KR20090010352A - Dispersible tablet containing coated pellet and preparation method thereof - Google Patents

Abstract

A suspension tablet containing coated pellet having excellent disintegration rate and dispersibility is provided to inhibit destruction in package, circulation or storage by maintaining the proper hardness, shield the unpleasant taste of drug, and easily adminstrate it to the patient. The suspension tablet contains (a) the pellet containing drug, (b) a coating layer including the water-insoluble polymer, the enteric coating material or their mixture formed on the pellet, (c) the binder for protecting the coating layer, and (d) the pharmaceutically acceptable excipients.

Description

Suspension tablets containing coated pellets and a method of manufacturing the same {DISPERSIBLE TABLET CONTAINING COATED PELLET AND PREPARATION METHOD THEREOF}

The present invention relates to a suspension tablet containing coated pellets and a method for producing the same, which are easy to store and maintain an appropriate hardness, can mask the unpleasant taste of the drug, and have excellent disintegration rate and dispersibility.

When swallowing a general tablet or capsule formulation, there are many patients who feel uncomfortable. In particular, it is urgently needed to provide convenience for patients who are difficult to swallow the formulation, such as children, the elderly, patients with poor swallowing ability.

Syrups that are mainly administered to children have the advantages of being easy to take, but have the disadvantages of inaccurate drug dosage, storage instability, use of preservatives, or inconvenience of carrying. Suspension tablets are known as formulations that are formulated to be convenient to take while addressing the disadvantages of these syrups. Suspension tablets are in the form of tablets, but they have the advantage of being taken as syrups by being suspended in a small amount of water before taking them, and at the same time, the disadvantages of the aforementioned syrups can be solved.

These suspension tablets must be fast in disintegration and maintain the appropriate hardness, and must not have a taste for the taste of the drug used. Recently, various studies have been conducted on such suspension tablets. For example, US Pat. No. 5,776,492 discloses formulations that disintegrate rapidly after 25-30 seconds while maintaining appropriate hardness by tableting with microcrystalline cellulose and a pharmaceutically acceptable excipient without using a binder.

In addition, U. S. Patent No. 5,698, 221 discloses suspension tablets dispersed within 3 minutes using swelling clay and other excipients, and U. S. Patent No. 5,780, 055 discloses wet granulation of components consisting of microcrystalline cellulose, disintegrants and drugs. Lyophilizable tablets prepared by lyophilization are disclosed.

However, the patents only disclose a method of preparing a suspension tablet by mixing the drug with other excipients and still do not solve the problem of patient rejection due to the unpleasant taste of the drug.

The present inventors have endeavored to develop a suspension tablet in which the unpleasant taste of the drug can be effectively masked. As a result, the present inventors have found that the drug coating layer for shielding the unpleasant taste can be effectively protected by using microcrystalline cellulose and a small amount of binder. Was completed.

Therefore, an object of the present invention is to maintain the appropriate hardness does not easily break during packaging, distribution or storage, masking the unpleasant taste of the drug can reduce the patient's rejection, oral tablets having excellent disintegration rate and dispersibility It is to provide a suspension tablet and a manufacturing method thereof that can be easily administered to infants and elderly patients, etc., difficult to administer.

In order to achieve the above object, the present invention provides a coating layer consisting of (a) a pellet containing a drug, (b) a water-insoluble polymer, an enteric coating material or a mixture thereof formed on the pellet, (c) the coating layer And (d) a pharmaceutically acceptable excipient.

In addition, the present invention

(1) coating the drug on an inert core or mixing the pellet with a pellet forming material to produce pellets;

(2) coating the drug-containing pellets with a water-insoluble polymer, an enteric coating material or a mixture thereof to obtain coated pellets; And

(3) mixing the coated pellets with a binder and a pharmaceutically acceptable excipient and tableting

It provides a method of manufacturing a suspension tablet.

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

Suspension tablets containing the coated pellets according to the invention comprise a coating layer for masking the unpleasant taste of the drug on the pellet containing the drug, and an appropriate amount of binder to protect the coating layer from breaking without delaying the suspension rate. Characterized in that.

The present invention can be applied to any drug that exhibits an unpleasant taste, such drugs being roxysomycin, clarithromycin, azithromycin, erdossteine, pamotidine, cefpodoxyl proxetyl, cepuroxime axetyl Acetaminophen or ivy extract.

In the present invention, the pellet containing the drug can be obtained by mixing the drug having an unpleasant taste with the pellet-forming substance to prepare the pellet by a conventional method or by coating the drug on an inert core by the conventional method (document (Int. J. Pharm., 290 , 15-23, 2005) and US Pat. No. 6,558,704.

Pellets containing the drug do not exhibit the desired fast disintegration time if the amount is too large and the amount of the preparation increases if the amount is too small, so that the amount of pellets is 10 to 50% by weight, preferably based on the total weight of the suspension tablet. Is 15 to 40% by weight.

As the pellet forming material, one or more materials selected from microcrystalline cellulose, low-substituted hydroxypropylcellulose, chitin and chitosan may be used. The ratio of drug to pellet forming material may vary depending on the drug, but may be preferably used in an amount of 1: 0.2 to 1:10. As the inert core, spherical particles of sugar having a diameter of 100 to 500 µm and spherical particles of microcrystalline cellulose are preferable.

In the present invention, the coating material used for the coating layer formed on the pellet may be a water-insoluble polymer, an enteric coating material or a mixture thereof. Examples of the water-insoluble high molecular material is an acrylic acid copolymer, polyvinylacetate or a cellulose derivative (for example, ethyl cellulose or cellulose acetate). The water-insoluble polymer may be used in the form of an aqueous suspension, an aqueous emulsion or a hydrous organic solvent solution. These include, for example, acrylic acid copolymers (e.g. Eudragit L30D-55, Eudragit FS30D, Eudragit RL30D, Eudragit RS30D and Eudragit NE30D, Deggusa); acrylic (acryl) -Eze, Colorcon, polyvinylacetate (e.g. Kollicoat SR 30D, BASF), cellulose derivatives (e.g., Surelease, Calacon; Aquacoat ) ECD and Aquacoat CPD, FMC). They can be used on their own or diluted with water.

The enteric coating material is an enteric polymer which is dissolved at a pH of 5 or more, methacrylic acid copolymers (Euradragit L, S and FS30D, Degussa), hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succi Nate or cellulose acetate phthalate, etc. can be used.

In the present invention, the plasticizer may be used together with the coating material in an amount of 1 to 30% by weight based on the weight of the coating material, if necessary. Examples of the plasticizer used in the present invention include polyethylene glycol, propylene glycol, triethyl citrate, triacetin, triacetin citrate, castor oil, dibutyl sebacate, dibutyl tartrate, diethyl phthalate or glycerin. Can be.

In the present invention, when coating the drug-containing pellets, in order to prevent the pellets from sticking, a lubricant may be added to the coating material in an amount of 10 to 50% by weight based on the total weight of the coating material. Examples of the lubricant used in the present invention include talc, silicon dioxide or glyceryl monostearate.

The coating liquid consisting of the coating material described above is sprayed by, for example, a top spray, bottom spray or tangential spray method using a fluidized bed coater commonly used for drug-containing pellets. Can be coated. The coating may be carried out under conventional conditions, for example, at a spray rate of 5 to 30 ml / min, a spray pressure of 1 to 3 bar in a temperature range of 25 to 45 ° C., and after the coating to 35 to It may be dried at 60 ° C for 0.5 to 1 hour to form a coating layer.

In the present invention, the greater the amount of the coating layer made of the coating material, the better the unpleasant taste shielding effect, but if too large, there is a disadvantage that the manufacturing cost increases and the tablet size increases. Thus, the amount of coating layer is 5 to 40% by weight, preferably 10 to 30% by weight relative to the total weight of the suspension tablet, and 10 to 100% by weight, preferably 30 to 70% by weight, based on the drug containing pellets.

The suspension tablet of the present invention includes a binder that can protect the coating layer of the pellets from breaking the coating layer without delaying the suspension speed, and a pharmaceutically acceptable excipient.

The binders usable in the present invention are copovidones (e.g., collidone VA64, BASF), hydroxypropylcellulose (e.g. HPC-L, Nisso), polyvinylpi Synthetic polymers such as rolidone (eg, collidone K30, BASF) or hydroxypropylmethylcellulose (eg, Pharmacoat 606, Shin-Etsu); Natural gums such as gum arabic or xanthan gum; And mixtures thereof. The amount of binder may be used in an amount of 1 to 8% by weight, preferably 2 to 6% by weight, based on the total weight of the suspension tablet.

Pharmaceutically acceptable excipients used in the present invention may be used in an appropriate amount of one or more components selected from microcrystalline cellulose, disintegrants, flavors, sweeteners or glidants commonly used in the pharmaceutical art.

Microcrystalline cellulose used in the present invention is supplied with various products according to the particle size, any one can be used regardless of the size of the particles. Examples include commercially available Avicel PH101 (FMC), Avicel PH102 or Avicel PH200, and the amount used is 30 to 70% by weight, preferably 40 to 60% by weight based on the total weight of the suspension tablet. Disintegrants used in the present invention include crospovidone (eg, collidone CL, BASF), croscarmellose sodium (eg, Ac-di-sol, FMC), sodium starch glycolate (eg, primogel ( Primojel, DMV), potassium carboxymethylcellulose, pregelatinized starch (e.g. Starch 1500, Calacon), low-substituted hydroxypropyl cellulose (e.g., L-HPC, Shin-Etsu) or There is a mixture of these, and the amount of disintegrant is 0.5 to 15% by weight, preferably 3 to 10% by weight, based on the total weight of the suspension tablet.

After the coating protective ingredient is mixed with the coated drug-containing pellets, the suspension tablet of the present invention can be obtained by tableting the mixture to a hardness of 3 to 5 kp in a conventional manner. The suspension tablet of the present invention has a disintegration rate of 5 to 60 seconds at a hardness of 3 to 5 kp.

Suspension tablets containing the coated pellets according to the present invention are not easily deformed at the time of packaging, distribution or storage by maintaining the appropriate hardness, can mask the unpleasant taste of the drug to reduce the patient's rejection, excellent disintegration rate and dispersibility It can be easily administered to infants, elderly patients, and the like, which are difficult to orally administer tablets.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

Example 1

(1) Preparation of Pellets Containing Drugs

The combined solution obtained by adding 650 g of ivy leaf extract (Finzelberg, Germany), 19.5 g of hydroxypropylmethylcellulose, and 19.5 g of talc to 2700 g of purified water was stirred using a fluidized bed coater under the conditions shown in Table 1 below (CELLETS). 200, Pharmatrans Sanaq Ag, Germany) was coated on 611g to obtain a pellet containing the ivy leaf extract.

(2) bitterness shielding layer coating

1200 g of the ivy leaf extract pellets obtained in (1) was coated with a bitterness shielding layer with the composition shown in Table 2, wherein the coating conditions are as shown in Table 3 below.

(3) suspension tablet manufacture

98 g of pellets coated with bitterness masking layer obtained in (2), 119.07 g of microcrystalline cellulose, copovidone 7.35 g, croscarmellose sodium 7.35 g, crospovidone 7.35 g, strawberry flavored coton 2.45 g, sucralose 0.98 g and sodium stearyl After mixing 2.45 g of fumarate, the mixture was compressed into a hardness of 3.5 to 4.0 kp with an 8 mm diameter circular punch.

Example 2

(1) Preparation of Pellets Containing Drugs

350 g of roxysomycin and 350 g of microcrystalline cellulose were placed in a centrifugal granulator (GPCG-1, Glatt, Germany) and mixed for about 1 minute. Pellets were prepared by spraying 700 g of water on a centrifugal granulator. The production conditions of the pellets are shown in Table 4 below, and the obtained pellets were mostly spherical with a diameter of 0.4 to 0.5 mm.

(2) bitterness shielding layer coating

To 700 g of the roxysomycin pellet obtained in (1) was coated with a bitterness shielding layer in the composition of Table 5, the coating conditions are as shown in Table 6.

(3) suspension tablet manufacture

98 g of the bitterness shielding layer coated in (2), microcrystalline cellulose 114.17 g, copovidone 12.25 g, crospovidone 14.7 g, strawberry flavored coton 2.45 g, sucralose 0.98 g and sodium stearyl fumarate 2.45 g were mixed Thereafter, the mixture was compressed into tablets having a diameter of 8 mm in a circular punch so as to have a hardness of 3.5 to 4.0 kp.

Example 3

(1) Preparation of Pellets Containing Drugs

350 g of clarithromycin and 350 g of microcrystalline cellulose were placed in a centrifugal granulator (GPCG-1, Glatt, Germany) and mixed for about 1 minute. Pellets were prepared under the same conditions as in Example 2 (Table 4) while spraying 600 g of water on a centrifugal granulator to obtain spherical pellets of about 0.2 to 0.4 mm.

(2) bitterness shielding layer coating

700 g of the clarithromycin-containing pellet obtained in (1) was coated with a bitterness masking layer with the composition of Table 7 under the coating conditions shown in Table 3.

(3) suspension tablet manufacture

98 g of pellets coated with bitterness shielding layer prepared in (2), 116.62 g of microcrystalline cellulose, 4.9 g of hydroxypropyl cellulose, 19.6 g of crospovidone, 2.45 g of strawberry flavored koton, 0.98 g of sucralose and 2.45 g of sodium stearyl fumarate After mixing, the mixture was compressed into tablets with a diameter of 8 mm in diameter to have a hardness of 3.5 to 4.0 kp.

Examples 4-6

The coated pellets obtained by carrying out the same method as in (1) and (2) of Example 1 were mixed together with the components shown in Table 8 below to prepare suspension tablets having a diameter of 8 mm and a hardness of 3 to 4 kp. The suspension tablets of Examples 4 to 6 were prepared to contain 1.0 to 3.0 wt% binder amount.

Examples 7 and 8 and Comparative Examples 1 and 2

The coated pellets obtained by carrying out the same method as in (1) and (2) of Example 1 were mixed together with the components shown in Table 9 below to prepare suspension tablets having a diameter of 8 mm and a hardness of 3 to 4 kp.

The suspension tablets of Examples 7 and 8 were prepared to contain 6.0 and 8.0 wt% of the binder, respectively, and the suspension tablet of Comparative Example 1 was 10.0 wt% of the binder and Comparative Example 2 did not contain the binder.

Test Example 1: Dissolution Test

Ten tablets prepared in Examples 4 to 8 and Comparative Examples 1 and 2 were taken and subjected to a dissolution test in accordance with the Korean Chemical Test General Dissolution Test Dissolution Test Method 1. However, the rotating speed was 100 rpm, 900 mL of water was used for the test liquid, 3 mL of the eluate was taken out 10 minutes after the start of the dissolution test, and the filtrate filtered by the filter was quantified under the following HPLC conditions. The results are shown in Table 10 below.

Column: Kromasil 150 × 4.6 mm, 5 um

Detector: UV 205 nm

Flow rate: 1 ml / min

Sample injection volume: 20 μL

Column Temperature: 40 ℃

Mobile phase: A: 0.001 mol / L phosphoric acid solution

         B: 10 ml of 0.1 mol / L phosphate solution + 1000 ml with acetonitrile

As can be seen in Table 10, Examples 4 to 8 containing the binder showed a lower dissolution rate than Comparative Example 2 containing no binder, it can be seen that the dissolution rate decreases as the amount of the binder is increased In addition, Comparative Example 1 containing a lot of binder was found that the dissolution rate is significantly low. From this, it was found that the binder contained in the suspension tablet protects the coating layer from being damaged during the tableting process.

Test Example 2: Disintegration Test

The suspension tablets prepared in Examples 4 to 8 and Comparative Examples 1 and 2 were tested using water as a test solution according to the pharmacopeia general test method disintegration test method, and the results are shown in Table 11 below.

As can be seen in Table 11, the suspension tablet of Comparative Example 1 containing 10% of the binder had a significantly longer average disintegration time of 159 seconds, and the suspension tablet of Comparative Example 2 without the binder contained an average disintegration time of 7 seconds. It was the shortest. On the other hand, the suspension tablets of Examples 4 to 8 had a disintegration time of 9 seconds to 60 seconds, which was an appropriate level as a suspension tablet.

As described above, the suspension tablet containing the coated pellet of the present invention maintains the appropriate hardness and is not easily deformed during packaging, distribution or storage, and can mask the unpleasant taste of the drug to reduce patient's rejection, and excellent disintegration. Because of its speed and dispersibility, tablets can be easily administered to infants and elderly patients who have difficulty oral administration of tablets.

Claims (16)

(a) a pellet containing a drug, (b) a coating layer consisting of a water-insoluble polymer, an enteric coating material or a mixture thereof, formed on the pellet, (c) a binder for protecting the coating layer, and (d) pharmaceutical Suspension tablets consisting of acceptable excipients. The method of claim 1, Suspension tablet, characterized in that the amount of the pellet containing the drug is 10 to 50% by weight relative to the total weight of the suspension tablet. The method of claim 1, Suspension tablet, characterized in that the amount of the coating layer is 5 to 40% by weight based on the total weight of the suspension tablet. The method of claim 1, Suspension tablet, characterized in that the water-insoluble polymer is an acrylic acid copolymer, polyvinylacetate or cellulose derivative. The method of claim 1, The enteric coating material is a suspension tablet characterized in that the enteric polymer is dissolved at a pH of 5 or more. The method of claim 5, The enteric polymer is a methacrylic acid copolymer, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate or cellulose acetate phthalate. The method of claim 1, Suspension tablet, characterized in that the coating layer further comprises a plasticizer in an amount of 1 to 30% by weight. The method of claim 1, The binder is synthetic polymer including copovidone, hydroxypropyl cellulose, polyvinylpyrrolidone and hydroxypropyl methyl cellulose; Natural gums, including gum arabic and xanthan gum; Or a mixture thereof. The method of claim 1, Suspension tablet, characterized in that the amount of the binder is 1 to 8% by weight based on the total weight of the suspension tablet. The method of claim 1, Suspension tablet, characterized in that the pharmaceutically acceptable excipient comprises at least one component selected from microcrystalline cellulose, disintegrant, flavoring agent, sweetener or glidant. The method of claim 10, The disintegrant is selected from the group consisting of crospovidone, croscarmellose sodium, sodium starch glycolate, potassium carboxymethyl cellulose, pregelatinized starch, low-substituted hydroxypropyl cellulose, and mixtures thereof. Suspension tablet. The method of claim 11, The amount of the disintegrant is suspended tablet, characterized in that 0.5 to 15% by weight based on the total weight of the suspended tablet. The method of claim 10, Suspension tablet, characterized in that the amount of the microcrystalline cellulose is 30 to 70% by weight based on the total weight of the suspended tablet. The method of claim 1, Suspension tablets comprising 15 to 40% by weight of the pellet containing the drug, 10 to 30% by weight of the coating layer, 2 to 6% by weight of the binder and the remaining amount of the pharmaceutically acceptable excipient relative to the total weight of the suspension tablet . The method of claim 1, Suspension tablets, characterized in that the hardness of the suspension tablet is 3 to 5 kp, the disintegration time is 5 to 60 seconds. (1) coating the drug on an inert core or mixing the pellet with a pellet forming material to produce pellets; (2) coating the drug-containing pellets with a water-insoluble polymer, an enteric coating material or a mixture thereof to obtain coated pellets; And (3) mixing the coated pellets with a binder and a pharmaceutically acceptable excipient and tableting Including, a suspension tablet manufacturing method.