Sustained-release enteric coating pellet and method for manufacturing same

Abstract

The present invention relates to a sustained-release enteric coating pellet and a method for manufacturing same and, more specifically, to a sustained-release enteric coating pellet and a method for manufacturing same, the sustained-release enteric coating pallet comprising: an inert core; a coating layer of an active ingredient formed on the core; a sustained-release coating layer formed on the coating layer of the active ingredient; and an enteric coating layer formed on the sustained-release coating layer, wherein: the active ingredient is tamsulosin or a pharmaceutically acceptable salt thereof; the sustained-release coating layer comprises a sustained-release agent and a coating stabilizer; the coating stabilizer is polyvinyl alcohol, such that the pellet allows for the sustained release in a continuous and stable manner under enteric conditions and exhibits high reproducibility even when manufactured under various environmental or process conditions.

Description

Sustained-release enteric-coated pellets and a method for manufacturing the same

[0001] The present invention relates to sustained-release enteric coating pellets and a method for manufacturing the same.

[0002] Tamsulosin hydrochloride is a drug that selectively acts on the genitourinary system by selectively inhibiting α-adrenoceptors. It is known to improve the rate of urine excretion by relaxing the smooth muscles surrounding the bladder and the prostate, and to alleviate the symptoms of benign prostatic hyperplasia, and is known to have very high efficacy and few side effects.

[0003] Tamsulosin hydrochloride is known to have some degree of water solubility due to its physicochemical properties, high absorption with a bioavailability of over 90%, and strong efficacy even at low doses due to its high selectivity for prostatic smooth muscle. The half-life of tamsulosin hydrochloride is 9 to 13 hours in normal individuals and is relatively long, approximately 14 to 15 hours, in patients with benign prostatic hyperplasia. Therefore, tamsulosin hydrochloride does not need to be in the form of a sustained-release formulation with a duration of 12 or 24 hours or longer; sufficient drug concentration can be maintained for 24 hours if it is released slowly with a sustained release of about 6 hours.

[0004] However, tamsulosin hydrochloride must be acid-resistant because tamsulosin is rapidly released upon reaching the stomach, making it difficult to release an effective amount of the drug upon reaching the intestines. Furthermore, if rapid release occurs after reaching the intestines, it can cause adverse effects such as orthostatic hypotension if the initial blood concentration rises excessively despite the high selectivity due to the high bioavailability and absorption of the above, so sustained-release capability must also be provided to enable continuous release.

[0005] Therefore, in the development of tamsulosin formulations, research is needed on release-controlled compositions capable of suppressing rapid drug release under acidic conditions and enabling continuous and stable drug release under enteric conditions. Since the manufacture of tamsulosin hydrochloride formulations requires high uniformity at low active ingredient concentrations, pellet coating via fluid bed coating may be desirable.

[0006] The manufacture of acid-resistant tamsulosin pellets through fluid bed coating has been attempted in Korean Registered Patent No. 10-2017-0073580 and Korean Published Patent No. 10-0582350; however, both exhibited relatively low acid resistance, with a dissolution rate of approximately 20% at pH 1.2 relative to the amount of sustained-release and enteric coating used. This necessitates the use of larger amounts of sustained-release and enteric bases to achieve selective intestinal release of the drug. Furthermore, even if acid resistance is secured with a smaller amount of base, controlling the coating process becomes more difficult as the usage of the sustained-release and enteric base decreases, which can result in variations in dissolution rate reproducibility. Consequently, an increase in base usage leads to a decrease in productivity due to increased unit costs and fluid bed coating process time, while a decrease in usage leads to a decrease in reproducibility.

[0007] Accordingly, the inventors conducted various studies on pellet coating compositions containing tamsulosin hydrochloride and developed a pellet composition that exhibits excellent acid resistance within 10% with the use of a small amount of sustained-release, enteric base, while also having high reproducibility regarding the dissolution rate with the use of a specific binder in the sustained-release coating, thereby completing the present invention.

[0008] The present invention aims to provide a sustained-release enteric coating pellet in which tamsulosin or a pharmaceutically acceptable salt thereof is slowly dissolved and released continuously and stably under enteric conditions.

[0009] The present invention aims to provide a sustained-release enteric coating pellet having a dissolution rate within a certain range even under a partially modified manufacturing process.

[0010] The present invention aims to provide a method for manufacturing sustained-release enteric coating pellets having high reproducibility in terms of dissolution rate.

[0011] 1. A sustained-release enteric coated pellet comprising an inert core, an active ingredient coating layer formed on the core, a sustained-release coating layer formed on the active ingredient coating layer, and an enteric coating layer formed on the sustained-release coating layer, wherein the active ingredient is tamsulosin or a pharmaceutically acceptable salt, and the sustained-release coating layer comprises a sustained-release base and a coating stabilizer, and the coating stabilizer is polyvinyl alcohol.

[0012] 2. Sustained-release enteric coating pellets according to 1, wherein the coating stabilizer is included in an amount of 0.5 to 5 parts by weight per 1 part by weight of the active ingredient.

[0013] 3. In the above 1, the sustained-release agent is included in an amount of 15 to 50 parts by weight per 1 part by weight of the active ingredient, and is a sustained-release enteric coated pellet.

[0014] 4. In the above 1, a sustained-release enteric coating pellet comprising 15 to 25 parts by weight of the sustained-release agent per 1 part by weight of the coating stabilizer.

[0015] 5. The sustained-release enteric coating pellet of 1 above, wherein the active ingredient coating layer comprises any one selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyethylene glycol, copovidone, and polyvinyl alcohol as a binder.

[0016] 6. The sustained-release enteric coating pellet of 1 above, wherein the sustained-release agent comprises any one selected from the group consisting of polyvinylpyrrolidone, ethylcellulose, methylcellulose, polyvinylpyrrolidone, sodium lauryl sulfate, and polyvinyl acetate.

[0017] 7. The sustained-release enteric coating pellet according to 1 above, wherein the sustained-release coating layer further comprises a plasticizer selected from the group consisting of triethyl citrate, polyethylene glycol, polypropylene glycol, triacetin, triacetin citrate, castor oil, dibutyl sebacate, dibutyl phthalate, diethyl phthalate, and glycerin.

[0018] 8. The sustained-release enteric coating pellet according to 1 above, wherein the enteric coating layer comprises any one enteric coating agent selected from the group consisting of hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate phthalate, shellac, methacrylic acid-methyl methacrylate copolymer, and methacrylic acid-ethyl acrylate copolymer.

[0019] 9. The sustained-release enteric coating pellet according to 1 above, wherein the enteric coating layer further comprises a plasticizer selected from the group consisting of triethyl citrate, polyethylene glycol, polypropylene glycol, triacetin, triacetin citrate, castor oil, dibutyl sebacate, dibutyl phthalate, diethyl phthalate, and glycerin.

[0020] 10. In the above 1, the inert core is a sustained-release enteric-coated pellet, which is a microcrystalline cellulose bead.

[0021] 11. A tablet comprising a sustained-release enteric-coated pellet of any one of claims 1 to 10 above.

[0022] 12. A method for manufacturing a sustained-release enteric coated pellet, comprising the steps of forming an active ingredient coating layer on an inert core, forming a sustained-release coating layer on the active ingredient coating layer, and forming an enteric coating layer on the sustained-release coating layer, wherein the active ingredient is tamsulosin or a pharmaceutically acceptable salt, and the sustained-release coating layer comprises a sustained-release base and a coating stabilizer, and the coating stabilizer is polyvinyl alcohol.

[0023] 13. A method for manufacturing a sustained-release enteric coating pellet according to 12 above, wherein the coating stabilizer is included in an amount of 0.5 to 5 parts by weight per 1 part by weight of the active ingredient, and the sustained-release agent is included in an amount of 15 to 50 parts by weight per 1 part by weight of the active ingredient.

[0024] 14. A method for manufacturing a sustained-release enteric coating pellet according to 12 above, wherein the sustained-release agent is included in an amount of 15 to 25 parts by weight per 1 part by weight of the coating stabilizer.

[0025] The sustained-release enteric coating pellet of the present invention has a dissolution rate within a certain range.

[0026] Tamsulosin or a pharmaceutically acceptable salt thereof of the sustained-release enteric coating pellet of the present invention is stably released in the intestine.

[0027] By using the method for manufacturing sustained-release enteric coating pellets of the present invention, it is possible to manufacture sustained-release enteric coating pellets in which tamsulosin or a pharmaceutically acceptable salt thereof is slowly dissolved and released continuously and stably under enteric conditions.

[0028] The method for manufacturing sustained-release enteric coating pellets according to the present invention maintains a constant elution rate of the pellets produced even under changes in some process conditions or various environments, thereby providing excellent process stability and high reproducibility of the elution of the produced pellets.

[0029] Figure 1 is the result of the elution evaluation of sustained-release enteric coating pellets according to Examples A3, A5, A6, B2, B3, C1, and C2.

[0030] Figure 2 is the result of evaluating the elution reproducibility of the sustained-release enteric coating pellet of Example A0.

[0031] Figure 3 is the result of evaluating the elution reproducibility of the sustained-release enteric coating pellet of Example A4.

[0032] Figure 4 shows the results of the elution reproducibility evaluation of sustained-release enteric coating pellets of Examples B3, C1, and C2.

[0033] Figure 5 is the result of evaluating the elution reproducibility of the sustained-release enteric coating pellet of Example A5.

[0034] Figure 6 is the result of evaluating the elution reproducibility of the sustained-release enteric coating pellet of Example A6.

[0035] The present invention provides a sustained-release enteric coating pellet.

[0036] The present invention provides a sustained-release enteric coating pellet comprising an inert core, an active ingredient coating layer formed on the core, a sustained-release coating layer formed on the active ingredient coating layer, and an enteric coating layer formed on the sustained-release coating layer, wherein the active ingredient is tamsulosin or a pharmaceutically acceptable salt (hereinafter referred to as 'tamsulosin'), and the sustained-release coating layer comprises a sustained-release base and a coating stabilizer, wherein the coating stabilizer is polyvinyl alcohol.

[0037] The sustained-release enteric coating pellet of the present invention contains tamsulosin as an active ingredient.

[0038] Tamsulosin is a drug that selectively acts on the genitourinary system by selectively inhibiting α-adrenoceptors, and can improve the rate of urine excretion by relaxing the smooth muscles surrounding the bladder and the prostate, and can improve the symptoms of benign prostatic hyperplasia.

[0039] The tamsulosin of the present invention may be, for example, tamsulosin hydrochloride, a compound of the following chemical formula 1.

[0040] [Chemical Formula 1]

[0041]

[0042] The present invention provides a sustained-release enteric coating pellet comprising tamsulosin as an active ingredient, an active ingredient coating layer formed on an inert core, a sustained-release coating layer formed on the active ingredient coating layer, and an enteric coating layer formed on the sustained-release coating layer.

[0043] The term 'sustained-release enteric-coated pellet' of the present invention may refer to a pellet manufactured by coating an active ingredient onto an inert core or core bead, and then performing a sustained-release layer and an enteric coating in stages.

[0044] The term "inert core" in this specification refers to a core formed according to the present invention made of an inert material, and may use a component selected from the group consisting of sugar nuclei, starch, mannitol, sucrose, microcrystalline cellulose, and mixtures thereof. The size of the inert core is preferably 100 to 1500 μm in consideration of process productivity and yield, and is preferably spherical to ensure sustained release and uniform formation of an enteric coating layer.

[0045] In one embodiment, the inert core is microcrystalline cellulose.

[0046] The above-mentioned inert core may be formed by including tamsulosin, which is an active ingredient, or may be formed by a coating layer containing an active ingredient formed on a pharmaceutically acceptable inert seed.

[0047] An active ingredient coating layer is formed on the above inert core.

[0048] The active ingredient coating layer may include a binder for coating the active ingredient.

[0049] The binder may be, for example, one or more selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyethylene glycol, copovidone, and polyvinyl alcohol, but is not limited thereto.

[0050] The sustained-release enteric coating pellet of the present invention includes a sustained-release coating layer.

[0051] The sustained-release coating layer of the present invention may be formed on an active ingredient coating layer formed on the core. The sustained-release coating layer may include a sustained-release agent and a coating stabilizer to control the release rate of the drug.

[0052] The above sustained-release agent may be one or more combinations selected from the group consisting of polyvinyl acetate, polyvinylpyrrolidone, ethylcellulose, and sodium lauryl sulfate, and may be used in the form of a mixture of the above components in powder or suspension. Preferably, a spray-dried form of polyvinyl acetate and polyvinylpyrrolidone or a form in which polyvinyl acetate, polyvinylpyrrolidone, and sodium lauryl sulfate are mixed and suspended in water may be selected.

[0053] The above sustained-release agent may be included in an amount of 15 to 50 parts by weight per 1 part by weight of the active ingredient, for example, 15 to 50 parts by weight, 15 to 45 parts by weight, 15 to 40 parts by weight, 15 to 35 parts by weight, 15 to 30 parts by weight, 15 to 25 parts by weight, 15 to 20 parts by weight, 15 to 19 parts by weight, or 15 to 18 parts by weight.

[0054] The above coating stabilizer can uniformly form a sustained-release coating layer and control the dissolution of the sustained-release coating layer.

[0055] The coating stabilizer is uniformly dispersed in the sustained-release coating layer, and when the final pellet of the present invention comes into contact with water, it dissolves rapidly compared to other parts of the sustained-release coating layer to form channels in the sustained-release coating layer, and can promote the release of the active ingredient through said channels.

[0056] The above coating stabilizer can act as a binder for the sustained-release coating layer and may include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, or a mixture thereof, but most preferably may be polyvinyl alcohol.

[0057] Due to its high hydrophilic properties, polyvinyl alcohol can reduce variability in elution rates and increase reproducibility.

[0058] The coating stabilizer may be included in an amount of 0.5 to 5 parts by weight per 1 part by weight of the active ingredient, for example, in an amount of 0.5 to 5 parts by weight, 0.5 to 4.5 parts by weight, 0.5 to 4 parts by weight, 0.5 to 3.5 parts by weight, 0.5 to 3 parts by weight, 0.5 to 2.5 parts by weight, or 0.5 to 2 parts by weight.

[0059] The sustained-release agent may be included in an amount of 15 to 25 parts by weight relative to 1 part by weight of the coating stabilizer, for example, in an amount of 15 to 25 parts by weight, 15 to 23 parts by weight, 15 to 20 parts by weight, or 15 to 19 parts by weight.

[0060] The Western coating layer may further contain a plasticizer.

[0061] The plasticizer of the present invention is a substance that facilitates the segmental movement of a polymer by increasing the free volume of the polymer, and can improve durability by imparting flexibility and elasticity to the coating layer.

[0062] The plasticizer may be one or more selected from the group consisting of, for example, triethyl citrate, polyethylene glycol, polypropylene glycol, triacetin, triacetin citrate, castor oil, dibutyl sebacate, dibutyl phthalate, diethyl phthalate, and glycerin.

[0063] The sustained-release enteric coating pellet of the present invention comprises an enteric coating layer.

[0064] The enteric coating layer of the present invention may be formed on the sustained-release coating layer.

[0065] The enteric coating layer possesses acid resistance, which suppresses rapid drug release under acidic conditions and enables continuous and stable drug release within the intestines.

[0066] The above enteric coating layer may include any one enteric coating agent selected from the group consisting of hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate phthalate, shellac, methacrylic acid-methyl methacrylate copolymer, and methacrylic acid-ethyl acrylate copolymer.

[0067] The above-mentioned enteric coating layer may further include a plasticizer.

[0068] The above plasticizer may be one or more selected from the group consisting of triethyl citrate, polyethylene glycol, polypropylene glycol, triacetin, triacetin citrate, castor oil, dibutyl sebacate, dibutyl phthalate, diethyl phthalate, and glycerin.

[0069] When a plasticizer is included in the enteric coating layer, the flexibility of the enteric coating layer increases, preventing it from easily tearing or separating due to external forces such as pressure during tablet compression, thereby enabling the formation of a stable coating layer on the core. Consequently, the acid resistance and stability of the manufactured pellets can be further improved.

[0070] The sustained-release enteric coating pellet of the present invention hardly elutes in strong acids of pH 1.2, and exhibits sustained-release of 6 hours or more at pH 6.8.

[0071] The present invention provides a tablet comprising the above sustained-release enteric-coated pellet.

[0072] In addition, the present invention provides a method for manufacturing sustained-release enteric coating pellets.

[0073] The method for manufacturing a sustained-release enteric coating pellet of the present invention comprises the steps of forming an active ingredient coating layer on an inert core, forming a sustained-release coating layer on the active ingredient coating layer, and forming an enteric coating layer on the sustained-release coating layer.

[0074] The inert core and active ingredients are as described above.

[0075] In the above manufacturing method, the step of forming an active ingredient coating layer, a sustained-release coating layer, or an enteric coating layer may be carried out by a fluid bed coating method or an upward spray method. Specifically, a liquid may be uniformly sprayed upwardly onto a fluid core layer formed by fluidizing a specific core with an airflow to uniformly coat the surface. By performing fluid bed coating, fluid bed granules can be uniformly applied, and sustained-release properties and enteric properties, i.e., acid resistance, can be imparted to the manufactured pellets.

[0076] The step of forming an active ingredient coating layer on an inert core may involve dissolving the active ingredient, tamsulosin, in a solvent and coating it onto the inert core, or may involve coating with the addition of a binder.

[0077] The above binder is as described above.

[0078] In one embodiment, a spray solution was prepared by adding tamsulosin to a solution dissolved in ethanol using hydroxypropylcellulose as a binder, and sprayed onto fluidized microcrystalline cellulose.

[0079] The step of forming a sustained-release coating layer on an active ingredient coating layer may involve dispersing a solution containing a sustained-release agent and a coating stabilizer and coating it onto the active ingredient coating layer. The solution containing the sustained-release agent and the coating stabilizer may further include a plasticizer. The plasticizer is as described above.

[0080] The coating stabilizer may be polyvinyl alcohol.

[0081] The coating stabilizer may be included in an amount of 0.5 to 5 parts by weight per 1 part by weight of the active ingredient, for example, in an amount of 0.5 to 5 parts by weight, 0.5 to 4.5 parts by weight, 0.5 to 4 parts by weight, 0.5 to 3.5 parts by weight, 0.5 to 3 parts by weight, 0.5 to 2.5 parts by weight, or 0.5 to 2 parts by weight.

[0082] The sustained-release agent may be included in an amount of 15 to 50 parts by weight per 1 part by weight of the active ingredient, for example, 15 to 50 parts by weight, 15 to 45 parts by weight, 15 to 40 parts by weight, 15 to 35 parts by weight, 15 to 30 parts by weight, 15 to 25 parts by weight, 15 to 20 parts by weight, 15 to 19 parts by weight, or 15 to 18 parts by weight.

[0083] The sustained-release agent may be included in an amount of 15 to 25 parts by weight relative to 1 part by weight of the coating stabilizer, for example, in an amount of 15 to 25 parts by weight, 15 to 23 parts by weight, 15 to 20 parts by weight, or 15 to 19 parts by weight.

[0084] The step of forming an enteric coating layer on a sustained-release coating layer may involve coating the sustained-release coating layer with a solution in which an enteric coating agent is dispersed. The solution in which the enteric coating agent is dispersed may further include a plasticizer.

[0085] The method for manufacturing sustained-release enteric coating pellets according to the present invention includes polyvinyl alcohol as a coating stabilizer, thereby maintaining a constant elution rate of the pellets produced under various environments, resulting in excellent process stability and high reproducibility of the elution of the manufactured pellets.

[0086] The present invention will be explained in more detail below through examples.

[0087]

[0088] Preparation Example 1, Preparation of an active ingredient coating layer

[0089] A main ingredient coated pellet was prepared by forming an active ingredient coating layer on an inert core. As shown in Table 1 below, 6.0 g of hydroxypropylcellulose was dissolved in 50% ethanol, and then 1.6 g of tamsulosin hydrochloride was added to prepare a spray solution. Then, 480 g of microcrystalline cellulose, which is an inert core, was introduced into a fluid bed coater and the spray solution was sprayed while fluidizing to form an active ingredient coating layer on the inert core.

[0090] Ingredients (g) Main Component Coating Pellet Fluidized Bed Coating Microcrystalline Cellulose (Cellet 350) 480 Tamsulosine Hydrochloride 1.6 Hydroxypropyl Cellulose 6.0 Ethanol 100 Purified Water 100 Total 487.6

[0091] As for the process conditions for forming the active ingredient coating layer, as shown in Table 2 below, the inlet temperature was set to 51, 53, and 55 degrees, the air flap to 40%, the injection pressure to 2.5 bar, and the pumping speed to 8 ml / min, and the corresponding product temperatures were set to 43, 45, and 47 degrees, respectively.

[0092] Equipment Used Ingredients (g) Preparation Example 1-1 Preparation Example 1-2 Preparation Example 1-3 Fluidized bed coater Inlet temperature (°C) 5 15 355 Product temperature (°C) 4 3 45 47 Air flap (%) 4 0 40 40 Spray pressure (bar) 2 5 2 5 2.5 Pumping speed (ml / min) 8 88

[0093] Preparation Example 2. Preparation of a sustained-release coating layer

[0094] A sustained-release coating layer formed on an active ingredient coating layer according to Preparation Example 1 was prepared. As shown in Table 3 below, for the evaluation of the reproducibility and acid resistance of polyvinyl alcohol as a binder when polypropylene glycol is used as a plasticizer, for Preparation Examples 1-1 to 1-3, 28g, 28g, 40g, and 60g of Colicote SR30D as a solid content were each included, and 1.4g, 1.4g, 2.0g, and 3.0g of polypropylene glycol as a plasticizer, 0.0g, 1.6g, 2.3g, and 4.8g of polyvinyl alcohol as a binder, and 2.2g, 2.2g, 3.1g, and 4.7g of talc were each diluted in purified water to prepare a spray solution, which was then spray-dried onto fluidized main component coated pellets, thereby Examples 0-1 to 0-3, 1-1 to 1-3, 2-1 to 2-3, and 3-1 to 3-3 was manufactured sequentially.

[0095] Meanwhile, to evaluate the reproducibility of polyvinyl alcohol, which is a binder, when triethyl citrate is used as a plasticizer, for Preparation Examples 1-1 to 1-3, 28g of Colicote SR30D as a solid, 1.4g of triethyl citrate as a plasticizer, 0.0g, 1.6g, and 4.8g of polyvinyl alcohol, and 2.2g of talc were each diluted in purified water to prepare a spray solution, and Examples 4-1 to 4-3, 5-1 to 5-3, and 6-1 to 6-3 were sequentially prepared by spray-drying on fluidized main component coated pellets.

[0096] Equipment Used Components (g) Example 0 (0-1, 2, 3) Example 1 (1-1, 2, 3) Example 2 (2-1, 2, 3) Example 3 (3-1, 2, 3) Example 4 (4-1, 2, 3) Example 5 (5-1, 2, 3) Example 6 (6-1, 2, 3) Fluidized bed coating base component coating Pellet 487.6487.6487.6487.6487.6487.6487.6 Colicot SR30D 28284060282828 Triethyl Citrate 1.4 1.4 1.4 Polypropylene Glycol 1.4 1.4 2.0 3.0--- Polyvinyl Alcohol 0.0 1.6 2.3 4.8 0.0 1.6 4.8 Talc 2.2 2.2 3.1 4.7 2.2 2.2 2.2 Water 80 80 11 4.3 17 1.4 80 80 80 Total 5 19.25 20.85 35.0 560.15 19.25 20.85 24.0

[0097] The process conditions for forming the coating layer were set as shown in Table 4 below.

[0098] Equipment Used Process Conditions (Examples 0 to 6)-1 (Examples 0 to 6)-2 (Examples 0 to 6)-3 Fluidized bed coating machine Inlet temperature (°C) 38 40 42 Product temperature (°C) 29 32 34 Air flap (%) 40 40 40 Spray pressure (bar) 2.5 2.5 2.5 Pumping speed (ml / min) 8 88

[0099]

[0100] Preparation Example 3. Preparation of an enteric coating layer

[0101] An enteric coating layer formed on a sustained-release coating layer according to Preparation Example 2 was prepared. As shown in Table 5 below, a spray solution was prepared by diluting 64 g of solids of Eudragit L30D 55 (Evonik: registered trademark) as an enteric base, 6.4 g of polypropylene glycol as a plasticizer, and 7.2 g of talc as a lubricant in purified water. Then, 519.2 g of the sustained-release coating pellets of Examples 0-1 to 0-3 were added and fluidized while spray-drying the spray solution to prepare the enteric pellets of Examples A0-1 to 3, respectively.

[0102] Ingredients of Equipment Used (g) Example A0 (A0-1,2,3) Fluid bed coating machine Sustained-release coating pellets 519.2 Eudragit L30D 5564 Polypropylene glycol 6.4 Talc 7.2 Purified water 200 Total 596.8

[0103] In addition, as shown in Table 6 below, 32g, 48g, and 64g of Eudragit L30D 55 (registered trademark) (EVONIK) as an enteric base (solid content), 3.2g, 4.8g, and 6.4g of polypropylene glycol as a plasticizer, and 2.4g, 4.8g, and 7.2g of talc as a lubricant were diluted in purified water to prepare a spray solution. Then, 520.8g of the sustained-release coated pellets of Example 1-2 were added and fluidized while spray-drying the spray solution to produce enteric pellets, Examples A1, B1, and C1, respectively. For the case of C1, Examples 1-1 to 1-3 were added to evaluate reproducibility and prepared according to process conditions. Additionally, Example 1, which did not undergo enteric coating, was compared together (Comparative Example 1).

[0104] Ingredients of Equipment Used (g) Comparative Example 1 Example A1 Example B1 Example C1 (C1-1,2,3) Fluid Bed Coating System Sustained-release Coating Pellet 5 20.85 20.85 20.85 20.8 Eudragit L30D 550 324 864 Polypropylene Glycol 03.24 86.4 Talc 02.44 87.2 Purified Water 01 00 150 200 Total 5 20.85 58.45 78.45 98.4

[0105] As shown in the table below, 32g, 48g, and 64g of Eudragit L30D 55 (registered trademark) (EVONIK) as an enteric base, 3.2g, 4.8g, and 6.4g of polypropylene glycol as a plasticizer, and 2.4g, 4.8g, and 7.2g of talc as a lubricant were diluted in purified water to prepare a spray solution. Then, 535.0g of the sustained-release coated pellet of Example 2-2 was added to fluidize the solution, and the spray solution was spray-dried to produce enteric pellets Examples A2, B2, and C2, respectively. For the case of C2, Examples 2-1 to 2-3 were added to evaluate reproducibility and prepared under different process conditions. Example 2, which did not undergo enteric coating, was also compared (Comparative Example 2).

[0106] Ingredients of Equipment Used (g) Comparative Example 2 Example A2 Example B2 Example C2 (C2-1,2,3) Fluid Bed Coating Machine Sustained-release Coating Pellet 535.0535.0535.0535.0 Yudragit L30D 550324864 Polypropylene Glycol 03.24.86.4 Talc 02.44.87.2 Purified Water 0100150200 Total 535.0572.6592.6612.6

[0107] As shown in the table below, 32g and 48g of Eudragit L30D 55 (registered trademark) (EVONIK) as an enteric base, 3.2g and 4.8g of polypropylene glycol as a plasticizer, and 2.4g and 4.8g of talc as a lubricant were diluted in purified water to prepare a spray solution. Then, 560.1g of the sustained-release coated pellet of Example 3-2 was added and fluidized while spray-drying the spray solution to produce enteric pellets, Examples A3 and B3, respectively. For the reproducibility evaluation of B3, Examples 3-1 to 3 were added and prepared under different process conditions.

[0108] In addition, 32g of Eudragit L30D 55 (registered trademark) (EVONIK) as a solid, 3.2g of triethyl citrate as a plasticizer, and 2.4g of talc were diluted in purified water to prepare a spray solution, and then 519.2g, 520.8g, and 524.0g of sustained-release coated pellets of Examples 4-1 to 3, 5-1 to 3, and 6-1 to 3 were added and fluidized while spray-drying the spray solution to produce enteric pellets of Examples A4-1 to 3, A5-1 to 3, and A6-1 to 3.

[0109] Ingredients (g) Example A3 Example B3 (B3-1,2,3) Example A4 (A4-1,2,3) Example A5 (A5-1,2,3) Example A6 (A6-1,2,3) Fluid Bed Coating Machine Sustained-release Coating Pellet 5 6 0.1 5 6 0.1 5 19.2 5 20.8 5 24.0 Yudragit L30D 5 5 3 24 8 3 23 23 Polypropylene Glycol 3.2 4.8 ---Triethyl Citrate--3.2 3.2 3.2 Talc 2.4 4.8 2.4 2.4 2.4 Purified Water 100 150 100 100 100 Total 597.76 17.75 56.85 58.45 61.6

[0110] The process conditions for forming the enteric coating layer were set as shown in the table below. The inlet temperature was set to 36, 38, and 40 degrees, the air flap to 40%, the injection pressure to 3.0 bar, and the pumping speed to 12 ml / min, respectively, and the corresponding product temperatures were 26, 28, and 31 degrees, respectively. Example 1 of Examples A0, C1, C2, B3, A4, A5, and A6 was carried out under the condition of a product temperature of 26 degrees, Example 2 of Examples A0, C1, C2, B3, A4, A5, and A6 was carried out under the condition of a product temperature of 28 degrees, and likewise Example 3 of the above examples was carried out under the condition of a product temperature of 31 degrees. The remaining Examples A1, B1, A2, B2, and A3 were carried out under the condition of a product temperature of 28 degrees.

[0111] Equipment Used Process Conditions A0, C1, C2, B3, A4, A5, A6 (hereinafter, N) Example N-1 Example N-2 and A1, B1, A2, B2, A3 Example N-3 Fluidized bed coating machine Inlet temperature (°C) 36 38 40 Product temperature (°C) 26 28 31 Air flap (%) 40 40 40 Spray pressure (bar) 3.0 3.0 3.0 Pumping speed (ml / min) 12 12 12

[0112] Test Example 1. Evaluation of Acid Resistance of Sustained-Release Enteric Coated Pellet

[0113] Acid resistance was evaluated according to the amount of the coating layer.

[0114] The process range was fixed to intermediate conditions, and for the same amount of samples used, Examples A0, 1, 2, 3, 4, 5, 6 / B1, 2, 3 / C1, 2 and Comparative Examples 1 to 2 were taken as test formulations, and GlaxoSmithKline's Duodat Tamsulosin pellets were taken as a control formulation to evaluate the acid resistance of 0.4 mg of Tamsulosin Hydrochloride. The acid resistance evaluation was conducted as follows, referring to the Comparative Dissolution Test Method [Appendix 5] of the Pharmaceutical Equivalence Test Standards.

[0115]

[0116] Device: Method 2 (Paddle Method) of the Dissolution Test Methods in the General Test Methods of the Korean Pharmacopoeia, 50 rpm

[0117] Test solution: Comparative dissolution test acidic conditions test solution pH 1.2

[0118] Test temperature: 37 ± 0.5°C

[0119] Test solution volume: 900mL

[0120] Time of sample collection: 120 minutes

[0121]

[0122] For sample collection and analysis, 5 mL of the eluent was collected 2 hours after the start of the test and filtered through a 0.45 μm PVDF filter. The filtrate was analyzed using a UV detector at a wavelength of 225 nm while injecting 100 μL at a flow rate of 1.3 mL / min using liquid chromatography (column: Discovery (ODS) (4.6 x 150 mm, 5 μm) C18, temperature: approximately 40°C, mobile phase: aqueous perchloric acid solution (pH adjusted to 2.0 with sodium hydroxide):acetonitrile (7:3)).

[0123] Dissolution Rate (%) Example A0 Example A1 Example B1 Example C1 Example A2 Example B2 Example C2 Example A3 Average 13.3 58.8 21.5 4.7 18.1 4.7 5.6 8.8 Deviation 7.1 1.9 5.1 0.9 0.2 0.5 0.2 0.3 Dissolution Rate (%) Example B3 Example A4 Example A5 Example A6 Comparative Example 1 Comparative Example 2 Control Preparation Average 5.7 12.1 7.2 8.1 78.6 71.2 3.9 Deviation 0.2 6.1 0.7 1.3 1.2 0.2 3.0

[0124] As a result, as shown in Table 10 above, it was confirmed that in Examples A1 and C1, acid resistance increased as the amount of enteric coating increased for the same amount, while in Comparative Examples 1 and 2, since there was no enteric coating, dissolution occurred at a level of 70%. The control formulation showed a dissolution rate of 3.9%, and it was confirmed that Examples A3, A5, A6, B2, B3, C1, and C2 showed a dissolution rate similar to the control formulation and excellent acid resistance.

[0125]

[0126] Test Example 2. Evaluation of dissolution of sustained-release enteric-coated pellets

[0127] Based on Examples A3, A5, A6, B2, B3, C1, and C2, which showed acid resistance similar to the control preparation in Test Example 1 above, GlaxoSmithKline’s Duodat tamsulosin pellets were taken as the control preparation, and a comparative dissolution test for 0.4 mg of tamsulosin hydrochloride was conducted. The comparative dissolution test was carried out as follows, referring to the comparative dissolution test method [Appendix 5] of the Pharmaceutical Equivalence Test Standards.

[0128]

[0129] Device: Method 2 (Paddle Method) of the Dissolution Test Methods in the General Test Methods of the Korean Pharmacopoeia, 50 rpm

[0130] Test solution: Comparative dissolution test acidic conditions test solution pH 6.8

[0131] Test temperature: 37 ± 0.5°C

[0132] Test solution volume: 900mL

[0133] Sample collection times: 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, 120 minutes, 180 minutes, 240 minutes, 300 minutes, 360 minutes

[0134]

[0135] The sample collection and analysis method was carried out in the same manner as Test Example 1 above.

[0136] As a result, as shown in Fig. 1, Examples B2 and A5 were found to have the most similar dissolution patterns to the control formulation, and sustained-release characteristics were also confirmed. However, since Example B2 requires a larger amount of sustained-release agent and enteric agent compared to Example A5 to secure acid resistance and a dissolution pattern similar to the control formulation, considering productivity, it was confirmed that the composition of Example A5, which uses a small amount of sustained-release agent and enteric agent, exhibited the best acid resistance and sustained-release effect.

[0137]

[0138] Test Example 3. Evaluation of dissolution reproducibility of sustained-release enteric-coated pellets

[0139] To evaluate the reproducibility of the dissolution rate according to the amount of polyvinyl alcohol used as a binder to form a sustained-release coating agent, a comparative dissolution test was conducted for 0.4 mg of tamsulosin hydrochloride using Examples A0-1 to 3, C1-1 to 3, C2-1 to 3, and B3-1 to 3, in which polypropylene glycol was used as a plasticizer with different process conditions and amounts, Examples A4-1 to 3, A5-1 to 3, and A6-1 to 3, in which triethyl citrate was used as a plasticizer with different process conditions and amounts, and Tamsulosin pellets from GlaxoSmithKline's Duodat as a control. The comparative dissolution test was conducted in the same manner as the evaluation method of Test Example 2.

[0140] As a result, as shown in FIGS. 2 to 6, in the case of Examples A0-1 to 3 and A4-1 to A4-3 which do not contain polyvinyl alcohol, it can be confirmed in FIGS. 2 and 3 that reproducibility is poor because the elution rate pattern appears different regardless of the type of plasticizer, even though the changes in process conditions are within a reasonable range. On the other hand, in the case of Examples C1-1 to 3, C2-1 to 3, and B3-1 to 3 which use polypropylene glycol as a plasticizer and contain 1 to 3 polyvinyl alcohol per 1 weight part of tamsulosin hydrochloride, and Examples A5-1 to 3 and A6-1 to 3 which use triethyl citrate as a plasticizer and contain 1 to 3 polyvinyl alcohol per 1 weight part of tamsulosin hydrochloride, it was confirmed that similar elution patterns were exhibited regardless of changes in process conditions ( FIGS. 4 to 6). Among these, A5-1 to A5-3 in Fig. 5 showed the most similar dissolution patterns to the control preparation, Duodat.

[0141] It was confirmed that the sustained-release enteric coating pellets of the present invention possess excellent acid resistance with only a small amount of sustained-release and enteric base material including polyvinyl alcohol, and furthermore, can be manufactured with high reproducibility through the use of plasticizers such as polypropylene glycol and triethyl citrate.

Claims

1. Includes an inert core, an active ingredient coating layer formed on the core, a sustained-release coating layer formed on the active ingredient coating layer, and an enteric coating layer formed on the sustained-release coating layer, The above active ingredient is tamsulosin or a pharmaceutically acceptable salt, and The above sustained-release coating layer comprises a sustained-release agent and a coating stabilizer, and The above coating stabilizer is polyvinyl alcohol, Sustained-release enteric-coated pellets.

2. A sustained-release enteric coating pellet according to claim 1, wherein the coating stabilizer is included in an amount of 0.5 to 5 parts by weight per 1 part by weight of the active ingredient.

3. The sustained-release enteric coating pellet of claim 1, wherein the sustained-release agent is included in an amount of 15 to 50 parts by weight per 1 part by weight of the active ingredient.

4. The sustained-release enteric coating pellet of claim 1, wherein the sustained-release agent is included in an amount of 15 to 25 parts by weight per 1 part by weight of the coating stabilizer.

5. The sustained-release enteric coating pellet of claim 1, wherein the active ingredient coating layer comprises any one selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyethylene glycol, copovidone, and polyvinyl alcohol as a binder.

6. A sustained-release enteric coating pellet according to claim 1, wherein the sustained-release agent comprises any one selected from the group consisting of polyvinylpyrrolidone, ethylcellulose, methylcellulose, polyvinylpyrrolidone, sodium lauryl sulfate, and polyvinyl acetate.

7. A sustained-release enteric coating pellet according to claim 1, wherein the sustained-release coating layer further comprises a plasticizer selected from the group consisting of triethyl citrate, polyethylene glycol, polypropylene glycol, triacetin, triacetin citrate, castor oil, dibutyl sebacate, dibutyl phthalate, diethyl phthalate, and glycerin.

8. The sustained-release enteric coating pellet of claim 1, wherein the enteric coating layer comprises any one enteric coating agent selected from the group consisting of hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate phthalate, shellac, methacrylic acid-methyl methacrylate copolymer, and methacrylic acid-ethyl acrylate copolymer.

9. A sustained-release enteric coating pellet according to claim 1, wherein the enteric coating layer further comprises a plasticizer selected from the group consisting of triethyl citrate, polyethylene glycol, polypropylene glycol, triacetin, triacetin citrate, castor oil, dibutyl sebacate, dibutyl phthalate, diethyl phthalate, and glycerin.

10. The sustained-release enteric coated pellet of claim 1, wherein the inert core is a microcrystalline cellulose bead.

11. A tablet comprising a sustained-release enteric-coated pellet according to any one of claims 1 to 10.

12. The method comprises the steps of forming an active ingredient coating layer on an inert core, forming a sustained-release coating layer on the active ingredient coating layer, and forming an enteric coating layer on the sustained-release coating layer. The above active ingredient is tamsulosin or a pharmaceutically acceptable salt, and The above sustained-release coating layer comprises a sustained-release agent and a coating stabilizer, and The above coating stabilizer is polyvinyl alcohol, Method for manufacturing sustained-release enteric-coated pellets.

13. A method for manufacturing a sustained-release enteric coating pellet according to claim 12, wherein the coating stabilizer is included in an amount of 0.5 to 5 parts by weight per 1 part by weight of the active ingredient, and the sustained-release agent is included in an amount of 15 to 50 parts by weight per 1 part by weight of the active ingredient.

14. A method for manufacturing a sustained-release enteric coating pellet according to claim 12, wherein the sustained-release agent is included in an amount of 15 to 25 parts by weight per 1 part by weight of the coating stabilizer.

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