KR100509886B1 - Formulation of quick-dissolved tablet containing ondansetron HCl and it's manufacturing process - Google Patents

Abstract

The present invention relates to fast disintegrating tablets containing ondansetron dihydrate hydrochloride, and according to the production method of the present invention, various disintegration accelerators can be effectively used in appropriate appropriate uses and concentrations without the need for additional treatment of crystalline ondansetron dihydrate. It may include a method of significantly improving, when manufacturing the onset of hydrochloric acid and dansetron in the manufacturing method of the present invention can be produced easily and easily mass production method without the complicated raw material pretreatment process of the existing formulation, the content of the composition This uniformly prepared, of course, relates to an ondansetron fast disintegrating tablet which can be expected to be very fast dissolution upon oral administration.

Description

Formulation of quick-dissolved tablet containing ondansetron HCl and it's manufacturing process

The present invention provides ondansetron (1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) -methyl] -4H-carbazole-4 as active ingredient Pharmaceutical composition, in particular a fast dissolving composition for oral administration.

Structure of ondansetron

Ondansetron is a 5-hydroxy-tryptamine 3 (5-Hydroxytriptamine, 5- HT3) at 5-HT3 receptors by drugs having antagonistic activity on the serotonin receptor is a compound having a molecular formula of C ₁₈ H ₁₉ N _3O a molecular weight of 293.37 It is highly selective and strongly antagonizes the inhibition of the action of 5-HT3 on the receptor, and is widely used for the prevention and treatment of nausea and vomiting caused by anticancer agents and radiation treatments used in the treatment of cancer patients. Chemotherapy and radiation therapy release 5-hydroxytryptane (5HT or serotonin) in the gastrointestinal tract, and 5HT binds to the 5-HT3 receptor present in the intestinal wall to activate the afferent vagus nerve to induce vomiting reflexes. Blocks this reflection. In addition, activation of the afferent vagus nerve releases 5-HT from the area postrema in the fourth ventricle and promotes vomiting due to central nervous system. Ondansetron antagonizes 5-HT3 receptors present in peripheral and central nerve cells. By suppressing vomiting. Therefore, it is widely used for the prevention and treatment of nausea and vomiting, postoperative nausea and vomiting by chemotherapy or radiation therapy that causes cytotoxicity. Preferred forms of ondansetron for administration to a patient have a molecular formula of C ₁₈ H ₁₉ N 3 _{O.HCl.2H 2} O in the form of hydrochloride dihydrate. Ondansetron dihydrate can be administered by injection, transdermal or oral, which is the most convenient and oral dosage form for patients. Ondansetron is known to have about 60% bioavailability when administered orally and is metabolized very widely and excreted in feces or urine. When ondansetron is orally administered, the time to reach the highest blood concentration is about 1-1.75 hours, and the half-life is reported to be about 3.1-3.2.

When ondansetron hydrochloride is used for the prevention and treatment of nausea and vomiting, the unit dosage of a drug suitable for oral administration is known to be 4-5 mg and 8-10 mg, and is prepared in the form of tablets using various excipients. At this time, the purpose of using ondansetron, that is, the nausea, vomiting, and other side effects that may be caused by the administration of anticancer drugs should be disintegrated and eluted in the shortest time in order to meet the treatment. Therefore, in the case of preparations containing ondansetron, a method of reducing the particle size of the drug is used to improve the solubility of the active substance, ondansetron. As a method of reducing the particle size of a drug, a method of using a grinder, a method of reducing particle size using a lyophilization method, and a method of reducing particle size by dissolving a drug in a co-solvent and removing a solvent under high temperature vacuum have been reported. have. In addition, there have been various attempts to reduce the particle size of ondansetron, but it has not yet produced a sufficiently small particle size of ondansetron dihydrate. For example, a method of milling crystals to obtain onset hydrochloride and dihydrate having a small particle size has been attempted, but it is not preferable because fine sieves and coarse particles of coarse particle size of onset hydrochloride are blocked when passing through the sieve. Can not do it. In addition, a method of obtaining hydrochloric acid onsetseton dihydrate powder having a particle size of less than 250 µm by passing the ondansetron dihydrate through a 60 mesh sieve (UK Patent No. 2153821B) has a problem of no commercial value.

On the other hand, ondansetron and dihydrate crystals obtained by simple crystallization of ondansetron hydrochloride and dried at room temperature and pressure using an aqueous solution of ondansetron hydrochloride have a large particle size of 250 μm or more, resulting in uniform homohydrogen ondansetron and dihydrate when preparing tablet compounds. It is difficult to be distributed easily. In other words, if tablets are made by using ondansetron hydrochloride crystals produced in this way, it is difficult to produce tablets containing uniform drugs, and the tablets are broken during molding, resulting in poor capping or laminating. Since this may be manufactured, it cannot be said to be a preferable method. In addition, a method of obtaining hydrophobic ondansetron dihydrate by reducing the particle size by attempting to rehydrate the ondansetron hydrochloride formed by drying the onset hydrochloride monohydrate at high temperature and reduced pressure or under atmospheric pressure (Korean Patent No. 90-9540) has been attempted. The particle size distribution of the crystals of ondansetron dihydrate obtained through the above has been reported to be less than 250 µm in total and 80% (weight fraction) of less than 63 µm. However, this method is a method of inducing crystallization by drying at least about 50 hours at a temperature of about 50 ° C. under a pressure of about 200 Torr or by removing the solvent by heating to a temperature of about 100 ° C. under atmospheric pressure. It is not easy to manufacture under the condition that this is also not a preferred method. In addition, Korean Patent Registration No.0262377 discloses a formulation that rapidly disintegrates in the oral cavity by inducing porosity by lyophilizing hydrochloric acid ondansetron. This is because the process is very complicated and the choice of packaging material has to be very carefully, and thus cannot be called an easy manufacturing method. In Korean Patent Publication No. 2001-0107754, in preparing a formulation containing ondansetron, a porous pore is formed by mixing the active ingredient and a sublimable material together, and then drying at a temperature of about 40-50 ° C. to remove the sublimed material. However, some sublimable substances may remain during the process, which requires special attention. Patients with dissatisfaction with their characteristic orientation may be used even if relatively harmless sublimable substances such as menthol are used. It is not a preferable formulation. In addition, Korean Patent Publication No. 99-000993 discloses a method for reducing the particle size of ondansetron hydrochloride by spray drying, which is generally used in the case of improving solubility by reducing the particle size of very poorly soluble drugs. Ondansetron hydrochloride, which is not a very poorly soluble drug, is not a suitable method. Moreover, when the ondansetron hydrochloride is prepared by the spray drying method, the particles are manufactured very finely, and thus, molding may be more inconvenient into tablets.

Therefore, the present inventors have studied existing methods of preparing fast disintegrating tablets without using ondansetron, which is an active substance with reduced porosity or freeze-drying, that is, crystalline ondansetron dihydrate. It has been found that the effective disintegration of various disintegrants or the preparation of tablets containing effervescent substances can dramatically reduce the disintegration time when taken orally, thus maximizing the therapeutic effect of nausea and vomiting. The invention has been completed.

Disclosure of Invention It is an object of the present invention to provide a fast disintegrating tablet capable of rapidly disintegrating nausea and vomiting due to its ease of workability and rapid disintegration upon oral administration, and a method for preparing the same.

In order to achieve the above object, the present inventors prepared an amorphous solid dispersion using a hydrophilic polymer and compared the solubility with crystalline ondansetron dihydrate, but the solubility did not increase significantly. In addition, the coprecipitate was prepared by dissolving a solvent using a co-solvent of a hydrophilic polymer and ondansetron, and then volatilizing only a solvent. It was found that the hydrophilic polymer was prepared in a state in which the drug was enclosed, which resulted in delaying the release of the drug. If the formulation was not disintegrated and eluted within a few seconds or minutes, and the drug was eluted for 10 minutes or more, the role of the hydrophilic polymer could be expected. Therefore, in the present invention, the disintegrating agent that best matches ondansetron was investigated by avoiding the method of reducing the particle size of the ondansetron hydrochloride to increase the dissolution rate. Disintegrants that can be used in the manufacture of current pharmaceuticals are starch, starch starch, sodium starch glycolate and other starches, starch derivatives, cellulose and derivatives thereof such as croscarmellose sodium, microcrystalline cellulose calcium salt, and crospovidone Crosslinked vinyl acetate copolymers, such as alginic acid may be used, and excipients may include mannitol, sorbitol, lactose, sugar, fructose, erythritol, glucose, xylitol, dextrin, and the like. In addition, effervescent tablets may be prepared using sodium bicarbonate having effervescent properties.

Hereinafter, the present invention will be described in detail.

The present invention, unlike conventional formulations to reduce the size of ondansetron to improve the disintegration and solubility, while using crystalline ondansetron hydrochloride as it is effectively formulated in combination with the disintegrating agent to facilitate mass production and good workability Provide a method. According to such an invention, in the present invention, a quick-drying tablet can be easily produced without using a special technique.

Stearic acid, magnesium stearate, talc and silicon dioxide may be used as lubricants for the smooth manufacture of tablets. Since the components having these lubricants have very hydrophobic properties, a minimum amount may be used to prepare fast disintegrating tablets as in the present invention. Should be used. The amount of lubricant added is very important. If it is added less than 0.5% of the total weight, it hardly affects the lubrication. If it is added more than 2%, the disintegration of the tablet is very delayed, which is incompatible with the object of the present invention. It may not result. In addition, since the tablet prepared by the method as in the present invention is very good disintegration in the oral cavity, it can be prepared as a chewable tablet by mixing sweeteners and flavoring agents.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are only intended to illustrate the present invention more easily to understand the scope of the present invention is not limited to this embodiment.

Example 1-3, Comparative Example 1-3

In Example 1 and Example 2, all components except magnesium stearate were sufficiently mixed, mixed with magnesium stearate, mixed well, and then compressed into tablets. Example 3 is an effervescent tablet, except for sodium bicarbonate and citric acid, wet granulated, dried and stipulated as in Comparative Example 1, followed by mixing and tableting sodium bicarbonate and citric acid to prepare a tablet.

Comparative Examples 1-3 were wet granulated with povidone solution prepared by dissolving only magnesium stearate in water beforehand, dried, and then mixed with magnesium stearate, mixed, and then compressed into tablets. The disintegration was slightly delayed when the wet method was prepared, whereas the moldability and hardness were slightly superior, and the disintegration rate was very fast when the direct method was used.

Table 1.

Ingredient name (mg) Example 1 Comparative Example 1 Example 2 Comparative Example 2 Example 3 Comparative Example 3 Hydrochloric acid ondansetron dihydrate 10 10 10 10 10 10 Disintegrant Microcrystalline cellulose 82 72 72 72 82 72 Povidone - 4 - 4 4 4 Crospovidone - - 30 50 - 30 Croscarmellose Sodium - 20 10 - - - Microcrystalline cellulose calcium salt 40 10 - - 15 20 Starch - 10 - - - 20 Pregelatinized starch - - - 10 - - Excipient Mannitol - 50 - 10 - 10 Sorbitol - - 40 - - - Lactose 114 70 84 90 70 80 Sodium bicarbonate (foaming agent) - - - - 55 - Citric acid (foaming agent) - - - - 10 - Magnesium Stearate (Lubricant) 2 2 2 2 2 - Tablet gross weight (mg) 248 248 248 248 248 248

[Test Example]

The dissolution test was performed using the tablets prepared in Examples and Comparative Examples of the present invention, and then the results were compared. For the dissolution test, paddle method, which was the second method of the Korean Pharmacopoeia, was used, and 500 milliliters of distilled water was used as the eluent. The temperature of the eluate was maintained at 37 ° C., and 5 ml of each sample was taken at 30 seconds, 1 minute, 1 minute 30 seconds, 2 minutes, 3 minutes, 5 minutes, 10 minutes, 15 minutes, and 20 minutes, and the filtrate was filtered. Was analyzed by high-performance liquid chromatography to obtain the amount of drug eluted.

Table 2.

Example Dissolution rate according to dissolution time (%) 30 seconds 1 minute 1 minute 30 seconds 2 minutes 3 minutes 5 minutes 10 minutes 15 minutes 20 minutes Example 1 22 37 41 54 63 85 95 100 100 Comparative Example 1 5 8 11 23 35 40 77 85 96 Example 2 10 22 31 43 50 71 83 94 100 Comparative Example 2 7 8 13 27 36 44 75 88 97 Example 3 23 35 39 50 61 86 96 100 100 Comparative Example 3 8 11 15 22 37 43 78 86 95

As can be seen in Table 2, the disintegration and dissolution of the ondansetron fast disintegrating tablets prepared in Examples 1 and 3 of the present invention was about 85% or more of drug dissolution at 5 minutes after the start of dissolution, and thus the whole drug was released within about 10 to 15 minutes. Is eluted. In addition, in Comparative Example 1-3, regardless of the added disintegrant, elution was delayed as a whole, and at least 15 minutes passed, more than 85% of the content was eluted. In the case of Example 1, in the case of the prescription completed in the present invention, the elution rate exceeds 85% of the content from 5 minutes after the start of the dissolution, and the effect is sufficiently exhibited.

Especially in the case of Example 1, the amount of disintegrant added is very important, but when added below 39% of the total weight has little effect on elution, and when added above 58%, the dissolution rate no longer increases. .

In the case of Example 1-3, the microcrystalline cellulose added in addition to the action of disintegrating agent to improve the fluidity for smoothing the binder and the binder to bind each component when the tableting, 27 to 38 compared to the total weight Using% gives sufficient effect. If it is used less than 27% of the total weight, sticking and capping phenomenon may occur when tableting and fluidity decreases, and dissolution rate is decreased due to disintegration delayed when using more than 38%.

     Crospovidone used as a disintegrant in Example 2 uses 10 to 16% of the total weight, the disintegration power is significantly reduced at 10% or less, and the tablet is gelled due to the hygroscopicity of crospovidone when used at 16% or less. It may lower the stability of the formulation in circulation. Croscarmellose sodium used in Example 2 is also used as a disintegration accelerator, using 2 to 6% of the total weight, but less than 2% does not affect the disintegration of the tablet, the disintegration power is used more than 6% It does not increase over.

     Crospovidone and croscarmellose sodium have poor disintegration when used, respectively, so that the dissolution rate of tablets is not significantly improved (Comparative Examples 1 and 2), and when used in combination, the disintegration ability is good. The action of crospovidone that absorbs and disintegrates by absorbing moisture, which is a characteristic of the cellulose disintegrating agent, is enhanced by disintegrating. It is also undesirable because an increase in the amount of disintegrant may increase the size of the formulation, which may be inconvenient to take. Most importantly, the interaction between the disintegrant used and the drug needs to be carefully examined and selected.

In the case of ondansetron, when the crospovidone or pregelatinized starch was used as a disintegrant, the disintegration ability was reduced more than celluloses. The reason is that the hygroscopicity of crospovidone and pregelatinized starch is the main cause. Since these two substances have a very strong hygroscopicity at room temperature, there is a tendency to form gel by increasing the amount of moisture in the formulation at the time of formulation. It becomes stronger and results in a delay of the disintegration time.

However, the microcrystalline cellulose calcium salt used as a disintegrant in the present invention is resistant to moisture in the air, but in the presence of excess water, it has a function of disintegrating the preparation and dissolving the drug by swelling by absorbing moisture very quickly. have. This may be very important information for the formulation design of fast disintegrating drugs, and especially for ondansetron, it can be said that the disintegrant used in the present invention may be the most suitable additive.

As in the case of conventional formulations, the ondansetron-containing fast disintegrating tablet composition can be relieved to reduce discomfort by increasing the dissolution rate by decreasing the particle size of ondansetron and to ensure reproducibility even in mass production. Therefore, it can be said that this result indicates that the patient has completed the formulation that can see the calming effect of nausea and vomiting within the shortest time after taking the drug.

An example showing similar dissolution results is Example 3, which is an example of using instantaneous effervescent properties to increase disintegration and dissolution of the drug. Formulations that give foaming properties in medicine are mainly applied to the preparation of oral and vaginal intercalating tablets. The disadvantage of these is that the burning of tissues may be caused by carbon dioxide generated during foaming. However, since the foaming time and disintegration can be controlled by controlling the amount of the foaming agent and the amount of the foaming agent, it can be used as a disintegrant for promoting disintegration of general medicines.

As a typical blowing agent, for example, sodium hydrogen carbonate used in the present invention is a very alkaline substance which is very useful for the human body, and has a characteristic of generating carbon dioxide by reacting with a foam inducing agent such as citric acid, succinic acid and tartaric acid. It is widely applied to oral disintegrating tablets and vitamin-containing preparations which are foamed into water for drinking. However, as mentioned above, the burning sensation is severely caused by the carbon dioxide generated during the foaming, so it is somewhat difficult to use in a therapeutic pharmaceutical formulation. In the present invention, however, foaming sodium hydrogen carbonate is used at about 22% of the total weight of the preparation, and even when a small amount or no organic or inorganic acid, which is a foaming induction agent, is used, it is 85% or more within 5 minutes or more within 10 minutes. More than 95% of the drug is eluted, so a very fast effect is expected.

The disintegration effect of these preparations was designed to disintegrate quickly in the stomach when taking the preparations by inducing non-irritating disintegration, not foaming, due to the inherent properties of the drug and the water added upon disintegration, thereby completing one aspect of the present invention. In particular, when added in excess, that is, more than 25% of the total weight to induce disintegration more quickly, the formulation has already swelled in the process of tableting and loses its value as a product. Due to its weak disintegration, rapid dissolution was expected. Therefore, the present inventors formulated the ondansetron-containing formulation by adding sodium bicarbonate at various concentrations. This is a very useful composition as an example of effectively using the general properties of the existing material in the formulation.

In addition, in the present invention, mannitol or sorbitol, which is known to be very hygroscopic, was used as a material for promoting disintegration, which shows that the disintegration power is remarkably inferior to that in the case of using microcrystalline cellulose calcium salt or sodium bicarbonate. This is thought to be because the moisture that penetrates into the tablet during the disintegration has reduced the effect on the disintegration because the moisture already contained in the atmosphere during the tabletting process. This may be a result showing that the production can be made only with a separate equipment for mass production of the formulation. Therefore, the preparation method of the ondansetron-containing tablet completed in the present invention can see the dissolution effect of the same drug even if the raw material is not treated as in the case of the conventional formulation, thereby greatly expanding the scope of application.

As described above, the composition used in the present invention has the advantage that no special apparatus or equipment for mass production is required, and the method or time required for preparing the tablet is complicated when compared with the method or time for preparing a general tablet. It is a method suitable for the preparation of ondansetron-containing fast dissolving tablets because it is not long or long.

Claims (6)

delete In the method for producing a fast disintegrating tablet containing hydrochloric acid onsetsetron containing 39 to 58% of a pharmaceutically acceptable disintegrant and 0.5 to 1.5% of a lubricant, the disintegrant may include microcrystalline cellulose, povidone, crospovidone, Fast disintegrating for oral administration including ondansetron hydrochloride comprising at least one material selected from croscarmellose sodium and microcrystalline cellulose calcium, and the lubricant is any one selected from stearic acid, magnesium stearate, talc and silicon dioxide. Method of Making Tablets. The fast disintegrating tablet for oral administration according to claim 2, wherein 32 to 38% by weight of microcrystalline cellulose and 14 to 20% by weight of microcrystalline cellulose calcium salt are used as the disintegrant. Manufacturing method. According to claim 2, oral containing ondansetron hydrochloride, characterized in that 27 to 33% by weight of microcrystalline cellulose, 10 to 16% by weight of crospovidone, 2 to 6% by weight of croscarmellose sodium are used as the disintegrant. Method for preparing fast disintegrating tablet for administration. The method for preparing orally disintegrating tablets for oral administration according to claim 2, further comprising a blowing agent and a foam inducing agent. The fast disintegrating agent for oral administration according to claim 5, wherein sodium bicarbonate is 20 to 24% by weight as the blowing agent and citric acid is used as the foaming agent as 2 to 6% by weight of the tablet. Method of Making Tablets.