% w / w, preferably 0.06 to 1.6% w / w, more preferably 0.19 to 0.75% w / w of at least one plasticizer, and Approximately 0.3 to 23% w / w, preferably 0.3 to 8.6% w / w, more preferably 1.3 to 5.15% w / w of at least one anti-blocking agent a sustained release coating comprising and Pellets C are optionally added by weight relative to the total weight of any pellets D. approximately 50-95% w / w, preferably 62-88% w / w, more preferably 70-80% w / w of pellets C, and an enteric coating, about 4-49.5% w / w, preferably 10-36%, more preferably 17.5-27.5% w / w, of at least one enteric agent, and Approximately 0.04 to 10% w / w, preferably 0.5 to 5.5% w / w, more preferably 1.4 to 3.3% w / w of at least one plasticizer an enteric coating comprising The pellet D contains or consists essentially of the above.

[0157] In some embodiments, pellet A or pellet B is present in an amount by weight relative to the total weight of pellet C. Approximately 75-93% w / w, preferably 82-88% w / w, of pellets A or pellets B, and A sustained release coating, about 11.25 to 119.1% w / w, preferably 6.25 to 12.25% w / w, of at least one sustained release agent, Approximately 0.4 to 1.6% w / w, preferably 0.25 to 0.75% w / w, of at least one plasticizer, and Approximately 2.25 to 8.6% w / w, preferably 1.75 to 5.15% w / w, of at least one anti-blocking agent a sustained release coating comprising The pellet C contains or essentially consists of:

[0158] In some embodiments, pellet A or pellet B is present in an amount by weight relative to the total weight of pellet C. Approximately 80-96.5% w / w, preferably 91-94% w / w, of pellets A or pellets B, and A sustained release coating, about 1.6 to 15.3% w / w, preferably 4.7 to 6.1% w / w, of at least one sustained release agent, Approximately 0.06 to 1.5% w / w, preferably 0.19 to 0.37% w / w, of at least one plasticizer, and Approximately 0.3 to 6.9% w / w, preferably 1.3 to 2.6% w / w, of at least one anti-blocking agent a sustained release coating comprising The pellet C contains or essentially consists of:

[0159] According to some embodiments, the pellets comprise a weight of about 100g of pellets E relative to the total weight of pellets E. about 50-95% w / w of pellets A described herein or pellets B described herein, and an enteric coating, about 4-49.5% w / w, preferably 10-36%, more preferably 17.5-27.5% w / w, of at least one enteric agent, and Approximately 0.04 to 10% w / w, preferably 0.5 to 5.5% w / w, more preferably 1.4 to 3.3% w / w of at least one plasticizer an enteric coating comprising The pellet E comprises or consists essentially of:

[0160] According to some embodiments, the pellets comprise, by weight relative to the total weight of pellets F, approximately 50-98% w / w, preferably 75-96.5% w / w, more preferably 82-94% w / w of pellets E, and A sustained release coating, about 0.5 to 47% w / w, preferably 1.6 to 19.1% w / w, more preferably 4.7 to 12.25% w / w of at least one sustained release agent, Approximately 0.02 to 0.7% w / w, preferably 0.06 to 1.6% w / w, more preferably 0.19 to 0.75% w / w of at least one plasticizer, and Approximately 0.3 to 23% w / w, preferably 0.3 to 8.6% w / w, more preferably 1.3 to 5.15% w / w of at least one anti-blocking agent a sustained release coating comprising The pellet F comprises or consists essentially of:

[0161] According to some embodiments, the pellets comprise a weight of Pellet A relative to the total weight of Pellet B. Approximately 24-95% w / w, preferably 43.3-91.5% w / w, more preferably 74-83.5% w / w of an inert core, a drug layer of about 5-76% w / w, preferably 8.5-56.7% w / w, more preferably 16.5-26% w / w, approximately 5-25% w / w, preferably 8-18% w / w, more preferably 11-15% w / w of silodosin, about 0.1 to 7.5% w / w, preferably 0.4 to 3.6% w / w, more preferably 0.88 to 1.8% w / w of a binder, Approximately 0-20% w / w, preferably 0.01-10% w / w, more preferably 0.022-0.09% of at least one antioxidant, and Approximately 0-25% w / w, preferably 2-13.5% w / w, more preferably 4.4-9% w / w of at least one anti-blocking and / or anti-static agent a drug layer comprising Pellet A comprising or consisting essentially of Pellet A is arbitrarily divided by the weight of pellet B. approximately 90-100% w / w, preferably 92.5-97.5% w / w, more preferably 94-96% w / w of pellets A, and At least one seal coating of about 0-10% w / w, preferably 2.5-7.5% w / w, more preferably 4-6% w / w, surrounding the drug layer and a pellet B comprising or consisting essentially of: The weight of pellet A or pellet B is the ratio of the total weight of pellet E to the total weight of pellet E. Approximately 50-95% w / w of pellet A or pellet B, and an enteric coating, about 4-49.5% w / w, preferably 10-36%, more preferably 17.5-27.5% w / w, of at least one enteric agent, and Approximately 0.04 to 10% w / w, preferably 0.5 to 5.5% w / w, more preferably 1.4 to 3.3% w / w of at least one plasticizer an enteric coating comprising and a pellet E comprising or consisting essentially of: Pellet E is the weight of pellet F relative to the total weight of pellet F. pellets E of about 50 to 98% w / w, preferably 75 to 96.5% w / w, more preferably 82 to 94% w / w, A sustained release coating, about 0.5 to 47% w / w, preferably 1.6 to 19.1% w / w, more preferably 4.7 to 12.25% w / w of at least one sustained release agent, Approximately 0.02 to 0.7% w / w, preferably 0.06 to 1.6% w / w, more preferably 0.19 to 0.75% w / w of at least one plasticizer, and Approximately 0.3 to 23% w / w, preferably 0.3 to 8.6% w / w, more preferably 1.3 to 5.15% w / w of at least one anti-blocking agent a sustained release coating comprising The pellet F comprises or consists essentially of:

[0162] Weight gain "Weight gain" refers to the increase in weight of a final object resulting from the process of applying at least one coating agent (e.g., a polymer) to a starting object (e.g., an inert core or pellet), thereby obtaining a final object in which the starting object is coated with at least one coating material. Weight gain is a parameter often used in the pharmaceutical field to characterize coating thickness, since direct measurement of coating thickness requires complex and costly methods, whereas weight gain can be easily estimated by weighing with common equipment, e.g., a laboratory scale. Weight gain after "n" applications of coating agent to a starting object, WG n (%) (where "n" is an integer greater than 0) is calculated as follows: n =100*(Wn ) / W0 (where W0 represents the weight of the starting object and W n represents the dry weight of the coating material, and W n and W0 are expressed in the same units (e.g., grams or "g"). In this application, unless otherwise specified, weight gain is expressed when only one coating is applied, i.e., when n is 1. For example, a statement such as "apply the [Coating 1] to [Pellet 0] at a weight gain of 10%" means that W0 is the weight of "Pellet 0" (the starting object), W1 is the dry weight of Coating 1, and 100*(W1) / W0=10%.

[0163] According to some embodiments, the drug layer is applied to the inert core at a weight gain ranging from about 5 to 318%, preferably 10 to 105%, more preferably 19 to 35%.

[0164] According to some embodiments, the optional seal coating is applied to the drug layer at a weight gain ranging from 0 to about 11%, preferably 2.5 to 8%, and more preferably 13.5 to 22%.

[0165] According to some embodiments, the sustained release coating is applied to the drug layer or any seal coating at a weight gain ranging from about 2 to 100%, preferably 3.5 to 33%, more preferably 6 to 22%.

[0166] According to some embodiments, the optional enteric coating is applied to the sustained release coating at a weight gain ranging from 0 to about 100%, preferably 13.5 to 61%, more preferably 25 to 43%.

[0167] According to some embodiments, the pellets comprise: (a) Inert core, (b) a drug layer applied to an inert core at a weight gain ranging from about 5 to 318%, preferably 10 to 105%, more preferably 19 to 35%; (c) an optional seal coating applied to the drug layer at a weight gain ranging from 0 to about 11%, preferably 2.5 to 8%, and more preferably 13.5 to 22%; (d) a sustained-release coating applied to the drug layer or any seal coating at a weight gain ranging from about 2 to 100%, preferably 3.5 to 33%, more preferably 6 to 22%, and / or (e) an optional enteric coating applied to the sustained-release coating at a weight gain ranging from 0 to about 100%, preferably 13.5 to 61%, more preferably 25 to 43%; Includes.

[0168] According to some embodiments, the enteric coating is applied to the drug layer or optional seal coat at a weight gain ranging from 0.1 to about 100%.

[0169] According to some embodiments, the sustained release coating is applied to the enteric coating at a weight gain ranging from about 2 to 100%.

[0170] According to some embodiments, the pellets comprise: (a) Inert core, (b) a drug layer applied to an inert core at a weight gain ranging from about 5 to 318%, preferably 10 to 105%, more preferably 19 to 35%; (c) an optional seal coating applied to the drug layer at a weight gain ranging from 0 to about 11%, preferably 2.5 to 8%, and more preferably 13.5 to 22%; (d) an enteric coating applied to the drug layer or optional seal coating at a weight gain ranging from 0.1 to about 100%, and / or (e) a sustained-release coating applied to the enteric coating at a weight gain ranging from about 2 to 100%; Includes.

[0171] Multiple pellets One object of the technology described herein is the plurality of pellets described herein.

[0172] According to some embodiments, at least one pellet is selected from Pellet A, Pellet B, Pellet C, Pellet D, Pellet E, and Pellet F described herein. In some embodiments, each pellet in the plurality of pellets has the same structure, i.e., each pellet is Pellet A, each pellet is Pellet B, each pellet is Pellet C, each pellet is Pellet D, each pellet is Pellet E, or each pellet is Pellet F. In some embodiments, the plurality of pellets includes at least two pellets selected from Pellet A, Pellet B, Pellet C, Pellet D, Pellet E, and Pellet F. In some embodiments, the plurality of pellets includes at least one pellet selected from Pellet A, Pellet B, and Pellet E and at least one pellet selected from Pellet C, Pellet D, and Pellet F. Pellet A, Pellet B, or Pellet E are particularly useful as intermediates in the production of another plurality of pellets.

[0173] In some embodiments, at least one pellet is selected from pellet A, pellet B, and pellet E described herein. In some embodiments, each pellet in the plurality of pellets has the same structure, i.e., each pellet is pellet A, each pellet is pellet B, or each pellet is pellet E. In some preferred embodiments, each pellet in the plurality of pellets is pellet A. In some preferred embodiments, each pellet in the plurality of pellets is pellet B. A plurality of pellets A, pellet B, or pellet E are particularly useful as part of a contraceptive composition.

[0174] In some embodiments, at least one pellet is selected from pellet C, pellet D, and pellet F described herein. In some embodiments, each pellet in the plurality of pellets has the same structure, i.e., each pellet is pellet C, each pellet is pellet D, or each pellet is pellet F. In some preferred embodiments, each pellet in the plurality of pellets is pellet C. In some preferred embodiments, each pellet in the plurality of pellets is pellet D. Plural pellets C, D, or F are particularly useful as part of a contraceptive composition.

[0175] composition Another object of the technology described herein is a composition comprising at least one pellet described herein.

[0176] According to some embodiments, the composition consists of a plurality of pellets described herein. According to some embodiments, the composition consists of one pellet described herein.

[0177] According to some preferred embodiments, the composition is a contraceptive composition.

[0178] According to some embodiments, the composition is in dosage form.

[0179] A "dosage form" refers to a form in which a dose (e.g., an "effective amount") of an active ingredient can be administered to a subject. The active ingredient is generally administered as part of a formulation that includes a non-medicinal agent (e.g., a pharmaceutically acceptable carrier). A dosage form has unique physical and pharmaceutical properties. A dosage form may contain at least one pharmaceutical composition. A dosage form may be, for example, a solid, liquid, or gas. "Dosage forms" include, for example, capsules (e.g., gel caplets [hard-shell or soft-shell capsules such as "gel-caps"]), tablets, caplets, syrups, liquid compositions, powders, concentrated powders, concentrated powders mixed with liquids, swallowable forms, granular forms, pellet forms, oral liquid solutions, and mixtures and / or combinations thereof. A dosage form may also include at least one of a subcutaneous implant, a transdermal patch, an injection, a nasal spray, an adhesive tablet, or a transmucosal delivery solution.

[0180] In some embodiments, the dosage form is a capsule. In some preferred embodiments, the capsule is a hard-shell capsule. In some embodiments, the capsule is a functional capsule. In some embodiments, the capsule is an enteric-coated capsule.

[0181] "Functional capsule" refers to a capsule (typically comprising a polymer) that contains an oral drug and imparts particular characteristics to the dissolution profile of said oral drug.

[0182] "Enteric-coated capsule" refers to a capsule (typically comprising a polymer) that contains an oral medication and prevents its dissolution or disintegration in the stomach environment. Enteric-coated capsules are useful in either protecting the medication from the acidity of the stomach, protecting the stomach from the harmful effects of the medication, or releasing the medication after the stomach (usually in the upper intestine). Typically, enteric-coated capsules are expected to dissolve at about 5.5 or above.

[0183] According to some embodiments, the composition is a pharmaceutical composition.

[0184] According to some embodiments, the composition is a medicament.

[0185] According to some embodiments, the pellets are lubricated with at least one anti-adherent agent before being filled into the dosage form. In some preferred embodiments, the anti-adherent agent is talc.

[0186] According to some embodiments, the composition comprises a plurality of pellets as described herein.

[0187] According to some embodiments, the composition comprises silodosin in an amount ranging from about 0.5 to 50 mg.

[0188] According to some embodiments, the composition contains silodosin in an amount ranging from about 0.5 to 4 mg, preferably from about 1 to 8 mg, more preferably from about 2 to 12 mg, and even more preferably from about 4 to 16 mg. In some embodiments, the composition contains silodosin in an amount ranging from about 1 to 8 mg. In some specific embodiments, the composition contains silodosin in an amount ranging from about 2 to 12 mg. In some further specific embodiments, the composition contains silodosin in an amount ranging from about 4 to 16 mg.

[0189] According to some embodiments, the composition comprises silodosin in an amount ranging from about 4 to 32 mg, preferably from about 8 to 28 mg, more preferably from about 12 to 24 mg, and even more preferably from about 16 to 20 mg. In some embodiments, the composition comprises silodosin in an amount ranging from about 8 to 28 mg. In some specific embodiments, the composition comprises silodosin in an amount ranging from about 12 to 24 mg. In some further specific embodiments, the composition comprises silodosin in an amount ranging from about 16 to 20 mg.

[0190] According to some embodiments, the composition contains silodosin in an amount ranging from about 5 to 50 mg, preferably from about 10 to 45 mg, more preferably from about 15 to 40 mg, and even more preferably from about 20 to 35 mg. In some embodiments, the composition contains silodosin in an amount ranging from about 10 to 45 mg. In some specific embodiments, the composition contains silodosin in an amount ranging from about 15 to 40 mg. In some further specific embodiments, the composition contains silodosin in an amount ranging from about 20 to 35 mg.

[0191] According to some embodiments, the composition contains about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg g, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg or about 50 mg of silodosin.

[0192] According to some preferred embodiments, the entire silodosin present in the composition is contained in the pellet or pellets described herein. According to some other embodiments, a portion of the silodosin present in the composition is not contained in the pellet or pellets described herein.

[0193] In some embodiments, the composition contains about 2.5-10 mg, preferably about 5 mg, of lubricating pellets (e.g., lubricating pellets C). In some embodiments, the composition contains about 125-500 mg, preferably about 250 mg, of lubricating pellets (e.g., lubricating pellets C). In some embodiments, the composition contains about 250-1000 mg, preferably about 500 mg, of lubricating pellets (e.g., lubricating pellets C).

[0194] According to some embodiments, the composition further comprises at least another contraceptive agent, i.e., a contraceptive agent other than silodosin.

[0195] kit Another object of the present disclosure is a kit of parts (abbreviated "kit") comprising the compositions described herein.

[0196] In some embodiments, the kit comprises an article of manufacture, such as a package or container. In some embodiments, the kit comprises instructions for use. The kit may be promoted, distributed, or sold as a unit for performing the methods or uses of the techniques described herein.

[0197] Methods and Uses Another object of the technology described herein is a method of contraception for a male subject, comprising administering to the male subject a composition described herein.

[0198] Another object of the technology described herein is the use of the compositions described herein in a method of contraception for male subjects.

[0199] Another object of the technology described herein is a composition described herein for use as a male contraceptive (i.e., a contraceptive for a male subject). Another object of the technology described herein is a composition described herein for use in a contraceptive method for a male subject.

[0200] Another object of the technology described herein is the use of the compositions described herein in the manufacture of a medicament for male contraception.Another object of the technology described herein is the use of the compositions described herein in the manufacture of a medicament for a contraceptive method for a male subject.

[0201] According to some embodiments, the method or use is non-therapeutic.

[0202] According to some embodiments, the method is non-hormonal or the use is for non-hormonal contraception, "non-hormonal" means that no hormones, particularly male hormones, are administered to the subject during the method or use.

[0203] According to some embodiments, the method or use comprises administering to a male subject an effective amount of a composition described herein.

[0204] An "effective amount" refers to an amount of an active ingredient (e.g., silodosin) sufficient to achieve a desired therapeutic or prophylactic effect (e.g., contraception) in a subject to which it is administered, without causing significant adverse or side effects to said subject.

[0205] According to some embodiments, the composition is or can be administered to said male subject at approximately the same time each day.

[0206] "Approximately the same time" means ±2 hours (±2h) ("plus or minus 2 hours" or "plus or minus 2 hours").

[0207] Manufacturing Process The pellet or pellets described herein may be produced by coating methods known in the art, such as, for example, spray coating.

[0208] Another object of the technology described herein is a process for producing a plurality of the pellets or compositions described herein.

[0209] According to some embodiments, the process comprises: (1-a) A step of preparing a drug solution or drug suspension, the drug solution or drug suspension comprising: a drug solution comprising silodosin, at least one binder, at least one solvent, and optionally at least one antioxidant, and optionally at least one anti-blocking and / or anti-static agent and then (1-b) applying a drug solution or drug suspension to a plurality of inert cores, thereby obtaining a plurality of pellets A; (2-a) optionally preparing a seal coating suspension containing at least one seal coating agent; (2-b) applying the seal coating suspension to a plurality of pellets A, thereby obtaining a plurality of pellets B; and applying a sustained release coating and optionally an enteric coating to a plurality of pellets A or pellets B, typically as described hereinafter. Includes.

[0210] According to some preferred embodiments, the process comprises: (3-a) preparing a sustained release coating suspension comprising at least one sustained release coating agent, at least one plasticizer, and at least one anti-tack agent; (3-b) applying the sustained-release coating suspension to a plurality of pellets A or any plurality of pellets B, thereby obtaining a plurality of pellets (“pellets C”) Further includes:

[0211] According to some preferred embodiments, the process comprises: (3'-a) preparing a sustained release coating suspension comprising at least one sustained release coating agent, at least one plasticizer, and at least one anti-tack agent; and (3'-b) applying the sustained release coating suspension to the plurality of pellets A or any plurality of pellets B, thereby obtaining a plurality of pellets C; (4'-a) preparing an enteric coating suspension containing at least one enteric coating agent and at least one plasticizer; (4'-b) applying the enteric coating suspension to a plurality of pellets C, thereby obtaining a plurality of pellets ("pellets D"). Further includes:

[0212] According to another embodiment, the process comprises: (3''-a) preparing an enteric coating suspension containing at least one enteric coating agent and at least one plasticizer; (3''-b) applying the enteric coating suspension to a plurality of pellets A or a plurality of any pellets B, thereby obtaining a plurality of pellets E; (4''-a) preparing a sustained release coating suspension comprising at least one sustained release coating agent, at least one plasticizer, and at least one anti-tack agent; (4''-b) applying the sustained-release coating suspension to a plurality of pellets E, thereby obtaining a plurality of pellets ("pellets F"). Further includes:

[0213] According to some embodiments, at least one of the drug layer and coating is applied by spraying. In some embodiments, the drug layer and each coating is applied by spraying. The application may be by spray coating methods well known in the art.

[0214] According to some embodiments, the solvent in the drug solution or suspension in step (1-a) is ethanol.

[0215] According to some embodiments, the process further comprises (5) filling the resulting plurality of pellets ("Pellet C," "Pellet D," or "Pellet F," depending on the previous step) into at least one container, thereby obtaining a dosage form described herein.

[0216] In some embodiments, the composition produced is in a dosage form. In some embodiments, the container filled in step (5) is a capsule. [Brief explanation of the drawings]

[0217] [Figure 1] FIG. 1 shows the main steps in the manufacture of pellets [pellets A, B, C, and D] and dosage forms [formulations (I), (III), (V), and (VI)] described herein. Reference symbols: (a) inert core, (b) drug layer containing silodosin, (c) optional seal coating, (d) sustained-release coating, (e) optional enteric coating, (f) conventional capsule, (g) functional enteric capsule. [Figure 2] 1 is a graph showing the dissolution profile at pH 6.8 of a modified release formulation (Ia) (black curve with diamonds on the right) compared to the dissolution profile of an immediate release (IR) formulation (grey curve with circles on the left). [Figure 3] 1 is a graph showing the dissolution profile of formulation Ia in 0.1 N HCl solution (black curve with upper circle symbols) and in pH 6.8 medium (gray curve with lower diamond symbols). [Figure 4] 1 is a graph showing the dissolution profiles of formulation (Ia) in a pH 6.8 medium at TO (black curve with a diamond mark in the middle), after 3 months of storage at 40°C and 75% relative humidity (RH) (grey curve with a triangle mark below), after 9 months of storage at 25°C and 60% RH (grey curve with a square mark above), and after 18 months of storage at 25°C and 60% RH (black curve with a circle mark above). [Figure 5]1 is a graph showing the dissolution profile at pH 6.8 of a modified release formulation (Va) (black curve with diamonds on the right) compared to the dissolution profile of an immediate release (IR) formulation (grey curve with circles on the left). [Figure 6] 1 is a graph showing the dissolution profile of formulation (Va) in media of progressive pH at TO (black curve with upper diamond symbols), after 3 months of storage at 40°C and 75% relative humidity (RH) (grey curve with lower triangle symbols) and after 9 months of storage at 25°C and 60% RH (grey curve with upper square symbols). [Figure 7] 1 is a graph showing the dissolution profile of comparative formulation (VII-a) in 0.1 N HCl solution (black curve with circles) and in pH 6.8 medium (gray curve with squares). [Figure 8] 1 is a graph showing the dissolution profile of comparative pellets (VII-b) in 0.1 N HCl solution at TO (black curve with upper diamond symbols), after 2 months of storage at 25°C and 60% RH (gray curve with middle square symbols), and after 2 months of storage at 40°C and 75% relative humidity (RH) (gray curve with lower triangle symbols). [Example]

[0218] The technology described herein is further illustrated by the following examples.

[0219] Example 1: Silodosin formulation according to the present invention Example 1-1: Preparation (Ia) Modified-release silodosin pellets were prepared as follows (see Figure 1 for a schematic diagram of the manufacturing process): (R)-silodosin was dissolved in an ethanolic solution of hydroxypropyl cellulose (HPC) and butylhydroxytoluene (BHT), thereby obtaining a silodosin solution. Calcium carbonate (CaCO3) was then added to this solution, thereby obtaining a drug-layered suspension. The composition of the layered (R)-silodosin suspension is detailed in Table 2. [Table 2]

[0220] The layered (R)-silodosin suspension was then sprayed onto inert cores (cellulose microspheres) (bottom spray) with continuous stirring. The initial parameters were set as follows: fluidization inlet air temperature: 56.0°C, air flow rate: 70 m 3 / h. The composition of the resulting pellet AIa is detailed in Table 3. [Table 3]

[0221] Next, the pellets AIa prepared above were sprayed with an aqueous solution of hydroxypropyl methylcellulose (HPMC) [Opadry Clear 03A6900067®]. The initial parameters were set as follows: fluidization inlet air temperature: 54.0°C, air flow rate: 70 m 3 The composition of the resulting pellet BIa is shown in Table 4. [Table 4]

[0222] The previously prepared coated pellets BIa were further coated by spraying with an aqueous suspension of polyvinyl acetate [Kollicoat® SR 30 D (KSR)] (14.6% w / w), triethyl citrate (TEC) (0.73% w / w), and talc (5.1% w / w) maintained under continuous stirring. The initial parameters were set as follows: fluidization inlet air temperature: 43.0°C, air flow rate: 75 m 3 The coated pellets were then cured for 120 minutes at 45° C. The composition of the resulting pellets, CIa, is shown in Tables 5 and 6. [Table 5] [Table 6]

[0223] An appropriate amount of the previously prepared pellets CIa, lubricated with 0.50% w / w talc, was filled into hypromellose hard capsules to a final (R)-silodosin content of 12 mg per capsule, thereby obtaining formulation (Ia).

[0224] Example 1-2: Formulation (Va) Modified-release silodosin pellets were prepared as follows (see Figure 1 for a schematic diagram of the manufacturing process): (R)-silodosin was dissolved in an ethanol solution of hydroxypropyl cellulose (HPC) and butylhydroxytoluene (BHT), thereby obtaining a silodosin solution. Calcium carbonate (CaCO) was then added to this solution, thereby obtaining a silodosin suspension. The composition of the layered (R)-silodosin suspension is detailed in Table 7. [Table 7]

[0225] The layered (R)-silodosin suspension was then sprayed onto inert cores (cellulose microspheres) (bottom spray) with continuous stirring. The initial parameters were set as follows: fluidization inlet air temperature: 56.0°C, air flow rate: 70 m 3 / h. The composition of the resulting pellets AVa is detailed in Table 8. [Table 8]

[0226] Next, an aqueous solution of hydroxypropyl methylcellulose (HPMC) [Opadry Clear 03A6900067®] was sprayed onto the pellets AVa prepared above. The initial parameters were set as follows: fluidization inlet air temperature: 54.0°C, air flow rate: 70 m 3 / hour. The composition of the resulting pellets BVa is shown in Table 9. [Table 9]

[0227] The previously prepared coated pellets BVa were further coated by spraying with an aqueous suspension of polyvinyl acetate [Kollicoat® SR 30 D (KSR)] (14.6% w / w), triethyl citrate (TEC) (0.73% w / w), and talc (5.1% w / w) maintained under continuous stirring. The initial parameters were set as follows: fluidization inlet air temperature: 43.0°C, air flow rate: 75 m 3 The coated pellets were then cured for 120 minutes at 45° C. The composition of the resulting pellets, CVa, is shown in Table 10. [Table 10]

[0228] A final coating was applied to the previously prepared pellets CVa by spraying thereon an aqueous suspension of methacrylic acid / ethyl acrylate copolymer [Kollicoat MAE 30 DP® (KMAE)] (60.6% w / w) and triethyl citrate (TEC) (1.82% w / w), maintained under continuous stirring. The initial parameters were set as follows: fluidization inlet air temperature: 41°C, air flow rate: 70 m 3 / hour. The composition of the resulting pellets DVa is shown in Tables 11 and 12. [Table 11] [Table 12]

[0229] An appropriate amount of the previously prepared pellets DVa, lubricated with 0.50% w / w talc, was filled into hypromellose hard capsules to a final (R)-silodosin content of 12 mg per capsule, thereby obtaining formulation (Va).

[0230] Example 2: In vitro studies of silodosin formulations according to the present invention Example 2-1: Preparation (Ia) Dissolution tests were performed according to the United States Pharmacopoeia method in a USP Type 2 apparatus at 37°C ± 0.5°C with direct UV detection in 900 mL of 0.1 N HCl (acidic medium) solution or pH 6.8 phosphate buffer (neutral medium) at 50 rpm, respectively.

[0231] The dissolution profile of formulation (Ia) at pH 6.8 is shown in Figure 2, which indicates that 85% of the silodosin amount is released in about 34 hours from formulation (Ia) and about 10 minutes from the comparative IR composition (RAPAFLO®), and the release rate of formulation (Ia) is much slower than that of the comparative IR composition (RAPAFLO®), as evidenced by the slopes of their respective dissolution profiles. Thus, formulation (Ia) is a modified-release formulation, in stark contrast to the comparative IR composition (RAPAFLO®). A "lag time" of about 1 hour appears in Figure 2, indicating that formulation (Ia) is a delayed-release formulation.

[0232] The dissolution profiles of Formulation IA in 0.1 N HCl and at pH 6.8 are shown in Figure 3 and show that 50% of silodosin is released in about 14 hours at pH 6.8 and about 3 hours in 0.1 N HCl, and that the release rate is much slower at pH 6.8 than in 0.1 N HCl, as evidenced by the slope of the dissolution profile. Thus, the dissolution profile of Formulation Ia is "pH dependent," with a faster release rate in acidic media.

[0233] Table 13 below shows the chemical stability of silodosin in formulation (Ia) over time (T0, after 3 months, after 9 months, and after 18 months) at two different storage conditions: 40° C. and 75% relative humidity (RH) or 25° C. and 60% relative humidity (RH). Dehydrosilodosin is the major degradation product of silodosin. [Table 13]

[0234] Table 13 confirms the chemical stability of silodosin in formulation (Ia) over time under both storage conditions, since no significant decrease in silodosin content and no significant increase in degradation product content is observed.

[0235] FIG. 4 shows that the dissolution profiles of formulation (Ia) after 3 months of storage at T0, 40° C. and 75% RH, after 9 months of storage at 25° C. and 60% RH, and after 18 months of storage at 25° C. and 60% RH are nearly overlapping, demonstrating that the dissolution profile of formulation (Ia) is not affected by storage (under both storage conditions) over time.

[0236] Example 2-2: Formulation (Va) Dissolution tests were performed according to the United States Pharmacopoeia method in a USP Type 2 apparatus at 37°C ± 0.5°C with direct UV detection in 900 mL of simulated gastric fluid for 2 hours, followed by phosphate buffer at pH 6.8 (also known as the "gradual pH medium" recommended by the USP for enteric-coated dosage forms) at 50 rpm, respectively.

[0237] The dissolution profiles of Formulation (Va) in gradual pH media are shown in Figure 5, which demonstrates that 85% of the silodosin content is released in approximately 10 hours from Formulation (Va) and in less than 10 minutes from the comparative IR composition (RAPAFLO®), and that the release rate of Formulation (Va) is much slower than that of the comparative IR composition (RAPAFLO®), as evidenced by the slopes of their respective dissolution profiles. Formulation (Va) is thus a modified-release formulation, in stark contrast to the comparative IR composition (RAPAFLO®). The approximately 2-hour delay apparent in Figure 5 indicates that Formulation (Va) is a delayed-release formulation.

[0238] Table 14 below shows the chemical stability of silodosin in formulation (Va) over time (T0, after 3 months, and after 9 months) at two different storage conditions: 40° C. and 75% relative humidity (RH) or 25° C. and 60% relative humidity (RH). Dehydrosilodosin is the major degradation product of silodosin. [Table 14]

[0239] Using a different batch of formulation (Va) prepared exactly as described in Example 1-2 above, it was also confirmed that the chemical stability of silodosin in formulation (Va) persisted for up to 12 months at 25°C / 60% RH (data not shown).

[0240] Figure 6 shows that the dissolution profile of formulation (Va) is not affected by storage (under both storage conditions) over time, as the dissolution profiles at TO, 3 months and 9 months are very similar.

[0241] Example 3: In vitro study of comparative silodosin formulations Example 3-1: Ethyl cellulose Example 3-1-1: Aquacoat® ECD 30 (Test 1) The manufacturing process for comparative formulation (VII-a) was essentially as described in Example 1-1 for formulation (Ia), except that BHT was replaced by the antioxidant α-tocopherol, thereby obtaining pellets A-VII-a having the composition shown in Table 15.

[0242] Furthermore, the coating applied to pellets B-VII-a was a suspension containing 12% w / w ethyl cellulose and 3% dibutyl sebacate (DBS), and the granules were then cured at 60°C for 4 hours while simultaneously spraying with water, thereby obtaining comparative pellets C-VII-a having the composition shown in Table 16. [Table 15] [Table 16]

[0243] An appropriate amount of the previously prepared comparative pellets C-VII-a was filled into hypromellose hard capsules to a final (R)-silodosin content of 12 mg per capsule, thereby obtaining comparative formulation (VII-a).

[0244] Dissolution tests were performed with direct UV detection at 37°C ± 0.5°C in a USP Type 2 apparatus in 900 mL of 0.1 N HCl solution or pH 6.8 phosphate buffer at 50 rpm according to the United States Pharmacopoeia method.

[0245] The dissolution profile of comparative formulation (VII-a) in 0.1% HCl at pH 6.8 is shown in Figure 7, which indicates that comparative formulation (VII-a) provided a slightly sustained-release profile in which 85% of silodosin was released in approximately 9 hours. Figure 7 also shows that this dissolution profile of comparative formulation (VII-a) is not pH-dependent, as the two curves are nearly overlapping.

[0246] Example 3-1-2: Aquacoat® ECD 30 (Test 2) The manufacturing process for comparative pellets (VII-b) was essentially the same as that described in Example 3-1-1 for comparative formulation (VII-a), except that the pellets were cured at 60°C for 2 hours without water spray, thereby obtaining comparative pellets C-VII-b having the composition shown in Table 17. [Table 17]

[0247] Dissolution tests were performed according to the United States Pharmacopoeia method in a USP Type 2 apparatus at 37°C ± 0.5°C with direct UV detection in 900 mL of 0.1 N HCl solution at 50 rpm.

[0248] The dissolution profile of comparative pellet (VII-b) in 0.1 N HCl solution is shown in Figure 8, which shows that the dissolution profile of comparative pellet (VII-b) after 2 months of storage at 25°C and 60% RH is much slower than that at TO, and even slower than that after 2 months of storage at 40°C and 65% RH. Thus, the dissolution profile of comparative pellet (VII-b) is not stable over time.

[0249] Therefore, the comparative pellet C-VII-b is not suitable for use as a continuous method of contraception.

[0250] Example 3-1-3: Surelease (registered trademark) Another commercially available aqueous suspension of ethyl cellulose (Surelease®, an ethyl cellulose suspension with multiple additives) was tested as an ER coating. Pellets were produced with a weight gain of approximately 25% of the ethyl cellulose.

[0251] The applicant found that the degradation of silodosin in these pellets was very high, far beyond the acceptable measurement range. Without being bound by theory, the applicant suspects a chemical incompatibility between silodosin and at least one component of Surelease®.

[0252] Example 3-2: Polymethacrylate The manufacturing process of comparative pellets C-VIII-a and C-IX-a results in the final ER coating being: (Pellets C-VIII-a) A suspension containing a neutral copolymer of ethyl acrylate and methyl methacrylate (commercially available under the trade name Eudragit® NM 30 D (Evonik, Germany)), hydroxypropyl methylcellulose (HPMC), polysorbate 80, and talc, or (Pellet C-IX-a) A suspension containing a copolymer of ethyl acrylate, methyl methacrylate, and a low content of methacrylic acid esters having quaternary ammonium groups (commercially available under the trade name Eudragit® RS 100 (Evonik, Germany)), triethyl citrate (TEC), and talc. The pellets were essentially as described in Example 1-1 for Pellet CIa, except that either The composition of the resulting comparative pellet C-VIII-a is shown in Table 18. [Table 18] The composition of the resulting comparative pellet C-IX-a is shown in Table 19. [Table 19]

[0253] Dissolution tests were performed according to the United States Pharmacopoeia method in a USP Type 2 apparatus at 37°C ± 0.5°C with direct UV detection in 900 mL of 0.1 N HCl solution or pH 6.8 phosphate buffer at 50 rpm.

[0254] When comparative pellets C-VIII-a were used, the release profile was almost immediate: 100% of silodosin was released in about 1 hour.

[0255] With the comparative pellet C-IX-a, the release profile is biphasic ("sigmoidal") with a very slow release phase from 0 to about 6 hours, followed by a rapid release phase from about 6 to about 11 hours, at which point 100% of silodosin is released.

[0256] Therefore, the comparative pellet C-VIII-a is not suitable for use in a continuous contraceptive method, and the comparative pellet C-IX-a is not advantageous for use as an ER composition in a continuous contraceptive method.

[0257] Example 4: In vivo studies of silodosin formulations according to the present invention material and method A study was conducted to evaluate the pharmacokinetic (PK) profile of the formulation of the present invention in the treatment of male subjects. A total of 24 subjects aged 20 to 48 years were enrolled in the double-blind study. Each subject received a single dose of Formulation (Ia) and Formulation (Va) in a crossover design. Plasma samples were collected 0 to 48 hours after administration for silodosin determination.

[0258] The possibility of burst was evaluated regarding the PK profile upon administration of the formulation.

[0259] result No burst was observed in the PK profile, demonstrating that formulations (Ia) and (Va) do not produce any significant burst release effect when administered to male subjects.

Claims

1. (a) an inert core; (b) at least one drug layer applied to the inert core, Silodosin, and at least one binder; a drug layer comprising (c) optionally, at least one seal coating surrounding the drug layer; (d) at least one sustained release coating surrounding the drug layer or any seal coating, the sustained release coating comprising at least one vinyl polymer; and Pellets containing

2. 2. The pellet of claim 1, wherein the binder is selected from cellulose polymers, preferably the binder is selected from hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose, methyl cellulose, ethyl cellulose, povidone, polyvinylpyrrolidone and mixtures thereof.

3. 3. The pellets of claim 1 or claim 2, wherein the optional seal coating comprises at least one cellulose polymer, preferably the cellulose polymer is selected from hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose, methyl cellulose, ethyl cellulose and mixtures thereof.

4. the inert core comprises cellulose polymers and mixtures thereof, preferably the inert core comprises microcrystalline cellulose; and / or The inert core has a particle size in the range of about 300 to 500 μm. The pellet according to any one of claims 1 to 3.

5. A pellet according to any one of claims 1 to 4, wherein the sustained release coating comprises at least one polyvinyl ester polymer, preferably a polyvinyl acetate polymer.

6. 6. The pellet of claim 5, wherein the sustained release coating comprises polyvinyl acetate (PVA).

7. 7. The pellet of claim 6, wherein the sustained release coating further comprises povidone (PVP).

8. 8. The pellet of claim 7, wherein the sustained release coating comprises about 90% w / w polyvinyl acetate (PVA) and about 9% w / w povidone (PVP) by weight of the sustained release coating.

9. The pellets are at least one antioxidant, preferably selected from phenol, vitamin E and its derivatives, vitamin C and its derivatives, propyl gallate and mixtures thereof, more preferably selected from butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), α-tocopherol, ascorbyl palmitate, propyl gallate and mixtures thereof, Preferably selected from inorganic carbonates, magnesium silicates and mixtures thereof, more preferably calcium carbonate (CaCO ３ ), at least one antiblocking and / or antistatic agent selected from talc and mixtures thereof, and / or at least one plasticizer selected from citric acid esters, more preferably triethyl citrate (TEC); The pellet according to any one of claims 1 to 8, further comprising:

10. The pellets are (e) at least one enteric coating and the enteric coating further comprises surrounding said sustained release coating, or - surrounded by said sustained release coating and surrounding said optional seal coating or said drug layer; The pellet according to any one of claims 1 to 9.

11. 11. The pellet of claim 10, wherein the enteric coating comprises at least one acrylate copolymer, preferably a methacrylic acid / ethyl acrylate (MAE) copolymer.

12. The pellets are mixed in a weight ratio relative to the total weight of pellets A. - about 24-95% w / w of said inert core; about 5-76% w / w of the drug layer, - about 5 to 25% w / w of said silodosin, - about 0.1 to 7.5% w / w of said binder; about 0-20% w / w of at least one antioxidant, and about 0-25% w / w of at least one anti-blocking and / or anti-static agent the drug layer comprising Pellets A essentially consisting of The pellets A may be optionally mixed by weight relative to the total weight of the pellets B. about 90-100% w / w of said pellets A, and - about 0-10% w / w of at least one seal coating; It is contained in pellet B consisting essentially of The weight of the pellet A or the optional pellet B is based on the total weight of the pellet C. about 50-98% w / w of said pellets A or said optional pellets B, and - a sustained release coating, - about 0.5-47% w / w of at least one sustained release agent; about 0.02-7% w / w of at least one plasticizer, and approximately 0.3-23% w / w of at least one anti-blocking agent a sustained release coating comprising and the pellet C essentially consists of The pellets C may be optionally added in an amount of 1000 to 10000 by weight relative to the total weight of any pellets D. about 50-95% w / w of said pellets C, and - an enteric coating, - about 4-49.5% w / w of at least one enteric agent, and about 0.04-10% w / w of at least one plasticizer an enteric coating comprising The pellet D essentially consists of The pellet according to any one of claims 1 to 11.

13. (b) the drug layer is applied to the inert core at a weight gain ranging from about 5 to 318%; (c) the optional seal coating is applied to the drug layer at a weight gain ranging from 0 to about 11%; (d) the sustained-release coating is applied to the drug layer or any seal coating at a weight gain ranging from about 2 to 100%; and / or (e) the optional enteric coating is applied to the sustained release coating at a weight gain ranging from 0 to about 100%. The pellet according to any one of claims 1 to 12.

14. The pellets are (a) one inert core comprising a cellulose microsphere; (b) at least one drug layer applied to the inert core, Silodosin, Hydroxypropyl cellulose (HPC), Calcium carbonate (CaCO ３ ), and Butylhydroxytoluene (BHT) a drug layer comprising (c) at least one seal coating surrounding the drug layer, the seal coating comprising hydroxypropyl methylcellulose (HPMC); and (d) at least one sustained-release coating surrounding the drug layer or any seal coating, Polyvinyl acetate (PVA), Polyvinylpyrrolidone (PVP), Triethyl citrate (TEC), and talc a sustained release coating comprising The pellet according to any one of claims 1 to 13, comprising:

15. The pellets are (e) at least one enteric coating surrounding or surrounded by the sustained-release coating and surrounding the optional seal coating or the drug layer, Methacrylic acid / ethyl acrylate copolymer (1:1) (“MAE(1:1)”), and Triethyl citrate (TEC) an enteric coating comprising 15. The pellet of claim 14, further comprising:

16. A dosage form comprising a plurality of pellets according to any one of claims 1 to 15.

17. 17. The dosage form of claim 16, wherein the plurality of pellets are contained in a capsule, preferably a hard shell capsule and / or a functional capsule (e.g., an enteric coated capsule).

18. 18. The dosage form of claim 16 or claim 17, wherein the plurality of pellets comprises silodosin in an amount ranging from about 4 to 32 mg, preferably from about 8 to 28 mg, more preferably from about 12 to 24 mg.

19. A method of contraception for a male subject, comprising administering to the male subject a dosage form according to any one of claims 16 to 18 at approximately the same time each day.

20. A process for producing a plurality of pellets according to any one of claims 1 to 15 or a dosage form according to any one of claims 16 to 18, comprising the steps of: (1-a) A step of preparing a drug solution or drug suspension, the drug solution or drug suspension comprising: a drug solution comprising silodosin, at least one binder, at least one solvent, and optionally at least one antioxidant, and optionally at least one antiblock and / or antistatic agent and then (1-b) applying the drug solution or drug suspension to a plurality of inert cores, thereby obtaining a plurality of pellets A; (2-a) optionally preparing a seal coating suspension containing at least one seal coating agent; (2-b) applying the seal coating suspension to the plurality of pellets A, thereby obtaining a plurality of pellets B; (3-a) preparing a sustained release coating suspension comprising at least one sustained release coating agent, at least one plasticizer, and at least one anti-tack agent; (3-b) applying the sustained release coating suspension to the plurality of pellets A or any of the plurality of pellets B, thereby obtaining the plurality of pellets according to any one of claims 1 to 15; or (3'-a) preparing a sustained release coating suspension comprising at least one sustained release coating agent, at least one plasticizer, and at least one anti-tack agent; (3'-b) applying the sustained release coating suspension to the plurality of pellets A or any of the plurality of pellets B, thereby obtaining a plurality of pellets C; (4'-a) preparing an enteric coating suspension containing at least one enteric coating agent and at least one plasticizer; (4'-b) applying the enteric coating suspension to the plurality of pellets C, thereby obtaining the plurality of pellets according to any one of claims 1 to 15; or (3''-a) preparing an enteric coating suspension containing at least one enteric coating agent and at least one plasticizer; (3''-b) applying the enteric coating suspension to the plurality of pellets A or any of the plurality of pellets B, thereby obtaining a plurality of pellets E; (4''-a) preparing a sustained release coating suspension comprising at least one sustained release coating agent, at least one plasticizer, and at least one anti-tack agent; (4''-b) applying the sustained release coating suspension to the plurality of pellets E, thereby obtaining a plurality of pellets according to any one of claims 1 to 15; and (5) Optionally, filling the obtained plurality of pellets into at least one capsule, thereby obtaining the dosage form according to any one of claims 16 to 18. A process involving:

Images