Orally disintegrating tablet comprising pregabalin or pharmaceutically acceptable salt thereof

Abstract

The present invention relates to an orally disintegrating tablet comprising pregabalin or a pharmaceutically acceptable salt thereof, sucralose as a sweetener, and tomatine.

Description

Orally disintegrating tablet containing pregabalin or a pharmaceutically acceptable salt thereof

[0001] The present invention relates to an orally disintegrating tablet comprising pregabalin, and more particularly to an orally disintegrating tablet comprising sucralose and thaumatin as sweeteners.

[0002] Pregabalin is an analogue of the endogenous inhibitory neurotransmitter gamma-aminobutyric acid (GABA), which regulates brain neuron activity. It is used to treat neuropathic pain, as an adjunctive treatment for partial-onset epilepsy, and as a first-line treatment for fibromyalgia. It is available in Korea in capsules and sustained-release tablets in various dosages ranging from 25 mg to 300 mg, and is in high demand domestically for the treatment of neuropathies.

[0003] Approximately 65% ​​of patients prescribed pregabalin in Korea are elderly, representing more than half, or even the majority, of the population. This suggests that pregabalin is primarily prescribed to elderly patients. Many elderly patients experience difficulty swallowing capsules or tablets, which can lead to medication resistance and compromise compliance. Furthermore, elderly patients desire rapid pain relief and prefer products with rapid onset of action.

[0004] Orally disintegrating tablets (ODTs) are oral preparations that dissolve in saliva in the mouth to exert their medicinal properties. They are easily administered to those who have difficulty swallowing conventional capsules or tablets, and they can be taken without water. Furthermore, they dissolve within seconds in the mouth, exerting their effects, resulting in highly quantifiable, uniform, and effective dosages. However, the ODT formulation suffers from the drawback of patients experiencing the bitter taste of the raw materials, which can hinder medication compliance.

[0005] Accordingly, the inventor of the present invention has conducted repeated research to develop an orally disintegrating tablet containing stable pregabalin while masking the bitter taste of the raw material, and as a result, has developed an orally disintegrating tablet containing pregabalin that exhibits an excellent bitter taste masking effect and is effective in alleviating pain, thereby completing the present invention.

[0006] An object of the present invention is to provide an orally disintegrating tablet comprising pregabalin or a pharmaceutically acceptable salt thereof, sucralose as a sweetener, and thaumatin.

[0007] This is explained in detail as follows. Meanwhile, each description and embodiment disclosed in the present invention can also be applied to each other description and embodiment. In other words, all combinations of the various elements disclosed in the present invention fall within the scope of the present invention. Furthermore, the scope of the present invention should not be considered limited by the specific descriptions described below.

[0008] The present invention provides an orally disintegrating tablet comprising pregabalin or a pharmaceutically acceptable salt thereof, sucralose as a sweetener, and thaumatin.

[0009] In the present invention, the pregabalin refers to a compound known as (S)-3-(aminomethyl)-5-methylhexanoic acid and derivatives thereof. Pregabalin is known to selectively bind to the alpha-2-delta subunit of calcium channels in the presynaptic membrane in the central nervous system, thereby reducing the influx of calcium ions into nerve cell terminals and reducing the secretion of various excitatory neurotransmitters, including glutamate and norepinephrine, thereby restoring the function of nerve cells to a normal level.

[0010] The above pregabalin is used as an effective drug for the treatment of patients with neuropathy and fibromyalgia, and the inventors of the present invention have developed an orally disintegrating tablet that improves the convenience of taking the tablet compared to existing commercial products containing pregabalin in capsule or tablet form and exhibits a rapid analgesic effect.

[0011] In the present invention, the pregabalin may exist in the form of a pharmaceutically acceptable salt. Useful salts include acid addition salts formed with a pharmaceutically acceptable free acid. The term "pharmaceutically acceptable salt" as used herein refers to any organic or inorganic acid addition salt of pregabalin, which has a concentration that is relatively non-toxic and harmless to the patient and exhibits an effective effect, and in which side effects due to the salt do not diminish the beneficial effects of pregabalin.

[0012] Acid addition salts are prepared by conventional methods, for example, by dissolving the compound in an excess of an aqueous acid solution and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone, or acetonitrile. Equal molar amounts of the compound and the acid or alcohol in water are heated, and the mixture is then evaporated to dryness, or the precipitated salt may be filtered off with suction.

[0013] At this time, inorganic acids and organic acids can be used as free acids, and inorganic acids such as hydrochloric acid, phosphoric acid, sulfuric acid, or nitric acid can be used, and organic acids such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, or hydroiodic acid can be used.

[0014] In the present invention, the content of pregabalin can be determined by considering the daily dosage and solubility in solvents that sufficiently exert pharmacological effects without causing side effects, and can be included in an amount of 25 to 300 mg per tablet. If the content of pregabalin is less than 25 mg, the concentration of pregabalin is low, making it difficult to exert sufficient pharmacological effects. On the other hand, if the content exceeds 300 mg, the concentration of pregabalin is high, resulting in the production of a physically unstable formulation, which is undesirable.

[0015] In the present invention, the weight of pregabalin or a pharmaceutically acceptable salt thereof is characterized in that it is included in an amount of 5 to 70 wt%, more specifically 15 to 60 wt%, and even more specifically 20 to 50 wt%, relative to the total weight of the orally disintegrating tablet. If the amount of pregabalin or a pharmaceutically acceptable salt thereof exceeds 70 wt% relative to the total weight of the orally disintegrating tablet, the dissolution rate of the orally disintegrating tablet is lowered, which is undesirable.

[0016] sweetener

[0017] The orally disintegrating tablet of the present invention comprises sucralose and thaumatin as sweeteners.

[0018] Orally disintegrating tablets are characterized by rapid disintegration using a small amount of moisture in the mouth, and since patients detect the taste of the drug, bitter, astringent, or rough tastes of the raw material can cause problems that reduce patient compliance. Methods to prevent patients from detecting the unwanted taste of the raw material include adding a sweetener to make them feel sweet, or coating the raw material with a polymer such as Eudragit EPO or Eudragit E100 to mask the taste. However, since the polymer coating method has the disadvantage of making it difficult to exhibit the drug effect quickly, the present invention induces a bitter taste masking effect using a sweetener without coating the main ingredient with a polymer.

[0019] In the present invention, the sweetener covers the very bitter taste of pregabalin and adds a sweet taste, thereby preventing the patient from feeling the bitter or rough taste of the raw material and providing the effect of significantly improving medication compliance.

[0020] The sweetener of the present invention comprises a combination of sucralose and thaumatin.

[0021] The content of the sweetener is characterized in that it is comprised in an amount of 2 wt% or more and less than 10 wt%, specifically 2 to 9.5 wt%, more specifically 2 to 8 wt%, and even more specifically 4 to 8 wt%, relative to the weight of the main ingredient pregabalin or a pharmaceutically acceptable salt thereof. If the content of the sweetener is less than 2 wt% relative to the weight of the main ingredient, the bitter and rough taste of pregabalin is not masked, and if it exceeds 10 wt%, the stability of the tablet is lowered, such as browning, which is not preferable.

[0022] In the present invention, the weight ratio of sucralose and thaumatin may be 10:1 to 1:10, more specifically 5:1 to 1:5, and even more specifically 3:1.

[0023] In a specific embodiment of the present invention, the results of a sensory evaluation of a composition mixed with the main ingredient pregabalin and the type and content of a sweetener showed that the composition containing both sucralose and thaumatin had the best effect in masking bitter and rough tastes (Experimental Example 1-1), and was confirmed to be stable without any particular change in properties under harsh conditions for two weeks (Experimental Example 1-2).

[0024] The orally disintegrating tablet of the present invention may further contain pharmaceutically acceptable additives in addition to pregabalin or a pharmaceutically acceptable salt thereof and a sweetener, within a range that does not impair the effects of the present invention.

[0025] Pharmaceutically acceptable excipients may include, for example, disintegrants, diluents, lubricants, flavorings, fragrances, excipients, binders, and coating agents.

[0026] disintegrant

[0027] In the present invention, the disintegrant plays a role in rapidly disintegrating the orally disintegrating tablet even with a small amount of saliva in the mouth when the patient takes the orally disintegrating tablet.

[0028] The disintegrant may be at least one of croscarmellose sodium, crospovidone, croscarmellose calcium, and sodium starch glycolate, and preferably includes both croscarmellose sodium and crospovidone.

[0029] The content of the disintegrant is characterized in that it is comprised in an amount of 3.5 to 12.5 wt%, more specifically 4 to 12 wt%, and even more specifically 5 to 11 wt%, based on the total weight of the orally disintegrating tablet. If the content of the disintegrant is less than 3.5 wt% based on the total weight of the orally disintegrating tablet, the disintegration time of the orally disintegrating tablet is reduced, and if it is more than 12.5 wt%, the tablet is broken even with a very small amount of moisture, which is not preferable because the stability is reduced.

[0030] In a specific embodiment of the present invention, the disintegration time of orally disintegrating tablets manufactured by mixing disintegrants according to content was compared, and when the content of the disintegrant was 3.5 wt% or more and less than 12.5 wt% of the total weight of the orally disintegrating tablet, the disintegration time was measured to be within 30 seconds, and was stable under accelerated conditions for one week, making it suitable for orally disintegrating tablets.

[0031] diluent

[0032] During the tableting process, pregabalin tends to undergo accelerated dehydration of the amino and carboxyl groups within the pregabalin molecule over time, forming a volatile compound that compromises stability. This intramolecular reaction will accelerate with increasing tableting pressure. Therefore, orally disintegrating tablets containing pregabalin must be easily compressed even under low tableting pressures.

[0033] In the present invention, the diluent serves to improve tableting properties by maintaining a fast disintegration time while providing the tablet with appropriate hardness and friability.

[0034] The above diluent is at least one of microcrystalline cellulose, low-substituted hydroxypropyl cellulose, D-mannitol, lactose monohydrate, sorbitol, corn starch, and pregelatinized starch.

[0035] Preferably, the diluent comprises a water-soluble diluent and a water-insoluble diluent.

[0036] Additionally, preferably, the diluent comprises D-mannitol and microcrystalline cellulose.

[0037] The content of the water-insoluble diluent may be included in an amount of 1 to 20 wt%, more specifically 3 to 15 wt%, and even more specifically 4 to 13 wt%, relative to the total weight of the orally disintegrating tablet. If the content of the water-insoluble diluent is less than 1 wt%, the hardness of the tablet is lowered, which may cause breakage during distribution, and if it exceeds 20 wt%, the hardness of the tablet is increased, which may shorten the disintegration time, which is not preferable.

[0038] In a specific embodiment of the present invention, tablets containing both D-mannitol and microcrystalline cellulose as diluents (Examples 8 to 10) had a hardness of 5 kP or more and a friability of 1.0% or less, making them suitable for manufacturing orally disintegrating tablets.

[0039] lubricant

[0040] In the present invention, the above-mentioned lubricant improves the flowability of particles or granules and prevents the capping phenomenon that may occur during tableting, thereby increasing the productivity of orally disintegrating tablets.

[0041] The above-mentioned lubricant is at least one of magnesium stearate, sodium stearyl fumarate, calcium stearate, talc, and hydrogenated castor oil, and preferably includes both magnesium stearate and sodium stearyl fumarate.

[0042] The content of the lubricant is characterized by being 1 to 6 wt%, more specifically 1.5 to 5.5 wt%, even more specifically 2 to 5 wt%, and even more specifically 2.5 to 5.0 wt%, based on the total weight of the orally disintegrating tablet. If the content of the lubricant is less than 1 wt% based on the total weight of the orally disintegrating tablet, the flowability of the particles is reduced, so that the discharge pressure of the tablet discharged from the die increases during tablet manufacturing, which may cause the punch and tableting machine to malfunction. If it exceeds 6 wt%, the binding force of the granules is greatly reduced, so that the problem of over-lubricating occurs in which the hardness is reduced even under the same tableting pressure, which is not preferable.

[0043]

[0044] In the present invention, the orally disintegrating tablet can be manufactured by any method known to those skilled in the art, and can be manufactured by, for example, a direct compression method or a wet granulation method.

[0045] The above wet granules can be manufactured by, but are not limited to, high-speed shear granulation or fluidized bed granulation.

[0046] The above wet granulation method can reduce the proportion of excipients included in the orally disintegrating tablet of the present invention and increase the proportion of the main ingredient, thereby reducing the mass of the entire tablet, and thus has the advantage of further improving the convenience of taking it compared to the direct compression method.

[0047]

[0048] The orally disintegrating tablet of the present invention disintegrates within 30 seconds and exhibits an excellent dissolution rate.

[0049] In a specific embodiment of the present invention, it was confirmed that the orally disintegrating tablet of the present invention exhibited a pregabalin dissolution rate superior to that of the control drug, the pregabalin capsule formulation (Control Example 1) and the tablet drug (Control Example 2) (Figure 2).

[0050]

[0051] It was confirmed that the orally disintegrating tablet of the present invention exhibits excellent sensory properties, with no bitter or gritty taste. Therefore, the orally disintegrating tablet of the present invention can be effectively used in the treatment of elderly patients with swallowing difficulties.

[0052] Figure 1 is a table showing the results of observing changes in the properties of tablets according to the content of sweetener.

[0053] Figure 2 is a graph showing the results of the dissolution test of Example 15, Control Example 1, and Control Example 2 of the present invention.

[0054] Figure 3 is a graph showing the results of the dissolution test according to the main component ratio.

[0055] Hereinafter, the present invention will be described in detail through examples and experimental examples. However, these examples and experimental examples are provided merely for the purpose of illustrative purposes to aid understanding of the present invention, and the scope of the present invention is not limited by the examples below.

[0056]

[0057] Manufacturing example: Manufacturing of orally disintegrating tablets containing pregabalin

[0058] Pregabalin was diluted with diluent, disintegrant, sweetener, flavoring agent, etc., sieved, and thoroughly mixed using a Bin Mixer at 25 RPM for 10 minutes. Afterwards, a lubricant was sieved and added, and thoroughly mixed using a Bin Mixer at 25 RPM for 4 minutes. The granules obtained above were compressed at a compression pressure of approximately 10 kN to obtain tablets.

[0059]

[0060] Experimental Example 1. Comparison of bitterness masking effects according to sweeteners.

[0061] Orally disintegrating tablets are characterized by rapid disintegration using a small amount of moisture in the mouth. Since patients perceive the taste of the medication when taking orally disintegrating tablets, the bitter or astringent taste of the raw materials can cause problems such as reduced medication compliance. Since the taste of sweeteners is not determined by type, but rather varies depending on the raw material and combination of sweeteners, sensory evaluation tests were conducted to compare the bitterness masking effects of different sweeteners.

[0062]

[0063] Experimental Example 1-1. Sensory Evaluation of Bitterness According to Type and Content of Sweetener

[0064] Comparative Examples 1 to 4 and Examples 1 to 5 were prepared in the form of a mixed powder by mixing pregabalin and a sweetener in the amounts shown in Table 1 below, and a taste sensory evaluation was performed on these, and the results are shown in Table 1 below.

[0065] [Table 1]

[0066]

[0067] (+++: Very bitter; +: Slightly bitter; -: Almost no bitterness, but slightly rough; ---: No bitterness or roughness at all)

[0068] As a result, as can be seen in Table 1, when no sweetener was included (Comparative Example 1) or aspartame (Comparative Example 2) and sucrose (Comparative Example 3) were used as sweeteners, the bitter taste of pregabalin was strongly felt and the bitterness masking effect was minimal, and when the same amount of sucralose (Example 2) was used, the bitterness of pregabalin was hardly felt. In the case of Examples 3 and 4 where the content of sucralose was increased, the bitterness was greatly improved, but the rough aftertaste of pregabalin remained. In the case of Example 5 which included both sucralose and thaumatin, no bitterness or rough taste was felt at all, showing the best bitterness masking effect.

[0069] Experimental Example 1-2. Evaluation of tablet stability according to sweetener content.

[0070] In the case of tablets containing sweeteners, browning may occur when stored at high temperatures, and when stored for a long period of time, the sugars in the sweetener may burn and black spots may appear. In order to confirm the stability of tablets when sucralose or sucralose and thaumatin were used as sweeteners, Comparative Example 4 and Examples 1 to 5 were compressed into tablets, and then stored under harsh conditions for two weeks to observe changes in appearance, and the results are shown in Figure 1.

[0071] As a result, as shown in Fig. 1, when the weight of the sweetener was 10% of the weight of pregabalin (Comparative Example 4 in Fig. 1), the surface of the tablet turned yellow and spots appeared, whereas in the cases of Examples 1 to 5, no special change in appearance was observed.

[0072]

[0073] As a result of the above experiments, it was confirmed that the use of sucralose as a sweetener alone (Examples 1 to 4) was effective in improving the bitter taste compared to other types of sweeteners, but a bitter aftertaste still remained. When sucralose and thaumatin were combined as sweeteners (Example 5), it was confirmed that both the bitter taste masking and the bitter aftertaste were sufficiently improved. In addition, it was confirmed that the sweetener was stable without discoloration when the weight of the sweetener was 2 wt% or more and less than 10 wt% based on the weight of the main ingredient pregabalin.

[0074]

[0075] Experimental Example 2. Evaluation of hardness and wear resistance according to diluent

[0076] Orally disintegrating tablets should have low friability and high hardness to prevent breakage during transportation and packaging. However, excessively high hardness can actually impair the tablet's disintegration ability. Furthermore, due to the nature of pregabalin raw materials, the dehydration reaction between the amino and carboxyl groups within the drug molecule accelerates over time during tableting, forming a volatile substance, which tends to reduce stability. This reaction is accelerated by increased external pressure, i.e., the tableting pressure applied during tablet manufacturing. Therefore, it is important for pregabalin tablets to be well compressed at relatively low tableting pressures.

[0077] According to the method described in the manufacturing examples above, tablets of Comparative Example 5 and Examples 6 to 10 were manufactured in the amounts shown in Table 2 below at the same pressing pressure (10 KN), and the hardness and friability of the tablets were measured. The measurement results are shown in Table 3.

[0078] [Table 2]

[0079]

[0080] LudiFlash in Table 2 above ®, BASF) is a mixture used in the manufacture of orally disintegrating tablets consisting of approximately 84% D-mannitol, approximately 6% crospovidone, approximately 6% polyvinyl alcohol, and approximately 2% povidone. The ratio of water-insoluble diluent to the total weight refers to the content ratio of water-insoluble diluent (low-substituted hydroxypropyl cellulose or microcrystalline cellulose) and not the diluent contained in LudiFlash.

[0081] [Table 3]

[0082]

[0083] As a result, as can be confirmed in Table 3, when only Rudi Flash was used as a diluent (Comparative Example 5), the hardness was very low and the friability was very high, whereas when Rudi Flash and a water-insoluble diluent of microcrystalline cellulose or low-substituted hydroxypropyl cellulose were used (Examples 6 to 10), high hardness and low friability were shown, confirming that the tableting property was improved. In addition, when microcrystalline cellulose was included (Examples 8 to 10), the effect of improving hardness and friability per content was superior to when low-substituted hydroxypropyl cellulose was included (Examples 6 and 7), so microcrystalline cellulose was selected for subsequent experiments. It was confirmed that as the content of microcrystalline cellulose increased, hardness and friability improved.

[0084]

[0085] Experimental Example 3. Evaluation of wetting speed, tablet thickness, and hardness according to disintegrant content.

[0086]

[0087] Experimental Example 3-1. Wetting Speed ​​Evaluation

[0088] In order for the drug contained in the orally disintegrating tablet to be absorbed quickly and effectively, it is advantageous for the disintegration time of the orally disintegrating tablet to be less than 30 seconds. In addition, since the amount of moisture in the oral cavity is limited, the tablet must disintegrate quickly even with a small amount of moisture. Therefore, in order to compare the effects according to the content of the disintegrant contained in the orally disintegrating tablet of the present invention through experiments, tablets of Comparative Examples 6 and 7 and Examples 11 to 14 were manufactured in the amounts shown in Table 4 below according to the manufacturing method of the examples, and the wetting speed was evaluated under moist conditions in the oral cavity.

[0089] [Table 4]

[0090]

[0091] The wetting speed evaluation was performed by dropping each tablet into a circular petri dish containing 30 mL of artificial saliva at 37°C and measuring the time required for the tablet to completely disintegrate. The results are shown in Table 5 below. The artificial saliva is manufactured to create an environment identical to the oral cavity conditions in which the orally disintegrating tablet works, and is a solution composed of a pH and composition (enzymes, etc.) similar to human saliva.

[0092] [Table 5]

[0093]

[0094] As a result, as can be seen in Table 5, when the amount of disintegrant was less than 3.5 wt% of the total weight (Comparative Example 6), it was confirmed that wetting took a long time, whereas when the amount of disintegrant was 3.5 wt% or more of the total weight (Comparative Example 7, Examples 11-14), a quick wetting time of less than 30 seconds was confirmed.

[0095]

[0096] Experimental Example 3-2. Tablet Stability Evaluation According to Disintegrant Content

[0097] Tablets containing excessive amounts of disintegrant, even when packaged, may be damaged by small amounts of moisture under accelerated conditions, or may absorb moisture and experience changes in their appearance, such as tablet swelling. To confirm this, the tablets of Comparative Examples 6 and 7 and Examples 11 to 14 were stored in open containers for one week under accelerated conditions of 40°C and 75% relative humidity, and changes in their appearance were observed. The results are shown in Table 6.

[0098] [Table 6]

[0099]

[0100] As shown in Table 6, when the content of disintegrant was excessive (Comparative Example 7), the thickness of the tablet increased and the hardness decreased. This confirmed that when an orally disintegrating tablet contains an excessive amount of disintegrant, the tablet is vulnerable to moisture stability.

[0101] Experimental Example 4. Comparison of tableting properties according to the content of the active agent.

[0102] In the case of microcrystalline cellulose, previously added to improve friability and disintegration, we confirmed that the particles existed in a thin, linear form, ensuring high hardness even at low tableting pressures. While this resulted in high tableting properties, it also significantly reduced flowability. Therefore, screening for lubricants was conducted to improve flowability.

[0103] Insufficient lubricant content impairs flowability and increases the discharge pressure from the die during the tableting process, potentially leading to failure of the punch and tableting machine. Furthermore, excessive lubricant significantly reduces the cohesiveness of the granules, resulting in a decrease in hardness at the same tableting pressure, a problem known as overlubricant. Therefore, to determine the optimal range of lubricant content, the following comparative tableting experiment was conducted.

[0104] Specifically, tablets of Comparative Examples 8 to 11 and Examples 14 to 17 were manufactured in the amounts shown in Table 7 according to the manufacturing method, and the occurrence of capping during rotary tableting was confirmed, and the initial tableting hardness and the tableting hardness after stirring were measured, and the results are shown in Table 8. In addition to the mixing time used in the manufacturing example, stirring was additionally performed at 25 RPM for 1 hour to evaluate the possibility of problems that may arise when the lubricant is excessively mixed, and the results are shown in Table 8.

[0105] [Table 7]

[0106]

[0107] [Table 8]

[0108]

[0109] As shown in Table 8, when a small amount of lubricant was added (Comparative Example 8), the tableting hardness decreased, and a capping phenomenon occurred during tableting, which lowered productivity. In addition, when an excessive amount of lubricant was added (Comparative Example 9), the tableting property decreased due to over-lubricating, and the hardness decreased rapidly after tableting. On the other hand, when magnesium stearate was used as a lubricant (Comparative Example 9), it was confirmed that the capping improvement effect was superior to that when sodium stearyl fumarate was used (Comparative Example 10). When magnesium stearate or sodium stearyl fumarate was used alone, problems of capping or over-lubricating occurred, respectively. However, when magnesium stearate and sodium stearyl fumarate were combined and used as a mixture (Examples 14 to 17), the capping prevention effect was superior, and it was confirmed that excellent hardness was achieved without over-lubricating.

[0110]

[0111] Experimental Example 5. Dissolution Test

[0112] The tablets of Example 15 in Table 9 were subjected to dissolution tests along with control examples. Control Example 1 is a capsule formulation containing pregabalin (Lyrica Capsules, Viatris Korea), and Control Example 2 is a pregabalin tablet (Hyundai Pregabalin Tablets, Hyundai Pharmaceutical). The conditions for the dissolution test are as follows.

[0113] - Dissolution test solution: 0.06M hydrochloric acid, 900mL

[0114] - Dissolution device: Dissolution test method 2 (paddle method) of the General Test Methods of the Korean Pharmacopoeia, using a sinker (for capsules)

[0115] - Rotation speed: 50 ± 2 rpm

[0116] - Temperature: 37 ± 0.5 ℃

[0117] <Analysis Conditions - HPLC>

[0118] - Column: Inertsil CN-3, (4.6 x 150 mm, 5 μm) or equivalent column

[0119] - Detector: UV 210nm

[0120] - Flow rate: 1.0ml / min

[0121] - Column temperature: 40℃

[0122] - Analysis time: 10 minutes

[0123] - Injection volume: 50 μL

[0124] - Mobile phase: Buffer*: ACN = 880:130

[0125] (* Buffer: Dissolve 9.41 g of sodium hexanesulfonate and 2 mL of triethylamine in 880 mL of purified water and adjust the pH to 3.1 with phosphoric acid.)

[0126] [Table 9]

[0127]

[0128] [Table 10]

[0129]

[0130] As a result, as shown in Table 10 and FIG. 2, it was confirmed that the pregabalin orally disintegrating tablet of Example 15 of the present invention had a very fast dissolution rate compared to the general capsules and tablets of Control Examples 1 and 2. At 3 minutes after the start of dissolution, the dissolution rate was measured to be 53.7% for Control Example 1 and 27.6% for Control Example 2, while Example 15 had a dissolution rate of 85.4%, confirming that the dissolution rate was significantly faster. This indicates that the orally disintegrating tablet formulation of the present invention dissolves at a much faster rate than general formulations, so that the efficacy of pregabalin can appear more quickly.

[0131]

[0132] Experimental Example 6. Process Study

[0133] In the manufacture of the orally disintegrating tablet of the present invention, in order to confirm whether a rapid absorption rate is maintained according to the manufacturing process, the manufacturing process was changed from the simple mixing direct pressing method of Manufacturing Example 1 to wet granulation to manufacture tablets.

[0134] Specifically, pregabalin, microcrystalline cellulose, and a portion of croscarmellose sodium were mixed well, and a wet granule portion was prepared using a binding solution (purified water). The wet granule portion was mixed with the post-mix portion, and then mixed with the final mixed portion to perform tableting, thereby obtaining tablets of Comparative Example 12 and Examples 18 to 21. The contents of each raw material used in tablet preparation are as shown in Table 11 below, and the results of the dissolution test are shown in Table 12 and Fig. 3.

[0135] [Table 11]

[0136]

[0137] [Table 12]

[0138]

[0139] As a result, as shown in Table 12, when the weight ratio of the main ingredient exceeded 70 wt% of the total weight (Comparative Example 12), the dissolution rate decreased. On the other hand, it was confirmed that an excellent dissolution rate was exhibited when the weight ratio of the main ingredient was within an appropriate range of 5 to 70 wt% of the total weight (Examples 18 to 21). Therefore, it was confirmed that the ratio of the main ingredient could be increased through wet granulation, and that the weight of the entire tablet could be reduced to obtain convenience of taking.

Claims

1. Orally disintegrating tablet containing pregabalin or a pharmaceutically acceptable salt thereof, sucralose and thaumatin as sweeteners.

2. An orally disintegrating tablet according to claim 1, wherein the pregabalin is contained in an amount of 5 to 70 wt% relative to the total weight of the orally disintegrating tablet.

3. An orally disintegrating tablet according to claim 1, wherein the sweetener is contained in an amount of 2% by weight or more and less than 10% by weight relative to the weight of pregabalin or a pharmaceutically acceptable salt thereof.

4. An orally disintegrating tablet according to claim 1, wherein the weight ratio of sucralose and thaumatin is 10:1 to 1:

10.

5. In the first paragraph, the orally disintegrating tablet comprises a disintegrating agent, a diluent, and a lubricant.

6. An orally disintegrating tablet in paragraph 5, wherein the disintegrant is at least one of croscarmellose sodium, crospovidone, croscarmellose calcium, and sodium starch glycolate.

7. An orally disintegrating tablet in paragraph 5, wherein the disintegrant is croscarmellose sodium and crospovidone.

8. An orally disintegrating tablet according to claim 5, wherein the disintegrant is contained in an amount of 3.5 to 12.5 wt% relative to the total weight of the orally disintegrating tablet.

9. In paragraph 5, the diluent is an orally disintegrating tablet comprising at least one of microcrystalline cellulose, low-substituted hydroxypropyl cellulose, D-mannitol, lactose monohydrate, sorbitol, corn starch, and pregelatinized starch.

10. In paragraph 5, the orally disintegrating tablet is a water-soluble diluent and a water-insoluble diluent.

11. An orally disintegrating tablet in paragraph 5, wherein the diluent is D-mannitol and microcrystalline cellulose.

12. An orally disintegrating tablet according to claim 10, wherein the water-insoluble diluent is contained in an amount of 1 to 20 wt% relative to the total weight of the orally disintegrating tablet.

13. An orally disintegrating tablet in paragraph 5, wherein the lubricant is at least one of magnesium stearate, sodium stearyl fumarate, calcium stearate, talc, and hydrogenated castor oil.

14. An orally disintegrating tablet in paragraph 5, wherein the lubricant is magnesium stearate and sodium stearyl fumarate.

15. In the fifth paragraph, the orally disintegrating tablet comprises 1 to 6 wt% of the lubricant relative to the total weight of the orally disintegrating tablet.

16. In the first paragraph, the orally disintegrating tablet is manufactured by a direct compression method or a wet granulation method.

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