Improved release silodosin compositions and their use in male contraception methods

Abstract

The present disclosure relates to improved release silodosin compositions comprising at least one pellet comprising a silodosin drug layer and a prolonged release coating. The drug layer may include silodosin and an adhesive. The pellet may also comprise a sealing coating. The pellet may also comprise an enteric coating. The disclosure also relates to the use of said composition in male contraception methods. The present disclosure also relates to methods of making pellets or dosage forms described herein.

Description

[0001] Cross - reference to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 427480, filed on November 23, 2022, under 35 U.S.C.§119(e), and the benefit of European Patent Office Application No. EP22208994.8, filed on November 23, 2022, under 35 U.S.C.§119(a), the entire contents of which are incorporated herein by reference. Field of the invention

[0003] The technology described herein relates to modified - release silodosin compositions comprising pellets loaded with silodosin, the pellets comprising a silodosin drug layer and an extended - release coating. This technology also relates to the use of said compositions in male contraceptive methods. Background of the invention

[0005] Contraceptive methods for female subjects, including contraceptive compositions, date back to the Middle Ages and even ancient times. In the 20th century, safer and more convenient female pharmaceutical solutions gradually emerged and are now part of everyday life around the world. In contrast, male contraception has historically been far less popular, and even today, male interest in pharmaceutical contraception remains rather limited. Despite the well - documented drawbacks and limitations of the latest male contraceptive methods, such as condoms or vasectomies, not much effort has been put into finding alternatives. As a result, men who are willing to use oral contraceptives (e.g., to relieve the mental burden on their female partners, take on birth control responsibility, or find an alternative to female contraception) have very few options available today.

[0006] When significant funding began to be invested in this research area, it was found that the development of male contraceptives was overly challenging. Similar to female contraceptive compositions, initial efforts mostly focused on hormone - based contraceptives. However, repeated administration of hormones to men results in psychological, behavioral, physiological, and sexual adverse reactions that are generally considered unacceptable by the male subjects themselves. Among these adverse reactions, decreased libido, "loss of masculinity" (e.g., erectile dysfunction, breast tenderness and breast tissue enlargement, testicular and penile atrophy, or loss of muscle mass), depression, possible suicidal thoughts, decreased mental acuity, weight gain, fatigue, and hot flashes have been documented. 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 therapies applicable to male menopause and male contraception.

[0007] Silodosin is an α1 - adrenergic receptor antagonist with high selectivity (uroselectivity) for the lower urinary tract (prostate, urethra, and bladder neck), and it is marketed for the treatment of the signs and symptoms of benign prostatic hyperplasia (“BPH”), and its trade names include (USA), or (EU), etc. α1 - adrenergic receptors are present in arterial, smooth muscle, and central nervous system tissues. An “α1 - adrenergic receptor antagonist” refers to a compound that inhibits these receptors. Thus, the hormone norepinephrine prevents the muscles that tighten the walls of smaller arteries and veins, and thus, administering an α1 - adrenergic receptor antagonist in the human body can keep blood vessels open and relaxed. This can improve blood flow and lower blood pressure. The smooth muscle of the male urinary tract contains a high density of α - 1 - adrenergic receptors, and thus, in the case of prostate dysfunction (such as BPH), using an α - 1 - adrenergic receptor antagonist such as silodosin can help improve urine flow.

[0008] In the process of treating BPH with silodosin, it has been found that silodosin may cause azoospermia, severe oligospermia, or severe oligospermia in male subjects in some cases, especially the absence of semen ejaculation (azoospermia) (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 they were initially considered side effects of BPH treatment, these results suggest that silodosin may be used as a male contraceptive, and further research has been carried out on this (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. is still very limited, especially due to the experimental settings. Therefore, BHAT et al. have at most demonstrated that silodosin may be used in an “on - demand” contraceptive method. In an “on - demand” contraceptive method, oral contraceptives are taken in advance before sexual intercourse. This is obviously inconvenient for the relevant subjects. More importantly, “on - demand” contraceptives do not provide continuous contraceptive effects, let alone safe and reliable continuous contraceptive effects.

[0009] Accordingly, early silodosin-based contraceptive compositions did not meet the needs of men who require a safe method of contraception, particularly a method that ensures a continuous contraceptive effect. In addition, it is known that silodosin administration can cause many adverse sex-related side effects, including ejaculatory discomfort, decreased orgasm quality, decreased erectile function, and decreased libido. Accordingly, immediate-release (IR) silodosin compositions known in the art, such as those marketed for the treatment of BPH, are not suitable for the purpose of repositioning silodosin as a contraceptive.

[0010] Patent application WO 2019 / 180217 A1 (LABORATOIRES MAJOR) discloses the use of an extended-release (ER) formulation comprising silodosin in a non-hormonal contraceptive method in male subjects. Specifically, WO 2019 / 180217 A1 discloses an (R)-silodosin ER granule labeled "Formulation A" having the structure and composition shown in Table 1 below.

[0011] Table 1: "Formulation A" of WO 2019 / 180217 A1

[0012]

[0013] ECD is an aqueous dispersion of ethylcellulose. Guar gum is a polysaccharide commonly used as a stabilizer or thickener. Dibutyl sebacate (DBS) is the dibutyl ester of sebacic acid and is commonly used as a plasticizer. In WO 2019 / 180217 A1, the ER formulation is administered once daily at approximately the same time each day, which triggers persistent reversible azoospermia, aspermia, or severe oligospermia in male subjects, and, notably, the contraceptive effect is not affected by subsequent daily intake delays after an initial period of at least two consecutive days. Accordingly, WO 2019 / 180217 A1 teaches that a male contraceptive method using "Formulation A" as a contraceptive composition provides safe contraception. The method of WO 2019 / 180217A1 represents a significant improvement over prior art methods and compositions, particularly with respect to the IR silodosin compositions used by BHAT et al. SUMMARY OF THE INVENTION

[0014] The present disclosure further improves the physicochemical and / or biological properties of a modified release silodosin formulation for male oral contraceptives, including addressing the chemical stability of silodosin, within-batch homogeneity, between-batch reproducibility, migration of silodosin within the modified release granules, time-dependent stability of the release profile (e.g., dissolution profile), adverse effects (particularly sex-related effects), and improvement in contraceptive reliability related to subject compliance. Compositions are also provided herein that allow for easy determination or adjustment of the optimal dose (“dose range”) of silodosin and / or the release rate of silodosin. Specifically, the compositions described herein prevent or limit the “burst release effect,” which is an unwanted and uncontrolled early rapid release of the active ingredient. Improvements in the manufacturing method also optimize parameters, such as in terms of silodosin degradation and coating yield.

[0015] Additional modified release compositions are described herein, the modified release effect of which is obtained through at least one pellet, the 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 or an optional sealing coating surrounding the drug layer. In certain embodiments, the pellet may further comprise at least one sealing coating surrounding the drug layer. In other embodiments, the pellet may further comprise at least one enteric coating comprising at least one polymer selected from acrylate polymers, cellulose polymers, and mixtures thereof. In the techniques described herein, the extended release coating comprises at least one vinyl polymer, and the applicant has surprisingly found that it can be identified as a very relevant material for preparing modified release silodosin compositions. Specifically, the use of vinyl polymers unexpectedly overcomes some significant limitations of cellulose-based ER coatings (such as ethyl cellulose) in silodosin contraceptive formulations.

[0016] In one aspect, a pellet is described herein that comprises: (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 surrounding the drug layer, wherein the extended release coating comprises at least one vinyl polymer.

[0017] In an embodiment of this aspect or any other aspect described herein, the pellet further comprises at least one sealing coating surrounding the drug layer, and wherein the extended release coating surrounds the sealing coating.

[0018] In another embodiment of this aspect or any other aspect described herein, the binder comprises a cellulose polymer. In another embodiment, the cellulose polymer is selected from the group consisting of hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose, methyl cellulose, ethyl cellulose, polyvinylpyrrolidone, polyvinylpyrrolidone, and mixtures thereof.

[0019] In another embodiment of this aspect or any other aspect described herein, the sealing coating comprises at least one cellulose polymer. In another embodiment of this aspect 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.

[0020] In another embodiment of this aspect or any other aspect described herein, the inert core comprises a cellulose polymer or a mixture thereof. In another embodiment of this aspect or any other aspect described herein, the inert core comprises microcrystalline cellulose.

[0021] In another embodiment of this aspect or any other aspect described herein, the particle size of the inert core ranges from about 300 to 500 μm.

[0022] In another embodiment of this aspect or any other aspect described herein, the extended-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 extended-release coating further comprises polyvinylpyrrolidone (PVP). In another embodiment of this aspect or any other aspect described herein, the extended-release coating comprises about 90% w / w of polyvinyl acetate (PVA) and about 9% w / w of polyvinylpyrrolidone (PVP), based on the weight of the extended-release coating.

[0023] In another embodiment of this aspect or any other aspect described herein, the pellets further comprise one or more of the following: at least one antioxidant; at least one anti-adherent and / or antistatic 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 butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), α-tocopherol, ascorbyl palmitate, propyl gallate, and mixtures thereof. In another embodiment of this aspect or any other aspect described herein, the anti-adherent and / or antistatic agent is selected from inorganic carbonates, magnesium silicate salts, and mixtures thereof. In another embodiment of this aspect or any other aspect described herein, the anti-adherent and / or antistatic agent is selected from calcium carbonate (CaCO3), talc, and mixtures thereof. In another embodiment of this aspect or any other aspect described herein, the plasticizer is a citrate ester. In another embodiment of this aspect or any other aspect described herein, the plasticizer is triethyl citrate (TEC).

[0024] In another embodiment of this aspect or any other aspect described herein, the pellets further comprise: at least one enteric coating, wherein the enteric coating either coats the extended-release coating or is coated by the extended-release coating and coats the seal coating or the drug layer.

[0025] In another embodiment of this aspect or any other aspect described herein, the enteric coating comprises at least one acrylate copolymer. In another embodiment of this aspect or any other aspect described herein, the acrylate copolymer is a methacrylic acid-ethyl acrylate (MAE) copolymer.

[0026] In another embodiment of this aspect or any other aspect described herein, the pellets comprise: Pellet A, which consists essentially of: about 24 to 95% w / w of an inert core; about 5 to 76% w / w of a drug layer, which comprises: 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-adherent and / or antistatic agent, based on the weight relative to the total weight of Pellet A.

[0027] In another embodiment of this aspect or any other aspect described herein, Pellet A is contained in Pellet B, which consists essentially of: about 90 to 100% w / w of Pellet A; and about 0 to 10% w / w of at least one seal coating, based on the weight relative to the total weight of Pellet B.

[0028] In another embodiment of this aspect or any other aspect described herein, pellet A or pellet B is contained within pellet C, which consists essentially of: about 50 to 98% w / w of pellet A or pellet B, and an extended-release coating comprising: about 0.5 to 47% w / w of at least one extended-release agent; about 0.02 to 7% w / w of at least one plasticizer; and about 0.3 to 23% w / w of at least one anti-adherent, based on the weight relative to the total weight of pellet C.

[0029] In another embodiment of this aspect or any other aspect described herein, pellet C is contained within pellet D, which consists essentially of: about 50 to 95% w / w of pellet C, and an enteric coating comprising: about 4 to 49.5% w / w of at least one enteric solvent; and about 0.04 to 10% w / w of at least one plasticizer, based on the weight relative to the total weight of pellet D.

[0030] In another embodiment of the pellets described herein: (a) the drug layer is applied to the inert core with a weight increment of about 5 to 318%; (b) the sealing coating agent is applied to the drug layer with a weight increment of 0 to about 11%; (c) the extended-release coating agent is applied to the drug layer or the sealing coating with a weight increment of about 2 to 100%; and / or (d) the enteric coating agent is applied to the extended-release coating with a weight increment of 0 to about 100%.

[0031] 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, wherein the drug layer comprises: silodosin, hydroxypropyl cellulose (HPC), calcium carbonate (CaCO3), and butylated hydroxytoluene (BHT); (c) at least one sealing coating covering the drug layer, wherein the sealing coating comprises hydroxypropyl methylcellulose (HPMC); and (d) at least one extended-release coating covering the drug layer or the optional sealing coating, wherein the extended-release coating comprises: polyvinyl acetate (PVA), polyvinylpyrrolidone (PVP), triethyl citrate (TEC), and talc.

[0032] In another embodiment of this aspect or any other aspect described herein, the pellet further comprises: (e) at least one enteric coating, wherein the enteric coating either covers the extended-release coating or is covered by the extended-release coating and covers the optional sealing coating or drug layer, wherein the enteric coating comprises: methacrylic acid-ethyl acrylate copolymer 1:1 (MAE 1:1) and triethyl citrate (TEC).

[0033] In another aspect, the present disclosure describes a pharmaceutical composition comprising a plurality of pellets as described herein. In one embodiment of this aspect or any other aspect described herein, the plurality of pellets are contained within 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 capsule.

[0034] In one embodiment of this aspect or any other aspect described herein, the plurality of pellets comprise from about 4 to 32 mg of silodosin. In another embodiment of this aspect or any other aspect described herein, the plurality of pellets comprise from about 8 to 28 mg of silodosin. In another embodiment of this aspect or any other aspect described herein, the plurality of pellets comprise from about 12 to 24 mg of silodosin.

[0035] In another aspect, the present disclosure describes a method of contraception for male subjects, which comprises the step of administering to a male subject the pharmaceutical composition as described herein at about the same time each day.

[0036] In another aspect, the present disclosure describes a method for manufacturing a plurality of pellets as described herein or a pharmaceutical composition as described herein, the method comprising the steps of: (1-a) preparing a drug solution or drug suspension comprising a drug solution containing 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 to obtain a plurality of pellets A; (2-a) applying a sealing coating suspension to the plurality of pellets A to obtain a plurality of pellets B; (3-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; and then (3-b) applying the extended-release coating suspension to the plurality of pellets A or the plurality of pellets B to obtain a plurality of pellets as described herein. In one embodiment of this aspect or any other aspect described herein, the step of preparing a sealing coating suspension comprising at least one sealing coating agent is carried out before step (2-a). In another embodiment of this aspect or any other aspect described herein, the drug solution of step (1-a) comprises at least one antioxidant. In another embodiment of this aspect or any other aspect described herein, the drug solution of step (1-a) comprises at least one anti-adherent and / or antistatic agent.

[0037] On the other hand, the present disclosure describes a method for manufacturing a plurality of pellets or pharmaceutical compositions described herein, wherein the method comprises the following steps: (1-a) preparing a drug solution or drug suspension, which contains a drug solution containing 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 sealing coating suspension to the plurality of pellets A, thereby obtaining a plurality of pellets B; (3-a) preparing an extended-release coating suspension containing at least one extended-release coating agent, at least one plasticizer, and at least one anti-adhesive; and then (3'-b) applying the extended-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 containing at least one enteric coating agent and at least one plasticizer; and 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, the step of preparing a sealing coating suspension containing at least one sealing coating agent is carried out before step (2-a). In another embodiment of this aspect 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 in step (1-a) contains at least one anti-adhesive and / or antistatic agent.

[0038] In another aspect, the present disclosure describes a method for manufacturing multiple pellets or pharmaceutical compositions as described herein, the method comprising the steps of: (1-a) preparing a drug solution or drug suspension, which comprises a drug solution containing 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 to obtain a plurality of pellets A; (2-a) applying a sealing coating suspension to the plurality of pellets A to obtain a plurality of pellets B; (3”-a) preparing an enteric coating suspension comprising at least one enteric coating agent and at least one plasticizer; and then (3”-b) applying the enteric coating suspension to the plurality of pellets A or the plurality of pellets B to obtain 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-adhesive; and then (4”-b) applying the extended release coating suspension to the plurality of pellets E to obtain a plurality of pellets as described herein. In one embodiment of this aspect or any other aspect described herein, the step of preparing a sealing coating suspension comprising at least one sealing coating agent is carried out before step (2-a). In another embodiment of this aspect or any other aspect described herein, the method further comprises the step of filling the obtained plurality of pellets into at least one capsule to obtain a pharmaceutical composition as described herein. In another embodiment of this aspect or any other aspect described herein, the drug solution or drug suspension in step (1-a) comprises at least one antioxidant. In another embodiment of this aspect or any other aspect described herein, the drug solution or drug suspension in step (1-a) comprises at least one anti-adhesive and / or antistatic agent.

[0039] The technology described herein relates to a pellet 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 sealing coating covering the drug layer; and / or (d) at least one extended release coating covering the drug layer or the optional sealing coating, wherein the extended release coating comprises at least one vinyl polymer.

[0040] 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, methylcellulose, ethylcellulose, polyvinylpyrrolidone, polyvinylpyrrolidone, and mixtures thereof.

[0041] According to some embodiments, the optional sealing coating comprises at least one cellulose polymer; preferably, the cellulose polymer is selected from hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose, methylcellulose, ethylcellulose, and mixtures thereof.

[0042] According to some embodiments, the inert core comprises a cellulose polymer and mixtures thereof, preferably the inert core comprises microcrystalline cellulose; and / or the inert core has a particle size of about 300 to 500 μm.

[0043] According to some embodiments, the extended release coating comprises at least one polyvinyl ester polymer, preferably polyvinyl acetate polymer, more preferably polyvinyl acetate (PVA).

[0044] According to some embodiments, the pellets further comprise at least one antioxidant; preferably, the antioxidant is selected from phenols, vitamin E and its derivatives, vitamin C and its derivatives, propyl gallate, and mixtures thereof; more preferably, the antioxidant is selected from butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), α-tocopherol, ascorbyl palmitate, propyl gallate, and mixtures thereof; at least one anti-adhesive and / or antistatic agent; preferably, the anti-adhesive and / or antistatic agent is selected from inorganic carbonates, magnesium silicate salts, and mixtures thereof; more preferably, the anti-adhesive and / or antistatic agent is selected from calcium carbonate (CaCO3), 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).

[0045] According to some embodiments, the pellets further comprise: (e) at least one enteric coating, wherein the enteric coating either coats the extended release coating or is coated by the extended release coating and coats an optional 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.

[0046] According to some embodiments, the pellets comprise:

[0047] Pellet A, which consists essentially of about 24 to 95% w / w of an inert core and about 5 to 76% w / w of a drug layer, the drug layer comprising: 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 and / or antistatic agent, based on the weight relative to the total weight of Pellet A;

[0048] wherein Pellet A is optionally contained in Pellet B, and Pellet B consists essentially of about 90 to 100% of Pellet A and about 0 to 10% w / w of at least one seal coating that coats the drug layer, based on the weight relative to the total weight of Pellet B;

[0049] Wherein, pellet A or optional pellet B is contained within pellet C, and pellet C consists essentially of from about 50 to 98% w / w of pellet A or optional pellet B and an extended-release coating, said extended-release coating comprising: from about 0.5 to 47% w / w of at least one extended-release agent, from about 0.02 to 0.7% w / w of at least one plasticizer, and from about 0.3 to 23% w / w of at least one anti-adherent; by weight relative to the total weight of pellet C; and

[0050] Wherein, pellet C is optionally contained within pellet D, and pellet D consists essentially of from about 50 to 95% w / w of pellet C and an enteric coating, said enteric coating comprising: from about 4 to 49.5% w / w of at least one enteric solvent, and from about 0.04 to 10% w / w of at least one plasticizer, by weight relative to the optional total weight of pellet D.

[0051] According to some embodiments, (b) a drug layer is applied to an inert core in a weight increment of from about 5 to 318%, (c) an optional sealing coating agent is applied to the drug layer in a weight increment of from 0 to about 11%, (d) an extended-release coating agent is applied to the drug layer or optional sealing coating in a weight increment of from about 2 to 100%, and / or (e) an optional enteric coating agent is applied to the extended-release coating in a weight increment of from 0 to about 100%.

[0052] The techniques described herein also relate to dosage forms comprising a plurality of the pellets described herein. According to some embodiments, the plurality of pellets are contained within a capsule, preferably a hard shell capsule and / or a functional capsule (e.g., an enteric capsule). According to some embodiments, the plurality of pellets comprise from about 4 to 32 mg, preferably from about 8 to 28 mg, more preferably from about 12 to 24 mg of silodosin.

[0053] The techniques described herein also relate to a method of contraception for male subjects, which comprises the step of administering to a male subject the dosage form described herein at about the same time each day.

[0054] The techniques described herein also relate to a method for manufacturing a plurality of pellets or dosage forms described herein, the method comprising the steps of: (1-a) preparing a drug solution or drug suspension comprising a drug containing silodosin, at least one binder, at least one solvent, and optionally at least one antioxidant; and optionally a drug solution comprising at least one antiadhesive and / or antistatic agent, and then (1-b) applying the drug solution or drug suspension to a plurality of inert cores to obtain a plurality of pellets A; (2-a) optionally, preparing a sealing coating suspension comprising at least one sealing coating agent; and then (2-b) applying the sealing coating suspension to the plurality of pellets A to obtain a plurality of pellets B; (3-a) preparing an extended-release coating suspension comprising at least one extended-release coating agent, at least one plasticizer, and at least one antiadhesive; and then (3-b) applying the extended-release coating suspension to the plurality of pellets A or the plurality of optional pellets B to obtain a plurality of pellets as described herein; or (3'-a) preparing an extended-release coating suspension comprising at least one extended-release coating agent, at least one plasticizer, and at least one antiadhesive; and then (3'-b) applying the extended-release coating suspension to the plurality of pellets A or the plurality of optional pellets B to obtain a plurality of pellets C; (4'-a) preparing an enteric coating suspension comprising at least one enteric coating agent and at least one plasticizer; and then (4'-b) applying the enteric coating suspension to the plurality of pellets C to obtain a plurality of pellets as described herein; or (3”-a) preparing an enteric coating suspension comprising at least one enteric coating agent and at least one plasticizer; and then (3”-b) applying the enteric coating suspension to the plurality of pellets A or the plurality of optional pellets B to obtain 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 antiadhesive; and then (4”-b) applying the extended-release coating suspension to the plurality of pellets E to obtain a plurality of pellets as described herein; and (5) optionally, filling the obtained plurality of pellets into at least one capsule to obtain a dosage form as described herein.

[0055] Definitions

[0056] In the present disclosure, unless otherwise specified, the following terms have the following meanings.

[0057] As used herein, "about" means approximately, roughly, around, or within the range of. When the term "about" is placed before a number, it means plus or minus ( "plus or minus" or "more or less") 10% of the value of that number. When the term "about" is used in conjunction with a numerical range, it modifies the range by expanding the upper and lower boundaries of the numerical values by 10% respectively.

[0058] "Active ingredient", "active pharmaceutical ingredient", or "drug" (collectively referred to as "API") are synonyms and generally refer to contraceptives, therapeutic agents, and agents that are both contraceptives and therapeutic agents.

[0059] "Administration" or its variants (e.g., "administering") means providing an active ingredient to a subject in need of contraception either alone or as part of a pharmaceutically acceptable composition.

[0060] "Aspermia" means the inability to produce or ejaculate semen.

[0061] "Azoospermia" means the absence of sperm in the semen.

[0062] "Binder" or "binding agent" means a substance that holds or attracts other substances or materials together by mechanical, chemical, adhesive, or cohesive forces to form a cohesive mass.

[0063] "Coating agent" means a substance that, when applied to the surface of a substrate and subjected to final processing steps as needed (e.g., curing, shaping, polymerization, or crosslinking), will produce a "coating material" (abbreviated as "coating") that covers the surface of the substrate.

[0064] "Contraception" refers to preventive or prophylactic measures where the aim is to prevent or at least reduce the risk of pregnancy. In the technologies described herein, the aim of contraception is to prevent fertilization, i.e., to avoid gamete fusion (e.g., the union of a human egg and sperm). The subjects in need of contraception are typically fertile subjects of reproductive age who wish to avoid pregnancy, regardless of their reproductive status. While contraception may be irreversible or reversible, many subjects prefer it to be reversible. When contraception is achieved by rendering a male subject infertile, this is referred to as "male contraception" (or "contraception of male subjects"). In preferred embodiments, contraception includes inducing persistent aspermia, azoospermia, or severe oligospermia in a male subject. In these embodiments, contraception is male contraception.

[0065] "Contraceptive agent" refers to a compound used for contraception and related to birth control. In particular, a contraceptive agent can be used to prevent pregnancy. A contraceptive agent can also be used to enhance the contraceptive activity of another contraceptive agent.

[0066] "Contraceptive composition" (abbreviated as "contraceptive") refers to a composition used for contraceptive purposes and related to birth control. In particular, a contraceptive composition can be used to prevent pregnancy. A contraceptive composition can also be used to enhance the contraceptive activity of another contraceptive composition.

[0067] "Contraceptive method" means a method whose purpose is to induce or maintain contraception in a subject. A contraceptive method may include a definition and / or an administration protocol for at least one subject.

[0068] "Delayed release" (abbreviated as "DR") refers to the release of an active ingredient (such as silodosin) from a composition, where the active ingredient (API) is not released immediately after administration to a subject, in contrast to an immediate-release (IR) composition containing the same API in the same dose. A "delayed-release composition" is a composition that is suitable for obtaining DR release of the API contained therein after its administration to a subject. A "delayed-release coating" is a coating that helps a composition achieve "delayed release" as defined herein. The European Pharmacopoeia defines "delayed release" as: "A delayed-release dosage form is a modified-release dosage form, usually administered orally, in which the onset of release of the active substance is adjusted to occur after a specific time or at a specific location in the gastrointestinal tract." Delayed release is achieved through special dosage form design and / or manufacturing methods. Delayed-release dosage forms include gastro-resistant preparations, which are consistent with the above definition.

[0069] "Enteric coating" refers to a barrier applied to an oral drug that prevents its dissolution or disintegration in the gastric environment, usually a polymeric coating. Enteric coatings can be used to protect a drug from gastric acid erosion, protect the stomach from the harmful effects of a drug, or release a drug after the stomach (usually in the upper part of the intestine). Generally, an enteric coating is expected to dissolve at a pH equal to or higher than about 5.5. In particular, an enteric coating helps avoid or reduce the effect of the acidic environment of the stomach on the release rate of the active ingredient. Based on this last type of effect, an enteric coating can be considered a specific type of "delayed release" coating. An "enteric solvent" is a substance that, when applied to the surface of a substrate and subjected to a final processing step (such as curing, shaping, polymerization, or crosslinking) when needed, will result in an "enteric coating" (as defined herein) covering the surface of the substrate.

[0070] "Extended-release" (abbreviated as "ER") refers to the release of an active ingredient (such as silodosin) from a composition, where the active ingredient (API) is released over time after administration to a subject, in contrast to an immediate-release (IR) composition containing the same API in the same dose. An "extended-release composition" is a pharmaceutical composition that is suitable for obtaining ER release of the API contained therein after its administration to a subject. An "extended-release coating" is a coating that helps a composition achieve "extended release" as defined herein. An "extended-release agent" is a substance that, when applied to the surface of a substrate and subjected to a final processing step (such as curing, shaping, polymerization, or crosslinking) when needed, will result in an "extended-release coating" (as defined herein) covering the surface of the substrate.

[0071] "Human" refers to male or female human subjects at any stage of development, including neonates, infants, children, 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.

[0072] "Modified-release" (abbreviated as "MR") means that, compared with an immediate-release (IR) composition containing the same dose of the same active ingredient (API), the release of the active ingredient (such as silodosin) from the composition involves at least one change in the release of the API after administration to a subject. According to some embodiments, "modified-release" refers to "extended-release" (ER) associated with at least one change in API release. In some embodiments, "modified-release" refers to "extended-release" (ER) and "delayed-release" (DR), i.e., release that is both extended and delayed (DR + ER). A "modified-release composition" is a pharmaceutical composition that is suitable for obtaining a modified release of the API contained therein after administration to a subject. A "modified-release coating" refers to a coating that helps the composition achieve "modified-release" as defined herein.

[0073] "Pellet" or "granule" refers to a small, compressed, hard mass of material. Generally, a pellet comprises a core coated with multiple layers of continuous coatings.

[0074] "Pharmaceutical composition" refers to a composition comprising at least one active ingredient (such as silodosin) and at least one pharmaceutically acceptable carrier. Thus, in the present disclosure, a contraceptive composition can also be regarded as a "pharmaceutical composition".

[0075] "Pharmaceutically acceptable" means that the components of the composition are compatible with each other and harmless to the subject to be administered.

[0076] "Pharmaceutically acceptable carrier" refers to an excipient that does not produce adverse reactions, allergic reactions or other unwanted reactions when administered to animals (preferably humans). It includes any and all solvents, dispersion media, coating agents, antibacterial agents, antifungal agents, isotonic agents, absorption delaying agents, etc. For human administration, the preparation should meet the sterility, pyrogenicity, general safety and purity standards stipulated by regulatory agencies (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), buffering substances (such as phosphates, glycine, sorbic acid, potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances (such as sodium carboxymethyl cellulose), polyethylene glycol, polyacrylates, waxes, polyethylene-polypropylene-block polymers, polyethylene glycol and lanolin.

[0077] "Plasticizer" or "plasticizing agent" refers to a substance added to a material to make the material softer and more flexible, increase its plasticity, reduce its viscosity and / or reduce the friction during its production and processing.

[0078] When the term "polymer" is preceded by a term referring to a large class of polymers (such as "acrylate polymer"), it refers to any homopolymer, copolymer and their mixtures belonging to the designated class. For example, the term "acrylate polymer" encompasses "acrylate homopolymer", "acrylate copolymer" and any mixture thereof. Copolymers can be block copolymers, alternating copolymers and / or random copolymers. Copolymers can also contain monomers that do not belong to the designated class but can be polymerized by the same route.

[0079] "Prodrug" refers to a pharmacologically acceptable derivative of an active ingredient (such as silodosin), the biotransformation product of which in vivo is the active ingredient (active drug). Prodrugs usually have the characteristic of increased bioavailability and are easily metabolized into active compounds in vivo. Non-limiting examples of prodrugs include amide prodrugs and carboxylate prodrugs.

[0080] "Severe oligozoospermia" refers to a low total sperm count or concentration in semen, usually less than or equal to about 5x10 6 sperm per ejaculation, preferably less than or equal to about 1x10 6 sperm per ejaculation.

[0081] "Solvate" refers to a molecular complex that contains a compound (e.g., silodosin) and contains a stoichiometric or sub-stoichiometric amount of one or more pharmaceutically acceptable solvent molecules (e.g., ethanol). The term "hydrate" refers to the case where the solvent is water.

[0082] "Subject" refers to an animal, typically a warm-blooded animal, particularly a mammal, more particularly a primate, preferably a human. A subject can be a "patient". A subject can be referred to as a "male subject" or a "female subject" according to their respective genders. In a preferred embodiment, the subject is a male subject. In a preferred embodiment, the subject requires contraception.

[0083] As used herein, the terms "comprising" or "including" are used to refer to the compositions, methods, and their corresponding components that are necessary for the present invention, but may also include unspecified elements, whether or not necessary.

[0084] As used herein, the term "consisting essentially of" refers to those elements required for a given embodiment. This term allows for the presence of other elements that do not materially affect the basic and novel or functional characteristics of this embodiment of the present invention.

[0085] The term "consisting of" refers to the compositions, methods, and their respective components described herein, which exclude any element not enumerated in the description of this embodiment.

[0086] As used in this specification and the appended claims, unless the context clearly dictates otherwise, the singular forms "a", "an", and "the" include plural meanings. Thus, for example, reference to "the method" includes one or more methods and / or steps of the type described herein and / or one or more methods and / or steps that will be apparent to those skilled in the art upon reading this disclosure, and so on. Detailed Description of the Invention

[0088] Pellets

[0089] An object of the technology described herein is a pellet comprising:

[0090] (a) An inert core;

[0091] (b) At least one drug layer applied to the inert core, the drug layer containing silodosin and at least one binder;

[0092] (d) At least one extended-release coating that coats the drug layer, wherein the extended-release coating contains at least one vinyl polymer.

[0093] According to some embodiments, the pellets have a near-spherical or spherical shape, i.e., the pellets are "spherical" or "spheroids". In some embodiments, the spheroids are filled spheroids (or "balls").

[0094] Inert core

[0095] "Inert core" means that the core is chemically inert (or "neutral"). Thus, it does not react with the active ingredient. The inertness of the core can be attributed, for example, to its material properties or the presence of a barrier coating.

[0096] According to some embodiments, the inert core has a near-spherical or spherical shape, i.e., the inert core is "spherical" or "spheroid". In some embodiments, the spheroid is a "hollow" spheroid. In some embodiments, the spheroid is a "filled" spheroid (or "ball").

[0097] According to some embodiments, the particle size range of the inert core is about 106 to 850 μm (85% or more of the particles fall within this range). In some embodiments, the particle size range of the inert core is about 106 to 212 μm (at least 85% of the particles fall within this range). In some embodiments, the particle size range of the inert core is about 150 to 300 μm (at least 85% of the particles fall within this range). In some embodiments, the particle size range of the inert core is about 300 to 500 μm (at least 85% of the particles fall within this range). In some embodiments, the particle size range of the inert core is about 500 to 710 μm (at least 85% of the particles fall within this range). In some embodiments, the particle size range of the inert core is about 710 to 850 μm (at least 85% of the particles fall within this range). In some preferred embodiments, the particle size range of the inert core is about 300 to 500 μm (at least 85% of the particles fall within this range).

[0098] According to some embodiments, the inert core has a particle size in the range of about 100 to 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 to 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 to 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 to 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 to 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 to 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 to 1400 μm (at least 85% of the particles fall within this range).

[0099] "Particle size" refers to the particle width measured by sieve analysis. The sieve set consists of multiple sieves with gradually increasing pore sizes. The sample is placed on the topmost sieve and then the sieve set is shaken. As a result, the particles are distributed among the respective sieves in the sieve set according to their sizes.

[0100] The applicant unexpectedly observed that in the production of silodosin compositions, the yield of the step of applying the drug layer (silodosin) to the inert core is high enough to meet industrial requirements. The applicant unexpectedly found that using inert cores with an average particle size of about 300 to 500 μm can significantly improve the coating performance of the drug layer on the inert cores (up to 95%).

[0101] According to some embodiments, the inert core comprises a cellulose polymer and mixtures thereof. In some specific embodiments, the inert core comprises microcrystalline cellulose (MCC). In some preferred embodiments, the microcrystalline cellulose is Celphere TM (Asahi Kasei Corporation, Japan).

[0102] Silodosin

[0103] "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).

[0104] According to some preferred embodiments, silodosin is in the form of its (R)-stereoisomer, i.e., “(R)-silodosin”. The official name of (R)-silodosin is (-)-(R)-1-(3-hydroxypropyl)-5-[2-[[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]amino]propyl]indoline-7-carboxamide. The structural formula of (R)-silodosin is as follows:

[0105]

[0106] (R)-Silodosin is a white or pale yellow / white powder (melting point range of about 105 to 109 °C). It is very soluble in acetic acid, freely soluble in alcohols, and very slightly soluble in water.

[0107] All references to “silodosin” include its salts, solvates, multicomponent complexes, and / or liquid crystals. All references to “silodosin” include its polymorphs and / or crystal habits. All references to “silodosin” include its pharmaceutically acceptable prodrugs. All references to “silodosin” include isotopically labeled silodosin, including deuterated silodosin.

[0108] Silodosin may exist in the form of pharmaceutically acceptable salts. Pharmaceutically acceptable salts of silodosin include its acid addition salts and base addition salts. Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, bisulfate / sulfate, borate, camphorsulfonate, citrate, cyclohexylsulfamate, edisylate, esylate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hippurate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, hydroxyethylsulfonate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / monohydrogenphosphate / dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and xinafoate. Suitable base addition salts are formed from bases that form non-toxic salts. Examples include aluminum salts, arginine salts, benzathine salts, calcium salts, choline salts, diethylamine salts, 2-(diethylamino)ethanol salts, diolamine salts, ethanolamine salts, glycine salts, 4-(2-hydroxyethyl)-morpholine salts, lysine salts, magnesium salts, meglumine salts, morpholine salts, olamine salts, potassium salts, sodium salts, tromethamine salts, and zinc salts.

[0109] Silodosin may be in polymorphic or amorphous form. According to some embodiments, silodosin is polymorphic. According to some embodiments, silodosin is amorphous.

[0110] Silodosin may exist in a pharmaceutically acceptable solvate form. Pharmaceutically acceptable solvates of silodosin include its hydrates.

[0111] Binder

[0112] 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).

[0113] Antioxidant

[0114] According to some embodiments, the pellets further comprise at least one antioxidant. In some preferred embodiments, the drug layer comprises at least one antioxidant.

[0115] In some embodiments, the antioxidant is selected from phenols, vitamin E and its derivatives, vitamin C and its derivatives (e.g., ascorbic acid), citric acid, propionic acid, isoascorbic acid (or “D-erythro-hex-2-enono-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, vitamin E derivatives are selected from d-α-tocopherol, dl-α-tocopherol, d-α-tocopheryl acetate, dl-α-tocopheryl acetate, d-α-tocopheryl acid succinate, dl-α-tocopheryl acid succinate, β-tocopherol, δ-tocopherol, γ-tocopherol, vitamin E polyethylene glycol succinate (tocophersolan) (also known as “vitamin E TPGS”), and mixtures thereof. In some embodiments, vitamin C derivatives are selected from ascorbic acid, ascorbyl palmitate, isoascorbic acid, sodium ascorbate, and mixtures thereof.

[0116] In some embodiments, the antioxidant is selected from phenols, vitamin E and its derivatives, vitamin C and its derivatives, propyl gallate, and mixtures thereof. In some embodiments, the antioxidant is selected from butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), α-tocopherol, ascorbyl palmitate, propyl gallate, and mixtures thereof.

[0117] In some embodiments, the antioxidant is selected from phenols. In some embodiments, the antioxidant is selected from butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), and mixtures thereof. In some preferred embodiments, the antioxidant is butylated hydroxytoluene (BHT).

[0118] In some embodiments, the antioxidant is selected from vitamin E and its derivatives. In some preferred embodiments, the antioxidant is α-tocopherol.

[0119] In some embodiments, the antioxidant is selected from vitamin C and its derivatives. In some embodiments, the antioxidant is ascorbyl palmitate.

[0120] Anti-adherent and / or antistatic agent

[0121] According to some embodiments, the pellets further comprise at least one anti-adherent and / or antistatic agent. In some preferred embodiments, the drug layer comprises at least one anti-adherent and / or antistatic agent. In some preferred embodiments, the extended-release coating comprises at least one anti-adherent and / or antistatic agent.

[0122] In some embodiments, the anti-adherent and / or antistatic agent is selected from calcium carbonate (CaCO3), talc, calcium phosphate, tricalcium silicate, colloidal silica, hydrophobic colloidal silica, magnesium oxide, magnesium silicate, magnesium trisilicate, and mixtures thereof.

[0123] In some embodiments, the anti-adherent and / or antistatic agent is selected from inorganic carbonates, magnesium silicate salts, and mixtures thereof. In some embodiments, the anti-adherent and / or antistatic agent is selected from calcium carbonate (CaCO3), talc, and mixtures thereof.

[0124] In some embodiments, the anti-adherent and / or antistatic agent is selected from inorganic carbonates. In some embodiments, the anti-adherent and / or antistatic agent is calcium carbonate (CaCO3). In some preferred embodiments, the drug layer comprises calcium carbonate (CaCO3).

[0125] In some embodiments, the anti-adherent and / or antistatic agent is selected from magnesium silicate salts. In some embodiments, the anti-adherent and / or antistatic agent is talc. In some preferred embodiments, the extended-release coating comprises talc.

[0126] Plasticizer

[0127] According to some embodiments, the pellets further comprise at least one plasticizer. In some preferred embodiments, the extended-release coating comprises at least one plasticizer. The pellets may further comprise an enteric coating as described below, and in some preferred embodiments, the optional enteric coating comprises at least one plasticizer.

[0128] In some embodiments, the plasticizer is selected from citrate esters. In some preferred embodiments, the plasticizer is triethyl citrate (TEC).

[0129] In some embodiments, the plasticizer is selected from diols. In some embodiments, the plasticizer is 1,2 - propanediol.

[0130] Sealing coating

[0131] According to some preferred embodiments, the pellets further comprise: at least one sealing coating (c) that coats the drug layer. Then, the extended - release coating coats the optional sealing coating, rather than the drug layer.

[0132] The applicant unexpectedly observed that in silodosin ER compositions, silodosin migration into the ER coating can sometimes be observed. The applicant surprisingly found that including an optional sealing coating can significantly prevent silodosin migration into the ER coating (especially ethylcellulose ER coating, such as ECD). In addition, the applicant surprisingly found that including a sealing coating can significantly prevent silodosin interaction with the ER coating (especially vinyl polymer ER coating, such as SR30D).

[0133] In some embodiments, the optional sealing coating comprises at least one cellulose polymer. In some embodiments, the cellulose polymer is selected from hydroxypropyl methylcellulose (HPMC), carboxymethylcellulose, methylcellulose, ethylcellulose, and mixtures thereof.

[0134] In some preferred embodiments, the optional sealing coating comprises hydroxypropyl methylcellulose (HPMC). In some preferred embodiments, the optional sealing coating is obtained by applying a coating agent (Colorcon, USA).

[0135] Extended - release coating

[0136] In the pellets described herein, the sealing coating (when present) and the extended - release coating are different coatings. In other words, the same coating cannot serve as both the "sealing coating" and the "extended - release coating" used in this application.

[0137] According to some embodiments, the extended-release coating comprises at least one polyvinyl ester polymer. In some embodiments, the extended-release coating comprises at least one polyvinyl acetate polymer. In some preferred embodiments, the extended-release coating comprises polyvinyl acetate (PVA), i.e., PVA as a homopolymer. In some preferred embodiments, the extended-release coating comprises polyvinylpyrrolidone (PVP) (commonly also referred to as "polyvidone" or "povidone"). In some embodiments, the extended-release coating comprises a mixture of vinyl polymers. In some preferred embodiments, the extended-release coating comprises polyvinyl acetate (PVA) and polyvinylpyrrolidone (PVP).

[0138] According to some embodiments, the extended-release coating comprises at least one additive typically included in coating agents. In some embodiments, the extended-release coating comprises at least one dispersant and / or at least one surfactant. Generally, a dispersant and / or a surfactant may be present in a polymer coating agent, for example, to stabilize a dispersion prior to applying the coating during the manufacturing process. In some embodiments, the extended-release coating comprises at least one dispersant. For example, the dispersant may comprise polyvinylpyrrolidone (PVP). In some embodiments, the extended-release coating comprises at least one surfactant. For example, the surfactant may comprise sodium lauryl sulfate (SLS).

[0139] In some embodiments, the extended-release coating comprises from about 70% to 99% w / w of a polyvinyl acetate (PVA) polymer or copolymer, based on the weight of the extended-release coating. In some embodiments, the extended-release coating comprises from about 75% to 99% w / w, preferably from about 80% to 98% w / w, more preferably from about 85% to 95% w / w of a polyvinyl acetate (PVA) polymer or copolymer, based on the weight of the extended-release coating. In some embodiments, the extended-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, based on the weight of the extended-release coating. In some preferred embodiments, the extended-release coating comprises about 90% w / w of a polyvinyl acetate (PVA) polymer or copolymer, based on the weight of the extended-release coating.

[0140] In some embodiments, the extended-release coating comprises from about 6% to 15% w / w of polyvinylpyrrolidone (PVP), by weight relative to the weight of the extended-release coating. In some embodiments, the extended-release coating comprises from about 6% to 15% w / w, preferably from about 7% to 13% w / w, more preferably from about 8% to 11% w / w of polyvinylpyrrolidone (PVP), by weight relative to the weight of the extended-release coating. In some embodiments, the extended-release coating comprises about 15% w / w or less, about 14% w / w or less, about 13% w / w or less, about 12% w / w or less, about 11% w / w or less, about 10% w / w or less or about 9% w / w or less of polyvinylpyrrolidone (PVP), by weight relative to the weight of the extended-release coating. In some preferred embodiments, the extended-release coating comprises about 9% w / w of polyvinylpyrrolidone (PVP), by weight relative to the weight of the extended-release coating.

[0141] In some preferred embodiments, the extended-release coating comprises sodium lauryl sulfate (SLS). In some embodiments, the extended-release coating comprises from about 0.6% to 1.5% w / w of sodium lauryl sulfate (SLS), by weight relative to the weight of the extended-release coating. In some embodiments, the extended-release coating comprises from about 0.6% to 1.5% w / w, preferably from about 0.7% to 1.3% w / w, more preferably from about 0.8% to 1.1% w / w of sodium lauryl sulfate (SLS), by weight relative to the weight of the extended-release coating. In some embodiments, the extended-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, about 1% w / w or less of sodium lauryl sulfate (SLS), by weight relative to the weight of the extended-release coating. In some preferred embodiments, the extended-release coating comprises about 1% w / w of sodium lauryl sulfate (SLS), by weight relative to the weight of the extended-release coating.

[0142] In some preferred embodiments, the extended-release coating is obtained by applying the coating agent " SR 30D" (BASF Pharma, Germany) (abbreviated as "KSR"). SR 30D is an aqueous dispersion with a solids content of 30%. The dispersion consists of 27% polyvinyl acetate (PVA), about 2.7% polyvinylpyrrolidone (PVP), about 0.3% sodium lauryl sulfate (SLS) and water.

[0143] The applicant unexpectedly found that in the case where the ER coating is ethyl cellulose (e.g. In the silodosin composition of ECD, the release curve of silodosin is unstable. An unstable release pattern may lead to an unstable and thus unreliable continuous contraceptive effect. The applicant has conducted extensive research and tested a large number of common ER polymers, but none of them obtained a suitable and / or sufficiently stable silodosin release curve. Finally, the applicant surprisingly found that using a vinyl polymer (such as SR 30D) as the ER coating significantly improved the stability of the silodosin release curve.

[0144] However, the applicant also surprisingly found that the release curve of the silodosin pellets described herein coated with an ER vinyl polymer (such as SR 30D) has a strong "pH-dependence", that is, the acidic pH of the environmental medium accelerates the release of silodosin. In the art, this property is generally considered unfavorable for therapeutic or contraceptive formulations because such "pH-dependent" compositions usually start to dissolve in the stomach (where the pH is very acidic), and the dissolution conditions cannot be properly controlled and may depend on the specific situation of the subject. Therefore, those skilled in the art strongly expect that such "pH-dependent" compositions will cause uncontrolled "burst release" (or "burst release effect") when passing through the stomach, thus limiting or inhibiting the ER effect.

[0145] In addition, the applicant also surprisingly found that the silodosin pellets described herein coated with an ER vinyl polymer (such as SR 30D) exhibit a "lag time" during in vitro assays, that is, the release of silodosin does not start immediately, but is delayed for a period of time (for example, about 1 hour). Therefore, these pellets belong to "delayed release" compositions in the sense of the present disclosure. In the art, this property is generally considered unfavorable for contraceptive formulations because one may hope to start the contraceptive effect as soon as possible after administration. However, when continuous contraception is required, the contraceptive composition is usually taken daily, so the limited delay in silodosin release does not affect the reliability of contraception. Therefore, as long as the "lag time" is relatively short compared to the total duration of the contraceptive effect, "delayed release" may be convenient for contraceptive purposes.

[0146] As explained above, due to the use of an ER vinyl polymer (such as The enteric-coated silodosin pellets have “pH-dependence”, so there is a significant risk of “burst release effect” when administered to a subject, resulting in the inability to maintain the silodosin ER release observed in vitro in vivo. However, the applicant surprisingly found that no burst release effect was observed in the treated subjects, which was completely unexpected according to the common knowledge in the art. Without being bound by theory, the applicant believes that there may be some association between the absence of “burst release effect” in vivo and the “lag time” observed in vitro, which can explain the surprising technical effects of the pellets and dosage forms described herein.

[0147] Enteric coating

[0148] According to some embodiments, the pellets further comprise: at least one enteric coating (e). In some preferred embodiments, the enteric coating coats the extended release coating. In some other embodiments, the enteric coating is coated by the extended release coating and coats the drug layer or the optional sealing coating. In some preferred embodiments, the drug layer or the optional sealing coating is coated by at least one extended release coating and then coated by at least one enteric coating. In some other embodiments, the drug layer or the optional sealing coating is coated by at least one enteric coating and then coated by at least one extended release coating.

[0149] In the pellets described herein, the sealing coating (when present) and the enteric coating are different coatings. In other words, the same coating cannot serve as both the “sealing coating” and the “enteric coating” used in this application at the same time.

[0150] In the pellets described herein, the extended release coating and the enteric coating are different coatings. In other words, the same coating cannot serve as both the “extended release coating” and the “enteric coating” used in this application at the same time.

[0151] In some embodiments, the enteric coating comprises at least one polymer selected from acrylate polymers, cellulose polymers, and mixtures thereof.

[0152] In some embodiments, the enteric coating comprises at least one acrylate polymer.

[0153] 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”).

[0154] In some embodiments, the enteric coating comprises at least one polymethacrylate polymer (e.g., NE).

[0155] In some embodiments, the enteric coating comprises from about 70% to 99% w / w of an acrylate copolymer, by weight relative to the weight of the enteric coating. In some preferred embodiments, the enteric coating comprises about 97% w / w of an acrylate copolymer, by weight relative to the weight of the enteric coating.

[0156] 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”).

[0157] In some embodiments, the enteric coating comprises from about 1.5% to 3% w / w of a polyethoxylated sorbitan fatty acid ester, by weight relative to the weight of the enteric coating. In some preferred embodiments, the enteric coating comprises about 2.3% w / w of a polyethoxylated sorbitan fatty acid ester, by weight relative to the weight of the enteric coating.

[0158] 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 a methacrylic acid - ethyl acrylate (MAE) copolymer and polysorbate 80.

[0159] In some preferred embodiments, the enteric coating is obtained by applying the coating agent “ MAE 30DP” (BASF Pharma, Germany) (abbreviated as “KMAE”). MAE 30DP is an aqueous dispersion with a solids content of 30% (w / w). Based on the solids content, the dispersion consists of 97% (w / w) of a methacrylic acid and ethyl acrylate copolymer (1:1), about 2.3% (w / w) of polysorbate 80, and about 0.7% (w / w) of sodium dodecyl sulfate.

[0160] 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., ), cellulose acetate phthalate (CAP), hypromellose phthalate (HPMPC), and mixtures thereof.

[0161] In some embodiments, the enteric coating comprises at least one poly(methyl vinyl ether / maleic anhydride) copolymer (e.g., Gantrez TM ).

[0162] In some embodiments, the enteric coating comprises at least one polyvinyl acetate phthalate (e.g., “ enteric”).

[0163] The applicant surprisingly found that adding an enteric coating (e.g., MAE 30DP) makes the pellets more acid-resistant, e.g., with no significant silodosin release within 2 hours in simulated gastric fluid.

[0164] Specific pellets

[0165] 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 antiadherent and / or antistatic agent.

[0166] The applicant unexpectedly observed that when manufacturing the drug layer of a silodosin composition on a laboratory scale (small-scale experiment), in order to improve the formation of the coating, it is advantageous to include a minimal amount of binder and a minimal amount of antiadherent and / or antistatic agent, but their presence was determined to be a possible cause of silodosin degradation. The applicant surprisingly found that including at least one antioxidant in the drug layer significantly prevents the degradation of silodosin during the manufacturing process.

[0167] According to some embodiments, the pellets comprise pellets that contain an inert core coated with a drug layer or consist essentially of an inert core coated with a drug layer (referred to herein as “pellets A”). Pellets A can be particularly used as an intermediate for manufacturing another pellet. Pellets A can also be particularly used as an immediate-release (IR) silodosin formulation.

[0168] According to some embodiments, the pellets comprise pellets that contain an inert core coated with a drug layer or consist essentially of an inert core coated with a drug layer, and the drug layer is coated with a sealing coating (referred to herein as “pellets B”). Pellets B can be particularly used as an intermediate for manufacturing another pellet. Pellets B can also be particularly used as an immediate-release (IR) silodosin formulation.

[0169] According to some embodiments, the pellets comprise pellets that contain an inert core coated with a drug layer or consist essentially of an inert core coated with a drug layer, the drug layer is optionally coated with a sealing coating, and the drug layer or the optional sealing coating is coated with an extended-release coating (referred to herein as “pellets C”). Pellets C can be particularly used as part of a contraceptive composition.

[0170] According to some embodiments, the pellets comprise pellets that contain an inert core coated with a drug layer or consist essentially of an inert core coated with a drug layer, the drug layer optionally being coated with a sealing coat, the drug layer or the optional sealing coat being coated with an extended release coat, and the extended release coat being coated with an enteric coat (referred to herein as "pellet D"). Pellet D can be particularly used as part of a contraceptive composition.

[0171] According to some embodiments, the pellets comprise pellets that contain an inert core coated with a drug layer or consist essentially of an inert core coated with a drug layer, the drug layer optionally being coated with a sealing coat, the drug layer or the optional sealing coat being coated with an enteric coat (referred to herein as "pellet E"). Pellet E can be particularly used as an intermediate for manufacturing another pellet. Pellet E can also be particularly used as a delayed release and immediate release silodosin formulation.

[0172] According to some embodiments, the pellets comprise pellets that contain an inert core coated with a drug layer or consist essentially of an inert core coated with a drug layer, the drug layer optionally being coated with a sealing coat, the drug layer or the optional sealing coat being coated with an enteric coat, and the enteric coat being coated with an extended release coat (referred to herein as "pellet F"). Pellet F can be particularly used as part of a contraceptive composition.

[0173] The applicant surprisingly found that when silodosin is formulated in the form of pellet C, pellet D or pellet F described herein, it is easier to determine or adjust the optimal dose ("dose range") of silodosin than with other ER compositions.

[0174] The applicant surprisingly found that when silodosin is formulated in the form of pellet C, pellet D or pellet F described herein, it is easier to determine or regulate the release rate of silodosin than with other ER compositions.

[0175] Specific formulations

[0176] According to some embodiments, the pellets comprise:

[0177] (a) An inert core containing cellulose microspheres;

[0178] (b) At least one drug layer applied to the inert core, wherein the drug layer comprises: silodosin, hydroxypropyl cellulose (HPC), calcium carbonate (CaCO3) and butylated hydroxytoluene (BHT);

[0179] (c) At least one sealing coat coating the drug layer, wherein the sealing coat comprises hydroxypropyl methyl cellulose (HPMC); and

[0180] (d) At least one extended-release coating that coats the drug layer or an optional sealing coating, wherein the extended-release coating comprises: polyvinyl acetate (PVA), polyvinylpyrrolidone (PVP), triethyl citrate (TEC), and talc.

[0181] In some embodiments, the pellets further comprise:

[0182] (e) At least one enteric coating, wherein the enteric coating either coats the extended-release coating or is coated by the extended-release coating and coats the optional sealing coating or the drug layer, and wherein the enteric coating comprises: methacrylic acid-ethyl acrylate copolymer 1:1 (MAE 1:1) and triethyl citrate (TEC).

[0183] Amount of ingredients

[0184] According to some embodiments, the pellets include Pellet A, which comprises the following or consists essentially of:

[0185] - An inert pellet core of about 24 to 95% w / w, preferably 43.3 to 91.5% w / w, more preferably 74 to 83.5% w / w,

[0186] - A drug layer of about 5 to 76% w / w, preferably 8.5 to 56.7% w / w, more preferably 16.5 to 26% w / w, which drug layer comprises:

[0187] - Silodosin of about 5 to 25% w / w, preferably 8 to 18% w / w, more preferably 11 to 15% w / w,

[0188] - An adhesive of 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,

[0189] - At least one antioxidant of about 0 to 25% w / w, preferably 0.01 to 10% w / w, more preferably 0.022 to 0.09%, and

[0190] - At least one anti-adherent and / or antistatic agent of about 0 to 25% w / w, preferably 2 to 13.5% w / w, more preferably 4.4 to 9% w / w,

[0191] By weight relative to the total weight of Pellet A.

[0192] According to some embodiments, the pellets include Pellet B, which comprises the following or consists essentially of:

[0193] - About 90 to 100% w / w, preferably 92.5 to 97.5% w / w, more preferably 94 to 96% w / w of Pellet A, and

[0194] - At least one sealing coating of about 0 to 10% w / w, preferably 2.5 to 7.5% w / w, more preferably 4 to 6% w / w,

[0195] by weight relative to the total weight of the pellets B.

[0196] According to some embodiments, the pellets comprise pellets C, which contain or consist essentially of:

[0197] - About 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

[0198] - An extended release coating, which comprises:

[0199] - About 0.5 to 47% w / w, preferably 1.6 to 19.1% w / w, more preferably 4.7 to 12.25%

[0200] w / w of at least one extended release agent,

[0201] - About 0.02 to 0.7% w / w, preferably 0.06 to 1.6% w / w, more preferably 0.19 to 0.75%

[0202] w / w of at least one plasticizer, and

[0203] - About 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-adhesive,

[0204] by weight relative to the total weight of the pellets C.

[0205] According to some embodiments, the pellets comprise pellets D, which contain or consist essentially of:

[0206] - About 50 to 95% w / w, preferably 62 to 88% w / w, more preferably 70 to 80% w / w of pellets C, and

[0207] - An enteric coating, which comprises:

[0208] - About 4 to 49.5% w / w, preferably 10 to 36%, more preferably 17.5 to 27.5% w / w of at least one enteric solvent, and

[0209] - About 0.04 to 10% w / w, preferably 0.5 to 5.5% w / w, more preferably 1.4 to 3.3%

[0210] w / w of at least one plasticizer,

[0211] by weight relative to the total weight of the pellets D.

[0212] According to some embodiments, the pellets comprise:

[0213] Pellet A, which comprises or consists essentially of:

[0214] - an inert pellet core of about 24 to 95% w / w, preferably 43.3 to 91.5% w / w, more preferably 74 to 83.5% w / w,

[0215] - a drug layer of about 5 to 76% w / w, preferably 8.5 to 56.7% w / w, more preferably 16.5 to 26% w / w, the drug layer comprising:

[0216] - silodosin of about 5 to 25% w / w, preferably 8 to 18% w / w, more preferably 11 to 15% w / w,

[0217] - a binder of 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,

[0218] - at least one antioxidant of about 0 to 20% w / w, preferably 0.01 to 10% w / w, more preferably 0.022 to 0.09%, and

[0219] - at least one anti-adherent and / or antistatic agent of about 0 to 25% w / w, preferably 2 to 13.5% w / w, more preferably 4.4 to 9% w / w,

[0220] by weight relative to the total weight of Pellet A;

[0221] wherein Pellet A is optionally contained in Pellet B, and Pellet B comprises or consists essentially of:

[0222] - about 90 to 100% w / w, preferably 92.5 to 97.5% w / w, more preferably 94 to 96% w / w of Pellet A, and

[0223] - at least one sealing coating for coating the drug layer of about 0 to 10% w / w, preferably 2.5 to 7.5% w / w, more preferably 4 to 6% w / w,

[0224] by weight relative to the total weight of Pellet B;

[0225] wherein Pellet A or Pellet B is contained in Pellet C, and Pellet C comprises or consists essentially of:

[0226] - about 50 to 98% w / w, preferably 75 to 96.5% w / w, more preferably 82 to 94% w / w of Pellet A or Pellet B, and

[0227] - an extended-release coating, which comprises:

[0228] - from about 0.5 to 47% w / w, preferably from 1.6 to 19.1% w / w, more preferably from 4.7 to 12.25%

[0229] w / w of at least one extended release agent,

[0230] - from about 0.02 to 0.7% w / w, preferably from 0.06 to 1.6% w / w, more preferably from 0.19 to 0.75%

[0231] w / w of at least one plasticizer, and

[0232] - from about 0.3 to 23% w / w, preferably from 0.3 to 8.6% w / w, more preferably from 1.3 to 5.15% w / w of at least one anti-adhesive agent;

[0233] by weight relative to the total weight of pellet C; and

[0234] wherein pellet C is optionally included in pellet D, and pellet D comprises or consists essentially of:

[0235] - from about 50 to 95% w / w, preferably from 62 to 88% w / w, more preferably from 70 to 80% w / w of pellet C, and

[0236] - an enteric coating, which comprises:

[0237] - from about 4 to 49.5% w / w, preferably from 10 to 36%, more preferably from 17.5 to 27.5% w / w of at least one enteric solvent, and

[0238] - from about 0.04 to 10% w / w, preferably from 0.5 to 5.5% w / w, more preferably from 1.4 to 3.3% w / w of at least one plasticizer,

[0239] by weight relative to the total weight of optional pellet D.

[0240] In some embodiments, pellet A or pellet B is included in pellet C, and pellet C comprises or consists essentially of:

[0241] - from about 75 to 93% w / w, preferably from 82 to 88% w / w of pellet A or pellet B; and

[0242] - an extended release coating, which comprises:

[0243] - from about 11.25 to 119.1% w / w, preferably from 6.25 to 12.25% w / w of at least one extended release agent;

[0244] - from about 0.4 to 1.6% w / w, preferably from 0.25 to 0.75% w / w of at least one plasticizer; and

[0245] - At least one anti-adhesive agent in an amount of about 2.25 to 8.6% w / w, preferably 1.75 to 5.15% w / w;

[0246] Based on the weight relative to the total weight of the pellets C.

[0247] In some embodiments, pellet A or pellet B is included in pellet C, and pellet C comprises or consists essentially of:

[0248] - Pellet A or pellet B in an amount of about 80 to 96.5% w / w, preferably 91 to 94% w / w; and

[0249] - An extended-release coating, which comprises:

[0250] - At least one extended-release agent in an amount of about 1.6 to 15.3% w / w, preferably 4.7 to 6.1% w / w;

[0251] - At least one plasticizer in an amount of about 0.06 to 1.5% w / w, preferably 0.19 to 0.37% w / w; and

[0252] - At least one anti-adhesive agent in an amount of about 0.3 to 6.9% w / w, preferably 1.3 to 2.6% w / w;

[0253] Based on the weight relative to the total weight of the pellets C.

[0254] According to some embodiments, the pellets include pellet E, and pellet E comprises or consists essentially of:

[0255] - Pellet A or pellet B as described herein in an amount of about 50 to 95% w / w, and

[0256] - An enteric coating, which comprises:

[0257] - At least one enteric agent in an amount of about 4 to 49.5% w / w, preferably 10 to 36%, more preferably 17.5 to 27.5% w / w, and

[0258] - At least one plasticizer in an amount of about 0.04 to 10% w / w, preferably 0.5 to 5.5% w / w, more preferably 1.4 to 3.3% w / w,

[0259] Based on the weight relative to the total weight of the pellets E.

[0260] According to some embodiments, the pellets include pellet F, and pellet F comprises or consists essentially of:

[0261] - Pellet E in an amount of about 50 to 98% w / w, preferably 75 to 96.5% w / w, more preferably 82 to 94% w / w, and

[0262] - Extended release coating, comprising:

[0263] - At least one extended release agent in an amount of about 0.5 to 47% w / w, preferably 1.6 to 19.1% w / w, more preferably 4.7 to 12.25%

[0264] w / w;

[0265] - At least one plasticizer in an amount of about 0.02 to 0.7% w / w, preferably 0.06 to 1.6% w / w, more preferably 0.19 to 0.75%

[0266] w / w, and

[0267] - At least one anti-adhesive agent in an amount of about 0.3 to 23% w / w, preferably 0.3 to 8.6% w / w, more preferably 1.3 to 5.15% w / w,

[0268] by weight relative to the total weight of the pellets F.

[0269] According to some embodiments, the pellets comprise:

[0270] Pellets A, which contain or consist essentially of:

[0271] - An inert core in an amount of about 24 to 95% w / w, preferably 43.3 to 91.5% w / w, more preferably 74 to 83.5% w / w,

[0272] - A drug layer in an amount of about 5 to 76% w / w, preferably 8.5 to 56.7% w / w, more preferably 16.5 to 26% w / w, the drug layer comprising:

[0273] - Silodosin in an amount of about 5 to 25% w / w, preferably 8 to 18% w / w, more preferably 11 to 15% w / w,

[0274] - An adhesive in an amount of 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,

[0275] - At least one antioxidant in an amount of about 0 to 20% w / w, preferably 0.01 to 10% w / w, more preferably 0.022 to 0.09%, and

[0276] - At least one anti-adhesive agent and / or antistatic agent in an amount of about 0 to 25% w / w, preferably 2 - 13.5% w / w, more preferably 4.4 to 9% w / w,

[0277] by weight relative to the total weight of the pellets A;

[0278] wherein the pellets A are optionally contained in the pellets B, and the pellets B contain or consist essentially of:

[0279] - from about 90 to 100% w / w, preferably from 92.5 to 97.5% w / w, more preferably from 94 to 96% w / w of pellet A, and

[0280] - from about 0 to 10% w / w, preferably from 2.5 to 7.5% w / w, more preferably from 4 to 6% w / w of at least one sealing coating for the coated drug layer,

[0281] by weight relative to the total weight of pellet B;

[0282] wherein pellet A or pellet B is contained in pellet E, and pellet E comprises or consists essentially of:

[0283] - from about 50% to 95% w / w of pellet A or pellet B, and

[0284] - an enteric coating, which comprises:

[0285] - from about 4 to 49.5% w / w, preferably from 10 to 36%, more preferably from 17.5 to 27.5% w / w of at least one enteric solvent, and

[0286] - from about 0.04 to 10% w / w, preferably from 0.5 to 5.5% w / w, more preferably from 1.4 to 3.3%

[0287] w / w of at least one plasticizer,

[0288] by weight relative to the total weight of pellet E.

[0289] wherein pellet E is contained in pellet F, and pellet F comprises or consists essentially of:

[0290] - from about 50 to 98% w / w, preferably from 75 to 96.5% w / w, more preferably from 82 to 94% w / w of pellet E,

[0291] - an extended release coating, which comprises:

[0292] - from about 0.5 to 47% w / w, preferably from 1.6 to 19.1% w / w, more preferably from 4.7 to 12.25%

[0293] w / w of at least one extended release agent,

[0294] - from about 0.02 to 0.7% w / w, preferably from 0.06 to 1.6% w / w, more preferably from 0.19 to 0.75%

[0295] w / w of at least one plasticizer, and

[0296] - from about 0.3 to 23% w / w, preferably from 0.3 to 8.6% w / w, more preferably from 1.3 to 5.15% w / w of at least one anti-adhesive agent,

[0297] Based on the weight relative to the total weight of the pellets F.

[0298] Weight increment

[0299] "Weight increment" refers to the weight increment of the final object, which is brought about by the step of applying at least one coating agent (e.g., 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. The weight increment is a parameter commonly used in the field of formulations to characterize the coating thickness, because directly measuring the coating thickness requires complex and expensive methods, while the increment can be simply estimated by weighing using common materials (e.g., a laboratory scale). The weight increment WG n (%) after applying "n" coating agents to the starting object ("n" is an integer greater than 0) is calculated as follows: WG n = 100 * (W n ) / W0, where W0 represents the weight of the starting object, and W n represents the dry weight of the coating agent, and W n and W0 are expressed in the same unit (e.g., grams or "g"). In this application, unless otherwise specified, the weight increment is expressed as the value when applying the coating only once, i.e., n is 1. For example, an expression such as "applying the [coating agent 1] to [pellet 0] with a weight increment of 10%" means that W0 is the weight of "pellet 0" (the starting object), W1 is the dry weight of coating agent 1, and 100 * (W1) / W0 = 10%.

[0300] According to some embodiments, the drug layer is applied to the inert core with a weight increment of about 5 to 318%, preferably 10 to 105%, more preferably 19 to 35%.

[0301] According to some embodiments, the optional sealing coating agent is applied to the drug layer with a weight increment of 0 to about 11%, preferably 2.5 to 8%, more preferably 13.5 to 22%.

[0302] According to some embodiments, the extended release coating agent is applied to the drug layer or the optional sealing coating with a weight increment of about 2 to 100%, preferably 3.5 to 33%, more preferably 6 to 22%.

[0303] According to some embodiments, the optional enteric coating agent is applied to the extended release coating with a weight increment of 0 to about 100%, preferably 13.5 to 61%, more preferably 25 to 43%.

[0304] According to some embodiments, the pellets comprise:

[0305] (a) an inert core,

[0306] (b) A drug layer applied to an inert pellet core with a weight increase of about 5 to 318%, preferably 10 to 105%, more preferably 19 to 35%;

[0307] (c) An optional sealing coating agent applied to the drug layer with a weight increase of 0 to about 11%, preferably 2.5 to 8%, more preferably 13.5 to 22%;

[0308] (d) An extended-release coating agent applied to the drug layer or the optional sealing coating with a weight increase of about 2 to 100%, preferably 3.5 to 33%, more preferably 6 to 22%; and / or

[0309] (e) An optional enteric coating agent applied to the extended-release coating with a weight increase of 0 to about 100%, preferably 13.5 to 61%, more preferably 25 to 43%.

[0310] According to some embodiments, the enteric coating agent is applied to the drug layer or the optional sealing coating with a weight increase of 0.1 to about 100%.

[0311] According to some embodiments, the extended-release coating agent is applied to the enteric coating with a weight increase of about 2 to 100%.

[0312] According to some embodiments, the pellets comprise:

[0313] (a) An inert pellet core,

[0314] (b) A drug layer applied to an inert pellet core with a weight increase of about 5 to 318%, preferably 10 to 105%, more preferably 19 to 35%;

[0315] (c) An optional sealing coating agent applied to the drug layer with a weight increase of 0 to about 11%, preferably 2.5 to 8%, more preferably 13.5 to 22%;

[0316] (d) An enteric coating agent applied to the drug layer or the optional sealing coating with a weight increase of 0.1% to about 100%; and / or

[0317] (e) An extended-release coating agent applied to the enteric coating with a weight increase of about 2% to 100%.

[0318] Multiple pellets

[0319] An object of the techniques described herein is multiple pellets as described herein.

[0320] 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 among a 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 comprises at least two types of pellets selected from pellet A, pellet B, pellet C, pellet D, pellet E, and pellet F. In some embodiments, the plurality of pellets comprises 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. The plurality of pellet A, pellet B, or pellet E can be particularly used as an intermediate for manufacturing another plurality of pellets.

[0321] In some embodiments, at least one pellet is selected from pellet A, pellet B, and pellet E described herein. In some embodiments, each pellet among a 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 among the plurality of pellets is pellet A. In some preferred embodiments, each pellet among the plurality of pellets is pellet B. The plurality of pellet A, pellet B, or pellet E can be particularly used as part of a contraceptive composition.

[0322] In some embodiments, at least one pellet is selected from pellet C, pellet D, and pellet F described herein. In some embodiments, each pellet among a 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 among the plurality of pellets is pellet C. In some preferred embodiments, each pellet among the plurality of pellets is pellet D. The plurality of pellet C, pellet D, or pellet F can be particularly used as part of a contraceptive composition.

[0323] Composition

[0324] Another object of the techniques described herein is a composition comprising at least one pellet described herein.

[0325] According to some embodiments, the composition consists of a plurality of pellets as described herein. According to some embodiments, the composition consists of one pellet described herein.

[0326] According to some preferred embodiments, the composition is a contraceptive composition.

[0327] According to some embodiments, the composition is a dosage form.

[0328] "Dosage form" refers to the form in which a dose of an active ingredient (e.g., its "effective amount") is administered to a subject. The active ingredient is typically administered as part of a formulation that includes non-pharmaceutical agents (e.g., pharmaceutically acceptable carriers). Dosage forms have unique physical and pharmaceutical properties. A dosage form can comprise at least one pharmaceutical composition. A dosage form can be, for example, solid, liquid, or gaseous. "Dosage form" can include, for example, capsules (e.g., hard-shell or soft-shell capsules, e.g., gel-cap tablets ["gel-cap"]), tablets, cachets, 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. Dosage forms can also include at least one subcutaneous implant, transdermal patch, injectable form, nasal spray, adhesive tablet, or transmucosal delivery solution.

[0329] 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 capsule.

[0330] "Functional capsule" refers to a capsule, typically a capsule containing a polymer, that contains an oral drug and imparts specific dissolution profile characteristics to the oral drug.

[0331] "Enteric capsule" refers to a capsule, typically a capsule containing a polymer, that contains an oral drug and prevents its dissolution or disintegration in the gastric environment. Enteric capsules can be used to protect a drug from the effects of gastric acid, protect the stomach from the harmful effects of a drug, or release a drug after the stomach (usually in the upper part of the intestine). Typically, an enteric capsule is expected to dissolve at a pH equal to or higher than about 5.5.

[0332] According to some embodiments, the composition is a pharmaceutical composition.

[0333] According to some embodiments, the composition is a drug.

[0334] According to some embodiments, prior to filling the pellets into the dosage form, the pellets are lubricated with at least one anti-adherent. In some preferred embodiments, the anti-adherent is talc.

[0335] According to some embodiments, the composition comprises a plurality of pellets as described herein.

[0336] According to some embodiments, the composition comprises silodosin in an amount of about 0.5 to 50 mg.

[0337] According to some embodiments, the composition comprises silodosin in an amount of about 0.5 to 4 mg, preferably about 1 to 8 mg, more preferably about 2 to 12 mg, and even more preferably about 4 to 16 mg. In some embodiments, the composition comprises silodosin in an amount of about 1 to 8 mg. In some specific embodiments, the composition comprises silodosin in an amount of about 2 to 12 mg. In some further specific embodiments, the composition comprises silodosin in an amount of about 4 to 16 mg.

[0338] According to some embodiments, the composition comprises silodosin in an amount of about 4 to 32 mg, preferably about 8 to 28 mg, more preferably about 12 to 24 mg, and even more preferably about 16 to 20 mg. In some embodiments, the composition comprises silodosin in an amount of about 8 to 28 mg. In some specific embodiments, the composition comprises silodosin in an amount of about 12 to 24 mg. In some further specific embodiments, the composition comprises silodosin in an amount of about 16 to 20 mg.

[0339] According to some embodiments, the composition comprises silodosin in an amount of about 5 to 50 mg, preferably about 10 to 45 mg, more preferably about 15 to 40 mg, and even more preferably about 20 to 35 mg. In some embodiments, the composition comprises silodosin in an amount of about 10 to 45 mg. In some specific embodiments, the composition comprises silodosin in an amount of about 15 to 40 mg. In some further specific embodiments, the composition comprises silodosin in an amount of about 20 to 35 mg.

[0340] According to some embodiments, the composition comprises silodosin in an amount of 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, 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.

[0341] According to some preferred embodiments, all of the silodosin present in the composition is contained in one or more of the pellets described herein. According to some other embodiments, a portion of the silodosin present in the composition is not contained in one or more of the pellets described herein.

[0342] In some embodiments, the composition comprises from about 2.5 to 10 mg, preferably about 5 mg of lubricated pellets (e.g., lubricated pellet C). In some embodiments, the composition comprises from about 125 to 500 mg, preferably about 250 mg of lubricated pellets (e.g., lubricated pellet C). In some embodiments, the composition comprises from about 250 to 1000 mg, preferably about 500 mg of lubricated pellets (e.g., lubricated pellet C).

[0343] According to some embodiments, the composition further comprises at least one other contraceptive agent, i.e., a contraceptive agent other than silodosin.

[0344] Kit

[0345] Another object of the present disclosure is a multi-component kit (abbreviated as "kit") comprising the composition described herein.

[0346] According to some embodiments, the kit comprises a manufacture, such as a package or a container. According to some embodiments, the kit comprises instructions for use. The kit may be promoted, distributed or sold as a unit for a method or use for practicing the techniques described herein.

[0347] Method and Use / Application

[0348] Another object of the techniques described herein is a method of contraception for male subjects, comprising the step of administering to a male subject the composition described herein.

[0349] Another object of the techniques described herein is the use of the composition described herein in a method of contraception for male subjects.

[0350] Another object of the techniques described herein is the composition described herein for use as a male contraceptive (i.e., a contraceptive for male subjects). Another object of the techniques described herein is the composition described herein for use in a method of contraception for male subjects.

[0351] Another object of the techniques described herein is the use of the composition described herein in the manufacture of a medicament for male contraception. Another object of the techniques described herein is the use of the composition described herein in the manufacture of a medicament for a method of contraception for male subjects.

[0352] According to some embodiments, the method or use / application is non-therapeutic.

[0353] According to some embodiments, the method is non-hormonal, or the use / application is for non-hormonal contraception. "Non-hormonal" means that no hormones, particularly no androgens, are administered to the subject during the course of the method or use / application.

[0354] According to some embodiments, the method or use / application comprises the step of administering an effective amount of the composition as described herein to a male subject.

[0355] "Effective amount" means an amount of an active ingredient (e.g., silodosin) sufficient to achieve the desired therapeutic, prophylactic or preventive effect (e.g., contraception) in a subject to whom the active ingredient (e.g., silodosin) is administered, without causing significant negative or adverse side effects to the subject.

[0356] According to some embodiments, the composition is administered or to be administered to the male subject at approximately the same time each day.

[0357] "Approximately the same time" means plus or minus (plus or minus more or less) 2 hours (±2h).

[0358] Manufacturing method

[0359] The pellets or plural pellets described herein can be manufactured by coating methods known in the art (e.g., spray coating).

[0360] Another object of the techniques described herein is a method of manufacturing plural pellets or a composition as described herein.

[0361] According to some embodiments, the method comprises the following steps:

[0362] (1-a) Preparing a drug solution or a drug suspension, which comprises:

[0363] - A drug solution comprising silodosin, at least one binder, at least one solvent and optionally at least one antioxidant; and

[0364] - Optionally, at least one anti-adherent and / or antistatic agent, then

[0365] (1-b) Applying the drug solution or the drug suspension to plural inert cores, thereby obtaining plural pellets A;

[0366] (2-a) Optionally, preparing a sealing coating suspension comprising at least one sealing coating agent; then

[0367] (2-b) Applying the sealing coating suspension to plural pellets A, thereby obtaining plural pellets B; and

[0368] Applying an extended release coating and optionally an enteric coating to plural pellets A or pellets B, generally as described below.

[0369] According to some preferred embodiments, the method further comprises the following steps:

[0370] (3-a) Prepare an extended-release coating suspension comprising at least one extended-release coating agent, at least one plasticizer, and at least one anti-adhesive agent; then

[0371] (3-b) Apply the extended-release coating suspension to a plurality of pellets A or a plurality of alternative pellets B, thereby obtaining a plurality of pellets (“pellets C”).

[0372] According to some preferred embodiments, the method further comprises the following steps:

[0373] (3'-a) Prepare an extended-release coating suspension comprising at least one extended-release coating agent, at least one plasticizer, and at least one anti-adhesive agent; then

[0374] (3'-b) Apply the extended-release coating suspension to a plurality of pellets A or a plurality of alternative pellets B, thereby obtaining a plurality of pellets C;

[0375] (4'-a) Prepare an enteric coating suspension comprising at least one enteric coating agent and at least one plasticizer; then

[0376] (4'-b) Apply the enteric coating suspension to a plurality of pellets C, thereby obtaining a plurality of pellets (“pellets D”).

[0377] According to other embodiments, the method further comprises the following steps:

[0378] (3”-a) Prepare an enteric coating suspension comprising at least one enteric coating agent and at least one plasticizer; then

[0379] (3”-b) Apply the enteric coating suspension to a plurality of pellets A or a plurality of alternative pellets B, thereby obtaining a plurality of pellets E;

[0380] (4”-a) Prepare an extended-release coating suspension comprising at least one extended-release coating agent, at least one plasticizer, and at least one anti-adhesive agent; then

[0381] (4”-b) Apply the extended-release coating suspension to a plurality of pellets E, thereby obtaining a plurality of pellets (“pellets F”).

[0382] According to some embodiments, at least one of the drug layer and the coating is applied by spraying. In some embodiments, the drug layer and each coating are applied by spraying. The application can be carried out by spray coating methods well known in the art.

[0383] According to some embodiments, the solvent in the drug solution or suspension in step (1-a) is ethanol.

[0384] According to some embodiments, the method further comprises the following step: (5) filling the obtained plurality of pellets ("pellet C", "pellet D" or "pellet F", depending on the previous steps) into at least one container, thereby obtaining the dosage form as described herein.

[0385] According to some embodiments, the manufactured composition is a dosage form. According to some embodiments, the container filled in step (5) is a capsule.

[0386] Brief Description of the Drawings

[0387] Figure 1 A diagram showing the main steps of manufacturing the pellets [pellets A, B, C and D] and dosage forms [formulations (I), (III), (V) and (VI)] described herein. References: inert pellet core (a), drug layer containing silodosin (b), optional sealing coating (c), extended release coating (d), optional enteric coating (e), conventional capsule (f), functional enteric capsule (g).

[0388] Figure 2 A diagram showing the dissolution curve of the modified release formulation (I-a) at pH 6.8 (right, black curve with diamond markers) compared to the dissolution curve of the immediate release (IR) formulation (left, grey curve with circular markers).

[0389] Figure 3 A diagram showing the dissolution curves of formulation I-a in 0.1N HCl solution (top, black curve with circular markers) and in pH 6.8 medium (bottom, grey curve with diamond markers).

[0390] Figure 4 A diagram showing the dissolution curves of formulation (I-a) in pH 6.8 medium at T0 (middle, black curve with diamond markers), after storage at 40 °C and 75% relative humidity (RH) for 3 months (bottom, grey curve with triangle markers), after storage at 25 °C and 60% RH for 9 months (top, grey curve with square markers), and after storage at 25 °C and 60% RH for 18 months (top, dark curve with circular markers).

[0391] Figure 5 A diagram showing the dissolution curve of the modified release formulation (V-a) at pH 6.8 (right, black curve with diamond markers) compared to the dissolution curve of the immediate release (IR) formulation (left, grey curve with circular markers).

[0392] Figure 6Graph showing the dissolution curves of formulation (V-a) at T0 (top, black curve with diamond markers) in a progressive pH medium, after storage at 40 °C and 75% relative humidity (RH) for 3 months (bottom, grey curve with triangle markers), and after storage at 25 °C and 60% RH for 9 months (top, grey curve with square markers).

[0393] Figure 7 Graph showing the dissolution curves of reference formulation (VII-a) in 0.1 N HCl solution (black curve with circular markers) and in pH 6.8 medium (grey curve with square markers).

[0394] Figure 8 Graph showing the dissolution curves of reference pellets (VII-b) at T0 (top, black curve with diamond markers) in 0.1 N HCl solution, after storage at 25 °C and 60% RH for 2 months (middle, grey curve with square markers), and after storage at 40 °C and 75% relative humidity (RH) for 2 months (bottom, grey curve with triangle markers). Examples

[0395] The techniques described herein will be further illustrated by the following examples.

[0396] Example 1: Silodosin Preparation of the Present Invention

[0397] Example 1-1: Formulation (I-a)

[0398] The preparation of the modified-release silodosin pellets is described below (see Figure 1 , which is a schematic diagram of the manufacturing method): (R)-Silodosin was dissolved in an ethanol solution of hydroxypropyl cellulose (HPC) and butylated hydroxytoluene (BHT) to obtain a silodosin solution. Then calcium carbonate (CaCO3) was added to the solution to obtain a drug layering suspension. The composition of the (R)-silodosin layering suspension is shown in detail in Table 2.

[0399] Table 2: Composition of the (R)-silodosin layering suspension

[0400]

[0401]

[0402] Then, the (R)-silodosin layering suspension was sprayed (bottom spray) onto inert cores (cellulose microspheres) 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 A-I-a is shown in detail in Table 3.

[0403] Table 3: Composition of Pellets A-I-a

[0404] Component % w / w (R)-Silodosin 13.0 HPC 1.3 <![CDATA[CaCO3]]> 6.5 BHT 0.4 Cellulose Microspheres 78.8

[0405] Then, an aqueous solution of hydroxypropyl methylcellulose (HPMC) [Opadry Clear 03A6900067 was sprayed onto the previously prepared pellets A-I-a. The initial parameters were set as follows: fluidization inlet air temperature: 54.0 °C, air flow rate: 70 m 3 / h. The composition of the resulting pellets B-I-a is shown in Table 4.

[0406] Table 4: Composition of Pellets B-I-a

[0407] Component % w / w Pellet A-I-a 95 HPMC 5

[0408] The previously prepared coated pellets B-I-a were further coated by spraying with an aqueous suspension of polyvinyl acetate SR 30D (KSR) (14.6% w / w), triethyl citrate (TEC) (0.73% w / w), and talc (5.1% w / w) with continuous stirring. The initial parameters were set as follows: fluidization inlet air temperature: 43.0 °C, air flow rate: 75 m 3 / h. Then, the coated pellets were cured at 45 °C for 120 min. The composition of the resulting pellets C-I-a is listed in Tables 5 and 6.

[0409] Table 5: Composition of Pellets C-I-a

[0410]

[0411] Table 6: Composition of Lubricated Pellets C-I-a

[0412]

[0413] An adequate amount of the previously prepared pellets C-I-a lubricated with 0.50% w / w talc was filled into hydroxypropyl methylcellulose hard capsules so that each capsule finally contained 12 mg of (R)-silodosin, thereby obtaining formulation (I-a).

[0414] Example 1-2: Formulation (V-a)

[0415] The preparation of the modified-release silodosin pellets is described as follows (see Figure 1, which is a schematic diagram of the manufacturing method: Dissolve (R)-silodosin in an ethanol solution of hydroxypropyl cellulose (HPC) and butylated hydroxytoluene (BHT) to obtain a silodosin solution. Then, add calcium carbonate (CaCO3) to the solution to obtain a silodosin suspension. The composition of the (R)-silodosin stratified suspension is shown in Table 7 in detail.

[0416] Table 7: Composition of the (R)-silodosin stratified suspension

[0417] Component % w / w (R)-Silodosin 9.19 HPC 0.92 <![CDATA[CaCO3]]> 4.60 BHT 0.29 Ethanol 85.0

[0418] Then, spray (bottom spray) the (R)-silodosin stratified suspension onto inert pellets (cellulose microspheres) under continuous stirring. The initial parameters are set as follows: Fluidization inlet air temperature: 56.0 °C, air flow rate: 70 m 3 / h. The composition of the obtained pellets A-V-a is shown in Table 8 in detail.

[0419] Table 8: Composition of pellets A-V-a

[0420] Component % w / w (R)-Silodosin 13.0 HPC 1.3 <![CDATA[CaCO3]]> 6.5 BHT 0.4 Cellulose Microspheres 78.8

[0421] Then, spray an aqueous solution of hydroxypropyl methylcellulose (HPMC) [Opadry Clear 03A6900067 onto the previously prepared pellets A-V-a. The initial parameters are set as follows: Fluidization inlet air temperature: 54.0 °C, air flow rate: 70 m 3 / h. The composition of the obtained pellets B-V-a is listed in Table 9.

[0422] Table 9: Composition of pellets B-V-a

[0423] Component % w / w Pellet A-V-a 95 HPMC 5

[0424] Further coat the previously prepared coated pellets B-V-a by spraying a water suspension of polyvinyl acetate SR 30D (KSR) (14.6% w / w), triethyl citrate (TEC) (0.73% w / w), and talc (5.1% w / w) under continuous stirring. The initial parameters are set as follows: Fluidization inlet air temperature: 43.0 °C, air flow rate: 75 m 3 / h. Then, cure the coated pellets at 45 °C for 120 min. The composition of the obtained pellets C-V-a is listed in Table 10.

[0425] Table 10: Composition of pellets C-V-a

[0426]

[0427] By spraying an aqueous suspension of methyl methacrylate-ethyl acrylate copolymer [Kollicoat MAE 30 (KMAE)] (60.6% w / w) and triethyl citrate (TEC) (1.82% w / w) that was kept under continuous stirring onto the previously prepared pellets C-V-a, a final coating was applied thereto. The initial parameters were set as follows: fluidization inlet air temperature: 41°C, air flow rate: 70 m 3 / h. The composition of the resulting pellets D-V-a is shown in Tables 11 and 12.

[0428] Table 11: Composition of pellets D-V-a

[0429]

[0430] Table 12: Composition of lubricated pellets D-V-a

[0431]

[0432]

[0433] An adequate amount of the previously prepared pellets D-V-a lubricated with 0.50% w / w talc was filled into hard gelatin capsules of hypromellose so that each capsule finally contained 12 mg of (R)-silodosin, thereby obtaining the preparation (V-a).

[0434] Example 2: In Vitro Study of the Silodosin Preparation of the Present Invention

[0435] Example 2-1: Preparation (I-a)

[0436] Dissolution tests were all carried out according to the United States Pharmacopeia method, in a USP Type 2 apparatus at 37°C ± 0.5°C at 50 rpm in 900 mL of 0.1 N HCl (acidic medium) solution or pH 6.8 phosphate buffer (neutral medium), and direct UV detection was employed.

[0437] Figure 2 The dissolution curve of the preparation (I-a) at pH 6.8 is shown, which shows that 85% of the amount of silodosin is released from the preparation (I-a) within about 34 hours, while it is released from the comparative IR composition within about 10 minutes, and the release rate of the preparation (I-a) is much slower than that of the comparative IR composition as shown by the slopes of their respective dissolution curves. Therefore, the preparation (I-a) is a modified release preparation, in sharp contrast to the comparative IR composition . Figure 2 There is a "lag time" of about 1 hour, indicating that the preparation (I-a) is a delayed release preparation.

[0438] Figure 3 The dissolution profiles of Formulation I-a in 0.1N HCl and at pH 6.8 are shown, which show that 50% of silodosin is released in about 14 hours at pH 6.8, while it is released in about 3 hours in 0.1N HCl, and the release rate at pH 6.8 is much lower than that in 0.1N HCl, as shown by the slope of the dissolution profile. Thus, the dissolution profile of Formulation I-a is "pH-dependent", with a faster release rate in acidic media.

[0439] Table 13 below shows the chemical stability of silodosin in Formulation (I-a) over time (T0, after 3 months, after 9 months, and after 18 months) under two different storage conditions (40 °C and 75% relative humidity (RH) or 25 °C and 60% relative humidity (RH)). Dehydro-silodosin is the main degradation product of silodosin.

[0440] Table 13: Contents of silodosin, dehydro-silodosin, and total silodosin degradation products in Formulation (I-a) over time

[0441]

[0442] Table 13 confirms the chemical stability of silodosin in Formulation (I-a) over time under the two storage conditions, as no significant decrease in the silodosin content and no significant increase in the content of degradation products were observed.

[0443] Figure 4 It shows that the dissolution profiles of Formulation (I-a) at T0, after storage at 40 °C and 75% RH for 3 months, after storage at 25 °C and 60% RH for 9 months, and after storage at 25 °C and 60% RH for 18 months almost overlap, demonstrating that the dissolution profile of Formulation (I-a) is not affected by the storage time (under the two storage conditions).

[0444] Example 2-2: Formulation (V-a)

[0445] All dissolution tests were carried out according to the United States Pharmacopeia method, in a USP Type 2 apparatus at 37 °C ± 0.5 °C at 50 rpm in 900 mL of simulated gastric fluid for 2 hours, and then in a pH 6.8 phosphate buffer (which is called the "progressive pH medium" and is recommended by the USP for enteric-coated formulations), with direct UV detection.

[0446] Figure 5 The dissolution profile of Formulation (V-a) in the progressive pH medium is shown, which shows that 85% of the silodosin amount is released from Formulation (V-a) in about 10 hours, while it is released from the comparative IR composition in less than 10 minutes is released, and the release rate of formulation (V-a) is much slower than that of the comparative IR composition as shown by the slopes of their respective dissolution curves. Thus, formulation (V-a) is a modified release formulation, in sharp contrast to the comparative IR composition . Figure 5 Shows a delay of approximately two hours, indicating that formulation (V-a) is a delayed release formulation.

[0447] Table 14 below shows the chemical stability of silodosin in formulation (V-a) over time (T0, after 3 months, and after 9 months) under two different storage conditions (40 °C and 75% relative humidity (RH) or 25 °C and 60% relative humidity (RH)). Dehydro-silodosin is the main degradation product of silodosin.

[0448] Table 14: Content of silodosin, dehydro-silodosin, and total silodosin degradation products in formulation (V-a) over time

[0449]

[0450] Using different batches of formulation (V-a) prepared exactly as described in Examples 1-2 above, the chemical stability of silodosin in formulation (V-a) was also confirmed to be sustainable for up to 12 months at 25 °C / 60% RH (data not shown).

[0451] Figure 6 Shows that the dissolution curve of formulation (V-a) was not affected over time (under both storage conditions), as the dissolution curves at T0, 3 months, and 9 months were very similar.

[0452] Example 3: In Vitro Study of Comparative Silodosin Preparation

[0453] Example 3-1: Ethylcellulose

[0454] Example 3-1-1: ECD 30 (Test 1)

[0455] The manufacturing process of the comparative formulation (VII-a) was essentially as described for formulation (I-a) in Example 1-1, except that BHT was replaced with another antioxidant, α-tocopherol, to obtain pellets A-VII-a, the composition of which is shown in Table 15.

[0456] In addition, the coating applied to pellets B-VII-a was a suspension containing 12% w / w ethylcellulose and 3% dibutyl sebacate (DBS), and the granules were then cured at 60 °C for 4 hours while spraying water, to obtain the comparative pellets C-VII-a, the composition of which is shown in Table 16.

[0457] Table 15: Composition of Pellets A-VII-a

[0458] Component % w / w Silodosin 13.000 HPC 1.300 <![CDATA[CaCO3]]> 6.500 α-Tocopherol 0.142 Cellulose Microspheres 79.058

[0459] Table 16: Composition of Comparative Pellets C-VII-a

[0460] Component % w / w Pellet B-VII-a 85％ Ethylcellulose 12％ DBS 3％

[0461] An adequate amount of the previously prepared comparative pellets C-VII-a was filled into hypromellose hard capsules such that each capsule finally contained 12 mg of (R)-silodosin, thereby obtaining the comparative preparation (VII-a).

[0462] Dissolution tests were carried out according to the United States Pharmacopeia method, in a USP type 2 apparatus at 37 °C ± 0.5 °C at 50 rpm in 900 mL of 0.1 N HCl solution or pH 6.8 phosphate buffer solution, and direct UV detection was employed.

[0463] Figure 7 The dissolution curves of the comparative preparation (VII-a) at 0.1 N HCl and pH 6.8 are shown, which show that the comparative preparation (VII-a) provides a slightly extended release curve, releasing 85% of silodosin in about 9 hours. Figure 7 It is also shown that the dissolution curve of the comparative preparation (VII-a) is not pH-dependent, as the two curves almost coincide.

[0464] Example 3-1-2: ECD 30 (Test 2)

[0465] The preparation method of the comparative pellets (VII-b) was substantially the same as that described for the comparative preparation (VII-a) in Example 3-1-1, except that the pellets were cured at 60 °C for 2 hours and no water was sprayed, thereby obtaining the comparative pellets C-VII-b, the composition of which is shown in Table 17.

[0466] Table 17: Composition of Comparative Pellets C-VII-b

[0467] Component % w / w Pellet B-VII-a 85％ Ethylcellulose 12％ DBS 3％

[0468] Dissolution tests were carried out according to the United States Pharmacopeia method, in a USP type 2 apparatus at 37 °C ± 0.5 °C at 50 rpm in 900 mL of 0.1 N HCl solution, and direct UV detection was employed.

[0469] Figure 8The dissolution curves of the comparative pellets (VII-b) in 0.1 N HCl solution are shown, which show that the dissolution curves of the comparative pellets (VII-b) after storage at 25 °C and 60% RH for 2 months are much slower than those at T0, and the dissolution curves after storage at 40 °C and 65% RH for 2 months are even slower. Therefore, the dissolution curves of the comparative pellets (VII-b) are not stable over time.

[0470] Therefore, the comparative pellet C-VII-b is not suitable for use in continuous contraceptive methods.

[0471] Example 3-1-3:

[0472] Another commercially available aqueous ethylcellulose suspension ( which is an ethylcellulose suspension with various additives) was tested as an ER coating. Pellets with a weight gain of about 25% of ethylcellulose were manufactured.

[0473] The applicant found that the degradation of silodosin in these pellets was very high, far exceeding the acceptable working range. Without being bound by theory, the applicant suspects that there is chemical incompatibility between silodosin and at least one component of

[0474] Example 3-2: Polymethacrylate

[0475] The manufacturing methods of the comparative pellets C-VIII-a and C-IX-a were basically the same as those described for pellet C-I-a in Example 1-1, except that the final ER coating was:

[0476] (Pellet C-VIII-a) contained a neutral copolymer of ethyl acrylate and methyl methacrylate (commercially available under the trade name NM 30D, Evonik Corporation, Germany), a suspension of hydroxypropyl methylcellulose (HPMC), polysorbate 80, and talc; or

[0477] (Pellet C-IX-a) a copolymer, a copolymer of ethyl acrylate, methyl methacrylate, and a low content of methacrylate with a quaternary ammonium group (commercially available under the trade name RS100, Evonik Corporation, Germany), triethyl citrate (TEC), and talc.

[0478] The composition of the obtained comparative pellet C-VIII-a is shown in Table 18.

[0479] Table 18: Composition of Comparative Pellet C-VIII-a

[0480]

[0481] The composition of the obtained comparative pellets C-IX-a is shown in Table 19.

[0482] Table 19: Composition of Comparative Pellets C-IX-a

[0483]

[0484] The dissolution test was carried out according to the United States Pharmacopeia method, in a USP type 2 apparatus at 37 °C ± 0.5 °C at 50 rpm in 900 mL of 0.1 N HCl solution or pH 6.8 phosphate buffer solution, and direct UV detection was employed.

[0485] For the comparative pellets C-VIII-a, the release curve of silodosin was almost immediate release. Within about one hour, 100% of silodosin was released.

[0486] For the comparative pellets C-IX-a, the release curve was biphasic (“S-shaped”), with a very slow release phase from 0 to about 6 h in the first stage; followed by a rapid release phase from about 6 h to about 11 h. At this time, 100% of silodosin was released.

[0487] Therefore, the comparative pellets C-VIII-a are not suitable for use in a sustained contraceptive method. In addition, the comparative pellets C-IX-a are not conducive to being used as an ER composition in a sustained contraceptive method.

[0488] Example 4: In Vivo Study of the Silodosin Preparation of the Present Invention

[0489] Materials and Methods

[0490] A study was conducted to evaluate the pharmacokinetic (PK) curve of the formulation of the present invention in male subjects. A total of 24 subjects aged between 20 and 48 years were included in the double-blind study. Each subject received a single dose of formulation (I-a) and formulation (V-a) in a crossover design. Plasma samples were collected at 0 to 48 hours after administration for the determination of silodosin.

[0491] The possibility of immediate release on the PK curve when the formulation was administered was evaluated.

[0492] Results

[0493] No immediate release was observed on the PK curve, which demonstrated that formulations (I-a) and (V-a) did not undergo any significant immediate release effect when administered to male subjects.

Claims

1. A pellet, 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 sealing coating covering the drug layer; and (d) At least one extended-release coating covering the drug layer or the optional sealing coating, wherein the extended-release coating comprises at least one vinyl polymer.

2. The pellet according to 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, polyvinylpyrrolidone, polyvinylpyrrolidone, and mixtures thereof.

3. The pellet according to claim 1 or claim 2, wherein the optional sealing 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 pellet according to any one of claims 1 to 3, wherein: The inert core comprises cellulose polymers and mixtures thereof, preferably the inert core comprises microcrystalline cellulose; and / or The particle size range of the inert core is about 300 to 500 μm.

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

6. The pellet according to claim 5, wherein the extended-release coating comprises polyvinyl acetate (PVA).

7. The pellet according to claim 6, wherein the extended-release coating further comprises polyvinylpyrrolidone (PVP).

8. The pellet according to claim 7, wherein the extended-release coating comprises about 90% w / w of polyvinyl acetate (PVA) and about 9% w / w of polyvinylpyrrolidone (PVP), based on the weight of the extended-release coating.

9. The pellet according to any one of claims 1 to 8, wherein the pellet further comprises: - At least one antioxidant; preferably, the antioxidant is selected from phenols, vitamin E and its derivatives, vitamin C and its derivatives, propyl gallate, and mixtures thereof; more preferably, the antioxidant is selected from butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), α-tocopherol, ascorbyl palmitate, propyl gallate, and mixtures thereof; - At least one anti-adhesive and / or antistatic agent; preferably, the anti-adhesive and / or antistatic agent is selected from inorganic carbonates, magnesium silicate salts, and mixtures thereof; more preferably, the anti-adhesive and / or antistatic agent is selected from calcium carbonate (CaCO3), 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).

10. The pellet according to any one of claims 1 to 9, wherein the pellet further comprises: (e) At least one enteric coating, wherein the enteric coating - Coating the extended-release coating, or - Being coated with the extended-release coating and coating the optional sealing coating or the drug layer.

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

12. The pellet according to any one of claims 1 to 11, wherein the pellet comprises: Pellet A, which consists essentially of: - Approximately 24 to 95% w / w of the inert core; - Approximately 5 to 76% w / w of the drug layer, the drug layer comprising: - Approximately 5 to 25% w / w of the silodosin, - Approximately 0.1 to 7.5% w / w of the binder, - Approximately 0 to 20% w / w of at least one antioxidant, and - Approximately 0 to 25% w / w of at least one anti-adherent and / or antistatic agent, Based on the weight relative to the total weight of Pellet A; Wherein Pellet A optionally comprises within Pellet B, which consists essentially of: - Approximately 90% to 100% w / w of Pellet A, and - Approximately 0 to 10% w / w of at least one sealing coating, Based on the weight relative to the total weight of Pellet B; Wherein Pellet A or the optional Pellet B is comprised within Pellet C, which consists essentially of: - Approximately 50 to 98% w / w of Pellet A or the optional Pellet B, and - An extended-release coating, which comprises: - Approximately 0.5 to 47% w / w of at least one extended-release agent, - Approximately 0.02 to 7% w / w of at least one plasticizer, and - Approximately 0.3 to 23% w / w of at least one anti-adherent, Based on the weight relative to the total weight of Pellet C; and Wherein Pellet C optionally comprises within Pellet D, which consists essentially of: - Approximately 50 to 95% w / w of Pellet C, and - An enteric coating, which comprises: - Approximately 4 to 49.5% w / w of at least one enteric solvent, and - Approximately 0.04 to 10% w / w of at least one plasticizer, Based on the weight relative to the total weight of the optional Pellet D.

13. The pellet according to any one of claims 1 to 12, wherein: (b) The drug layer is applied to the inert core with a weight increment of approximately 5% to 318%, (c) The optional sealing coating agent is applied to the drug layer with a weight increment of 0 to approximately 11%, (d) The extended-release coating agent is applied to the drug layer or the optional sealing coating with a weight increment of approximately 2% to 100%, and / or (e) The optional enteric coating agent is applied to the extended-release coating with a weight increment of 0 to approximately 100%.

14. The pellet according to any one of claims 1 to 13, wherein the pellet comprises: (a) An inert core comprising cellulose microspheres; (b) At least one drug layer applied to the inert core, wherein the drug layer comprises: Silodosin, Hydroxypropyl cellulose (HPC), Calcium carbonate (CaCO3), and Butylated hydroxytoluene (BHT); (c) At least one sealing coating covering the drug layer, wherein the sealing coating contains hydroxypropyl methylcellulose (HPMC); and (d) At least one extended-release coating covering the drug layer or the optional sealing coating, wherein the extended-release coating contains: Polyvinyl acetate (PVA), Polyvinylpyrrolidone (PVP), Triethyl citrate (TEC), and Talcum powder.

15. The pellets according to claim 14, wherein the pellets further contain: (e) At least one enteric coating, wherein the enteric coating covers the extended-release coating, or is covered by the extended-release coating and covers the optional sealing coating or the drug layer, wherein the enteric coating contains: Methacrylic acid-ethyl acrylate copolymer 1:1 (MAE1:1), and Triethyl citrate (TEC).

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

17. The dosage form according to claim 16, wherein the plurality of pellets are contained in a capsule, preferably a hard capsule and / or a functional capsule (such as an enteric capsule).

18. The dosage form according to claim 16 or claim 17, wherein the plurality of pellets contain about 4 to 32 mg, preferably about 8 to 28 mg, more preferably about 12 to 24 mg of said silodosin.

19. A contraceptive method for male subjects, which comprises the step of administering to the male subject the dosage form according to any one of claims 16 to 18 at about the same time every day.

20. A method for manufacturing 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, wherein the method comprises the following steps: (1-a) Preparing a drug solution or a drug suspension, which contains: - A drug solution containing silodosin, at least one binder, at least one solvent and optionally at least one antioxidant; and - Optionally, at least one anti-adhesive and / or antistatic agent, and then (1-b) Applying the drug solution or the drug suspension to a plurality of inert cores, thereby obtaining a plurality of pellets A; (2-a) Optionally, preparing a sealing coating suspension containing at least one sealing coating agent; Then (2-b) Applying the sealing coating suspension to the plurality of pellets A, thereby obtaining a plurality of pellets B; (3-a) Preparing an extended-release coating suspension, which contains at least one extended-release coating agent, at least one plasticizer and at least one anti-adhesive; Then (3-b) Applying the extended-release coating suspension to the plurality of pellets A or applying it to the plurality of optional pellets B, thereby obtaining the plurality of pellets according to any one of claims 1 to 15; Or (3'-a) Preparing an extended-release coating suspension, which contains at least one extended-release coating agent, at least one plasticizer and at least one anti-adhesive; then (3'-b) Applying the extended-release coating suspension to the plurality of pellets A or the plurality of optional pellets B, thereby obtaining a plurality of pellets C; (4'-a) Prepare an enteric coating suspension comprising at least one enteric coating agent and at least one plasticizer; Then (4'-b) Apply the enteric coating suspension to the plurality of pellets C to obtain a plurality of pellets according to any one of claims 1 to 15; Or (3”-a) Prepare an enteric coating suspension comprising at least one enteric coating agent and at least one plasticizer; then (3”-b) Apply the enteric coating suspension to the plurality of pellets A or the plurality of optional pellets B to obtain a plurality of pellets E; (4”-a) Prepare an extended release coating suspension comprising at least one extended release coating agent, at least one plasticizer and at least one anti-adhesive agent; Then (4”-b) Apply the extended release coating suspension to the plurality of pellets E to obtain a plurality of pellets according to any one of claims 1 to 15; And (5) Optionally, fill the obtained plurality of pellets into at least one capsule to obtain a dosage form according to any one of claims 16 to 18.

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