KR101809886B1 - Minimized Oral Dosage Formulation of Clarithromycin - Google Patents

Abstract

The present invention relates to a compact clarithromycin preparation which ensures enhanced convenience in administration, and also exhibits improved or the same level of effects as available formulations in terms of stability, elution, and disintegration. The present invention further relates to a production method thereof. More specifically, the present invention relates to a compact clarithromycin preparation which contains at least 70 wt% of clarithromycin with respect to the total weight of the preparation for oral administration in addition to microcrystalline cellulose and croscarmellose sodium, and also exhibits superior effects as a pharmaceutical preparation. The present invention further relates to a production method thereof.

Description

Minimized Oral Dosage Formulation of Clarithromycin < RTI ID = 0.0 >

The present invention relates to a pharmaceutical preparation containing claritromycin as an active ingredient and a method for producing the same.

Generally, oral administration formulations of medicines are prepared by adding excipients such as excipients to the main ingredients. At this time, when the main component is 40 wt% or more of the total weight of the preparation, the amount of the additive including the excipient etc. is increased in proportion to the amount of the main ingredient to process the preparation, so that the weight or the volume of the whole tablet increases, There is a problem that the dosage of the patients is lowered.

Clarithromycin is a Macrolide family of antibiotics, the chemical name is 6-O-Methylerythromycin (6-O-methylerythromycin) and the molecular formula is C ₃₉ H ₆₉ NO ₁₉ . When the commercial product of claritromycin (Korea market) is checked, the main ingredient amount is about 40 ~ 50w% of the total weight of tablets. Moreover, clarithromycin has poor flow, density characteristics, and relatively high doses of a single dose, which is prone to penile disorders. Particularly, capping (a phenomenon in which the upper part of the tablet is peeled off in a hat shape) and laminating (a phenomenon in which tablets are separated in layers) frequently occur.

To increase the binding force of the granules, the amount of the binder or excipient is increased or the viscosity of the binder is increased so that the binding force of the granules is increased so that the tableting disorder is not caused. However, when the amount of the binder or the excipient is increased, the weight or volume of the tablet increases, and when the viscosity of the binder is increased, the dissolution rate of the drug slows down and the desired dissolution rate does not appear. The disadvantage of increasing the amount of the disintegrant is that the weight and volume of the tablet eventually increase.

Therefore, there is a need to develop claritromic agents that minimize the amount of additive. As a part of this, Japanese Patent Application Laid-Open No. 2005-15363 discloses a miniaturized tablet containing claritromycin as a main component. The patent uses crospovidone as a disintegrant to reduce the total weight of the formulation and uses povidone, polyvinyl alcohol or copolypodone as a binder.

However, according to the above-mentioned patent, there is no data about the problems normally expected in miniaturized formulations other than the miniaturization of the preparation, for example, the tablet trouble, the dissolution rate and the disintegration rate, and it is questionable whether the problems are solved.

JP 2005-15363 A

Accordingly, a problem to be solved by the present invention is to provide a small-sized clarithromycin preparation exhibiting the same or improved effect as a commercially available preparation in terms of stability, dissolution and disintegration while minimizing the amount of additives, Method.

In order to solve the above-mentioned problems, the present invention provides a miniaturized oral administration preparation containing claritromycin as an active ingredient and a method for producing the same.

More specifically, the present invention provides the following oral dosage forms and methods for their manufacture:

As an oral preparation containing claritromycin as an active ingredient,

Claritromycin is contained in an amount of at least 70% by weight based on the total weight of the preparation,

Microcrystalline cellulose, and croscarmellose sodium.

[Characteristics of the preparation]

The formulation according to the invention does not indicate a penile disorder.

A penile disorder refers to a disorder that occurs during tableting, for example, sticking, capping, or laminating. In the sticking, powder is adhered to the surface of the punch and scratches are formed on the surface of the tablet. Chipping refers to cracking in the tablet, accompanied by debris broken around the rounded periphery of the tablet due to expansion during pressure release , And picking means that irregular surface spots appear on the surface of the tablet. Capping refers to the phenomenon that the upper part of the tablet peels off in the shape of a cap, and laminating refers to the phenomenon that the tablets are peeled off in layers.

The formulation according to the present invention has a disintegration rate that is equivalent to the disintegration rate of a commercial formulation (Korean Abbott, clarithoid tablet).

The preparation according to the present invention may be a disintegration speed range in which the disintegration time measured in water according to the Korean Pharmacopoeia Disintegration Test is 9 to 11 minutes. This is equivalent to the disintegration rate of a commercial formulation (Korean Abbott, Clarithoid) measured under the same test conditions. According to a specific example of the present invention, the disintegration time measured in water according to the Korean Pharmacopoeia Disintegration Test was 9 to 10 minutes.

When the preparation according to the present invention was rotated for 30 minutes at a rotation speed of 50 rpm in 900 mL of a dissolution test liquid at 37 ° C, water and pH 6.0 according to the second pharmacopoeia assay of Korean Pharmacopoeia, the dissolution rate of clarithromycin was as follows same:

25-40% at 5 minutes, 70-80% at 10 minutes, and 85-95% at 15 minutes.

More preferably, 25 to 35% at 5 minutes, 70 to 75% at 10 minutes, and 85 to 90% at 15 minutes.

When the preparation according to the present invention was rotated for 30 minutes at a rotation speed of 50 rpm in 900 mL of a dissolution test liquid at 37 DEG C, water and pH 1.2 according to the Korean Pharmacopoeia dissolution assay Method 2 paddle method, the dissolution rate of clarithromycin As follows:

10 to 18% at 10 minutes, 20 to 35% at 30 minutes, and 35 to 50% at 60 minutes.

More preferably, 10 to 18% at 10 minutes, 24 to 32% at 30 minutes, and 40 to 46% at 60 minutes.

The dissolution rate of clarithromycin described above is equivalent to the dissolution rate of a commercially available preparation (Korean Abbott, Clarified Tablets) measured under the same test conditions.

In addition, in the present invention, when the total weight of claritromycin contained in the preparation is 250 mg and 500 mg, the dissolution rate of clarithromycin is similarly indicated.

When the total weight of clarithromycin contained in the preparation according to the present invention is 250 mg and the total weight of claritromycin is 500 mg, the same clarithromycin dissolution rate is shown.

The term, "equivalent ", as used herein, means that the difference value is less than 1%, more preferably less than 0.1%, and most preferably 0% when comparing the dissolution rates of clarithromycin at the same time.

In the present invention, the term "excessively fast" used in connection with the dissolution rate means that when measured under the same test conditions, the dissolution rate of clarithromycin in the above- Quot; means that the dissolution rate is higher than the dissolution rate range of clarithromycin described above. More specifically, it means that the clarithromycin dissolution rate value at the same time point is 2 times or more, preferably 1.5 times or more, more preferably more than 1 times as high as the upper limit value of the clarithromycin dissolution rate range. For example, when 900 mL of a dissolution test liquid at 37 DEG C, water and pH 6.0 was spun at a rotation speed of 50 rpm for 30 minutes in accordance with Korean Pharmacopoeia dissolution assay method 2 method paddle method, the dissolution rate of clarithromycin was 80% , 60% or more, and more preferably 40% or more.

In the present invention, the application used in relation to the dissolution rate, "excessively slow" means that the dissolution rate of clarithromycin at the same time point is greater than that of clarithromycin in the above- Which is lower than the dissolution rate of one claritromicin. More specifically, it means that the clarithromycin dissolution rate value at the same time point is 2 times or less, preferably 1.5 times or less, more preferably 1 times or less than the lower limit value of the clarotromicin dissolution rate range described above. For example, when 900 mL of a dissolution test liquid at 37 DEG C, water and pH 6.0 was spun at a rotation speed of 50 rpm for 30 minutes in accordance with Korean Pharmacopoeia dissolution assay method second method paddle method, the dissolution rate of clarithromycin was 12.5% , 16.7% or less, and more preferably less than 25%.

The preparation according to the present invention exhibits storage stability. The change in content of claritromycin for 4 weeks after storage at 40 ° C / RH 75%, which is an accelerated test condition, is 0.1% or less. Excellent storage stability.

[Clarithromycin]

And Retro class azithromycin compound name 6-O-Methylerythromycin (6- O- methyl erythromycin) of (Clarithromycin), molecular formula is C ₃₉ H ₆₉ NO ₁₉ antibiotics of the Macrolide series. The chemical formula of claritromycin is as follows.

In the present invention, the term " claritromycin " means a claritromycin free base or a pharmaceutically acceptable salt thereof. Claritromycin is a compound of the above formula. Unless the purpose of the present invention is not obviated, all modifications (including modified derivatives) of compounds of the above formula, solvates, hydrates, and crystalline forms thereof (hereinafter referred to as modified products) have. Therefore, the preparation according to the present invention may include the above-mentioned variant having a pharmacological activity equivalent to claritromycin in place of or in addition to claritromycin.

As used herein, the term " pharmaceutically acceptable salt " refers to a concentration of a relatively non-toxic, harmless effective action in a patient, wherein any adverse side effects caused by the salt are any organic or inorganic that does not degrade the beneficial efficacy of claritromycin Suitable acid addition salts are the hydrochlorides, bromates, iodates, nitrates, sulfates, bisulfates, phosphates, acid phosphates, isonicotinates, acetates, lactates, salicylates, citrates, tartrates, But are not limited to, benzenesulfonate, benzenesulfonate, methanesulfonate, benzenesulfonate, benzenesulfonate, benzenesulfonate, benzenesulfonate, benzenesulfonate, benzenesulfonate, benzenesulfonate, benzenesulfonate , p-toluenesulfonate, and pamoate salts. Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc and diethanolamine salts.

Clarithromycin can be prepared by chemical modification, either by isolation from a natural source, by obtaining it from a natural source, by chemical modification, or by chemical synthesis readily known to those of ordinary skill in the art by known synthetic methods, You can purchase and use the product.

In the present invention, claritromycin may be contained in an amount of 70 wt% or more and 85 wt% or less based on the total weight of the preparation, and the weight% is calculated on the basis of clarithromycin free base.

In the present invention, for example, the total weight of claritromycin included in the formulation may be 250 mg or 500 mg, and the weight is based on claritromycin free base. For example, if the total weight of clarithromycin relative to the total weight of the formulation is greater than or equal to 70% and less than or equal to 85% by weight and the total weight of claritromycin included in the formulation is 250 mg, the total weight of the formulation will be greater than or equal to about 294 mg 357 mg or less. When the total weight of clarithromycin is not less than 70% by weight and not more than 85% by weight based on the total weight of the preparation and the total weight of the claritromycin contained in the preparation is 500 mg, the total weight of the preparation is not less than about 588 mg and not more than about 714 mg .

[Microcrystalline cellulose and Croscarmellose Sodium]

In the present invention, oral administration preparations include microcrystalline cellulose and croscarmellose sodium.

Microcrystalline cellulose is a white, odorless, tasteless crystalline powder and a porous particle, which is a partially purified, depolymerized cellulosic.

Croscarmellose sodium is a cross-linking polymer of sodium carboxymethylcellulose and is a white to yellowish white powder with no odor or taste.

In the present invention, croscarmellose sodium is included as a disintegrant, and the total weight of croscarmellose sodium based on the total weight of the disintegrant contained in the preparation is 95 wt% or more and 100 wt% or less, more preferably 99 wt% % Or more and 100 weight% or less. In the preparation according to the present invention, it may preferably be substantially free of croscarmellose sodium as the disintegrant. For example, in the formulation according to the present invention, substantially no crospovidone is present as a disintegrant. However, If it is included, it may contain, for example, carboxymethylcellulose calcium (CMC-Ca), carboxymethylcellulose sodium (CMC-Na), starch sodium gluconate, corn starch, wheat starch, May be used. In addition, compounds exhibiting other uses (e.g., excipients, adsorbents, etc.) together with a disintegrant are not included in the disintegrants defined in the present invention and are interpreted as being excluded.

In the present invention, the microcrystalline cellulose is contained as a bulking agent (particularly, a bulking agent), and the total weight of the microcrystalline cellulose with respect to the total weight of the bulking agent contained in the preparation is 95 wt% or more and 100 wt% or less, And may be 99 wt% or more and 100 wt% or less. In the preparation according to the present invention, it may preferably be substantially free of other than microcrystalline cellulose as a bulking agent. However, if the bulking agent is included, it may be added in the group consisting of calcium phosphate dibasic anhydride, carboxymethylcellulose calcium, corn starch, pregelatinized starch, dextrose, dextrin, lactose (anhydrous or lactose hydrate) A compound which exhibits other uses (for example, a stabilizer) together with a bulking agent is not included in the bulking agent defined in the present invention and is interpreted as being excluded.

In the present invention, "substantially free of (C)" means less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.1% ≪ / RTI > The basis of the total weight can be interpreted in place of the preparation according to the context of the specification of the present invention by replacing it with a disintegrating agent or the like.

In the present invention, microcrystalline cellulose and croscarmellose sodium may be contained in an amount of 1 wt% or more and 20 wt% or less based on the total weight of the preparation. More preferably 1 wt% or more and 17 wt% or less. If the amount is less than 1% by weight based on the total weight of the preparation, the disintegration and dissolution rate of the formulation is excessively slow and the tableting disability is caused. If it exceeds 20% by weight, disintegration and dissolution rate are excessively fast and it is difficult to obtain the desired dissolution data.

In the present invention, the weight ratio of microcrystalline cellulose to croscarmellose sodium is 1.5: 1 to 1: 1 (microcrystalline cellulose: croscarmellose sodium), more preferably 1.2: 1 to 1: 1. If the content ratio of croscarmellose sodium to microcrystalline cellulose is more than 1.5: 1, excessively fast elution and disintegration occur. If the content is less than 1: 1, excessively slow elution and disintegration occur.

In the present invention, the weight ratio of cromacromel sodium to clarithromycin is 1: 9 to 1: 125 (croscarmellose sodium: croscarmellose sodium). If the content ratio of clathromarose sodium to clarithromycin exceeds 1: 125 by weight, excessive elution and disintegration will occur excessively. If the ratio is less than 1: 1, excessively slow elution and disintegration will occur.

In the present invention, the weight ratio of claritol cellulose to clarithromycin is 1:13 to 1: 125 (microcrystalline cellulose: croscarmellose sodium). If the content ratio of the microcrystalline cellulose to clarithromycin exceeds 1: 125 by weight, excessively fast elution and disintegration occur. If the content is less than 1:13 by weight, excessive slow dissolution and disintegration occur.

In the present invention, the microcrystalline cellulose is contained in an amount of 0.5 wt% or more and 12 wt% or less based on the total weight of the preparation. If the weight of the microcrystalline cellulose is less than 0.5% by weight based on the total weight of the preparation, excessively slow elution and disintegration will occur, and if it exceeds 12% by weight, excessive elution and disintegration will occur.

In addition, croscarmellose sodium may be included in an amount of 0.5 wt% or more and 8 wt% or less based on the total weight of the preparation. If the weight of croscarmellose sodium is less than 0.5% by weight based on the total weight of the formulation, excessively slow elution and disintegration will occur, and if it exceeds 8% by weight, excessive elution and disintegration will occur.

In the present invention, the microcrystalline cellulose is contained in an amount of 0.5 wt% to 13 wt% based on the total weight of the claritromycin contained in the preparation, and exhibits an excessively fast dissolution and disintegration rate when it is contained in an amount exceeding 13 wt%.

In the present invention, croscarmellose sodium is contained in an amount of not less than 0.5% by weight and not more than 11% by weight based on the total weight of claritromycin contained in the preparation, and when it is contained in an amount of more than 11% by weight, .

 [Binder and lubricant]

Binder refers to an additive that imparts a bonding force to a powder to facilitate molding.

As binders usable in the present invention, for example, gelatin, starch, glucose, cellulose derivatives, povidone or a mixture thereof may be used. Preferably, povidone can be used.

In the present invention, the binder may be contained in an amount of 4 wt% or more and 6 wt% or less based on the total weight of the preparation, and for example, povidone as a binder may be contained in an amount of 3 wt% or more and 5 wt% or less .

A glidant is an additive used to improve the fluidity of the powder and improve the filling of the die.

Examples of the lubricant usable in the present invention include magnesium stearate (magnesium stearate), stearic acid, calcium stearate, sodium stearyl fumarate (SSF), polyethylene glycol (PEG) 4000-8000, Mixtures thereof may be used. Preferably, talks can be used.

In the present invention, the lubricant may be contained in an amount of 3.8 wt% or more and 4 wt% or less based on the total weight of the preparation, and for example, the talc as a lubricant may be contained in an amount of 3.8 wt% or more and 4 wt% .

[Other additives]

The formulation according to the present invention may further include pharmaceutically acceptable additives such as surfactants, diluents, adsorbents, lubricants and the like in addition to the above-mentioned components.

Such pharmaceutically acceptable additives are referred to in the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association, Washington 6 edition and earlier editions, which are incorporated herein by reference.

Surfactants that can be used in the present invention include sodium salts of fatty alcohol sulfates, such as sodium lauryl sulfate, sulfosuccinates, such as sodium dioctyl sulfosuccinate, partial fatty acid esters of polyhydric alcohols, e.g., Such as glycerol monostearate, partial fatty acid esters of sorbitan, such as sorbitan monolaurate, partial fatty acid esters of polyhydroxyethylenesorbitan, such as polyethylene glycol sorbitan monolaurate, monostearate, or monooleate Component selected from the group consisting of polyoxyethylene fatty alcohol ether, polyhydroxyethylene fatty alcohol ether, polyhydroxyethylene fatty acid ester, ethylene oxide-propylene oxide block copolymer (Pluronic®) or ethoxylated triglyceride, and mixtures thereof But it is not limited to this. The.

The diluent that can be used in the present invention may be selected from the group consisting of lactose (anhydrides as well as hydrates), mannitol, sorbitol, phosphates, and mixtures thereof, but is not limited thereto.

Examples of adsorbents that can be used in the present invention include silica, colloidal silica (for example, light anhydrous silicic acid (Aerosil 200), colloidal silicon dioxide, magnesium aluminum silicate, magnesium trisilicate, calcium silicate, And mixtures thereof, but the present invention is not limited thereto.

[Formulation of preparation]

The preparations according to the present invention may be formulated into oral dosage forms, for example, tablets, hard capsules, granules, pellets, powders and the like, preferably tablets and hard capsules. Most preferably, it may be a coating formulation for oral administration. Preferably, conventional mixing methods such as granulation, mixing, filling and compression may be used to formulate tablets, for example, granulation processes and / or direct tabletting processes may be used.

The preparation according to the present invention is miniaturized, and the term 'miniaturization' means a relatively small size compared to a commercial product. For example, the coating definition size according to the present invention represents less than 1, less than 0.8, based on the size of a commercial formulation (Korean Abbott, Clarithoid). For example, when the total weight of claritromycin is 250 mg, the long axis is less than 1 cm and less than 1.5 cm, and when the total weight is 500 mg, the longer axis is less than 1.5 cm and less than 2.0 cm.

[Preparation method of preparation]

The preparation according to the present invention can be produced by the following method, but is not limited thereto, and can be formulated according to a conventional method known in the art.

Mixing claritromycin and microcrystalline cellulose, optionally adding a binding liquid, and then mixing croscarmellose sodium and optionally a lubricant to prepare a mixture; And

Formulating into a formulation for oral administration.

Drying, tableting, and the like may be included during the above-described formulation.

According to the present invention, there is provided a compacted claritromic agent having the same or improved effect as a commercially available preparation in terms of stability, dissolution and disintegration while increasing convenience for taking, and a method for producing the same.

BRIEF DESCRIPTION OF THE DRAWINGS The accompanying drawings, which are incorporated in and constitute a part of the specification, illustrate exemplary embodiments of the invention and, together with the description of the invention, It should not be construed as limited.
Fig. 1 shows the sizes of commercially available formulations (Korean Abbott, Lot No. 1029548) and formulations according to the present invention (coated tablets of Example 5).

Hereinafter, embodiments of the present invention will be described in detail to facilitate understanding of the present invention. However, the embodiments according to the present invention can be modified into various other forms, and the scope of the present invention should not be construed as being limited to the following embodiments. Embodiments of the invention are provided to more fully describe the present invention to those skilled in the art.

≪ Preparation of Examples 1 to 12 >

Claritromycin preparations were prepared according to the ingredients in Table 1 below.

Raw material name Comparative Example
2 Comparative Example 3 Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 Example 10 Example 11 Example 12 Claritromycin 250.0 250.0 250.0 250.0 250.0 250.0 250.0 250.0 250.0 250.0 250.0 250.0 250.0 250.0 Povidone K-30 12.5 17.5 15.0 15.0 15.0 15.0 15.0 15.0 15.0 15.0 15.0 15.0 15.0 15.0 Microcrystalline cellulose - 97.3 32.5 16.0 8.0 4.0 2.0 - 4.0 - 32.5 32.5 37.5 35.0 Sodium croscarmellose sodium - 21.4 27.5 16.0 8.0 4.0 2.0 - - 4.0 32.5 30.0 27.5 27.5 Crospovidone 31.25 - - - - - - - - - - - - - Pregelatinized starch - 25.6 - - - - - - - - - - - - Magnesium stearate 6.25 3.8 6.0 6.0 6.0 6.0 6.0 6.0 6.0 6.0 6.0 6.0 6.0 6.0 Talc - 4.8 13.5 13.5 13.5 13.5 13.5 13.5 13.5 13.5 13.5 13.5 13.5 13.5 Colloidal silicon dioxide 6.25 4.8 5.5 5.5 5.5 5.5 5.5 5.5 5.5 5.5 5.5 5.5 5.5 5.5 Gross weight (mg) 306.3 425.2 350.0 322.0 306.0 298.0 294.0 290.0 294.0 294.0 335.0 335.0 355.0 352.5 Content of active ingredient relative to dry weight (%) 81.6 58.8 71.4 77.6 81.7 83.9 85.0 86.2 85.0 85.0 70.4 70.9 70.4 70.9

More specifically, clarithromycin and microcrystalline cellulose are mixed and povidone (binder) is dissolved in purified water and ethanol, and the mixture is added to the mixture. Then, the resulting product is mixed with croscarmellose sodium, magnesium stearate, talc, Silicon were mixed to prepare a mixture.

≪ Comparative Example 1 &

250 mg of clarithide (Korean Abbott, Lot No. 1029548) containing 250 mg of claritromycin film-coated tablet was used as Comparative Example 1.

≪ Comparative Example 2 &

Comparative Example 2 was prepared in the same manner as in Example 1 prescribed in Japanese Patent Application Laid-Open No. 2005-320267.

≪ Comparative Example 3 &

Comparative Example 3 was prepared by titrating the same as the OF ₇ formulation presented in the literature Int J Pharm Pharm Sci, Vol 4, Suppl 5, 352-357.

EXPERIMENTAL EXAMPLE 1:

The mixtures prepared in Examples 1 to 12 were prepared by tableting at a tableting pressure of 0.9 to 1.0 metric tons. Table 2 shows the results of the automatic hardness tester (Erweka, TBH125, Germany) for tablets that did not show any penile disorder while confirming the occurrence of the tableting problems (sticking, capping, laminating).

More specifically, the tablets were placed in the center of the tabs and the hardness of the tablets was checked by measuring the strength of the force at which the tablet was crushed when the tablets were pressed to a certain degree of force by pressing the tabs.

division Comparative Example Example 2 3 One 2 3 4 5 6 7 8 9 10 11 12 Heart failure radish radish radish radish radish radish radish U U U radish radish radish radish Roughness
Principal component weight% 81.6 58.8 71.4 77.6 81.7 83.9 85.0 86.2 85.0 85.0 70.4 70.9 70.4 70.9 Hardness (kP) 9-10 9-10 9-10 9-10 9-10 9-10 9-10 - - - 11-12 11-12 11-12 11-12

As can be seen from the above Table 2, it was confirmed that the tablets produced by Examples 1 to 5 and Examples 9 to 12 did not cause a tableting trouble.

Examples 1 to 5 and Examples 9 to 12 each contain less than 85% by weight of the main component with respect to the weight of the base material, and both croscarmellose sodium and microcrystalline cellulose.

<Experimental Example 2> Disintegration Test>

The disintegration time in water was measured and the disintegration rate was confirmed based on the Korean Pharmacopoeia Disintegration Test Method in Examples and Comparative Examples 1, 2 and 3 in which the tableting disability was not observed in Experimental Example 1,

Comparative Example Example Disintegration test liquid One 2 3 One 2 3 4 5 9 10 11 12 water 9-11 3 to 4 2 to 3 9-10 9-10 9-10 9-10 9-10 6 to 7 6 to 7 6 to 7 6 to 7

As shown in Table 3, it can be confirmed that the products of Examples 1 to 5 have a disintegration rate similar to that of Comparative Example 1, which is a commercially available product. On the other hand, it was confirmed that Comparative Examples 2 and 3 exhibited a disintegration rate which was 6 to 8 minutes faster than Comparative Example 1 and Examples 1 to 5. It was also found that Examples 9 to 12 had a higher disintegration rate than Comparative Example 1.

<Experimental Example 3> Dissolution Test>

In the above Comparative Examples 1 to 3 and Examples 1 to 5, 900 mL of an eluted solution of 37, pH 6.0 (0.05 M disodium hydrogenphosphate-citric acid mixture) and 0.1 mL of a pH 1 solution were prepared according to the second method in the Korean Pharmacopoeia General Test Method Dissolution Test Method. 2 dissolution test was carried out in artificial gastric juice at a rotation speed of 50 rpm. Then, the dissolution rate of clarithromycin was measured under the following HPLC conditions, and the measurement results are shown in Table 4. [

HPLC conditions

- Detector: Ultraviolet absorptiometer (measuring wavelength 210 nm)

- Column: 4.0 X 150 mm, 5 탆, C18

- Column temperature: 50

- Mobile phase: diluted 0.2 M potassium dihydrogen phosphate solution (1 → 3) acetonitrile mixture (13: 7)

- Flow rate: 1.1 mL / min

division Clarithromycin dissolution rate (%) Low mass
(mg) Principal component weight% pH 1.2 pH 6.0 10 minutes 30 minutes 60 minutes 5 minutes 10 minutes 15 minutes Comparative Example 1 17.4 31.8 45.2 26.7 75.7 88.9 528.5 47.3 Comparative Example 2 20.5 53.1 85.7 52.7 75.7 88.4 306.3 81.6 Comparative Example 3 21.9 55.4 87.9 59.6 88.2 95.6 425.2 58.8 Example 1 12.6 27.0 41.0 31.0 73.3 89.5 350.0 71.4 Example 2 11.9 25.4 40.4 29.9 72.5 88.1 322.0 77.6 Example 3 10.9 25.1 40.1 29.5 71.8 87.9 306.0 81.7 Example 4 11.4 26.3 41.0 30.1 73.2 89.8 298.0 83.9 Example 5 10.8 24.9 41.2 29.7 72.7 88.2 294.0 85.0 Example 9 24.2 48.6 66.5 54.6 92.2 96.3 355.0 70.9 Example 10 21.7 43.8 62.3 50.3 90.4 95.2 352.5 70.4 Example 11 23.3 45.2 63.6 53.8 92.0 95.8 355.0 70.9 Example 12 18.1 40.0 59.8 50.6 91.2 95.1 352.5 70.4

As shown in Table 4, it can be seen that Comparative Example 1, which is a commercially available product, and Examples 1 to 5 have similar dissolution patterns. On the contrary, in the case of Comparative Examples 2 to 3 and Examples 9 to 12, it was found that the elution pattern was faster than in Examples 1 to 5 at pH 1.2 and pH 6.8. The results of this experiment show that although the compact claritromic agent according to the present invention has a smaller watt% of the active ingredient clarithromycin as compared to the market formulation and the prior art, And it was confirmed that the hardness, disintegration and dissolution rate were different depending on the weight of microcrystalline cellulose and croscarmellose sodium in the groups of Examples 1 to 5 and Examples 9 to 12 in particular Could.

EXPERIMENTAL EXAMPLE 4. COMPARISON OF THE COMPOSITION BETWEEN MINIMIZED AND PRESERVED PRODUCTS OF THE INVENTION [

The comparison between the coating formulations of Example 7 and Comparative Example 1, which is a commercial tablet, is shown in Fig. As a result, it can be seen that Example 5 according to the present invention is a miniaturized form which is significantly smaller in size than commercial tablets.

<Experimental Example 5: Stability Test>

The contents of clarithromycin were measured by HPLC with the passage of time after storage in the accelerated test conditions of 40% RH and 75% of Examples 1 and 5 above. The content change was measured according to the HPLC conditions in the dissolution test, and the results of the change in claritromycin content over time are shown in Table 5 below. At this time, the content (%) of claritromycin is a relative value expressed by setting the initial concentration of claritromycin to 100%.

division Claritromycin content (%) Initial 1 week 2 weeks 4 weeks Example 1 100.0 100.0 99.9 99.9 Example 5 100.0 100.0 99.8 99.7

 As shown in Table 5, it was found that the miniaturized claritromycin preparation is excellent in stability.

&Lt; Preparation of Example 9 and Example 10 >

Examples 13 and 14 were prepared by increasing the content of each component in Examples 1 and 5 by two times as shown in Table 6 below.

More specifically, clarithromycin and microcrystalline cellulose are mixed, and povidone is dissolved in purified water and ethanol, and the mixture is put in a mixture. The resultant mixture is mixed with croscarmellose sodium, magnesium stearate, talc and colloidal silicon dioxide To prepare a mixture, which was then tableted at a tableting pressure of 0.9 to 1.0 metric tons to prepare Examples 13 and 14. In all of Examples 13 and 14, no penile disorder was observed.

Raw material name Example 13 Example 14 Claritromycin 500 500 Povidone K-30 30 30 Microcrystalline cellulose 65 4 Sodium croscarmellose sodium 55 4 Magnesium stearate 12 12 Talc 27 27 Colloidal silicon dioxide 11 11 Gross weight (mg) 700 588 Container content (%) 71.4 85.0 Heart failure radish radish

Experimental Example 6 Disintegration Test [

The disintegration rate was measured by conducting the disintegration test in Examples 13 and 14 as in Experimental Example 2. Disintegration time was measured in water to confirm disintegration rate and it is shown in Table 7. When the disintegration rates of Examples 1 and 5 and Examples 13 and 14 were compared, it was confirmed that disintegration times were the same.

division Disintegration time (minutes) Disintegration test liquid
water Example 1 Example 5 Example 13 Example 14 9-10 9-10 9-10 9-10

<Experimental Example 7> Dissolution Test>

In Examples 9 and 10, dissolution tests were carried out as in Experimental Example 3, and the dissolution rates of claritromycin were shown in Table 8. [ When the dissolution patterns of Examples 1 and 5 and Examples 9 and 10 were compared, it was confirmed that they had a similar dissolution pattern.

Clarithromycin dissolution rate (%) pH 6.0 5 minutes 10 minutes 15 minutes Example 9 30.4 72.9 88.8 Example 10 30.6 72.6 88.6

Claims (16)

As an oral preparation containing 250 mg or 500 mg of claritromycin as an active ingredient,
Claritromycin is contained in an amount of at least 70% by weight based on the total weight of the preparation,
Microcrystalline cellulose and croscarmellose sodium,
Wherein the weight ratio of the microcrystalline cellulose: croscarmellose sodium is 1.5: 1 to 1: 1, the weight ratio of croscarmellose sodium: claritromycin is 1: 9 to 1: 125, and the microcrystalline cellulose: claritromycin Is in the range of 1:13 to 1: 125. (Provided that the total weight of the formulation does not exceed 100% by weight). The orally administered preparation according to claim 1, wherein the clarithromycin is contained in an amount of 70% by weight or more and 85% by weight or less based on the total weight of the preparation. The orally administered preparation according to claim 1, wherein the orally administered preparation exhibits the following clarithromycin dissolution rate:
When the test compound was rotated for 30 minutes at a rotation speed of 50 rpm in 900 mL of a dissolution test liquid at 37 DEG C, water and pH 6.0 according to the Method 2 Method paddle method, the dissolution rate of clarithromycin was 25 to 40% 70 to 80% at 10 minutes, and 85 to 95% at 15 minutes; or
When rotated at a rotation speed of 50 rpm for 30 minutes in 900 mL of a dissolution test liquid at 37 DEG C, water and pH 1.2 according to Method 2 of the Korean Pharmacopoeia Dissolution Test Method, the dissolution rate of clarithromycin was 10 to 18% 20 to 35% at 30 minutes, and 35 to 50% at 60 minutes. The orally administered preparation according to claim 1, which exhibits an equivalent clarithromycin dissolution rate when the total weight of clarithromycin contained in the preparation is 250 mg and the total weight of clarithromycin is 500 mg. The oral administration preparation according to claim 1, characterized in that the following formula shows the following clarithromycin dissolution rate when the total weight of claritromycin contained in the preparation is 250 mg and the total weight of claritromycin is 500 mg: :
When the test compound was rotated for 30 minutes at a rotation speed of 50 rpm in 900 mL of a dissolution test liquid at 37 DEG C, water and pH 6.0 according to the Method 2 Method paddle method, the dissolution rate of clarithromycin was 25 to 40% 70 to 80% at 10 minutes, and 85 to 95% at 15 minutes; or
When rotated at a rotation speed of 50 rpm for 30 minutes in 900 mL of a dissolution test liquid at 37 DEG C, water and pH 1.2 according to Method 2 of the Korean Pharmacopoeia Dissolution Test Method, the dissolution rate of clarithromycin was 10 to 18% 20 to 35% at 30 minutes, and 35 to 50% at 60 minutes. The oral preparation according to claim 1, wherein the formulation has a disintegration time of 9 to 11 minutes measured in water according to the Korean Pharmacopoeia Disintegration Test. The orally administered preparation according to claim 1, wherein the sodium croscarmellose and the microcrystalline cellulose are contained in an amount of 1 wt% or more and 20 wt% or less based on the total weight of the preparation. 2. The orally administered formulation according to claim 1, wherein the orally administered preparation is substantially free of crospovidone. delete The microcrystalline cellulose according to claim 1, wherein the microcrystalline cellulose is contained in an amount of 0.5 to 12 wt% based on the total weight of the preparation, and the croscarmellose sodium is contained in an amount of 0.5 to 8 wt% Or a pharmaceutically acceptable salt thereof. The pharmaceutical composition according to claim 1, wherein the microcrystalline cellulose is contained in an amount of not less than 0.5% by weight and not more than 13% by weight based on the total weight of claritromycin contained in the preparation, and croscarmellose sodium is contained in an amount of 0.5 By weight to 11% by weight or less. The orally administered preparation according to claim 1, wherein the preparation further comprises povidone as a binder, talc as a lubricant or a mixture thereof. 13. The orally administered preparation according to claim 12, wherein the povidone is contained in an amount of 4 to 6% by weight based on the total weight of the preparation, and the talc is contained in an amount of 3 to 5% by weight. 2. The orally administered preparation according to claim 1, wherein the orally administered preparation is formulated into tablets. A coated tablet according to claim 1, wherein the orally administered preparation is formulated and coated with a tablet. [16] The method according to claim 15, wherein the coating has a size of 1 cm or more and less than 1.5 cm and a major axis of 1.5 cm or more and less than 2.0 cm when the total weight of clarithromycin is 250 mg. Coating solution.

Images