KR20200008373A - Orally Disintegrating Tablet Comprising Nalfurafine - Google Patents

Abstract

The present invention provides an orally disintegrating tablet containing nalfurafine, a 2-(dimethylamino)ethyl methacrylate ·methyl methacrylate copolymer, tocopherol polyethyleneglycol succinate as an antioxidant, and sodium lauryl sulfate as a solubilizer. The orally disintegrating tablet containing nalfurafine according to the present invention disintegrates rapidly in the oral cavity and leaves no foreign body.

Description

Orally Disintegrating Tablet Comprising Nalfurafine}

The present invention relates to oral disintegrating tablet containing nalpurapine, and more particularly, to ensure the stability of the nalpurapine while maintaining the appropriate hardness and wear even without a separate coating layer and nalpurapine-containing oral disintegration quickly in the oral cavity It is about a disintegrating tablet.

In the case of hemodialysis, refractory pruritus causes unbearable pain. Hemodialysis patients suffer from pruritus due to central sensory dysregulation, renal dysfunction, and skin dryness. In general, more than 35% of hemodialysis patients suffer from pruritus.

Nalfurafine is a drug used to treat pruritus in patients with severe hemodialysis, and it acts selectively on kappa opioid receptors in hemodialysis patients with end-stage renal disease, in which conventional antihistamines and anti-allergic drugs are inaudible. It is known to effectively suppress uremic pruritus appearing. Nalpurapine has now been shown to be effective against itching in clinical trials in Japan and Europe, and is safe for long-term administration of more than one year and has no tolerance, habitability or dependence.

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

Nalfurin formulations are commercially available as Remitch in the form of soft capsules. However, soft capsule formulations have the disadvantage of being taken with water. It is necessary to formulate nalpurapine in the form of oral disintegrating tablets.

However, oral disintegrating tablets have a disadvantage in that they have a low hardness, have high abrasion resistance, are easily broken, and are not easy in terms of handling because they seek a faster disintegration rate compared to tablets.

In addition, nalpurapine is chemically unstable with respect to heat, light, oxygen, and moisture. Accordingly, when formulated into oral disintegrating tablets, it is necessary to take measures such as low temperature storage, shading, and inert gas replacement during storage.

Due to such formulation characteristics and unstable properties of naphrapine drugs, Korean Patent No. 10-1682965 proposes a method for preparing oral disintegrating tablets having improved wear resistance by forming a coating layer using a polyvinyl alcohol-based resin. In addition, the orally disintegrating tablet prepared by the above method is commercially available under the commercial name of Remitch OD. However, the above method is cumbersome in that a coating process must be performed to form a coating layer during the manufacturing process.

Republic of Korea Patent No. 10-1682965

It is an object of the present invention to provide a nalfurapine-containing oral disintegrating tablet which disintegrates rapidly in the oral cavity while maintaining appropriate hardness and wear and tear even without a separate coating layer while ensuring the stability of nalfurafin.

It is another object of the present invention to provide a method for preparing the nalpurapine-containing oral disintegrating tablet.

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

On the other hand, the present invention

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

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

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

The oral disintegrating tablet containing nalfurapine according to the present invention can maintain the hardness and friability without requiring a separate coating layer while ensuring the stability of the nalfurafin. In addition, the nalpurapine-containing oral disintegrating tablet according to the present invention disintegrates rapidly in the oral cavity and does not leave a foreign body.

Therefore, the nalpurapine-containing oral disintegrating tablet according to the present invention can be simplified in the manufacturing process, can reduce the water intake of the patient can be advantageously applied to the treatment of pruritus in the hemodialysis patient.

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

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

In one embodiment of the present invention, the nalpurapine may be used as an active ingredient in the form of free base, pharmaceutically acceptable salts, hydrates, racemates, enantiomers, isomers or solvates, and the like. . The pharmaceutically acceptable salts include salts of inorganic acids such as hydrochloride, bromate, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc .; And salts of organic acids such as maleate, fumarate, salicylate, succinate, citrate, acetate, lactate, tartarate, benzoate and methanesulfonate. Preferably, nalpurapine hydrochloride can be used.

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

The nalfurapins, in particular nalfurapine hydrochloride, are not easy to formulate into oral disintegrating tablets because they have strong humidity and poor stability to moisture and light.

However, nalfurafin-containing oral disintegrating tablets according to one embodiment of the present invention are nalfura by containing dimethylaminoethyl methacrylate methyl methacrylate copolymer, tocopherol polyethylene glycol succinate as an antioxidant and sodium lauryl sulfate as a solubilizer. It is possible to ensure the stability of pins, especially nalfurapine hydrochloride.

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

The dimethylaminoethyl methacrylate and methyl methacrylate copolymers are characterized by 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 total orally disintegrating tablet. When the dimethylaminoethyl methacrylate methyl methacrylate copolymer is included in an amount of less than 4% by weight, the effect of increasing stability of nalpurapine may not be exhibited, and when included in an amount of more than 20% by weight, the dimethylamino methacrylate Since the weight ratio of the ethyl methyl methacrylate copolymer to the formulation increases, the amount of other components to the total formulation weight may be insufficient.

In one embodiment of the present invention, the tocopherol polyethylene glycol succinate serves as an antioxidant and can improve the stability of nalfurapine with dimethylaminoethyl methacrylate methyl methacrylate copolymer and sodium lauryl sulfate described below. 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 orally disintegrating tablet. When the tocopherol polyethylene glycol succinate is included in an amount of less than 0.5% by weight may not exhibit a stabilizing effect, when contained in an amount of more than 4% by weight may disintegrate the oral disintegrating tablet.

In one embodiment of the present invention, the sodium lauryl sulfate acts as a solubilizer and can improve the stability of nalfurapine with the above-mentioned dimethylaminoethyl methacrylate methyl methacrylate copolymer and tocopherol polyethylene glycol succinate. 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 orally 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 included in an amount of more than 4% by weight, disintegration of the tablet may be delayed.

The orally disintegrating tablet according to one embodiment of the present invention may further include a pharmaceutically acceptable additive. Since oral disintegrating tablets should disintegrate in a short time, it is preferable to use an additive suitable for oral disintegrating tablets.

Examples of the pharmaceutically acceptable additive include excipients, adsorbents, disintegrants, plasticizers, lubricants, stabilizers, sweeteners, binders, preservatives, bulking agents, foaming agents, diluents, thickeners, solvents, isotonic agents, buffers, bases, and the like. Can be mentioned.

The excipient serves to improve the ease of tableting and maintain the form of oral disintegrating tablets.

As the excipient, it is preferable to use an excipient which accelerates disintegration and exhibits no foreign body in the oral cavity. Specifically, as the excipient, pregelatinized starch, lactose, dextrose, sucrose, maltose, corn starch, mannitol-corn starch and the like can be used alone or in combination of two or more kinds, in particular corn starch mixed with mannitol It is preferable to use mannitol-corn starch as an excipient. The mannitol-corn starch has a 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 orally 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 included in an amount of more than 80% by weight, the weight ratio of the formulation increases, so that the amount of the other components to the total formulation weight may be insufficient.

The adsorbent serves to improve the fluidity of the mixture used in the preparation of oral disintegrating tablets, and has the property of adsorbing a solvent. As the adsorbent, anhydrous calcium hydrogen phosphate, dicalcium phosphate, calcium silicate, or the like may be used, and calcium silicate is particularly preferable.

The adsorbent may be included in an amount of 1 to 11% by weight based on 100% by weight of the orally disintegrating tablet. If the adsorbent is included in an amount of more than 11% by weight it may cause difficulties in granulation.

The disintegrant serves to promote disintegration by penetrating moisture into the tablet. As the disintegrant, croscarmellose sodium, sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose, and the like can be used, and in particular, it is preferable to use low-substituted hydroxypropyl cellulose.

The disintegrant may be included in an amount of 9 to 18% by weight based on 100% by weight of the orally disintegrating tablet. If the disintegrant is included in an amount of less than 9% by weight can be disintegrated in the oral cavity, when contained in an amount of more than 18% by weight may cause the matrix of the tablet to collapse quickly.

The plasticizer serves to facilitate the dimethylaminoethyl methacrylate and methyl methacrylate copolymer to be dissolved smoothly. As the plasticizer, triethyl citrate, tributyl citrate, triacetin, or the like having a pour point of -10 ° C. or less can be used singly or in combination of two or more thereof. Particularly, triethyl citrate is preferably used.

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

The glidant improves the fluidity of the granules to increase the filling ability to the die which is the lower part of the tableting machine, and the friction between the granules and the punch-die which is the upper part of the granules and the tableting machine. Reduction to facilitate compression and release of the tablets. As the lubricant, sodium stearyl fumarate, magnesium stearate, talc, and the like may be used. Particularly, when sodium stearyl fumarate is used, the hardness of the tablet may be increased and desired disintegration and dissolution data may be obtained.

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

Oral disintegrating tablet containing nalpurapine according to an embodiment of the present invention can be disintegrated in water within 1 minute according to the Korean Pharmacopoeia disintegration test method, it shows a higher stability than the commercial product (limit OD).

One embodiment of the present invention relates to a method for producing oral disintegrating tablets, the method of the present invention

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

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

(iii) tableting the granules.

In one embodiment of the invention, step (i) is a step of obtaining a nalfurapine containing solution for producing granules.

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

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

Step (ii) is a step of wet granulation of the nalpurapine-containing solution.

In step (ii) the nalfuraffin containing solution may be wet granulated with a mixture of excipients, adsorbents and disintegrants. Through this wet granulation method, nalfurapine is primarily dispersed uniformly in dimethylaminoethyl methacrylate and methyl methacrylate copolymer, and uniformly dispersed in a mixture of excipients, adsorbents and disintegrants in a coated state. Can be. Accordingly, oral disintegrating tablets may exhibit a high disintegration rate and may exhibit excellent stability, particularly high stability to 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 2L.

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

In step (iii) above, a pharmaceutically acceptable additive may be further used with the granules.

Hereinafter, the present invention will be described in more detail with reference to Examples, Comparative Examples and Experimental Examples. These Examples, Comparative Examples and Experimental Examples are only for illustrating the present invention, it is apparent to those skilled in the art that the scope of the present invention is not limited thereto.

Example  1 to 3 and Comparative example  1: according to the presence and ratio of the polymer Nalfurapins  Containing oral disintegrating tablets

To prepare a oral disintegrating tablet containing nalpurapine according to the following method to the composition of Table 1 (unit: parts by weight).

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

After granulating the granules to a certain size, the granules were mixed with the other additives and compressed to prepare oral disintegrating tablets.

ingredient Example 1 Example 2 Example 3 Comparative Example 1 Active ingredient Nalfurapins 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: Evaluation of stability according to the presence and ratio of polymer

In order to determine the stability according to the presence and proportion of dimethylaminoethyl methacrylate and methyl methacrylate copolymer, the stability test of the nalfurafin-containing oral disintegrating tablets of Examples 1 to 3 and Comparative Example 1 was carried out as follows. Proceeded.

After sealing the oral disintegrating tablet containing nalfurapine prepared in Examples 1 to 3 and Comparative Example 1 with aluminum pouch, and stored for 7 days at 70 ℃, the content of the drug in the oral disintegrating tablet ultra-high performance liquid chromatography (UPLC) Was measured, and the residual ratio was calculated to evaluate the stability.

The results are shown in Table 2 below.

Drug Retention Rate (%) Comparative Example 1 28.8 Example 1 75.2 Example 2 86.8 Example 3 96.0

Through the above Table 2, it was confirmed that the oral disintegrating tablets of Examples 1 to 3 containing dimethylaminoethyl methacrylate and methyl methacrylate copolymer as polymers had high drug retention and excellent stability of nalpurapine. However, the orally disintegrating tablets of Comparative Example 1, which did not contain dimethylaminoethyl methacrylate or methyl methacrylate copolymer, were found to have a very low drug retention rate, which greatly reduced the stability of nalfurafin. In addition, it was found from Examples 1 to 3 that the stability of nalfurafin increased as the ratio of dimethylaminoethyl methacrylate and methyl methacrylate copolymer increased.

Example  4 to 6 and Comparative example  2: depending on the presence and ratio of antioxidants Nalfurapins  contain Oral Disintegration Tablets  Produce

To the composition of Table 3 was prepared in the same manner as in Example 1 nalpurapine-containing oral disintegrating tablets (unit: parts by weight).

ingredient Example 4 Example 5 Example 6 Comparative Example 2 Active ingredient Nalfurapins 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: Evaluation of stability according to the presence and ratio of antioxidant

In order to determine the stability according to the presence and proportion of tocopherol polyethylene glycol succinate, the nalfurafin containing oral disintegrating tablets of Examples 4 to 6 and Comparative Example 2 was conducted as follows.

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

The results are shown in Table 4 below.

Drug Retention 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 to which tocopherol polyethylene glycol succinate was added as an antioxidant have excellent drug retention and high stability of nalfurafin. However, the orally disintegrating tablet of Comparative Example 2 containing no tocopherol polyethylene glycol succinate was confirmed that the drug residual rate is very low, the stability of nalfurapine is greatly reduced. In addition, it can be seen from Examples 4 to 6 that the stability of nalfurafin increases as the ratio of tocopherol polyethylene glycol succinate increases.

Example  7 to 8 and Comparative example  3: depending on the presence and ratio of solubilizer Nalfurapins  contain Oral Disintegration Tablets  Produce

To the composition of Table 5 was prepared in the same manner as in Example 1 nalpurapine-containing oral disintegrating tablets (unit: parts by weight).

ingredient Example 7 Example 8 Comparative Example 3 Active ingredient Nalfurapins 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 according to the presence and ratio of solubilizer

In order to determine the stability according to the presence and ratio of sodium lauryl sulfate, the stability test was carried out as follows for the nalfurin-containing oral disintegrating tablets of Examples 7 to 8 and Comparative Example 3.

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

The results are shown in Table 6 below.

Drug Retention 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 to which sodium lauryl sulfate was added as a solubilizer have high drug retention and excellent stability of nalfurafin. However, the orally disintegrating tablet of Comparative Example 3 containing no sodium lauryl sulfate was confirmed that the drug residual rate is very low, the stability of nalfurapine is greatly reduced. In addition, it can be seen from Examples 7 to 8 that the stability of nalfurafin increases as the ratio of sodium lauryl sulfate increases.

Experimental Example  4: reference drug Remitchi  Comparison of stability with OD

To compare the stability with the reference drug, each formulation was packaged with PTP / Alu and Alu / Alu at 70 ° C. for stability testing. The drug content in the formulation was measured by ultra-high performance liquid chromatography (UPLC) over the initial, 7th and 20th days, and the residual ratio was calculated to evaluate the stability.

The results are shown in Table 7 below.

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

Experimental Example  5: stability evaluation under accelerated conditions

The oral disintegrating tablets of Examples 4 to 6 and Comparative Examples 1 to 2 were subjected to a content test for 10 tablets at predetermined intervals while being stored at 40 ° C accelerated storage test conditions.

The results are shown in Table 8 below.

Duration (months) 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, but the initial result value is maintained up to 1 month, the oral disintegrating tablets of Comparative Examples 1 to 2 did not maintain the initial result value after one month. After 6 months, the orally disintegrating tablets of Examples 5 and 6 showed the best stability.

Example  9: to ensure stability Nalfurapins  contain Oral Disintegration Tablets  Produce

Based on the stability test results of the oral disintegrating tablets of Examples 1 to 8, nalfurapine-containing oral disintegrating tablets were obtained by the same method as Example 1 with the composition of Table 9 below (unit: parts by weight). .

ingredient Example 9 Active ingredient Nalfurapins 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 mouth and in the water Disintegration time  compare

For the orally disintegrating tablets of Examples 4 to 6 and 9, the disintegration time in the oral cavity and in water was compared with the control. The disintegration time in the oral cavity was measured by five testers consisting of healthy adult males and females.

The results are shown in Table 10 below.

Disintegration time in water Intraoral Disintegration Time Reference Drug (Remit OD) 14 sec 32 sec Example 4 20 sec 20 sec Example 5 23 sec 37 seconds Example 6 32 sec 38 sec Example 9 18 sec 35 sec

Through the Table 10, the oral disintegrating tablet of Example 4 shows a faster intraoral disintegration time than the reference drug, and the oral disintegrating tablets of Examples 5, 6 and 9 can be confirmed to show an oral disintegration time similar to the reference 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 the tablet hardness and disintegration time in water were compared.

The results are shown in Table 11 below.

Storage condition Tablet hardness (kp) Disintegration time in water Reference Drug (Remit OD) Early 5.5 14 sec Opening / 40 degrees Celsius / 75% RH / 7 days 1.6 133 seconds Opening / 40 degrees Celsius / 75% RH / 21 days 1.7 204 seconds Opening / 25 degrees Celsius / 60% RH / 7 days 1.8 10 sec Opening / 25 degrees Celsius / 60% RH / 21 days 1.8 40 sec Example 9 Early 3.5 18 sec Opening / 40 degrees Celsius / 75% RH / 7 days 1.1 11 sec Opening / 40 degrees Celsius / 75% RH / 21 days 1.2 11 sec Opening / 25 degrees Celsius / 60% RH / 7 days 2.0 13 sec Opening / 25 degrees Celsius / 60% RH / 21 days 2.0 12 sec

Through Table 11, the orally disintegrating tablet of Example 9 can be seen to exhibit a small hardness change compared to the initial hardness compared to the reference drug. In addition, the reference drug increased the disintegration time, whereas the oral disintegrating tablet of Example 9 was maintained at a reduced initial disintegration time.

Experimental Example  8: tablets Masson  evaluation

The wear and tear of the orally disintegrating tablet of Example 9 was measured. The hardness of the orally disintegrating tablet of Example 9 was 3.5 kp, according to the known method of measuring the wear and tear of oral disintegrating tablets (Jpn. J. Pharm. Health Care Sci. Vol. 32 (2006) No. 6 P511-516). Wear and tear were measured.

The results are shown in Tables 12 and 13 below.

Damage due to single drop test (Number of tablets under test: 50) Example 9 Incidence of appearance damage (%) Total weight Weight change (%) I'm after 0 7.0320 7.0310 0.01

Example 9 Damage due to continuous drop test of 10 tablets
(Number of tablets under test: 100) Count Incidence 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 friability of less than 0.1%.

Having described the specific part of the present invention in detail, it is apparent to those skilled in the art that this specific technology is only a preferred embodiment, which is not limited to the scope of the present invention. Do. Those skilled in the art to which the present invention pertains will be able to perform various applications and modifications within the scope of the present invention based on the above contents.

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

Claims (14)

An oral disintegrating tablet containing nalfurafin, dimethylaminoethyl methacrylate, methyl methacrylate copolymer, tocopherol polyethyleneglycol succinate as an antioxidant and sodium lauryl sulfate as a solubilizer. The orally disintegrating tablet according to claim 1, wherein the nalpurapine is in the form of a free base, a pharmaceutically acceptable salt, hydrate, racemate, enantiomer, homologue or solvate. The orally disintegrating tablet according to claim 2, wherein the pharmaceutically acceptable salt of nalfurapine is nalfurapine hydrochloride. The oral disintegrating tablet according to claim 1, wherein the dimethylaminoethyl methacrylate and methyl methacrylate copolymer is contained in an amount of 4 to 20% by weight based on 100% by weight of the total oral disintegrating tablet. The orally disintegrating tablet 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 orally disintegrating tablet. The orally disintegrating tablet 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 orally disintegrating tablet. The orally disintegrating tablet 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 total orally disintegrating tablet. The orally disintegrating tablet according to claim 1, further comprising at least one selected from the group consisting of excipients, adsorbents, disintegrants, plasticizers and lubricants. The orally disintegrating tablet according to claim 8, wherein the excipient comprises mannitol-corn starch. The orally disintegrating tablet of claim 8, wherein the plasticizer comprises triethyl citrate. (i) dissolving nalpurapine, dimethylaminoethyl methacrylate, methyl methacrylate copolymer, tocopherol polyethyleneglycol succinate and sodium lauryl sulfate in a solvent to obtain a nalpurapin-containing solution;
(ii) wet granulating the nalfuraffin containing solution to obtain granules; And
(iii) a method for producing oral disintegrating tablet comprising the step of tableting the granules. The method of claim 11, wherein the solvent in step (i) is a mixed solvent of ethanol and water. The method for preparing orally disintegrating tablet according to claim 11, wherein the plasticizer is further dissolved in a solvent in step (i) to obtain a nalfurapine-containing solution. The method for preparing orally disintegrating tablet according to claim 11, wherein in the step (ii), the nalfurafin-containing solution is wet granulated with a mixture of an excipient, an adsorbent, and a disintegrant to obtain granules.