Dual-release preparation and application thereof

Abstract

The invention provides a dual-release preparation and application thereof, and particularly relates to a dual-release preparation containing silodosin and finasteride and a preparation method of the dual-release preparation, and the dual-release preparation can enable the silodosin to realize a slow release effect and enable the finasteride to realize a quick release effect.

Description

A dual-release preparation and its application

[0001] This application claims priority to Chinese patent application No. 2023103973011, filed April 13, 2023. This application incorporates the entirety of the aforementioned Chinese patent application. Technical Field

[0002] The present invention belongs to the field of medical technology, and particularly relates to a dual-release preparation containing silodosin and finasteride and a preparation method thereof. Background Art

[0003] Silodosin is an α1-adrenergic receptor antagonist developed by Tachibana Pharmaceuticals of Japan. α1-adrenergic receptor antagonists can improve urethral resistance by relaxing the smooth muscles of the prostate and bladder neck and are used to treat benign prostatic hyperplasia (BPH). Marketed formulations are tablets and capsules, with a dosage of 4 mg twice daily. Its chemical name is 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indole-7-carboxamide. The structure is shown below:

[0004] Finasteride is a 5α-reductase inhibitor. 5α-reductase inhibitors primarily inhibit the conversion of testosterone to dihydrotestosterone by inhibiting 5α-reductase, thereby reducing prostate hyperplasia caused by the accumulation of dihydrotestosterone in the prostate. It can be used to treat and control benign prostatic hyperplasia (BPH) and prevent urinary system events. Its chemical name is N-tert-butyl-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide, and its structure is shown below:

[0005] Finasteride is administered in the form of oral tablets, the inactive ingredients of which include lactose hydrate, microcrystalline cellulose, pregelatinized starch, sodium carboxymethyl starch, hydroxypropyl cellulose LF, hydroxypropyl methylcellulose, magnesium stearate, and coating materials.

[0006] Document 1 discloses a sustained-release tablet containing silodosin as the sole active ingredient. The sustained-release tablet uses high-viscosity hydroxypropyl methylcellulose and stearic acid as a mixed material skeleton matrix, and acrylic resin as a release regulator.

[0007] Silodosin and finasteride have different therapeutic effects in the treatment of BPH. There are no reports in the prior art on the combined use of silodosin and finasteride for the treatment of benign prostatic hyperplasia, nor on the preparation of silodosin and finasteride into a dual-release preparation.

[0008] Document 1CN102283816 A.

[0009] Summary of the Invention

[0010] In a first aspect, the present invention provides a method for the combined use of silodosin and finasteride, wherein the combined use of the two drugs can achieve a synergistic effect in treating symptoms and signs caused by benign prostatic hyperplasia (BPH). In particular, the combination of silodosin and finasteride in a specific ratio can achieve a significant synergistic effect.

[0011] In the combination of the present invention, the ratio of silodosin to finasteride is preferably 0.5 to 8:1 by weight (mg); more preferably, the ratio of silodosin to finasteride is 1 to 4:1.

[0012] Specifically, in the combination of silodosin and finasteride, the dosage of silodosin can be 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, or 16 mg; and the dosage of finasteride can be 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg. In a preferred embodiment of the present invention, the dosage of silodosin is 4 to 12 mg; the dosage of finasteride is 1 to 5 mg; in a further preferred embodiment, the dosage of finasteride is 5 mg.

[0013] The combined use method of the present invention can include both silodosin and finasteride in the formulation, or silodosin and finasteride can be administered in separate formulations, such as simultaneous, separate, or staggered administration of the silodosin-containing formulation and the finasteride-containing formulation. Preferably, the formulation of the present invention includes both silodosin and finasteride, particularly a solid formulation prepared with different release modes, wherein the release mode includes a sustained-release portion and an immediate-release portion.

[0014] In another aspect, the present invention provides a dual-release preparation comprising:

[0015] (1) sustained-release portion;

[0016] and (2) immediate-release portion;

[0017] The sustained-release portion contains silodosin and a hydrophilic gel matrix sustained-release material; and the rapid-release portion contains finasteride and a rapid-release material.

[0018] The sustained-release portion of the dual-release preparation can release silodosin within a specific time range to achieve a sustained-release effect. Specifically, the sustained-release portion has the following release characteristics in pH 6.8 phosphate buffer:

[0019] The time for dissolution of 70% of silodosin is not less than 4 hours and not more than 24 hours;

[0020] and / or, the time for dissolution of 70% of silodosin is not less than 4 hours and not more than 20 hours;

[0021] and / or, the time for dissolution of 70% of silodosin is not less than 4 hours and not more than 16 hours;

[0022] The immediate-release portion of the dual-release preparation can release finasteride within a specific time range to achieve an immediate-release effect. Specifically, the immediate-release portion has the following release characteristics in aqueous solution:

[0023] Within 15 minutes, the amount of finasteride dissolved is not less than 60%;

[0024] and / or, within 15 minutes, the amount of finasteride dissolved is not less than 70%;

[0025] and / or, within 60 minutes, the amount of finasteride dissolved is not less than 80%.

[0026] The hydrophilic gel skeleton material sustained-release material of the present invention can be a cellulose derivative, such as methyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxymethyl cellulose, sodium hydroxymethyl cellulose, and the like.

[0027] The hydrophilic gel skeleton material sustained-release material of the present invention may also be non-cellulose polysaccharides, such as glucose, chitin, chitosan, galactomannan, and the like.

[0028] The hydrophilic gel skeleton material sustained-release material of the present invention can also be natural gum, such as pectin, sodium alginate, potassium alginate, agar, carrageenan, locust bean gum, guar gum, sweet potato gum and the like.

[0029] The hydrophilic gel skeleton material sustained-release material of the present invention may also be a vinyl polymer or an acrylic polymer, such as polyvinyl alcohol, polyethylene oxide, and the like.

[0030] The sustained-release material can meet the release characteristics of the sustained-release portion of silodosin of the present invention, and can have the following release characteristics in pH 6.8 phosphate buffer:

[0031] The time for dissolution of 70% of silodosin is not less than 4 hours and not more than 24 hours;

[0032] and / or, the time for dissolution of 70% of silodosin is not less than 4 hours and not more than 20 hours;

[0033] and / or, the time for dissolution of 70% of silodosin is not less than 4 hours and not more than 16 hours;

[0034] The preferred hydrophilic gel skeleton material sustained-release material of the present invention can be a cellulose derivative, such as methyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxymethyl cellulose, sodium hydroxymethyl cellulose, and the like.

[0035] The present invention has found that when the hydrophilic gel skeleton sustained-release material has a viscosity of 1000 mPa.s or above in a 1-2% aqueous solution at 20-25°C, the sustained-release effect of silodosin in the sustained-release portion of the present invention can be better achieved, and the dual-release preparation has excellent stability.

[0036] Therefore, suitable hydrophilic gel matrix materials for the present invention include cellulose derivatives with a viscosity of 1000 mPa·s or greater. Suitable hydrophilic gel matrix sustained-release materials include hydroxypropyl methylcellulose, methylcellulose, hydroxyethyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, sodium hydroxymethyl cellulose, and sodium carboxymethyl cellulose. The hydrophilic gel matrix sustained-release material can be a single material or a combination of two or more.

[0037] Suitable hydroxypropyl methylcellulose refers to hydroxypropyl methylcellulose with a viscosity of 1000mPa.s and above, which is referred to as "high viscosity hydroxypropyl methylcellulose" in the present invention. Preferably, the hydroxypropyl methylcellulose has a viscosity of 4000mPa.s and above. Different types of hydroxypropyl methylcellulose have different viscosities. As long as the viscosity meets the requirements, it can be used as the sustained-release material of the sustained-release part of the present invention. The high-viscosity hydroxypropyl methylcellulose includes: hydroxypropyl methylcellulose K4M (viscosity 4000mPa.s), hydroxypropyl methylcellulose K15M (viscosity 15000mPa.s), hydroxypropyl methylcellulose K35M (viscosity 35000mPa.s), hydroxypropyl methylcellulose K100M (viscosity 100000mPa.s), and hydroxypropyl methylcellulose K200M (viscosity 200000mPa.s).

[0038] Suitable methylcellulose has a viscosity of 1000 mPa·s or above, preferably methylcellulose with a viscosity of 1000-40000 mPa·s.

[0039] Suitable sodium carboxymethyl cellulose has a viscosity of 1500-20000 mPa.s;

[0040] Suitable hydroxyethyl cellulose has a viscosity of 5000-50000 mPa·s.

[0041] Suitable hydroxypropyl cellulose has a viscosity of 1000-10000 mPa·s.

[0042] The weight (mg / mg) ratio of the sustained-release material in the sustained-release part of the present invention is 10-90%; the preferred weight (mg / mg) ratio of the sustained-release material in the sustained-release part is 10-80%; the further preferred weight (mg / mg) ratio of the sustained-release material in the sustained-release part is 15-55%.

[0043] The sustained-release material of the present invention is high-viscosity hydroxypropyl methylcellulose, and its weight (mg / mg) ratio in the sustained-release part is 10-90%; the preferred weight (mg / mg) ratio is 10-80%; and the further preferred weight (mg / mg) ratio is 15-55%.

[0044] The sustained-release portion of the dual-release formulation of the present invention may optionally contain a pharmaceutical excipient with a viscosity of 200 mPa.s or less. This high-viscosity pharmaceutical excipient can improve the sustained-release properties of the sustained-release portion, particularly in situations where the drug is not fully released at the end of the sustained-release phase. For example, a 24-hour dissolution rate of silodosin below 90%, particularly below 85%, can be improved by the addition of a pharmaceutical excipient with a viscosity of 200 mPa.s or less. Adding a low-viscosity pharmaceutical excipient to the sustained-release portion of the dual-release formulation can also accelerate the gelation rate of the sustained-release material, facilitating drug release in the colon.

[0045] In a preferred embodiment of the present invention, the sustained-release portion may further include a pharmaceutical excipient having a viscosity of 200 mPa.s or less, such as low-viscosity hydroxypropyl methylcellulose.

[0046] Low viscosity hydroxypropyl methylcellulose includes hydroxypropyl methylcellulose K100LV, hydroxypropyl methylcellulose E50, etc.

[0047] In a preferred embodiment of the present invention, the sustained-release portion contains at least one cellulose derivative with a viscosity of 1000 mPa.s or more and at least one pharmaceutical excipient with a viscosity of 200 mPa.s or less.

[0048] In a preferred embodiment of the present invention, the weight ratio (mg / mg) of the low viscosity hydroxypropyl methylcellulose in the sustained-release portion is 1-30%, preferably 1-25% in the sustained-release portion, more preferably 1-20% in the sustained-release portion; more preferably 1-15% in the sustained-release portion.

[0049] In a preferred embodiment of the present invention, the sustained-release portion contains high-viscosity hydroxypropyl methylcellulose and low-viscosity hydroxypropyl methylcellulose.

[0050] In the dual-release preparation of the present invention, if a known finasteride preparation is directly used in the dual-release preparation of the present invention, it is difficult to achieve a rapid-release effect. The rapid-release portion of the dual-release preparation of the present invention contains finasteride and a rapid-release material. The rapid-release portion can release finasteride within a specific time range to achieve a rapid-release effect. Specifically, the rapid-release portion has the following release characteristics in aqueous solution:

[0051] Within 15 minutes, the amount of finasteride dissolved is not less than 60%;

[0052] and / or, within 15 minutes, the amount of finasteride dissolved is not less than 70%;

[0053] and / or, within 60 minutes, the amount of finasteride dissolved is not less than 80%.

[0054] The immediate-release portion and the sustained-release portion of the dual-release preparation of the present invention can be prepared into multi-layer tablets, coated tablets or capsules.

[0055] In a preferred embodiment of the present invention, the dual-release preparation is a multi-layer tablet; preferably a bi-layer tablet, wherein the sustained-release portion is a silodosin sustained-release layer, and the immediate-release portion is a finasteride immediate-release layer.

[0056] The silodosin sustained-release layer of the multi-layer tablet contains a hydrophilic gel skeleton sustained-release material, and the hydrophilic gel skeleton material is a cellulose derivative with a viscosity of 1000 mPa.s or above.

[0057] In a preferred embodiment of the present invention, the hydrophilic gel matrix material of the silodosin sustained-release layer is high-viscosity hydroxypropyl methylcellulose.

[0058] In a preferred embodiment of the present invention, the silodosin sustained-release layer further contains low-viscosity hydroxypropyl methylcellulose.

[0059] In a preferred embodiment of the present invention, the silodosin sustained-release layer contains high-viscosity hydroxypropyl methylcellulose and low-viscosity hydroxypropyl methylcellulose.

[0060] In the immediate-release layer of the multi-layer tablet, the immediate-release material contains a disintegrant;

[0061] Suitable disintegrants include: sodium carboxymethyl starch, corn starch, carboxymethyl cellulose calcium, pregelatinized starch, cross-linked polyvinyl pyrrolidone, sodium starch glycolate, cross-linked sodium hydroxymethyl cellulose, cross-linked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, or a combination of two or more thereof.

[0062] Preferred disintegrants are sodium carboxymethyl starch, calcium carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose, or a combination of two or more thereof; further preferred disintegrants are sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose; further preferred disintegrants are a combination of sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose.

[0063] The weight ratio of the disintegrant in the immediate-release portion is 1-30%, preferably 5-25%, and more preferably 5-20%.

[0064] Optionally, the double-layer tablet can be coated to obtain a coated preparation.

[0065] In another preferred embodiment of the present invention, the dual-release preparation is a coated tablet.

[0066] In a specific embodiment of the present invention, in the coated tablet, the sustained-release portion is the tablet core, and the immediate-release portion is the immediate-release coating;

[0067] The immediate-release material of the finasteride immediate-release coating layer contains a film-forming material. Suitable film-forming materials include gelatin, gum arabic, starch, dextrin, polyvinyl alcohol (PVA), methacrylate-methacrylic acid copolymer, ethylene-vinyl acetate copolymer (EVA), hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, alginic acid, etc.

[0068] The weight (mg / mg) ratio of the film-forming material in the immediate-release portion is 1.0 to 90%, and the preferred weight ratio is 10 to 70%.

[0069] In a preferred embodiment of the present invention, the film-forming material is hydroxypropyl methylcellulose.

[0070] Optionally, an isolation layer may be added between the silodosin sustained-release tablet core and the finasteride immediate-release coating layer of the present invention.

[0071] The sustained-release part and the immediate-release part of the dual-release preparation of the present invention may optionally contain pharmaceutical excipients such as fillers, plasticizers, glidants, surfactants, lubricants, adhesives, antioxidants, etc.

[0072] Suitable fillers include: mannitol, lactose or its hydrate, lactose-cellulose, starch, pregelatinized starch, microcrystalline cellulose, dextrin, sucrose, glucose, maltose, sorbitol, powdered sugar, calcium sulfate, calcium hydrogen phosphate, calcium carbonate; the preferred fillers of the present invention are mannitol, lactose, lactose-cellulose, etc.

[0073] Suitable surfactants include sodium lauryl sulfate, docusate sodium, etc.

[0074] Suitable glidants include: colloidal silicon dioxide, talc, stearic acid, etc.;

[0075] Suitable plasticizers include: polyethylene glycol (molecular weight range 1000-10000), etc.

[0076] Suitable lubricants include: gelatinized starch, magnesium stearate, calcium stearate, colloidal silicon dioxide, polyethylene glycol, talc, docusate sodium, sodium lauryl sulfate, sodium stearyl fumarate, sodium carboxymethyl cellulose, etc.;

[0077] Suitable binders include: hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl pyrrolidone, copovidone, polyvinyl alcohol, ethyl cellulose, starch, etc.;

[0078] Suitable antioxidants include ascorbic acid, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, tocopherol, sodium sulfite, sodium bisulfite, and the like.

[0079] In another aspect, the present invention provides a method for preparing a dual-release preparation, wherein the dual-release preparation is a multi-layer tablet, the method comprising the following steps:

[0080] Step 1: uniformly mix silodosin, hydrophilic gel matrix sustained-release material and other pharmaceutical excipients, and granulate;

[0081] Step 2: Evenly mix finasteride, immediate-release material and other excipients;

[0082] Step 3: The granules from step 1 and the powder from step 2 are compressed into multilayer tablets.

[0083] Optionally, the prepared multilayer tablet can be coated by conventional methods.

[0084] In another aspect, the present invention provides a method for preparing a dual-release preparation, wherein the dual-release preparation is a coated tablet, the method comprising the following steps:

[0085] Step 1: uniformly mixing silodosin, hydrophilic gel matrix sustained-release material and other pharmaceutical excipients, granulating the mixture, and pressing the mixture into tablet cores;

[0086] Step 2: dissolving finasteride, immediate-release material and other excipients to obtain a coating solution;

[0087] Step 3: Coat the silodosin core tablets with the finasteride coating solution.

[0088] Optionally, after the silodosin tablet core is prepared, it can be coated with a conventional coating material to form an isolation layer between the tablet core and the finasteride coating layer.

[0089] In the preparation method of the present invention, the granulation method in step 1 adopts a conventional method, such as dry granulation, wet granulation or fluidized bed granulation.

[0090] In another aspect, the present invention provides a silodosin sustained-release preparation, which contains the sustained-release portion of the dual-release preparation of the present invention.

[0091] The silodosin sustained-release preparation of the present invention contains silodosin and a hydrophilic gel skeleton sustained-release material.

[0092] The silodosin sustained-release preparation of the present invention has at least one of the following release characteristics in pH 6.8 phosphate buffer:

[0093] The time for dissolution of 70% of silodosin is not less than 4 hours and not more than 24 hours;

[0094] and / or, the time for dissolution of 70% of silodosin is not less than 4 hours and not more than 20 hours;

[0095] and / or, the time required for 70% dissolution of silodosin is not less than 4 hours and not more than 16 hours.

[0096] Preferred hydrophilic gel matrix sustained-release materials are cellulose derivatives, such as methylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose, sodium hydroxymethylcellulose, etc. The hydrophilic gel matrix sustained-release material can be one or a combination of two or more.

[0097] The hydrophilic gel matrix sustained-release material of the present invention is a cellulose derivative having a viscosity of 1000 mPa·s or above, and high-viscosity hydroxypropyl methylcellulose is more preferred.

[0098] In a preferred embodiment of the present invention, the silodosin sustained-release preparation contains silodosin and high-viscosity hydroxypropyl methylcellulose.

[0099] In the silodosin sustained-release preparation of the present invention, the weight (mg / mg) ratio of the sustained-release material to the silodosin sustained-release preparation is 10-90%; the preferred weight (mg / mg) ratio of the sustained-release material to the silodosin sustained-release preparation is 10-80%; and the further preferred weight (mg / mg) ratio of the sustained-release material to the silodosin sustained-release preparation is 15-55%.

[0100] The sustained-release material is high-viscosity hydroxypropyl methylcellulose, and its weight (mg / mg) ratio in the silodosin sustained-release preparation is 10-90%; the preferred weight (mg / mg) ratio is 10-80%; and the further preferred weight (mg / mg) ratio is 15-55%.

[0101] In a preferred embodiment of the present invention, the silodosin sustained-release preparation may further include a pharmaceutical excipient having a viscosity of 200 mPa·s or less, preferably low-viscosity hydroxypropyl methylcellulose.

[0102] In a preferred embodiment of the present invention, the weight ratio (mg / mg) of the low-viscosity pharmaceutical excipient in the silodosin sustained-release preparation is 1-30%, preferably 1-25%, more preferably 1-20%, and more preferably 1-15%.

[0103] In a preferred embodiment of the present invention, the silodosin sustained-release preparation further contains low-viscosity hydroxypropyl methylcellulose.

[0104] In a preferred embodiment of the present invention, the weight ratio (mg / mg) of the low-viscosity hydroxypropyl methylcellulose in the silodosin sustained-release preparation is 1-30%, preferably 1-25%, more preferably 1-20%, and more preferably 1-15%.

[0105] In a preferred embodiment of the present invention, the silodosin sustained-release preparation contains at least one cellulose derivative with a viscosity of 1000 mPa.s or above and at least one pharmaceutical excipient with a viscosity of 200 mPa.s or below.

[0106] In a preferred embodiment of the present invention, the silodosin sustained-release preparation contains silodosin, high-viscosity hydroxypropyl methylcellulose and low-viscosity hydroxypropyl methylcellulose.

[0107] The silodosin sustained-release preparation of the present invention may optionally contain pharmaceutical excipients such as fillers, plasticizers, glidants, surfactants, lubricants, adhesives, and antioxidants.

[0108] Preferred fillers are mannitol, lactose or its hydrate, lactose-cellulose, starch, pregelatinized starch, microcrystalline cellulose, dextrin, sucrose, glucose, maltose, sorbitol, powdered sugar, calcium sulfate, calcium hydrogen phosphate, and calcium carbonate; preferred fillers of the present invention are mannitol, lactose, lactose-cellulose, and the like.

[0109] Suitable surfactants include sodium lauryl sulfate, docusate sodium, etc.

[0110] Suitable glidants include: colloidal silicon dioxide, talc, stearic acid, etc.;

[0111] Suitable plasticizers include: polyethylene glycol (molecular weight range 1000-10000), etc.

[0112] Suitable lubricants include: gelatinized starch, magnesium stearate, calcium stearate, colloidal silicon dioxide, fumed silicon dioxide, polyethylene glycol, talc, sodium docusate, sodium lauryl sulfate, sodium stearyl fumarate, sodium carboxymethyl cellulose, glyceryl behenate, etc.; preferred lubricants are magnesium stearate, calcium stearate, colloidal silicon dioxide, fumed silicon dioxide, talc, and glyceryl behenate.

[0113] Suitable binders include: hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl pyrrolidone, copovidone, polyvinyl alcohol, ethyl cellulose, starch, etc.;

[0114] Suitable antioxidants include ascorbic acid, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, tocopherol, sodium sulfite, sodium bisulfite, etc.; preferred antioxidants are ascorbic acid and butylated hydroxytoluene (BHT).

[0115] The silodosin sustained-release preparation of the present invention may be coated or uncoated.

[0116] The coating agent is selected from film coating, preferably gastric soluble film coating. The coating contains film-forming material, and the film-forming material is preferably hypromellose or polyethylene glycol.

[0117] The silodosin sustained-release preparation of the present invention can be optionally in the form of sustained-release tablets or sustained-release capsules.

[0118] Preferably, the silodosin sustained-release preparation of the present invention is a sustained-release coated tablet.

[0119] In another aspect, the present invention provides a method for preparing a silodosin sustained-release preparation, wherein the silodosin sustained-release preparation is a tablet, and the method comprises the following steps:

[0120] Step 1: uniformly mix silodosin, hydrophilic gel matrix sustained-release material and other pharmaceutical excipients, and granulate;

[0121] Step 2: Compress the granules from step 1 into tablets.

[0122] Optionally, the prepared tablets can be coated by conventional methods.

[0123] In the preparation method of the present invention, the granulation method in step 1 adopts a conventional method, such as dry granulation, wet granulation or fluidized bed granulation.

[0124] In another aspect, the present invention provides a dual-release formulation for use in the preparation of a medicament for treating benign prostatic hyperplasia (BPH) or the symptoms and signs thereof. The dual-release formulation comprises:

[0125] (1) sustained-release portion;

[0126] and (2) immediate release portion

[0127] The sustained-release portion contains silodosin and a hydrophilic gel matrix sustained-release material; and the rapid-release portion contains finasteride and a rapid-release material.

[0128] In another aspect, the present invention provides a use of a silodosin sustained-release preparation in the preparation of a medicament for treating benign prostatic hyperplasia (BPH) or symptoms and signs caused by the BPH. BRIEF DESCRIPTION OF THE DRAWINGS

[0129] Figure 1. Blood drug concentration-time curves in animals. DETAILED DESCRIPTION

[0130] Explanation of terms

[0131] "Low viscosity" refers to a substance with a viscosity of 200 mPa.s or less in a 1-2% aqueous solution at 20-25°C; for example, "low viscosity hydroxypropyl methylcellulose" means hydroxypropyl methylcellulose with a viscosity of 200 mPa.s or less in a 1-2% aqueous solution at 20-25°C.

[0132] "High viscosity" means a viscosity of 1000 mPa.s or more in a 1-2% aqueous solution at 20-25°C; for example, "high viscosity hydroxypropyl methylcellulose" means hydroxypropyl methylcellulose with a viscosity of 1000 mPa.s or more in a 2% aqueous solution at 20°C;

[0133] The present invention is described in detail below by the following examples, but the present invention is not limited to the following examples. The chemical substances, reagents, experimental animals, experimental materials, etc. used in the examples of the present invention were obtained by conventional methods in the art.

[0134] Animal experiment: Evaluation of the effects of silodosin and finasteride in inhibiting phenylephrine-induced prostate smooth muscle contraction in rats.

[0135] Male SD rats weighing 300-350g were selected, and their prostates were removed and transferred to Krebs-Henseleit buffer. The dorsolateral lobe of the prostate was separated into prostate glandular tissues of 2×10mm in size (4 tissues per rat). The separated tissues were transferred to an organ bath containing 95% O2 and 5% CO2 at 37°C Krebs-Henseleit buffer. The two ends of the glandular tissue were fixed to the bottom of the bath and the force sensor, respectively, and the force sensor was connected to a multichannel physiological recorder. Each tissue was stabilized under 0.2 standard tension for 1 hour, and then 10 -5Phenylephrine was used to induce prostate tissue contraction. After contraction stabilized, silodosin and / or finasteride or dutasteride were administered according to the dosing schedule in Table 1. The control group did not receive silodosin and / or finasteride or dutasteride. The contraction rate of the control group was considered 100%, and the contraction rate of the experimental group was calculated as [(experimental group contraction amount / control group contraction amount) × 100%). Data were obtained using four glandular tissues for each experiment, and values ​​are presented as the mean ± standard deviation of the contraction percentage.

[0136] Table 1 Evaluation of the relaxing effect on rat prostate tissue

[0137] As shown in Table 1, compared to the administration of silodosin, finasteride, or dutasteride alone, the combined use of silodosin and finasteride, or silodosin and dutasteride, demonstrated a more potent relaxation of prostate smooth muscle, indicating a synergistic effect. Furthermore, at the same dose, the combined use of silodosin and finasteride demonstrated a more significant relaxation of prostate smooth muscle in rats than the combined use of silodosin and dutasteride. The combined use of silodosin and finasteride demonstrated superior efficacy compared to the combined use of silodosin and dutasteride.

[0138] When the weight ratio of silodosin to finasteride is 0.8-8:1, the combined medication can achieve a good synergistic effect. Preferably, the weight ratio of silodosin to finasteride is 0.8-4:1. More preferably, the weight ratio of silodosin to finasteride is 1-2:1. More preferably, the weight ratio of silodosin to finasteride is 1-2:1. Most preferably, the weight ratio of silodosin to finasteride is 1.6:1. The combined use of silodosin and finasteride can be used to inhibit the contraction of prostate smooth muscle and treat or prevent BPH and the symptoms and signs it causes.

[0139] Effects of silodosin and finasteride on prostate weight and smooth muscle mass in the penis of rats.

[0140] According to the ratio of silodosin to finasteride in Table 2 below, silodosin and finasteride were fully mixed and suspended in CMC-Na (sodium hydroxymethylcellulose) to form a silodosin and finasteride composition.

[0141] 150 male SD rats weighing 300-350g were selected and randomly divided into 15 groups, each with 10 rats, namely a normal group, a control group, and experimental groups 1-13. Each rat in experimental groups 1-13 received a subcutaneous injection of the male hormone testosterone propionate (5 mg / kg) dissolved in olive oil every day for 30 consecutive days. At the same time, each rat in experimental groups 1-13 was orally administered a combination of silodosin and / or finasteride every day for 30 consecutive days according to the dosing schedule shown in the table below. The normal group did not receive an injection of testosterone propionate (5 mg / kg) and did not receive silodosin and / or finasteride. The control group only received an injection of testosterone propionate (5 mg / kg) and did not receive silodosin and / or finasteride. On day 31, the rats were killed, the prostate was collected and weighed, and the prostate organ coefficient (PI) value [(prostate weight / rat body weight) × 100%) was calculated. The rat penis was collected and sliced ​​into cross sections. The sections were stained and images were taken using a digital camera and a stereo microscope. ImageJ software was used to measure parameters and calculate the area of ​​smooth muscle in the cross section of the penis (mm 2 ) and the surface density of smooth muscle (Sv) was measured using the point counting method. The prostate organ index (PI) value, the area of ​​smooth muscle in the penile cross section, and the surface density of smooth muscle in each group of rats are expressed as mean ± standard deviation.

[0142] Table 2 Effects on the number of smooth muscles in the prostate and penis of rats

[0143] As shown in Table 2, the combined use of silodosin and finasteride significantly reduced prostate weight in rats compared to either drug alone, demonstrating a synergistic effect. Smooth muscle is the primary contractile component of the corpus cavernosum. In rat models, decreased smooth muscle mass is often associated with ED. The combined use of silodosin and finasteride significantly improved the symptoms of decreased smooth muscle mass in the rat penis.

[0144] Therefore, the combined use of silodosin and finasteride can be used to inhibit prostate proliferation, can be used to prevent or treat BPH and the symptoms and signs caused by it, and can also be expected to be used to improve adverse reactions such as sexual dysfunction (such as ED) caused by the use of finasteride alone in the treatment of BPH.

[0145] Evaluation of the effects of silodosin and finasteride in prolonging the micturition interval in rats.

[0146] Twenty-four male rats were selected and randomly divided into 8 groups, 3 rats in each group, and anesthetized with urethane. An incision was made along the midline of the abdomen, and the ureters on both sides were ligated and cut, keeping the renal end open. A cannula was inserted into the bladder through the top of the bladder dome and connected to a three-way connector. The other end of the cannula was connected to a pressure sensor to measure the pressure in the bladder. Saline was continuously dripped into the bladder (3.6 mL / h), and acetic acid solution (0.25%) was continuously dripped into the bladder (3.6 mL / h) to shorten the urination interval. After obtaining a stable urination interval, the urination interval of the three groups (the time from the occurrence of urination to the next urination) was measured, and the average value was taken, which was the average urination interval before administration. Experimental Groups 1-8 were administered silodosin and / or finasteride via femoral intravenous injection according to the dosages listed in Table 3 below. The total number of urinations occurring within 30 minutes after administration was measured, and the average urination interval after administration was calculated. The prolongation rate compared to the average urination interval before administration was evaluated [((average urination interval after administration - average urination interval before administration) / (average urination interval before administration)) × 100%]. The results are shown in Table 3. The prolongation rate of the urination interval for each group is expressed as mean ± standard deviation.

[0147] Table 3 Effects on urination interval of rats

[0148] As shown in Table 3, the combined use of silodosin and finasteride significantly prolonged the urination interval of rats compared to either drug alone. The combined use of finasteride and silodosin is extremely effective in preventing or treating urinary frequency or urinary incontinence, and can be used to treat or prevent BPH and the symptoms and signs caused by it.

[0149] The following examples of the preparation of the formulations are provided to further illustrate the technical solution of the present invention. The dissolution (or release) of the present invention is tested by the following method:

[0150] The dissolution of "silodosin" in the sustained-release part was determined according to the first method of the release rate determination method (Chinese Pharmacopoeia 2020 Edition Part II 0931) using the basket method. The dissolution medium was 900 ml of pH 6.8 phosphate buffer, the medium temperature was 37°C ± 0.5°C, and the rotation speed was 100 rpm.

[0151] The dissolution of "finasteride" in the immediate-release part was determined according to the first method of the release rate determination method (Chinese Pharmacopoeia 2020 Edition Part II 0931) using the basket method. The dissolution medium was 900 ml of aqueous solution, the medium temperature was 37°C ± 0.5°C, and the rotation speed was 100 rpm.

[0152] Example 1

[0153] Preparation of sustained-release portion

[0154] Silodosin and mannitol were mixed in equal increasing amounts. The resulting mixture, high-viscosity hydroxypropyl methylcellulose (K100M), low-viscosity hydroxypropyl methylcellulose (K100LV), and colloidal silicon dioxide were added to a multi-directional motion mixer and mixed thoroughly. Finally, the magnesium stearate prepared by dry granulation was added and mixed thoroughly. After dry granulation, the dry granules were taken and the additional magnesium stearate was added and mixed thoroughly to obtain the final mixed granules. The sustained-release granules were punched into sustained-release tablets, each containing 8 mg of silodosin.

[0155] According to the above method, the following preparation formula is prepared:

[0156] “ / ” means not included.

[0157] Dissolution testing

[0158] The preparation of Example 1 was subjected to the release rate determination method (Chinese Pharmacopoeia 2020 Edition Part II 0931) using the first method of the basket method. The dissolution medium was 900 ml of pH 6.8 phosphate buffer, the medium temperature was 37°C ± 0.5°C, the rotation speed was 100 rpm, and the average value was taken. The results are as follows:

[0159] Gelation test

[0160] Determine the initial diameter (Dini) of the silodosin sustained-release tablets. According to the disintegration time test method of the 2020 edition of the "Chinese Pharmacopoeia", the silodosin sustained-release tablets with measured diameters are placed in a hanging basket. The solution medium is 900 ml of pH 6.8 phosphate buffer, and the medium temperature is 37°C ± 0.5°C. The tablets are taken out at different time points to peel off the gel layer, and the diameter of the ungelled tablet core (Dcore) is recorded. The gelation index (GEI) of the tablets at each time point is calculated according to the following formula. GEI = 1-(Dini / Dcore) to the power of 3. The gelation index of the silodosin sustained-release preparations of Examples 1-2, 1-3, 1-4, and 1-5 was determined by the above method. Six tablets were taken for testing in each example, and the data were averaged. The results are shown in the following table:

[0161] Gelation index of silodosin sustained-release preparations

[0162] “ / ” means not tested

[0163] The results showed that the addition of low-viscosity polymer materials to the prescription could significantly accelerate the gelation rate of the sustained-release tablets. The gelation of the sustained-release tablets could be completed within 6 hours, which was beneficial to the release of the drug in the colon.

[0164] Sustained-release portions using different sustained-release materials (Examples 1-8)

[0165] The silodosin sustained-release part was prepared in a similar manner using polyoxyethylene (PEO) (which has a viscosity of 2000-6000 mPa·s in a 1-2% aqueous solution at 20-25° C.) as the sustained-release material.

[0166] Examples 1-9

[0167] The following silodosin sustained-release tablets were prepared according to the method of Example 1, and the formulation composition is as follows.

[0168] Stability test

[0169] Test conditions: 40°C, 75% relative humidity. Stored in high-density polyethylene bottles with desiccant, the content of related substances in silodosin sustained-release preparations was determined at 0 and 6 months of storage.

[0170] The cellulose derivatives of the present invention with a viscosity of 1000 mPa·s or above have better formulation stability than non-cellulose derivatives, such as PEO.

[0171] Example 2

[0172] Preparation of dual-release formulations (coated core tablets)

[0173] (1) Preparation of silodosin sustained-release part:

[0174] The silodosin sustained-release tablet core was prepared by referring to the preparation method of the sustained-release portion in Example 1.

[0175] Then, a coating solution with a concentration of 12% (W / W) was prepared using Opadry film coating premix (gastric soluble type) and coated on the tablet cores. The coating weight gain was 6%.

[0176] (2) Preparation of the immediate-release portion of finasteride:

[0177] Hydroxypropyl methylcellulose E5 was added to purified water (80°C) under magnetic stirring and stirred to completely disperse. Docusate sodium was added to purified water (50°C) and completely dissolved under magnetic stirring. Then, it was added to the above-mentioned hydroxypropyl methylcellulose E5 solution. The remaining purified water (room temperature) was added and stirred until completely dissolved. Then, polyethylene glycol 6000 and polyethylene glycol 8000 were added in sequence and stirred until completely dissolved. Finally, talc and finasteride were added and stirred until completely dispersed to obtain a drug-containing coating solution.

[0178] (3) Preparation of compound preparations:

[0179] The silodosin isolation layer tablet core was coated with the finasteride drug-containing layer coating solution, and the coating weight gain was 6%.

[0180] Preparation prescription:

[0181] Example 3

[0182] Preparation of dual-release formulations (bilayer tablets)

[0183] (1) Preparation of silodosin sustained-release part:

[0184] Silodosin and mannitol were premixed in a fluidized bed. The inlet air temperature was set at 60-70°C. The air volume, peristaltic pump speed, and atomization pressure were adjusted to maintain a good boiling state for the granules. 5% low-viscosity hydroxypropyl cellulose was used as a binder for fluidized-bed granulation. After granulation, the granules were dried until the drying loss reached ≤1.0%. The granules were sieved to obtain dry granules. The dry granules, high-viscosity hydroxypropyl methylcellulose, low-viscosity hydroxypropyl methylcellulose, and colloidal silicon dioxide were added to a multi-directional mixer and mixed. Finally, magnesium stearate was added and mixed to obtain sustained-release granules.

[0185] (2) Preparation of the immediate-release portion of finasteride:

[0186] Add the prescribed amount of mannitol, finasteride, sodium starch glycolate, low-substituted hydroxypropyl cellulose, sodium lauryl sulfate, and colloidal silicon dioxide to a multi-directional mixer and mix for 5 minutes. After mixing, sieve the mixture and pour it back into the multi-directional mixer and continue mixing for 20 minutes. Add magnesium stearate and mix thoroughly to obtain the immediate-release layer mixture.

[0187] (3) Preparation of compound preparations:

[0188] The sustained-release layer mixed granules and the immediate-release layer mixed powder were punched into 10.5 mm shallow concave round tablets, each containing 8 mg of silodosin and 5 mg of finasteride.

[0189] Preparation prescription

[0190] Example 4

[0191] A bilayer tablet containing silodosin-finasteride was prepared according to the following formulation using a method similar to Example 3.

[0192] Example 5

[0193] Preparation of dual-release formulations (coated bilayer tablets)

[0194] Referring to a method similar to Example 3, a double-layer tablet was prepared according to the following formulation, and then the double-layer tablet was coated.

[0195] Double-layer tablet coating: using Opadry The film coating premix (gastric soluble type) was prepared into a coating solution with a concentration of 12% (W / W), and the tablet cores were coated.

[0196] Example 6

[0197] Referring to a method similar to Example 3, a double-layer tablet was prepared according to the following formulation, and then the double-layer tablet was coated.

[0198] Double-layer tablet coating: using Opadry The film coating premix (gastric soluble type) was prepared into a coating solution with a concentration of 12% (W / W), and the tablet cores were coated.

[0199] Dissolution Testing of Dual-Release Formulations

[0200] Six tablets of each dual-release preparation prepared in Examples 3-5 were taken for dissolution determination and the average values ​​were taken. The results are as follows: Dissolution rate of silodosin (%)

[0201] Dissolution rate of finasteride (%)

[0202] “ / ” means not tested.

[0203] Example 7

[0204] A bilayer tablet containing silodosin-finasteride was prepared according to the following formulation using a method similar to Example 3.

[0205] Example 8

[0206] A bilayer tablet containing silodosin-finasteride was prepared according to the following formulation using a method similar to Example 3.

[0207] Example 9

[0208] Animal experiments on dual-release formulations

[0209] Using a randomized, parallel control design, nine healthy male beagle dogs were randomly divided into Groups A, B, and C. Each group consisted of three dogs. Each group was orally administered a reference formulation (commercially available silodosin capsules, 4 mg, twice daily) or the dual-release formulation of the present invention once daily. Blood concentrations (0.5 ml) were collected from the forelimb vein at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours before and after administration, and the results were averaged. The experimental results are shown in Figure 1. The experiments demonstrate that the dual-release formulation of the present invention achieves a significant sustained-release effect.

Claims

1. A dual release formulation comprising: (1) sustained-release portion; and (2) an immediate-release portion; The sustained-release part contains silodosin and a hydrophilic gel skeleton sustained-release material; and the rapid-release part contains finasteride and a rapid-release material.

2. The dual release formulation according to claim 1, wherein the dual release formulation has at least one of the following release characteristics: the sustained-release portion has at least one of the following release characteristics in a pH 6.8 phosphate buffer: The time for dissolution of 70% of silodosin is not less than 4 hours and not more than 24 hours; and / or, the time for dissolution of 70% of silodosin is not less than 4 hours and not more than 20 hours; and / or, the time for dissolution of 70% of silodosin is not less than 4 hours and not more than 16 hours; And / or the immediate-release portion has at least one of the following release characteristics in aqueous solution: Within 15 minutes, the amount of finasteride dissolved is not less than 60%; and / or, within 15 minutes, the amount of finasteride dissolved is not less than 70%; And / or, within 60 minutes, the amount of finasteride dissolved is not less than 80%.

3. The dual-release preparation according to claim 1, wherein the hydrophilic gel skeleton sustained-release material is a cellulose derivative having a viscosity of 1000 mPa.s or more.

4. The dual release preparation according to claim 1, wherein the hydrophilic gel matrix sustained-release material is selected from one or a combination of two or more of methyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxymethyl cellulose and sodium hydroxymethyl cellulose.

5. The dual release preparation according to claims 1-3, wherein the weight ratio of the hydrophilic gel matrix sustained-release material in the sustained-release part is 10-90%, preferably 15-55%.

6. The dual release preparation as claimed in claim 1, wherein the sustained-release portion optionally contains a pharmaceutical excipient having a viscosity of 200 mPa.s or less.

7. The dual release preparation according to claim 6, wherein the pharmaceutical excipient is low viscosity hydroxypropyl methylcellulose.

8. The dual-release preparation according to claim 6, wherein the weight ratio of the pharmaceutical excipient with high viscosity in the sustained-release portion is 1-30%, preferably 1-25%, more preferably 1-20%.

9. The dual release preparation according to claims 1 to 8, which is a multi-layer tablet, a coated tablet or a capsule.

10. The dual release preparation according to claim 1, which is a multi-layer tablet.

11. The dual release preparation according to claim 10, wherein the rapid-release material of the multi-layer tablet contains at least one disintegrant.

12. The dual-release preparation according to claim 11, wherein the weight ratio of the disintegrant in the immediate-release portion is 1-30%, preferably 5-25%, and more preferably 5-20%.

13. The dual-release formulation according to claim 11, wherein the disintegrant is selected from one or a combination of two or more of microcrystalline cellulose, sodium carboxymethyl starch, corn starch, calcium carboxymethyl cellulose, pregelatinized starch, cross-linked polyvinyl pyrrolidone, sodium starch glycolate, cross-linked sodium hydroxymethyl cellulose, cross-linked polyvinyl pyrrolidone, and low-substituted hydroxypropyl cellulose.

14. The dual release preparation according to claims 1-10, wherein the weight ratio of silodosin to finasteride is 1 to 4:

1.

15. A silodosin sustained-release preparation comprising the sustained-release portion according to any one of claims 1 to 8.

16. The silodosin sustained-release preparation according to claim 15, wherein the silodosin sustained-release preparation has at least one of the following release characteristics in a pH 6.8 phosphate buffer: The time for dissolution of 70% of silodosin is not less than 4 hours and not more than 24 hours; and / or, the time for dissolution of 70% of silodosin is not less than 4 hours and not more than 20 hours; And / or, the time required for dissolution of 70% of silodosin is not less than 4 hours and not more than 16 hours.

17. The silodosin sustained-release preparation according to claim 15, wherein the hydrophilic gel skeleton sustained-release material is a cellulose derivative having a viscosity of 1000 mPa.s or more.

18. The silodosin sustained-release preparation according to claim 15, wherein the hydrophilic gel matrix sustained-release material is selected from one or a combination of two or more of methyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxymethyl cellulose and sodium hydroxymethyl cellulose.

19. The silodosin sustained-release preparation according to claim 15, wherein the weight ratio of the sustained-release material in the silodosin sustained-release preparation is 10-90%, preferably 15-55%.

20. The silodosin sustained-release preparation according to claim 15, optionally comprising a pharmaceutical excipient having a viscosity of 200 mPa.s or less, wherein the pharmaceutical excipient is preferably low-viscosity hydroxypropyl methylcellulose.

21. The silodosin sustained-release preparation according to claim 20, wherein the weight ratio of the low-viscosity pharmaceutical excipient in the silodosin sustained-release preparation is 1-30%, preferably 1-25%, and more preferably 1-20%.

22. The silodosin sustained-release preparation according to claim 15, which is a tablet.

23. The silodosin sustained-release preparation according to claim 15, optionally further comprising an antioxidant.

24. The silodosin sustained-release preparation according to claim 23, wherein the antioxidant is selected from ascorbic acid, butylated hydroxytoluene, propyl gallate, tocopherol, sodium sulfite, and sodium bisulfite.

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