KR102120720B1 - Orally Disintegrating Tablet Comprising Nalfurafine - Google Patents

Abstract

The present invention provides an oral disintegrating tablet containing nalfuraffin, dimethylaminoethyl methacrylate, methyl methacrylate copolymer, tocopherol polyethylene glycol succinate as an antioxidant, and sodium lauryl sulfate as a solubilizer.

Description

Oral Disintegrating Tablet Comprising Nalfurafine

The present invention relates to oral disintegrating tablets containing nalfuraffin, and more specifically, while maintaining stability of nalfurafine while maintaining proper hardness and abrasion degree without a separate coating layer, nalfuraffin-containing oral cavity rapidly disintegrating in the oral cavity. It is about disintegrating tablets.

In patients with hemodialysis, refractory pruritus causes unbearable pain. Hemodialysis patients suffer from pruritus due to central sensory dysfunction, renal dysfunction, and skin dryness, and generally, it is shown that more than 35% of hemodialysis patients suffer from pruritus.

Nalfurafine is a drug for treating pruritus in patients with severe hemodialysis, and selectively acts on kappa opioid receptors in hemodialysis patients with end-stage renal disease, where conventional antihistamines and anti-allergic drugs do not work well. It is known to effectively suppress uremic uriosis. According to clinical trials conducted in Japan and Europe, nalfuraffin has been confirmed to be effective against itching, and it is not only safe for long-term administration of more than 1 year, but also has no resistance, habit, and dependence.

On the other hand, patients with hemodialysis, whose kidney function is remarkably poor, should remove most of the water accumulated in the body by hemodialysis. For this reason, hemodialysis patients should drink limited water. Therefore, in order to reduce intake of even a small amount of water, it is necessary to improve the method of taking the existing formulation.

Nalfuraffin preparations are commercially available in the form of soft capsules, Remitch. However, soft capsule formulations have the disadvantage of taking with water. Therefore, it is necessary to formulate nalfuraffin in the form of an oral disintegrating tablet.

However, oral disintegrating tablets have a disadvantage that they have a low hardness and have high wear resistance and can be easily broken because they seek a faster disintegration rate compared to tablets, and are not easy to handle.

In addition, nalfuraffin is chemically unstable to heat, light, oxygen, and moisture. Accordingly, when formulated as an oral disintegrating tablet, it is necessary to take measures such as cold storage, shading, and inert gas replacement during storage.

Due to these formulation characteristics and unstable properties of nalpurapine drug, Korean Patent Registration No. 10-1682965 proposed a method of manufacturing an orally disintegrating tablet with improved wear resistance by forming a coating layer using polyvinyl alcohol-based resin. Orally, disintegrating tablets prepared by the above method are marketed under the commercial name Remitch OD (Remitch OD). However, the above method has a hassle that requires coating to be formed to form a coating layer during the manufacturing process.

Republic of Korea Registered Patent No. 10-1682965

An object of the present invention is to provide an oral disintegrating tablet containing nalfuraffin that disintegrates rapidly in the oral cavity while maintaining proper hardness and abrasion without a separate coating layer while securing the stability of nalfuraffin.

Another object of the present invention is to provide a method for preparing the oral disintegrating tablet containing nalfuraffin.

On the other hand, the present invention provides an oral disintegrating tablet containing nalfuraffin, dimethylaminoethyl methacrylate, methyl methacrylate copolymer, tocopherol polyethylene glycol succinate as an antioxidant, and sodium lauryl sulfate as a solubilizer.

On the other hand, the present invention

(i) dissolving nalfuraffin, dimethylaminoethyl methacrylate, methyl methacrylate copolymer, tocopherol polyethylene glycol succinate and sodium lauryl sulfate in a solvent to obtain a nalfuraffin-containing solution;

(ii) wet granulating the nalfuraffin-containing solution to obtain granules; And

(iii) provides a method for manufacturing an oral disintegrating tablet comprising the step of tableting the granules.

The oral disintegrating tablet containing nalfuraffin according to the present invention can maintain proper hardness and wear resistance without a separate coating layer while securing stability of nalfuraffin. In addition, the oral disintegrating tablet containing nalfuraffin according to the present invention disintegrates quickly in the oral cavity and does not leave a foreign body feeling.

Therefore, the oral disintegrating tablet containing nalfuraffin according to the present invention can simplify the manufacturing process and reduce the water intake of the patient, and thus can be advantageously applied to the treatment of pruritus in hemodialysis patients.

Hereinafter, the present invention will be described in more detail.

One embodiment of the present invention relates to oral disintegrating tablets containing nalfuraffin, dimethylaminoethyl methacrylate, methyl methacrylate copolymer, tocopherol polyethylene glycol succinate as an antioxidant, and sodium lauryl sulfate as a solubilizer.

In one embodiment of the present invention, the nalfuraffin is an active ingredient, and may be used in the form of a free base, a pharmaceutically acceptable salt, hydrate, racemate, enantiomer, isomer or solvate. . The pharmaceutically acceptable salts include salts of inorganic acids such as hydrochloride, bromate, hydrobromide, hydroiodide, sulfate, nitrate and phosphate; And salts of organic acids such as maleate, fumarate, salicylate, succinate, citrate, acetate, lactate, tartrate, benzoate, and methanesulfonate. Preferably, nalfuraffin hydrochloride can be used.

The content of nalfuraffin is preferably 2.5 to 5.0 μg, particularly 2.5 μg, and the maximum daily dose is 5 μg once a day.

The nalfuraffin, especially nalfuraffin hydrochloride, is not easy to formulate as an orally disintegrating tablet because of its strong convention and poor stability against moisture and light.

However, the oral disintegrating tablet containing nalfuraffin according to one embodiment of the present invention comprises dimethylaminoethyl methacrylate/methyl methacrylate copolymer, tocopherol polyethylene glycol succinate as an antioxidant, and sodium lauryl sulfate as a solubilizing agent. The stability of fins, especially nalfuraffin hydrochloride, can be ensured.

In one embodiment of the present invention, the dimethylaminoethyl methacrylate/methyl methacrylate copolymer can uniformly disperse nalfurafine and improve the stability of nalfurafine by acting as a stabilizer, binder, and coating base. It plays a role.

The dimethylaminoethyl methacrylate/methyl methacrylate copolymer exhibits high solubility in low pH solutions and low solubility in high pH solutions.

The dimethylaminoethyl methacrylate/methyl methacrylate copolymer may be contained in an amount of 4 to 20% by weight based on 100% by weight of the entire oral disintegrating tablet. When the methacrylate aminoethyl methacrylate and methyl methacrylate copolymer are included in an amount of less than 4% by weight, the effect of increasing stability of nalfurafine may not be exhibited, and when it is included in an amount of more than 20% by weight, the dimethylamino methacrylate Since the weight ratio of the ethyl methyl methacrylate copolymer in the formulation increases, the amount of other components may be insufficient compared to the total formulation weight.

In one embodiment of the present invention, the tocopherol polyethylene glycol succinate serves as an antioxidant, and can improve the stability of nalfurafine together with dimethylaminoethyl methacrylate/methyl methacrylate copolymer and sodium lauryl sulfate described later. have.

The tocopherol polyethylene glycol succinate may be contained in an amount of 0.5 to 4% by weight, preferably 1.5 to 4% by weight based on 100% by weight of the entire oral disintegrating tablet. When the tocopherol polyethylene glycol succinate is included in an amount of less than 0.5% by weight, the stabilizing effect may not be exhibited, and when it is included in an amount of more than 4% by weight, the disintegration rate of the oral disintegrating tablet may be slowed down.

In one embodiment of the present invention, the sodium lauryl sulfate serves as a solubilizing agent, and can improve the stability of nalfuraffin together with the dimethylaminoethyl methacrylate/methyl methacrylate copolymer and tocopherol polyethylene glycol succinate described above. have.

The sodium lauryl sulfate may be contained in an amount of 0.7 to 4% by weight based on 100% by weight of the oral disintegrating tablet. If the sodium lauryl sulfate is included in an amount of less than 0.7% by weight, the dissolution rate may drop, and when it is included in an amount of more than 4% by weight, disintegration of the tablet may be delayed.

Orally disintegrating tablets according to an embodiment of the present invention may further include a pharmaceutically acceptable additive. Due to the characteristics of the oral disintegrating tablet, it is preferable to use an additive suitable for the oral disintegrating tablet because the tablet must disintegrate within a short time.

Examples of the pharmaceutically acceptable additives include excipients, adsorbents, disintegrants, plasticizers, lubricants, stabilizers, sweeteners, binders, preservatives, bulking agents, blowing agents, diluents, thickeners, solvents, isotonic agents, buffers, bases, etc. Can be lifted.

The excipients serve to improve the ease of tableting and maintain the shape of the oral disintegrating tablet.

As the excipient, it is preferable to use an excipient that disintegrates quickly and does not exhibit a foreign feeling in the oral cavity. Specifically, as the excipients, pregelatinized starch, lactose, dextrose, sucrose, maltose, corn starch, mannitol-corn starch, or the like can be used alone or in combination of two or more, particularly corn starch mixed with mannitol It is preferable to use mannitol-corn starch as an excipient. The mannitol-corn starch has good flavor, excellent stability, and easy disintegration.

The excipient may be included in an amount of 50 to 80% by weight, preferably 50 to 75% by weight based on 100% by weight of the oral disintegrating tablet. If the excipient is included in an amount of less than 50% by weight, the density of the granules may be lowered, and when it is included in an amount of more than 80% by weight, the weight ratio of the formulation increases, so that the amount of other components compared to the total formulation weight may be insufficient.

The adsorbent serves to improve the fluidity of the mixture used for the preparation of oral disintegrating tablets, and has the property of adsorbing a solvent. As the adsorbent, anhydrous calcium phosphate, dicalcium phosphate, calcium silicate, and the like can be used. In particular, it is preferable to use calcium silicate.

The adsorbent may be included in an amount of 1 to 11% by weight based on 100% by weight of the oral disintegrating tablet. If the adsorbent is included in an amount of more than 11% by weight, difficulty in granulation may occur.

The disintegrant serves to promote disintegration by penetrating moisture inside the tablet. As the disintegrant, croscarmellose sodium, sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose, etc. may be used, and it is particularly preferable to use low-substituted hydroxypropyl cellulose.

The disintegrating agent may be included in an amount of 9 to 18% by weight based on 100% by weight of the entire oral disintegrating tablet. When the disintegrant is included in an amount of less than 9% by weight, disintegration in the oral cavity may be delayed, and when it is included in an amount of more than 18% by weight, a matrix of the tablet may quickly collapse.

The plasticizer serves to promote the smooth dissolution of the dimethylaminoethyl methacrylate/methyl methacrylate copolymer. As the plasticizer, triethyl citrate, tributyl citrate, triacetin, etc. having a pour point of -10°C or less may be used alone or in combination of two or more, and it is particularly preferable to use triethyl citrate.

The plasticizer may be included in an amount of 0.4 to 2% by weight based on 100% by weight of the oral disintegrating tablet. When the plasticizer is included in an amount of less than 0.4% by weight, the content and uniformity of the content may appear low, and when used in an amount of more than 2% by weight, the stability of the tablet may be lowered.

The lubricant improves the fluidity of the powder and increases the filling property to the die, which is the bottom of the tableting machine, and reduces friction between the powder and the punch-die between the powder and the tableting machine. It serves to reduce compression and release of tablets. As the lubricant, sodium stearyl fumarate, magnesium stearate, talc, etc. may be used. In particular, when sodium stearyl fumarate is used, the hardness of the tablet is increased and desired disintegration and dissolution data are preferable.

The lubricant may be included in an amount of 0.5 to 5% by weight based on 100% by weight of the oral disintegrating tablet. If the lubricant is contained in an amount of less than 0.5% by weight, tableting may be difficult, and when it is included in an amount of more than 5% by weight, disintegration of the formulation may be delayed.

The oral disintegrating tablet containing nalfuraffin according to an embodiment of the present invention may disintegrate within 1 minute in water according to the Korean Pharmacopoeia disintegration test method, and exhibits higher stability than a commercial product (Remitchi OD).

One embodiment of the present invention relates to a method for manufacturing the oral disintegrating tablet, the manufacturing method of the present invention

(i) dissolving nalfuraffin, dimethylaminoethyl methacrylate, methyl methacrylate copolymer, tocopherol polyethylene glycol succinate and sodium lauryl sulfate in a solvent to obtain a nalfuraffin-containing solution;

(ii) wet granulating the nalfuraffin-containing solution to obtain granules; And

(iii) tableting the granules.

In one embodiment of the present invention, step (i) is a step of obtaining a solution containing nalfuraffin for preparing granules.

In the step (i), as long as it can dissolve all the components as a solvent, it can be used without limitation. In particular, a mixed solvent of ethanol and water may be used as the solvent. The mixed solvent of ethanol and water may preferably contain 4 to 5 parts by weight of ethanol per 1 part by weight of water. It can exhibit excellent solubility in the range of the mixing ratio.

In step (i), a plasticizer may be further dissolved in a solvent to obtain a nalfuraffin-containing solution.

The step (ii) is a step of wet granulating the solution containing nalfuraffin.

In step (ii), the nalfuraffin-containing solution may be wet granulated with a mixture of excipients, adsorbents, and disintegrants. Through this wet granulation method, nalfuraffin is firstly uniformly dispersed in dimethylaminoethyl methacrylate/methyl methacrylate copolymer and secondarily uniformly dispersed in a mixture of excipients, adsorbents, and disintegrants while coated. Can be. Accordingly, the oral disintegrating tablet may exhibit a fast disintegration rate and excellent stability, particularly high stability against moisture and light.

Step (ii) may be performed using a speed mixer. The speed of the stirring impeller can be adjusted to 200 to 300 rpm based on 2 L.

In one embodiment of the present invention, step (iii) is a step of tableting the granules, and may be performed using a conventional tableting method.

In step (iii), a pharmaceutically acceptable additive can be additionally used together with the granulate.

Hereinafter, the present invention will be described in more detail with reference to Examples, Comparative Examples and Experimental Examples. It is apparent to those skilled in the art that these examples, comparative examples and experimental examples are only for describing the present invention, and the scope of the present invention is not limited to them.

Example 1 to 3 and Comparative example 1: Depending on the presence and proportion of polymer Raw furafin Preparation of oral disintegrating tablets

The oral disintegrating tablet containing nalfuraffin was prepared according to the following method with the composition of Table 1 (unit: parts by weight).

After dissolving dimethylaminoethyl methacrylate, methyl methacrylate copolymer, triethyl citrate, tocopherol polyethylene glycol succinate, sodium lauryl sulfate and nalfuraffin in a mixed solvent of water and ethanol (1:4, w/w), The solution was wet granulated with a mixture of excipients, adsorbents and disintegrants using a speed mixer and then dried with a fluid bed granulator to obtain granules.

After the granules were sized to a certain size, oral disintegrating tablets were prepared by mixing and tableting the remaining additives.

ingredient Example 1 Example 2 Example 3 Comparative Example 1 Active ingredient Raw furafin 0.002 0.002 0.002 0.002 Excipient Mannitol-corn starch 71.2 60.8 55.0 75.4 absorbent Calcium silicate 9.5 9.5 9.5 9.8 Disintegrant Low substituted hydroxypropyl cellulose 9.5 15.4 9.6 9.9 Polymer Dimethylaminoethyl methacrylate, methyl methacrylate copolymer 3.7 7.4 18.4 - Plasticizer Triethyl citrate 0.4 0.7 1.8 1.9 Antioxidant Tocopherol Polyethylene Glycol Succinate 3.2 3.7 3.2 0.7 Solubilizer Sodium lauryl sulfate 1.5 1.5 1.5 1.3 Lubricant Sodium stearyl fumarate 1.0 1.0 1.0 1.0 Total (parts by weight) 100 100 100 100

Experimental Example 1: Stability evaluation according to the presence and proportion of polymer

In order to determine the stability according to the presence or absence and ratio of dimethylaminoethyl methacrylate/methyl methacrylate copolymer, stability tests were performed as follows for oral disintegrating tablets containing nalfurafine in Examples 1 to 3 and Comparative Example 1. Proceeded.

After sealing the oral disintegrating tablet containing nalfurapin prepared in Examples 1 to 3 and Comparative Example 1 with an aluminum pouch, and preserving at 70°C for 7 days, the content of the drug in the oral disintegrating tablet was ultra-high performance liquid chromatography (UPLC). The stability was evaluated by measuring with and calculating the residual rate.

The results are shown in Table 2 below.

Drug residual rate (%) Comparative Example 1 28.8 Example 1 75.2 Example 2 86.8 Example 3 96.0

Through Table 2, it was confirmed that the oral disintegrating tablets of Examples 1 to 3 containing dimethylaminoethyl methacrylate/methyl methacrylate copolymer as a polymer had a high drug residual rate and excellent stability of nalfuraffin. However, it was confirmed that the oral disintegrating tablet of Comparative Example 1, which did not contain dimethylaminoethyl methacrylate/methyl methacrylate copolymer, had a very low drug residual rate and significantly reduced stability of nalfuraffin. In addition, through Examples 1 to 3, it was found that the stability of nalfuraffin increased as the ratio of dimethylaminoethyl methacrylate/methyl methacrylate copolymer increased.

Example 4 to 6 and Comparative example 2: depending on the presence and proportion of antioxidants Raw furafin contain Orally disintegrating tablet Produce

The oral disintegrating tablet containing nalfuraffin was prepared in the same manner as in Example 1 with the composition shown in Table 3 (unit: parts by weight).

ingredient Example 4 Example 5 Example 6 Comparative Example 2 Active ingredient Raw furafin 0.002 0.002 0.002 0.002 Excipient Mannitol-corn starch 56.3 55.6 54.9 57.0 absorbent Calcium silicate 9.8 9.6 9.5 9.8 Disintegrant Low substituted hydroxypropyl cellulose 9.9 9.7 9.6 9.9 Polymer Dimethylaminoethyl methacrylate, methyl methacrylate copolymer 19.1 18.8 18.6 19.1 Plasticizer Triethyl citrate 1.9 1.9 1.9 1.9 Antioxidant Tocopherol Polyethylene Glycol Succinate 0.7 1.9 3.2 - Solubilizer Sodium lauryl sulfate 1.3 1.3 1.3 1.3 Lubricant Sodium stearyl fumarate 1.0 1.0 1.0 1.0 Total (parts by weight) 100 100 100 100

Experimental Example 2: Stability evaluation according to the presence and proportion of antioxidants

In order to examine the stability of tocopherol polyethylene glycol succinate according to the presence or absence, the stability test was conducted as follows for the oral disintegrating tablets containing nalfurafine of Examples 4 to 6 and Comparative Example 2.

After sealing the oral disintegrating tablet containing nalfurapin prepared in Examples 4 to 6 and Comparative Example 2 with an aluminum pouch, and preserving at 70°C for 7 days, the content of the drug in the oral disintegrating tablet was ultra-high performance liquid chromatography ( UPLC), and the residual ratio was calculated to evaluate stability.

The results are shown in Table 4 below.

Drug residual rate (%) Comparative Example 2 82.4 Example 4 90.1 Example 5 95.2 Example 6 96.2

Through Table 4, it was confirmed that the oral disintegrating tablets of Examples 4 to 6 in which tocopherol polyethylene glycol succinate was added as an antioxidant had a high drug residual rate and excellent stability of nalfuraffin. However, it was confirmed that the oral disintegrating tablet of Comparative Example 2, which did not contain tocopherol polyethylene glycol succinate, had a very low drug residual rate and significantly reduced stability of nalfuraffin. In addition, through Examples 4 to 6, it was found that the stability of nalfuraffin increased as the proportion of tocopherol polyethylene glycol succinate increased.

Example 7 to 8 and Comparative example 3: depending on the presence and proportion of solubilizer Raw furafin contain Orally disintegrating tablet Produce

The oral disintegrating tablet containing nalfuraffin was prepared in the same manner as in Example 1 with the composition shown in Table 5 below (unit: parts by weight).

ingredient Example 7 Example 8 Comparative Example 3 Active ingredient Raw furafin 0.002 0.002 0.002 Excipient Mannitol-corn starch 61.0 60.2 61.7 absorbent Calcium silicate 9.7 9.7 9.7 Disintegrant Low substituted hydroxypropyl cellulose 15.7 15.7 15.7 Polymer Dimethylaminoethyl methacrylate, methyl methacrylate copolymer 7.5 7.5 7.5 Plasticizer Triethyl citrate 0.7 0.7 0.7 Antioxidant Tocopherol Polyethylene Glycol Succinate 3.7 3.7 3.7 Solubilizer Sodium lauryl sulfate 0.7 1.5 - Lubricant Sodium stearyl fumarate 1.0 1.0 1.0 Total (parts by weight) 100 100 100

Experimental Example 3: Evaluation of stability depending on the presence and proportion of solubilizer

To examine the stability of sodium lauryl sulfate and its presence, the stability test was conducted as follows for the oral disintegrating tablets containing nalfurafine in Examples 7 to 8 and Comparative Example 3.

After sealing the oral disintegrating tablet containing nalfurapin prepared in Examples 7 to 8 and Comparative Example 3 with an aluminum pouch, and preserving at 70°C for 7 days, the content of the drug in the oral disintegrating tablet was ultra-high performance liquid chromatography ( UPLC), and the residual ratio was calculated to evaluate stability.

The results are shown in Table 6 below.

Drug residual rate (%) Comparative Example 3 86.8 Example 7 90.5 Example 8 93.8

Through Table 6, it was confirmed that the oral disintegrating tablets of Examples 7 to 8 in which sodium lauryl sulfate was added as a solubilizer had a high drug residual rate and excellent stability of nalfuraffin. However, it was confirmed that the oral disintegrating tablet of Comparative Example 3, which did not contain sodium lauryl sulfate, had a very low drug residual rate and significantly reduced stability of nalfuraffin. In addition, it was found through Examples 7 to 8 that the stability of nalfuraffin increased as the proportion of sodium lauryl sulfate increased.

Experimental Example 4: Reference drug Remitchi Stability comparison with OD

In order to compare the stability with the reference drug, each formulation was packaged with PTP/Alu and Alu/Alu at 70° C. to conduct a stability test. During the initial, 7th, and 20th days, the drug content in the formulation was measured by ultra high performance liquid chromatography (UPLC), and the residual ratio was calculated to evaluate stability.

The results are shown in Table 7 below.

Reference
(Remitchi OD) Example 4 Example 5 Example 6 Comparative Example 1 Comparative Example 2 Early PTP/Alu 99.8 100.2 100.7 101.1 100.0 100.0 7 days PTP/Alu 90.4 92.6 95.2 95.5 64.1 90.7 Alu/Alu - 90.1 95.2 96.2 29.3 86.3 20 days PTP/Alu 80.6 83.6 87.7 88.5 50.0 75.1 Alu/Alu - 81.1 86.6 86.4 16.1 74.4

Through Table 7, the oral disintegrating tablets of Examples 4 to 6 exhibited a high residual rate and a remarkably good stabilizing effect compared to the control drug. From the above results, it can be seen that the stability increases with the addition of the polymer, antioxidant and solubilizer.

Experimental Example 5: Evaluation of stability under accelerated conditions

For the oral disintegrating tablets of Examples 4 to 6 and Comparative Examples 1 to 2, the content test was carried out for 10 tablets every specified period of time while being stored at 40°C accelerated storage test conditions.

The results are shown in Table 8 below.

Period (month) Early One 3 5 6 PTP/Alu Alu/Alu PTP/Alu Alu/Alu PTP/Alu Alu/Alu PTP/Alu Alu/Alu Example 4 100.3 100.7 100.1 97.3 96.7 96.0 95.6 94.7 94.7 Example 5 101.3 101.8 101.5 98.7 99.3 98.3 98.7 98.1 98.5 Example 6 101.2 101.1 100.2 98.3 99.6 98.7 99.7 98.6 99.6 Comparative Example 1 100.0 96.5 93.0 86.0 84.2 80.9 74.5 78.9 74.2 Comparative Example 2 100.0 99.1 99.2 96.2 95.3 93.7 93.3 93.3 92.6

Through Table 8, the oral disintegrating tablets of Examples 4 to 6 had an initial result value of up to 1 month, but the oral disintegrating tablets of Comparative Examples 1 to 2 did not maintain the initial result value after 1 month. After 6 months, the oral disintegrating tablets of Examples 5 and 6 exhibited the best stability.

Example 9: Secured stability Raw furafin contain Orally disintegrating tablet Produce

Based on the results of the stability test of the oral disintegrating tablets of Examples 1 to 8, oral disintegrating tablets containing nalfuraffin which secured stability were prepared in the same manner as in Example 1 with the composition shown in Table 9 below (unit: parts by weight). .

ingredient Example 9 Active ingredient Raw furafin 0.002 Excipient Mannitol-corn starch 60.5 absorbent Calcium silicate 10.7 Disintegrant Low substituted hydroxypropyl cellulose 15.0 Polymer Dimethylaminoethyl methacrylate, methyl methacrylate copolymer 8.9 Plasticizer Triethyl citrate 0.9 Antioxidant Tocopherol Polyethylene Glycol Succinate 2.1 Solubilizer Sodium lauryl sulfate 1.4 Lubricant Sodium stearyl fumarate 0.5 Total (parts by weight) 100

Experimental Example 6: In the oral cavity and in water Disintegration time compare

The disintegration times in the oral cavity and water were compared with the reference drug for the oral disintegrating tablets of Examples 4 to 6 and 9 prepared above. The disintegration time in the oral cavity was measured by five testers consisting of healthy adult males and females, and the disintegration time in water was measured according to the Korean Pharmacopoeia Disintegration Test Method.

The results are shown in Table 10 below.

Disintegration time in water Disintegration time in the oral cavity Reference drug (Remitchi OD) 14 seconds 32 sec Example 4 20 seconds 20 seconds Example 5 23 seconds 37 sec Example 6 32 sec 38 sec Example 9 18 sec 35 sec

Through Table 10, it can be seen that the oral disintegrating tablet of Example 4 exhibits a faster disintegration time in the oral cavity than the reference drug, and the oral disintegrating tablets of Examples 5, 6 and 9 exhibit disintegration time in the oral cavity similar to the control drug. have.

Experimental Example 7: Comparison of changes over time according to storage conditions

The oral disintegrating tablet and the control drug of Example 9 prepared above were stored under different storage conditions, and tablet hardness and disintegration time in water were compared.

The results are shown in Table 11 below.

Storage conditions Tablet hardness (kp) Disintegration time in water Reference drug (Remitchi OD) Early 5.5 14 seconds Open/40℃/75% RH/7 days 1.6 133 seconds Open/40℃/75% RH/21 days 1.7 204 seconds Open/25℃/60% RH/7 days 1.8 10 seconds Open/25℃/60% RH/21 days 1.8 40 seconds Example 9 Early 3.5 18 sec Open/40℃/75% RH/7 days 1.1 11 seconds Open/40℃/75% RH/21 days 1.2 11 seconds Open/25℃/60% RH/7 days 2.0 13 sec Open/25℃/60% RH/21 days 2.0 12 seconds

Through Table 11, it can be seen that the oral disintegrating tablet of Example 9 shows a small change in hardness compared to the initial hardness compared to the control drug. In addition, while the control drug increased disintegration time, the oral disintegrating tablet of Example 9 was maintained by decreasing from the initial disintegration time.

Experimental Example 8: Tablet Masondo evaluation

Abrasion degree was measured for the oral disintegrating tablet of Example 9 prepared above. The hardness of the oral disintegrating tablet of Example 9 was 3.5 kp, according to a known method of measuring the disintegration of an oral disintegrating tablet (Jpn. J. Pharm. Health Care Sci. Vol. 32 (2006) No.6 P511-516) The wear degree was measured.

The results are shown in Tables 12 and 13 below.

Damage by single drop test (Number of tablets tested: 50) Example 9 The rate of appearance damage (%) Total weight Weight change (%) I'm after 0 7.0320 7.0310 0.01

Example 9 Damage by continuous drop test of 10 tablets
(Number of tablets under test: 100) Count The rate of appearance damage (%) Total weight Weight change (%) I'm after One 0 1.4103 1.4097 0.04 2 0 1.4094 1.4093 0.01 3 0 1.4064 1.4061 0.02 4 0 1.4092 1.4091 0.01 5 0 1.4070 1.4060 0.07 6 0 1.4085 1.4083 0.01 7 0 1.4071 1.4071 0.00 8 0 1.4085 1.4085 0.00 9 0 1.4073 1.4068 0.04 10 0 1.4069 1.4063 0.04 sum 0 1.4080 1.4077 0.02

Through Table 12 and Table 13, it can be seen that the oral disintegrating tablet of Example 9 having a tablet hardness of 3.5 kp has a low wear resistance of 0.1% or less.

Since the specific parts of the present invention have been described in detail above, it is obvious that for those skilled in the art to which the present invention pertains, this specific technology is only a preferred embodiment, and the scope of the present invention is not limited thereto. Do. Those skilled in the art to which the present invention pertains will be able to make various applications and modifications within the scope of the present invention based on the above.

Accordingly, the substantial scope of the present invention will be defined by the appended claims and their equivalents.

Claims (14)

Nalfuraffin, dimethylaminoethyl methacrylate, methyl methacrylate copolymer, tocopherol polyethylene glycol succinate as an antioxidant, and sodium lauryl sulfate as a solubilizer. An oral disintegrating tablet for treatment of pruritus dispersed in a copolymer. The oral disintegrating tablet according to claim 1, wherein the nalfurapin is in the form of a free base, a pharmaceutically acceptable salt, hydrate, racemate, enantiomer or solvate. The oral disintegrating tablet for treating pruritus according to claim 2, wherein the pharmaceutically acceptable salt of nalfuraffin is nalfuraffin hydrochloride. The oral disintegrating tablet for treating pruritus according to claim 1, wherein the dimethylaminoethyl methacrylate/methyl methacrylate copolymer is contained in an amount of 4 to 20% by weight based on 100% by weight of the oral disintegrating tablet. The oral disintegrating tablet for treating pruritus according to claim 1, wherein the tocopherol polyethylene glycol succinate is contained in an amount of 0.5 to 4% by weight based on 100% by weight of the entire oral disintegrating tablet. The oral disintegrating tablet for treating pruritus according to claim 5, wherein the tocopherol polyethylene glycol succinate is contained in an amount of 1.5 to 4% by weight based on 100% by weight of the oral disintegrating tablet. The oral disintegrating tablet for treating pruritus according to claim 1, wherein the sodium lauryl sulfate is contained in an amount of 0.7 to 4% by weight based on 100% by weight of the oral disintegrating tablet. The oral disintegrating tablet for treating pruritus according to claim 1, further comprising at least one selected from the group consisting of excipients, adsorbents, disintegrants, plasticizers and lubricants. The oral disintegrating tablet of claim 8, wherein the excipient comprises mannitol-corn starch. The oral disintegrating tablet for treating pruritus according to claim 8, wherein the plasticizer comprises triethyl citrate. (i) dissolving nalfuraffin, dimethylaminoethyl methacrylate, methyl methacrylate copolymer, tocopherol polyethylene glycol succinate and sodium lauryl sulfate in a solvent to obtain a nalfuraffin-containing solution;
(ii) wet granulating the nalfuraffin-containing solution to obtain granules; And
(iii) A method of manufacturing an oral disintegrating tablet comprising the step of tableting the granules. 12. The method of claim 11, wherein the solvent in step (i) is a mixed solvent of ethanol and water. The method of claim 11, wherein in step (i), a plasticizer is further dissolved in a solvent to obtain a solution containing nalfuraffin. 12. The method of claim 11, wherein in step (ii), the nalfuraffin-containing solution is wet granulated with a mixture of excipients, adsorbents, and disintegrants to obtain granules.