KR20130067695A - Orally disintegrating tablet and process for preparing the same - Google Patents

Abstract

PURPOSE: An orally disintegrating tablet is provided to enable stable sustained release, to improve hardness, and to ensure convenient process, storage, and drug administration. CONSTITUTION: An orally disintegrating tablet contains a particle and a disintegrating agent. A method for manufacturing the orally disintegrating tablet comprises: a step of coating an inactive core with a drug layer containing tamsulosin or a pharmaceutically acceptable salt thereof; a step of coating the drug layer with a first coating layer containing a first sustained release polymer and a water soluble polymer; a step of coating the first coating layer with a second layer containing a second sustained release polymer and plasticizer with a pour point less than -10 deg. C; and a step of mixing the formed particle and tableting. [Reference numerals] (AA) Tamsulosin elution rate according to hardness at pH 1.2; (BB) Elution rate(%); (CC) Comparative example 1; (DD) Example 1; (EE) Example 2; (FF) Example 3; (GG) Example 4

Description

Oral disintegrating tablet and manufacturing method thereof {Orally disintegrating tablet and process for preparing the same}

The present invention relates to oral disintegrating tablets and a method of manufacturing the same. More specifically, the present invention relates to a tamsulosin-containing oral disintegrating tablet having a high hardness and low abrasion while rapidly disintegrating in the oral cavity and a method for preparing the same.

Urinary disorders due to enlarged prostate gland are common diseases for men only. The disease is closed by the enlarged prostate gland, the exit of the bladder, the alpha-1 receptor increases in the prostate gland to induce excessive contraction of prostate smooth muscles to thicken the bladder muscle to discharge urine, bladder with a strong bladder contraction It is a symptom that the internal pressure is increased and the mucous membrane between the muscle fibers is compressed.It is difficult to discharge urine during urination, it is difficult to urinate, the strength and thickness of urine stem are reduced, and the start of urination is delayed. do.

Tamsulosin is an alpha1-receptor antagonist that is used to treat prostatic hyperplasia. In particular, among the alpha1-receptors selectively acts on the alpha1-receptor that is predominantly distributed in the human prostate gland, as compared with other alpha1-receptor antagonists commonly used to treat prostatic hyperplasia, other types of blood vessels are present in the blood vessels. It is known that there are relatively few side effects due to antagonism in the a1-receptor.

However, due to the strong drug efficacy of tetracycline, the dosage is low and the in vivo absorption is also very rapid, adverse effects such as orthostatic hypotension may occur when the initial blood drug concentration is excessively elevated despite the high selectivity for prostate smooth muscle. Therefore, the preferred dosage form of the testosterone is known as slow-release and sustained-release sustained-release preparations. By designing tamsulosin as a sustained release agent, not only can these dose-dependent side effects be reduced, but also the number of doses can be reduced to improve patient compliance and to maintain optimal therapeutic concentrations over the long term to maximize therapeutic effects. Can be.

Meanwhile, patients who have difficulty swallowing conventional tablet formulations, namely those with swallowing disorders, account for 35% of the general population, especially shock, Parkinson's, AIDS, thyroid extraction, head and neck radiation therapy and other neurological disorders. Patients with symptoms such as stroke have difficulty in taking tablets for treatment.

Therefore, orally dispersible tablets or orally disintegrating tablets (ODTs), which are tablets that disintegrate rapidly in the oral cavity, may increase patient compliance as well as patient convenience.

Oral disintegrating tablets are rapidly disintegrated and dissolved by saliva in the oral cavity without water, and are in solution or suspension, and are sequentially moved to the absorption site along with saliva. Oral disintegrating tablets can be taken without water for a wide range of patients, such as elderly and infants with swallowing disorders or water intake, not only improve medication compliance, but also have fast and sufficient properties.

Korean Patent No. 0530546 discloses a humidification process, a heating process, a cooling process, and the like when preparing tablets by preparing particles by saccharides and granulation to prepare fast disintegrating formulations after preparing sustained-release particulates. . However, these manufacturing methods require additional manufacturing equipment due to the complicated manufacturing process, there is a problem that can affect the stability of the drug by the humidification process and heating process. Moreover, the hardness of the obtained tablet was low, and there existed a problem that it was easy to produce abrasion damage and a crack at the time of transport.

Korean Patent No. 0912351 discloses a method for preparing a rapid preparation for oral administration by filling a packaging powder containing a pharmaceutically active ingredient and xylitol or sorbitol for 1 to 30 seconds at a temperature of 200 to 1,000 ° C. Posted. However, the method does not have a process of molding into tablets and thus cannot maintain a constant form, thus increasing the risk of breakage during packaging and storage, and may affect the stability of the drug due to the high temperature process.

Although various oral disintegrating tablets and methods for producing the same are known as described above, since both good disintegration properties and tablet strengths are opposite properties, compatibility between the two properties is difficult. Tablets are not only broken during the manufacturing and distribution process, but also must be able to withstand the packaging by automatic packaging machines in pharmacies and the like, thus increasing the desired level of tablet strength. In particular, it is difficult to develop tablets which contain both an excipient, a disintegrant, and the like added in addition to the active ingredient which contributes to good rapid disintegration and sufficient strength, and are excellent in both rapid disintegration and tablet strength in the oral cavity.

In order to solve the problems of the prior art as described above, an object of the present invention is to provide a tamsulosin-containing oral disintegrating tablet having a high hardness and low wear and tear while rapidly disintegrating in the oral cavity.

In addition, an object of the present invention is to provide a method for producing oral disintegrating tablets with low wear and tear without the help of complicated equipment, heating and humidification process.

In order to achieve the above object, the present invention is a drug layer formed on the inert core, the inert core and comprising a tamsulosin or a pharmaceutically acceptable salt thereof, and formed on the drug layer and the first Particles comprising a first coating layer comprising a sustained release polymer and a water-soluble polymer, a second coating layer formed on the first coating layer and including a second sustained release polymer and a plasticizer having a pour point of -10 ° C. or less; And it provides an oral disintegrating tablet comprising a disintegrant.

In addition, the present invention comprises the steps of coating a drug layer comprising a tamsulosin or a pharmaceutically acceptable salt thereof on the inert core; Coating a first coating layer comprising a first sustained release polymer and a water soluble polymer on the drug layer; Forming a particle by coating a second coating layer including a second sustained release polymer and a plasticizer having a pour point of -10 ° C. or less on the first coating layer; And it provides a method for producing oral disintegrating tablet comprising the step of mixing the formed particles and a disintegrant.

According to one embodiment of the invention, the plasticizer having a pour point of -10 ℃ or less may be at least one selected from the group consisting of triethyl citrate, tributyl citrate and triacetin.

According to the oral disintegrating tablet of the present invention, by including a plasticizer having a pour point of -10 ℃ or less in the second coating layer, the stretching force of the second coating layer is increased to minimize the damage of the tablet due to pressure during tableting oral disintegration quickly in the oral cavity Disintegrating tablets may be provided.

In addition, according to the method for producing oral disintegrating tablet of the present invention, it is possible to provide a method for producing oral disintegrating tablet with low wear and tear without the help of additional additional equipment or heating, humidification process using existing equipment.

The oral disintegrating tablet according to the present invention includes a plasticizer having a Pour Point of -10 ° C. or lower in the second coating layer, thereby increasing the softening power of the tablet, and there is almost no damage to the tablet even during tableting pressure. In addition, it is possible to obtain a stable sustained release elution profile without affecting the dissolution rate of tamsulosin by the tableting process. Therefore, by providing a oral disintegrating tablet showing a stable sustained-release dissolution while rapidly disintegrating in the oral cavity in a simple and reproducible process, it is possible to simultaneously satisfy the ease of processing, ease of storage and movement and ease of taking.

1 is a graph showing the dissolution rate according to hardness at pH 1.2 for Examples 1 to 4 and Comparative Example 1 of the present invention.
2 is a graph showing the dissolution rate with time at pH 6.8 for Example 2 and Comparative Example 1 of the present invention.

Oral disintegrating tablet of the present invention is formed on the inert core, the inert core and comprises a drug layer containing tamsulosin or a pharmaceutically acceptable salt thereof, formed on the drug layer and the first sustained-release polymer and Particles comprising a first coating layer comprising a water-soluble polymer, a second coating layer formed on the first coating layer and comprising a second sustained release polymer and a plasticizer having a pour point of -10 ° C. or less; And disintegrants.

The method for preparing oral disintegrating tablet of the present invention comprises the steps of coating a drug layer comprising a tamsulosin or a pharmaceutically acceptable salt thereof on an inert core; Coating a first coating layer comprising a first sustained release polymer and a water soluble polymer on the drug layer; Coating particles on the first coating layer to form a particle by coating a second coating layer including a second sustained release polymer and a plasticizer having a pour point of -10 ° C or less; And tableting by mixing the formed particles and the disintegrant.

Hereinafter, the oral disintegrating tablet of the present invention and a method for producing the same will be described in detail.

Unless specifically stated throughout this specification, "comprising" or "containing" means including any component (or component) without particular limitation, and excludes the addition of other components (or components). Cannot be interpreted as.

Oral disintegrating tablet of the present invention is an oral disintegrating tablet in the form of a tablet, a drug layer formed on the inert core, the inert core and containing a tamsulosin or a pharmaceutically acceptable salt thereof, the drug layer Particles formed on the first coating layer comprising a first sustained-release polymer and a water-soluble polymer, a second coating layer formed on the first coating layer and a second coating layer comprising a plasticizer having a pour point of less than -10 ℃ ; And disintegrants.

In the orally disintegrating tablet of the present invention, the particle including the active ingredient tamsulosin has a form in which three layers of a drug layer, a first coating layer, and a second coating layer are sequentially coated around an inert core.

Inert cores in the particles may be used as long as they are commonly used in the manufacture of tablets, for example, water-soluble or non-water-soluble cores, sugar spheres or cell spheres may be used. The cell spear is a mixture of microcrystalline cellulose, starch, mannitol, povidone, lactose, carnauba wax and the like.

The inert core may be spherical or near spherical in shape. In addition, a core having a particle diameter of about 10 to about 500 um, preferably about 50 to about 200 um may be used, but is not limited thereto. The size may be appropriately adjusted as necessary.

The inert core may include about 40 to about 70 parts by weight based on 100 parts by weight of the particles.

In the oral disintegrating tablet of the present invention, the particles comprise a drug layer formed on the inert core and comprising tamsulosin or a pharmaceutically acceptable salt thereof.

The drug layer includes tamsulosin or a pharmaceutically acceptable salt thereof, and may preferably include tamsulosin hydrochloride.

In addition, the drug layer may further include a water-soluble polymer, for example, may be methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol or polypropylene glycol, and the like. , Preferably hydroxypropyl methylcellulose.

The drug layer may be formed by dissolving tamsulosin or a pharmaceutically acceptable salt thereof in a solvent such as alcohol and / or water and coating the inert core in a liquid state, followed by volatilization of the solvent. At this time, the coating method or the device is not particularly limited, and may be performed using a device such as a general coating machine, a fluidized bed coater, a fluidized bed process machine, or a fluidized bed particle machine.

The drug layer may include about 1 to about 5, preferably about 1 to about 2 parts by weight based on 100 parts by weight of the particles.

The particles of the orally disintegrating tablet of the present invention includes a first coating layer, wherein the first coating layer is formed on the drug layer and includes a first sustained-release polymer and a water-soluble polymer.

The first coating layer is formed to surround the above-described drug layer and serves to control the release of tamsulosin, the active ingredient included in the drug layer.

Specifically, the first sustained release polymer included in the first coating layer may be a water-insoluble cellulose ether, a water-insoluble acrylic acid copolymer, or a mixture thereof. For example, ethyl cellulose, methyl methyl methacrylate, methyl methacrylate. Copolymer, methyl methacrylate, ethyl acrylate copolymer, polyvinylacetate, Eudragit And so on. According to an embodiment of the present invention, the first sustained release polymer may include ethyl cellulose.

The water-soluble polymer included in the first coating layer may be, for example, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, polypropylene glycol, and the like. According to one embodiment it may be hydroxypropyl methylcellulose.

The first coating layer may include about 5 to about 20, preferably about 7 to about 11 parts by weight based on 100 parts by weight of the particles.

In addition, the first sustained release polymer and the water-soluble polymer included in the first coating layer may be included in a weight ratio of about 10: 1 to about 10: 5, preferably about 10: 1 to about 10: 2, within the above range By properly controlling the content of the first sustained-release polymer and the water-soluble polymer in the can exhibit good sustained-release dissolution properties.

The first coating layer may be formed by dissolving the first sustained release polymer and the water-soluble polymer in a solvent such as alcohol and / or water, coating the drug layer in a liquid state, and then volatilizing the solvent. In addition, the method or device for coating the first coating layer is not particularly limited, and may be performed using a device such as a general coating machine, a fluidized bed coater, a fluidized bed process machine, or a fluidized bed particle machine.

Particles of the oral disintegrating tablet of the present invention comprises a second coating layer, the second coating layer is formed on the first coating layer and comprises a second sustained-release polymer and a plasticizer having a pour point of -10 ℃ or less.

The second sustained release polymer included in the second coating layer is, for example, ethyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxymethyl ethyl cellulose phthalate, cellulose acetate phthalate, cellulose acetate Succinate, cellulose acetate maleate, methyl cellulose phthalate, carboxymethyl ethyl cellulose, styrene acrylic acid copolymer, methyl acrylate acrylic acid copolymer, methyl methacrylate acrylic acid copolymer, butyl styrene acrylate acrylic acid copolymer, methacrylic Acid, methyl acrylate copolymer, methacrylic acid, ethyl acrylate copolymer, ethyl methacrylate, methyl methyl methacrylate, methyl acrylate, methacrylic acid, octyl acrylate copolymer, vinyl acetate maleic anhydride copolymer, ethylene Resan anhydride may be a copolymer, a phthalate, polyvinyl alcohol phthalate, polyvinyl acetal phthalate, polyvinyl butylate phthalate, polyvinyl acetal acetamide. According to one embodiment of the present invention, the second sustained-release polymer is selected from the group consisting of ethyl acrylate methyl methyl methacrylate copolymer, methyl methacrylate methyl ethyl acrylate copolymer, and hydroxypropyl methyl cellulose phthalate. It may contain the above.

According to one embodiment of the invention, the second sustained release polymer may be an enteric polymer. Enteric polymer (enteric polymer) refers to a polymer exhibiting a pH condition dependent (pH dependent), for example, may be stable in acidic conditions of less than pH 5 and may exhibit a property to dissolve in mildly acidic or neutral conditions of pH 5 or more.

In addition, the second coating layer includes a plasticizer having a Pour Point of -10 ° C or less.

Pour Point represents the lowest temperature at which the liquid maintains fluidity before reaching the freezing point. Examples of plasticizers having a pour point of −10 ° C. or lower include triethyl citrate, tributyl citrate, triacetin, and the like, and preferably triethyl citrate can be used. The use and effect of increasing the hardness by applying to the pharmaceutical composition for the plasticizer has not been found. In the oral disintegrating tablet of the present invention, by including a plasticizer having a pour point of -10 ° C or lower, such as triethyl citrate, tributyl citrate, triacetin, and the like, the wear strength is reduced by increasing the elongation of the coating layer without affecting the dissolution rate of the drug. The effect can be obtained.

The plasticizer having the pour point of −10 ° C. or less may be included in an amount of about 1 wt% to about 30 wt% based on the weight of the second coating layer. When the plasticizer is contained in an amount of less than 1% by weight, the wear loss is hardly reduced. On the other hand, when the plasticizer is included too much, pellets are agglomerated during the coating process due to the low pour point of the plasticizer. May affect

The second coating layer may include about 10 to about 50, preferably about 10 to about 30 parts by weight based on 100 parts by weight of the particles.

The second coating layer may be formed by dissolving the second sustained release polymer and a plasticizer having a pour point of −10 ° C. or lower in a solvent such as alcohol and / or water, coating the first coating layer in a liquid state, and then volatilizing the solvent. have. In addition, the method or apparatus for coating the second coating layer is not particularly limited, and may be performed using a device such as a general coating machine, a fluidized bed coater, a fluidized bed process machine, or a fluidized bed particle machine.

As described above, particles including the active ingredient may be formed by sequentially coating the drug layer, the first coating layer, and the second coating layer on the inert core.

In the oral disintegrating tablet of the present invention, the particle portion exhibits increased stretching force by including a plasticizer having a pour point of -10 ° C or lower in the second coating layer. Therefore, in spite of the external pressure applied during the tableting process, damage such as cracking of the coating layer hardly occurs, and thus stability of the tablet form may be secured. In addition, since the second coating layer including the plasticizer having the pour point of −10 ° C. or less may be formed by a general coating process, there is no need to add a special process and equipment.

Oral disintegrating tablets of the present invention include a disintegrant.

According to the method for preparing oral disintegrating tablets of the present invention, tablets for oral disintegration can be obtained by mixing a disintegrant with the particles formed as described above, and further mixing other excipients as necessary.

The tableting step is not particularly limited as long as it is a method of molding the pharmaceutical composition. For example, a method of directly manufacturing a tablet by mixing the drug and an appropriate additive and then compressing directly without performing a granulation and drying step, a method of manufacturing a tablet by granulating and mixing a lubricant, and then manufacturing a tablet. Can be.

According to one embodiment of the present invention, as a disintegrant, in general, all disintegrants that can be orally administered can be used. For example, one or more disintegrants selected from the group consisting of carboxymethyl cellulose sodium, hydroxypropyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, crystalline cellulose and crospovidone can be used. According to one embodiment of the invention, crospovidone may be used.

The disintegrant may be included in about 5 to about 30, preferably about 5 to about 20 parts by weight when the total weight of the orally disintegrating tablet of the present invention to 100 parts by weight.

Excipients used in the present invention are generally excipients that can be orally administered, and include sugars, sugar alcohols, water-soluble polymers, water-insoluble polymers, surfactants, stabilizers, binders, lubricants, sweeteners, glidants, fillers and complexes. A fragrance etc. can be used. In addition, the excipient may be orally administered in general and may use any pharmaceutically acceptable excipient.

Examples of the binder include stearic acid, magnesium stearate, calcium stearate, light silicic anhydride, sucrose fatty acid, talc, hydroxypropyl cellulose, polyvinylpyrrolidone and hydroxypropyl methyl cellulose. The above lubricant may be used, and in accordance with an embodiment of the present invention, light silicic anhydride, magnesium stearate, or the like may be used.

In addition to the materials exemplified above, other excipients may also be included without limitation, if desired.

The oral disintegrating tablet according to the present invention includes a plasticizer having a pour point of -10 ° C. or lower in the second coating layer of the particles, thereby increasing the elongation to decrease the wear and tear of about 2 to about 10 kPa, preferably about 3 to about 6 kPa. More preferably about 4.5 to about 6 kPa.

In addition, oral disintegrating tablet according to the present invention may have the hardness as described above without changing the dissolution rate, when tested according to the dissolution test method method 2 method paddle method of the Korean Pharmacopoeia, for the eluate of pH 1.2, which is the active ingredient Less than 22% by weight of the total amount of tamsulosin or a pharmaceutically acceptable salt thereof elutes within 2 hours, and for eluates having a pH of 6.8, from 16 to 46% by weight of the total amount of tamsulosin or its pharmaceutically acceptable salts Elution within 30 minutes, 42-72% by weight elutes within 60 minutes, and 79% by weight or more can be suitable for tamsulosin sustained release formulations with an elution pattern.

EMBODIMENT OF THE INVENTION Hereinafter, although this invention is demonstrated in detail based on an Example, this invention is not limited to these Examples.

< Example >

Example  One

Cellulite 100 containing microcrystalline cellulose and having an average particle diameter of about 100 μm as an inert core, and preparing a coating solution for forming a drug layer, a first coating layer, and a second coating layer, respectively, using the composition according to Table 1 below, the cellet 100 Coating was carried out sequentially. At this time, the coating was performed using a fluidized bed coater (GPCG-2) and the bottom spay method.

1506 g of coated particles, 5044 g of mannitol, and 1500 g of crospovidone were mixed with a fluid mixer. The mixture was placed in a mixer, and then 1800 g of mannitol, 50 g of hard silicic anhydride and 100 g of magnesium stearate were added and mixed.

The final mixture was prepared into tablets using a KISAN tablet press.

layer ingredient weight Inert Core Sellet 100 950 g Drug layer Tamsulosin hydrochloride 10g HPMC2910 (5cps) 15 g ethanol 400g Purified water 55g First coating layer Ethyl cellulose 129 g HPMC2910 (5cps) 24 g ethanol 2500 g Purified water 600 g 2nd coating layer Ethyl methacrylate acrylate copolymer dispersion 600g (30% dispersion) Ethyl methacrylate copolymer dispersion 600g (30% dispersion) Triethyl citrate 18g

Example  2

Oral disintegrating tablets were prepared in the same manner as in Example 1, except that the components were mixed as shown in Table 2 below.

layer ingredient weight Inert Core Sellet 100 950 g Drug layer Tamsulosin hydrochloride 10g HPMC2910 (5cps) 15 g ethanol 400g Purified water 55g First coating layer Ethyl cellulose 129 g HPMC2910 (5cps) 24 g ethanol 2500 g Purified water 600 g 2nd coating layer Ethyl methacrylate acrylate copolymer dispersion 600g (30% dispersion) Ethyl methacrylate copolymer dispersion 600g (30% dispersion) Triethyl citrate 36 g

Example  3

Oral disintegrating tablets were prepared in the same manner as in Example 1, except that the components were mixed as in Table 3 below.

layer ingredient weight Inert Core Sellet 100 1000 g Drug layer Tamsulosin hydrochloride 10g HPMC2910 (5cps) 15 g ethanol 400g Purified water 55g First coating layer Ethyl cellulose 129 g HPMC2910 (5cps) 24 g ethanol 2500 g Purified water 600 g 2nd coating layer Hydroxypropylmethylcellulose phthalate 294 g Triethyl citrate 58 g ethanol 1800 g Acetone 1800 g

Example  4

Oral disintegrating tablets were prepared in the same manner as in Example 1, except that the components were mixed as shown in Table 4 below.

layer ingredient weight Inert Core Sellet 100 950 g Drug layer Tamsulosin hydrochloride 10g HPMC2910 (5cps) 15 g ethanol 400g Purified water 55g First coating layer Ethyl cellulose 129 g HPMC2910 (5cps) 24 g ethanol 2500 g Purified water 600 g 2nd coating layer Ethyl methacrylate acrylate copolymer dispersion 606g (30% dispersion) Ethyl methacrylate copolymer dispersion 606g (30% dispersion) Triethyl citrate 108 g

Comparative example  One

Oral disintegrating tablets were prepared in the same manner as in Example 1, except that the components were mixed as in Table 5 below.

layer ingredient weight Inert Core Sellet 100 950 g Drug layer Tamsulosin hydrochloride 10g HPMC2910 (5cps) 15 g ethanol 400g Purified water 55g First coating layer Ethyl cellulose 129 g HPMC2910 (5cps) 24 g ethanol 2500 g Purified water 600 g 2nd coating layer Ethyl methacrylate acrylate copolymer dispersion 600g (30% dispersion)

< Experimental Example >

Experimental Example  One

Hardness, Massono  And Disintegration  Speed experiment

In order to measure the physical properties of the tablets obtained in Examples 1 to 3, the average hardness was set to 1.5 kPa, 3.0 kPa, 4.5 kPa and 6.0 kPa, and the average wear and disintegration rate were measured after tableting. The results are shown in Table 6 below. Hardness, wear and tear rate were measured by the following method.

Hardness: Five samples were taken and measured using a hardness tester (ERWEKA ^® ).

Friction: After taking 10 tablets and weighing them, the abrasiveness tester (LABFINE ^® was put in a rotation for 4 minutes and weighed to determine the degree of wear according to the following formula.

Friability = (pretest weight-posttest weight) / pretest weight x 100

Disintegration rate: The disintegration rate was tested according to the disintegration test method of the Korean Pharmacopoeia General Test Methods. Disintegration time was measured by taking 6 tablets at 37 ° C in water and putting them in a disintegration tester (JISICO ^® ) and performing 30 vertical movements per minute until the samples completely disintegrated.

Average hardness
(kPa) 1.5 3.0 4.5 6.0 Example 1 Wear and tear (%)
(n = 10) 1.59 0.43 0.32 0.23 Disintegration (seconds)
(n = 6) 13 19 25 29 Example 2 Wear and tear (%)
(n = 10) 1.62 0.47 0.29 0.20 Disintegration (seconds)
(n = 6) 15 19 27 32 Example 3 Wear and tear (%)
(n = 10) 1.65 0.41 0.30 0.22 Disintegration (seconds)
(n = 6) 15 19 25 29

Referring to Table 6, when the tablets were molded to increase the average hardness of Examples 1 to 3 of the present invention, the wear and tear is greatly reduced, it can be seen that can be applied commercially without problems, production, storage, transport, etc. have. The disintegration rate tends to decrease as the average hardness of the tablet increases, but the disintegration time of about 30 seconds was shown even when the average hardness was 6.0 kPa, showing a suitable result within 1 minute, which is the disintegration time of the oral disintegrating tablet.

Referring to the results of Table 6, the hardness of the tablet within the range suitable for the rate of disintegration by simply including triethyl citrate as a plasticizer in the secondary coating layer of the oral disintegrating tablet without the need to add a heating or humidification process to increase the hardness Can be increased.

Experimental Example  2

pH  Elution Pattern Experiment at 1.2

For the orally disintegrating tablets of Examples 1 to 4 and Comparative Example 1, tablets were tableted to have an average hardness of 1.5 kPa, 3.0 kPa, 4.5 kPa, and 6.0 kPa, respectively, followed by pH according to Method 2 of the Korean Pharmacopoeia A dissolution test was conducted to evaluate the dissolution pattern in 1.2. More specific test conditions are as follows.

Elution conditions: Method 2 (paddle method)

Eluent: pH1.2

Eluent amount: 900mL

Elution RPM: 100rpm

Temperature: 37 ± 0.5 ℃

Sampling time: 2 hours after start

The change in dissolution rate according to each hardness condition is shown in Table 7 below, and the graph is shown in FIG. 1.

Hardness Comparative Example 1 Example 1 Example 2 Example 3 Example 4 1.5 kPa 12.5 9.3 10.1 7.4 9.4 3.0 kPa 20.2 10.6 9.7 7.5 9.5 4.5 kPa 25.0 9.9 9.2 8.1 9.7 6.0 kPa 30.9 10.9 10.4 8.7 9.6

Referring to Table 7 and FIG. 1, in Examples 1 to 4 of the two-layer coating layer, even when the hardness increased to 6.0 kPa, there was almost no change in the dissolution rate of tamsrosine at pH 1.2. In addition, the dissolution rate at about 2 hours was about 10%, indicating good sustained release dissolution.

On the other hand, in Comparative Example 1, which does not include a plasticizer, the dissolution rate of tamsulosin rapidly increased at pH 1.2 as the hardness increased. In particular, when the hardness was 4.5 kPa or more, the dissolution rate at 2 hours was over 20%. It can be seen that the coating layer of the oral disintegrating tablet was not tolerated and over-release occurred.

However, in the embodiment of the present invention, the plasticizer triethyl citrate included in the second coating layer increases the elongation of oral disintegrating tablets and prevents cracking of the coating layer of the particles, thereby maintaining the over-release at pH 1.2. Can be evaluated

Experimental Example  3

pH  Elution Pattern Experiment in 6.8

For oral disintegrating tablets of Example 2 and Comparative Example 1, after tableting with an average hardness of 4.5 kPa, a dissolution test was performed to evaluate the dissolution pattern at pH 6.8 according to the second method of the Korean Pharmacopoeia Was carried out. More specific test conditions are as follows.

Elution conditions: Method 2 (paddle method)

Eluent: pH 6.8

Eluent amount: 500mL

Elution RPM: 100rpm

Temperature: 37 ± 0.5 ℃

Sampling time: 30 minutes, 60 minutes, 120 minutes, 180 minutes, 240 minutes after start

The change in dissolution rate with time is shown in Table 8 and the graph is shown in FIG. 2.

time Dissolution Rate of Comparative Example 1
(unit: %) Dissolution Rate of Example 1
(unit: %) 30 minutes 52.8 25.0 60 minutes 78.6 52.9 120 minutes 93.1 86.2 180 minutes 97.1 95.5 240 minutes 98.7 96.0

Referring to Table 8 and Figure 2, it can be seen that Example 2 shows the properties of the sustained release formulation at pH 6.8. On the other hand, Comparative Example 1, which does not contain the plasticizer triethyl citrate in the second coating layer, showed a dissolution of 52.8% at 30 minutes and 78.6% at 60 minutes. There was a bunch. This is because triethyl citrate, which is a plasticizer included in the second coating layer, increases the stretching force and maintains the effect of sustained-release elution even after excessive compression.

Claims (14)

A drug layer formed on an inert core, the inert core and comprising tamsulosin or a pharmaceutically acceptable salt thereof, a first layer formed on the drug layer and comprising a first sustained release polymer and a water soluble polymer Particles comprising a coating layer, a second coating layer formed on the first coating layer and including a second sustained release polymer and a plasticizer having a pour point of -10 ° C. or less; And disintegrating tablets.
The orally disintegrating tablet of claim 1, wherein the plasticizer having a pour point of −10 ° C. or lower comprises at least one selected from the group consisting of triethyl citrate, tributyl citrate, and triacetin.
The orally disintegrating tablet according to claim 1, wherein the plasticizer having a pour point of −10 ° C. or less comprises 1 to 30 wt% based on the total weight of the second coating layer.
The orally disintegrating tablet according to claim 1, wherein the first sustained-release polymer is one or more selected from the group consisting of ethyl cellulose, eudragit, and polyvinyl acetate.
The orally disintegrating tablet according to claim 1, wherein the water-soluble polymer comprises at least one selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, and polyethylene glycol.
The method of claim 1, wherein the second sustained-release polymer is at least one selected from the group consisting of ethyl cellulose, ethyl methacrylate methyl copolymer, ethyl methacrylate acrylate, hydroxypropyl methyl cellulose phthalate, and polyvinylacetate. Oral disintegrating tablet comprising a.
The orally disintegrating tablet of claim 1, wherein the inert core has a particle diameter of 10 to 500 μm.
The method of claim 1,
When tested according to the Dissolution Test Method No. 2 Paddle Method of the Korean Pharmacopoeia,
for an eluate having a pH of 1.2, eluting to less than 22% by weight of the total amount of tamsulosin or a pharmaceutically acceptable salt thereof within 2 hours;
For eluates having a pH of 6.8, 16 to 46% by weight of the total amount of tamsulosin or its pharmaceutically acceptable salts elute within 30 minutes, 42 to 72% by weight elute within 60 minutes and at least 79% by weight Oral disintegrating tablets with an elution pattern that elutes within 4 hours.
The orally disintegrating tablet according to claim 1, having a hardness of 3 to 6 kPa.
Coating a drug layer comprising tamsulosin or a pharmaceutically acceptable salt thereof on the inert core;
Coating a first coating layer comprising a first sustained release polymer and a water soluble polymer on the drug layer;
Forming a particle by coating a second coating layer including a second sustained release polymer and a plasticizer having a pour point of -10 ° C. or less on the first coating layer; And
Method for preparing oral disintegrating tablet comprising the step of mixing the formed particles and a disintegrant.
The method of claim 10, wherein the particles and the disintegrant are further mixed with a pharmaceutically acceptable additive.
The method of claim 11, wherein the pharmaceutically acceptable additive is a group consisting of sugars, sugar alcohols, water soluble polymers, water insoluble polymers, surfactants, stabilizers, binders, lubricants, sweeteners, glidants, fillers and flavoring agents. Oral disintegrating tablet manufacturing method comprising at least one selected from.
The method of claim 10, wherein the plasticizer having a pour point of −10 ° C. or less comprises one or more selected from the group consisting of triethyl citrate, tributyl citrate, and triacetin.
The method of claim 10, wherein the plasticizer having a pour point of −10 ° C. or less comprises 1 to 30 wt% based on the total weight of the second coating layer.

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