KR100457458B1 - Rapidly dissolving tablet and process for preparing same - Google Patents

Abstract

The present invention relates to a method for preparing fast dissolving tablets which disintegrate or dissolve in the oral cavity and tablets produced by the present invention, the method of the present invention comprises the steps of (a) preparing granules with water-soluble sugars, (b) prepared granules Preparing a tablet by mixing a drug, an effervescent ingredient, and a suitable excipient, (c) contacting the prepared tablet with moisture to have a porosity, and (d) drying the prepared tablet. Tablets are characterized by a porous structure and can easily disintegrate or dissolve in the oral cavity, thereby increasing patient compliance.

Description

Sokyongjeong and its manufacturing method {RAPIDLY DISSOLVING TABLET AND PROCESS FOR PREPARING SAME}

The present invention relates to a fast dissolving tablet and a method for preparing the same, which dissolves or dissolves easily in the oral cavity. And mixing a suitable excipient to prepare the tablet, (c) contacting the prepared tablet with moisture to have a porosity, and (d) drying the prepared tablet.

In recent years, the social composition ratio of the elderly population is increasing due to the extension of life expectancy. These elderly people are deteriorated in vision, hearing, memory, and physical ability as well as pharmacokinetic changes. In particular, there is a difficulty in taking general tablets or capsules, and in view of this, there is a need for an alternative preparation for oral administration for the elderly.

Fast dissolving tablets that disintegrate or dissolve easily in the oral cavity can be taken without water, making it very useful for children, people with disabilities, patients lying in bed, and busy modern people, as well as elderly people who have difficulty taking tablets or capsules. It is possible to prescribe the solution in place of tablets or capsules for the elderly and children, but liquid formulations have the disadvantage that the stability is less than tablets. In particular, because the drug can be absorbed into the oral mucosa can also bypass the hepatic bypass effect, the fast dissolving tablets can be applied to drugs that receive a lot of hepatic metabolism among drugs absorbed from the digestive tract.

Easily soluble formulations in the oral cavity are marketed under the trade name Zydis ^R by R. P Sherer, but these formulations are made by lyophilization technology, which results in high manufacturing costs and very slow work processes. . In addition, lyophilized formulations may be broken during distribution because of their low hardness.

In order to solve the above disadvantages, many studies have been attempted. In US Pat. No. 5,576,014, sugars having low compressive properties such as lactose and mannitol are generally coated with sugars having high compressive properties such as maltose and maltitol to make granules. The tablet was compressed into a manufacturing method of a tablet to prepare a tablet having a sufficient hardness not to be broken during distribution. However, it is difficult to produce porous tablets that can easily penetrate saliva and disintegrate or dissolve when placed in the mouth.

US Pat. No. 5,635,210 uses a spray dryer to make porous particles so as to disintegrate or dissolve easily in the mouth, and then mixed with a drug and appropriate excipients to prepare fast dissolving tablets. However, this method has a problem in that the porosity is reduced by tableting pressure in the manufacture of tablets.

On the other hand, US Patent No. 5,837,285 in a small amount of water, such as xylitol, mannitol, put a small amount of water and coalesce and then compressed to prepare a fast tablet. However, this method makes it difficult to form porous structures in tablets.

On the other hand, foamed tablets containing foaming components are generally used in dental denture cleaners, laundry detergents, bathroom tablets and pharmaceuticals, and these formulations react with water when acid and base in the foaming components react to form carbon dioxide gas. By using it is to disintegrate quickly.

In US Pat. No. 6,066,335, active substances (drugs) and carriers (sweeteners, flavorings, colorants, etc.) are mixed with propylene glycol or glycerin as binders at a relative humidity of 25% or higher, and sherbet is added to the mixture at a relative humidity of 25% or lower. ) Was added and the resulting mixture was compressed into tablets. However, this is a general method for producing effervescent tablets, and the tablets prepared by this method must be dissolved in large amounts (150 ml) of water and have a problem of severe irritation due to the generation of carbon dioxide gas in the mouth.

The present inventors have made efforts to solve the above disadvantages, as a result of preparing a tablet containing a foaming component as a general method for producing a tablet, and then exposed to water to produce a carbon dioxide gas is a porous tablet produced quickly without irritation in the mouth Appropriate prescription, relative humidity, and drying temperature conditions to ensure disintegration or dissolution, and to prevent the surface of the tablet from becoming rough or collapsing during the generation of carbon dioxide gas during exposure to moisture and drying. Confirmed through numerous experiments to complete the present invention.

An object of the present invention is to provide a fast dissolving tablet which is easily disintegrated or dissolved in the oral cavity and is easy to take without water.

Another object of the present invention is to provide a method for producing the fast dissolving tablet.

1 and 2 show the results of measuring the nitrogen adsorption amount under the equilibrium pressure by the BET nitrogen adsorption method for the fast dissolving tablets of Example 5 and Comparative Example 1, respectively.

The fast dissolving tablet of the present invention includes water-soluble sugars, foaming ingredients composed of suitable acids and bases, and drugs as essential ingredients, and may further include suitable excipients such as disintegrants, binders, sweeteners, fragrances, lubricants.

Specifically, the fast dissolving tablet of the present invention is based on the total weight of the tablet 40 to 90% by weight, preferably 55 to 85% by weight of water-soluble sugars; 0.1 to 10% by weight, preferably 0.3 to 5% by weight, of foam components consisting of stoichiometric amounts of suitable acids and bases; And 0.1 to 50% by weight of the drug, preferably 1 to 30% by weight, to which suitable excipients such as disintegrants, sweeteners, fragrances, glidants and the like can be mixed.

In the present invention, as the water-soluble sugars, mannitol, sorbitol, maltitol, xylitol, erythritol, or lactose having high solubility in water may be used alone or in combination with each other.

The acid constituting the foaming component may be selected from citric acid, tartaric acid, alginic acid and malic acid, and the base may be selected from sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate. As the foaming component, the selected acid and base may be appropriately mixed in an approximate stoichiometric amount, and the following components and weight ratios are particularly preferable:

Citric acid: sodium bicarbonate, 1: 1.3

Tartaric Acid: Sodium Hydrogen Carbonate, 1: 1.12

Citric acid: Tartaric acid: Sodium bicarbonate, 1: 2: 3.5

The drug can be administered orally, and can be administered orally, including anti-allergic agents (e.g. loratadine, cetirizine hydrochloride, mequitazine, evastin, asestizol), antibiotics (e.g. ampicillin, amoxicillin, cephalexin , Erythromycin ethyl succinate, bacampicillin hydrochloride, minocycline hydrochloride, erythromycin), peptic ulcer drugs (e.g. cimetidine, ranitidine, pamotidine, omeprazole), antidiabetics (e.g., glybenclamide, tolbutamide) , Glipizide), antihyperlipidemic agents (e.g. cholestipol hydrochloride, lovastatin, provastatin, simvastatin), antiemetic agents (e.g. meclizin hydrochloride, domperidone, chlorpromazine hydrochloride), anti-inflammatory agents (e.g. , Mephenamic acid, indomethacin, sullindac, ibuprofen, phenopropene, naproxen, ketoprofen, diclofenac), analgesics (e.g. mefenamic acid, ibuprofen, naproxen, phenopropene, pyroxicam, diclofenac, codeine Drugs such as diltiazem, nifedipine, propranolol, nadolol, captopril), and vitamins (e.g. vitamin B ₁ , vitamin B ₂ , vitamin B ₆ , vitamin B ₁₂ , vitamin C, folic acid) Can be illustrated.

Examples of disintegrants that can be used in the present invention include crospovidone, starch, cellulose derivatives, and the like, and examples of the binder include povidone, starch, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose. A wide variety of artificial and natural sweeteners can be exemplified, and the lubricants include magnesium stearate, stearic acid, talc, waxes, polyethylene glycols and the like.

The fast dissolving tablet of this invention can be manufactured by the following method.

First, granules are prepared using a fluidized bed granulator capable of producing porous granules by selecting at least one component from sugars that are well soluble in water such as mannitol, sorbitol, maltitol, xylitol, erythritol, and lactose. At this time, the sugar is used in an amount of 40 to 90% by weight, preferably 55 to 85% by weight of the total weight of the tablet.

Next, to the granules obtained above, a tablet is prepared by mixing the stoichiometric amount of the foaming ingredient, the drug and the appropriate excipient composed of the appropriate acid and base. At this time, the foaming component is used in an amount of 0.1 to 10% by weight, preferably 0.3 to 5% by weight based on the total weight of the tablet, and the drug is 0.1 to 50% by weight, preferably based on the total weight of the tablet. It is used in the amount of 1-30 weight%. Excipients include, but are not limited to, disintegrants, sweeteners, fragrances, lubricants, and the like, and any excipients used in the art may be used.

Next, the tablets are exposed to moisture to impart porosity to the tablets prepared above. For example, porosity can be imparted by exposing the tablet to humidified air, wherein the tablet is treated with humidified air at a relative humidity of 70 to 99% for 0.1 to 6 hours, preferably at a relative humidity of 80 to 95%. Treat with humidified air for 0.5 to 4 hours.

Finally, the porous tablet prepared above is dried using an oven, a hot air circulation dryer, a reduced pressure dryer, or the like at 40 to 70 ° C.

In addition, in the above method for preparing fast dissolving tablets, the tablet may be exposed to moisture and then dried.

The fast dissolving tablet prepared by the method of the present invention has a porosity of 25% or more, preferably 25% to 90%, hardness of 1.0 to 3.0 Kp, and oral disintegration time of 10 to 60 seconds.

The fast dissolving tablet of the present invention includes sugars that dissolve well in water so as to disintegrate or dissolve quickly when contacted with saliva, and the granules of sugars prepared using a fluidized bed granulator have a porous structure to quickly melt in the mouth and provide a soft feeling. to provide. In addition, since pores formed by the release of carbon dioxide from the foaming component by contact with moisture are highly porous to the tablet, the disintegration rate is further increased in the oral cavity, and since the emission of carbon dioxide is mostly completed, it has little irritation in the oral cavity. There is this.

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention, and the scope of the present invention according to the gist of the present invention is not limited to these examples.

Example 1

After dissolving 100 g of sorbitol (Roquette, France) in 1 L of water to prepare a solution, granules were prepared by coating 1500 g of mannitol (Roquette, France) with a sorbitol solution using a fluidized bed granulator (Freund, Japan). The fluidized bed granulator was operated under the conditions of a spray rate of 20 ml / min, an intake temperature of 45 ° C, and an exhaust temperature of 35 ° C of the sorbitol solution.

Example 2

Granules were prepared in the same manner as in Example 1, using erythritol (Borac, South Korea) instead of sorbitol.

Example 3

Granules were prepared in the same manner as in Example 1 using 50 g of sorbitol and 50 g of erythritol instead of 100 g of sorbitol.

Example 4

Granules were prepared in the same manner as in Example 1 using lactose (Meggle, Germany) instead of mannitol.

Example 5

After mixing 1460g of lactose and 500g of pamotidine (Cadila, India), 40g of povidone (BASF, Germany) as a binder for 10 minutes with a coalition machine (Icheon Industries, Korea), granulated with No. 20 sieve, 50 Dry at 6 ° C. for 6 hours. The dried product was formed into a No. 30 sieve and then coated with 400 g of Eudragit (Rohm, Germany) using a fluidized bed granulator.

51.2 g of the obtained coating and 118.8 g of the granules of Example 1, 0.86 g of citric anhydride (Merck, USA), 1.14 g of sodium bicarbonate (Duksan, South Korea), 20 g of low-substituted hydroxypropyl cellulose (Shin-Etsu, Japan) , 6 g of crospovidone (ISP, USA), 1 g of polyethylene glycol 6000 (Duksan, South Korea) and 1 g of magnesium stearate (Stabilchem, Malaysia) were mixed and tableted to a weight of 200 mg. This tablet was exposed to humidified air (relative humidity 90%) for about 1 hour and dried at 60 ° C. The diameter of the tablet was 8 mm and the hardness was 2.3 Kp.

Example 6

Tablets were prepared in the same manner as in Example 5 using the granules of Example 2 instead of the granules of Example 1. This tablet was exposed to humidified air (relative humidity 70%) for about 5 hours and dried at 60 ° C. The diameter of the prepared tablet was 8 mm and the hardness was 2.1 Kp.

Example 7

Tablets were prepared in the same manner as in Example 5 using the granules of Example 3 instead of the granules of Example 1. This tablet was exposed to humidified air (relative humidity 75%) for about 4 hours and dried at 60 ° C. The diameter of the prepared tablet was 8 mm and the hardness was 2.2 Kp.

Example 8

Tablets were prepared in the same manner as in Example 5 using the granules of Example 4 instead of the granules of Example 1. This tablet was exposed to humidified air (relative humidity 88%) for about 2 hours and dried at 60 ° C. The diameter of the prepared tablet was 8 mm and the hardness was 2.3 Kp.

Example 9

160 g of the granules of Example 1, 10 g of loratadine (Srini, India), 0.86 g of anhydrous citric acid, 1.14 g of sodium bicarbonate, 20 g of low-substituted hydroxypropyl cellulose, 6 g of crospovidone, 1 g of polyethylene glycol 6000, and 1 g of magnesium stearate The mixture was compressed into tablets having a weight of 200 mg. This tablet was exposed to humidified air (relative humidity 90%) for 30 minutes and dried at 60 ° C. for 1 hour. The diameter of the tablet after repeating this operation 3 times was 8 mm and hardness was 1.5 Kp.

Comparative Example 1

It was compressed in the same composition and method as in Example 5, and the operation of exposing the resulting tablet to humidified air was excluded. The diameter of the tablet was 8 mm and the hardness was 2.3 Kp.

Comparative Example 2

Except for the anhydrous citric acid and sodium hydrogen carbonate of the foaming component was compressed in the same composition and method as in Example 9, the operation of exposing the tablet to humidified air was excluded. The diameter of the tablet was 8 mm and the hardness was 1.5 Kp.

Test Example 1 : Disintegration Test

The disintegration test was performed on each of seven samples of Examples 5 to 9 and Comparative Examples 1 and 2 according to the disintegration test method of the Korean Pharmacopoeia, and the disintegration time is shown in Table 1 below.

Prescription Example 5 Example 6 Example 7 Example 8 Example 9 Comparative Example 1 Comparative Example 2 Disintegration time (seconds) 26 31 29 24 25 45 30

When the disintegration time of the tablets of Examples 5 to 8 in Table 1 is shorter than the disintegration time of the tablet of Comparative Example 1, it was confirmed that the fast dissolving tablet of the present invention treated with humidified air disintegrated more effectively than untreated. In the disintegration test results of the tablets of Example 9 and Comparative Example 2, it was found that the fast dissolving tablet of the present invention treated with humidified air disintegrated more quickly.

Test Example 2 : BET Measurement

Nitrogen adsorption was measured for each tablet of Example 5 and Comparative Example 1 using a BET system (Micrometrics, USA) under adsorption gas N ₂ , adsorption temperature 77.5 ° K, saturation pressure 779 mmHg. In the region of the adsorption isotherm where the relative pressure ratio P / P ₀ is in the range of 0.05 to 0.35, V _m is obtained from the relation between 1 / [V (P ₀ / P-1)] and P / P ₀ using the BET equation below. Was measured.

V : volume of gas adsorbed per gram of powder at pressure P (cm 3)

P ₀ : Saturated vapor pressure of liquefied nitrogen at test temperature

P : Pressure of gas at experimental temperature

c is a constant representing the difference between the heat of adsorption of the adsorbent (nitrogen) and the heat of liquefaction

Vm : The amount of vapor adsorbed per unit mass when the gas is completely adsorbed into the monolayer.

M / ρ : 22.4ℓ / mol (molar volume of gas)

N : 6.02 × 10 ²³ (Number of Avogadro)

A _m : 16.2Å ² (area of one molecule of closest packed nitrogen adsorbed as monolayer on the particle surface

1 and 2 show the results of measurement of the nitrogen adsorption at the equilibrium pressure by the BET nitrogen adsorption method for the tablets of Example 5 and the tablets of Comparative Example 1, respectively, of Example 5 and Comparative Example 1 obtained from this figure. The specific surface areas were 2.3317 m 2 / g and 1.9513 m 2 / g, respectively. From this result, it can be confirmed that the purified tablet of Example 5 had a porous structure and had a specific surface area larger than that of Comparative Example 1.

Test Example 3 Measurement of Porosity

For each sample of Examples 5 to 8 and Comparative Example 1, porosity was measured using a mercury porosimetry (Micrometrix, USA). Porosity (%) is shown in Table 2 below.

Prescription Example 5 Example 6 Example 7 Example 8 Comparative Example 1 Porosity (%) 29.0 27.7 28.1 28.5 22.3

In Table 2, the porosity of the tablets of Examples 5 to 8 showed a larger value than the tablets of Comparative Example 1. As can be seen from the results, the humidified tablet of Example 5 showed a greater porosity than the tablet of Comparative Example 1 was not humidified, and thus can easily disintegrate or dissolve when saliva penetrates into the mouth.

Test Example 4 : Oral Disintegration Test

When six healthy volunteers put the tablets of Example 9 and Comparative Example 2 into their mouths and measured the time of disintegration in the oral cavity, the results of the oral disintegration test showed that Example 9 was 45 seconds and Comparative Example 2 was 57 seconds. . From this result, it was evaluated that the tablet of Example 9 treated with humidified air became porous and disintegrated more quickly in the oral cavity than Comparative Example 2.

The fast dissolving tablet of the present invention can be prepared in a simple and economical process, easily disintegrated or dissolved in the oral cavity, easy to take without water, and can increase the medication compliance of patients having difficulty swallowing general tablets or capsules. .

Claims (10)

(a) preparing granules with water-soluble sugars, (b) preparing a tablet by mixing the orally administrable drug and effervescent component with the prepared granules, (c) contacting the prepared tablets with moisture to have a porosity, and (d) drying the prepared tablet Method of producing a fast-acting tablet comprising a. The method of claim 1, further mixing the excipient in step (b). The method of claim 1, (C) the step of treating the tablet in a humidified air of a relative humidity of 70 to 99% for 0.1 to 6 hours. The method of claim 1, 40 to 90% by weight of sugars, 0.1 to 50% by weight of drug, and 0.1 to 10% by weight of foam based on the total weight of the tablet. The method according to claim 1 or 4, Wherein the sugar is selected from the group consisting of mannitol, sorbitol, maltitol, xylitol, erythritol, lactose and mixtures thereof. The method according to claim 1 or 4, The drug is characterized in that pamotidine, loratadine, cetirizine hydrochloride, domperidone or lovastatin. The method according to claim 1 or 4, A foam component comprising a stoichiometric amount of acid and base. The method of claim 7, wherein The acid is selected from the group consisting of citric acid, tartaric acid, alginic acid and malic acid, and the base is selected from the group consisting of sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate. delete delete