KR101399514B1 - A stable tablet form containing polaprezinc - Google Patents

Abstract

The present invention relates to a stable tablet formulation which contains polaprezinc and can expect smooth productivity and stable expression of efficacy. The present invention provides the stable tablet formulation containing polaprezinc which is excellent in stability during storage and distribution, facilitates mass production, and has outstanding dissolution rate and bioavailability.

Description

[0001] A STABLE TABLET FORM CONTAINING POLAFREZINC [0002]

The present invention relates to a tablet formulation containing polyprepink and having ensured productivity and stability, in particular, stability related to dissolution rate and bioavailability, and a method for producing the same.

The fact that polaprezinc is a complex of zinc and L-carnosine shows the therapeutic action of peptic ulcer was disclosed in Japanese Patent Laid-Open Publication No. 1984-033270. In Japan, granules and mouthwashes containing polyfrenzin have been introduced and marketed as medicines for the treatment of gastritis and gastric ulcers. However, granules and oral cavity disintegrators are expensive to manufacture, and in particular granules are somewhat uncomfortable for the patient to take, and some of the active ingredients may be lost during the administration.

Accordingly, the present inventors have made various attempts to produce a pharmaceutical formulation containing polyfrenzin at a low cost and easy to take, but have various problems in terms of storage stability, mass productivity, dissolution rate and bioavailability.

Japanese Patent Application Laid-Open No. 1984-033270

Accordingly, a problem to be solved by the present invention is to provide a granule formulation which is excellent in stability during storage and distribution, is easy to mass-produce, and has a different dissolution rate and bioavailability, The present invention provides a pharmaceutical composition of the present invention.

In order to solve the above problems, the present invention is characterized in that the d90 of the particle size of the active ingredient is 500 탆 or less, more preferably the d90 is 300 탆 or less, and most preferably the d90 is 30 to 300 탆 ≪ / RTI >

When the particle size of the polylazinc, which is an effective ingredient of the tablets of the present invention, is in the above-mentioned range, it is not only preferable to the dissolution rate and bioavailability, but also remarkably has a very favorable effect on storage stability and mass production easiness.

When the particle size of the polarized precious zinc is too large, the dissolution rate after the application slows down and it is difficult to expect a sufficient effect of the drug. Further, in the compressed form such as tablets, the elapsed time- . Also, when the particle size of the polar prepreg is too small or too large, problems may arise in mass production such as uneven mixing, poor fluidity, and sticking.

In describing the particle size of the active ingredient in the present specification, it is described as "d90" For example, "d90 = 100 μm" means that at least 90% of the active ingredient particles have an equivalent spherical volume diameter of less than 100 μm. This equivalent spherical volume diameter can be measured using, for example, a Mastersizer (Malvern Instruments), a HELOS Particle Size Analysis (Sympatec) or the like, but the present invention is not limited to such a particle size measuring instrument.

The polar pharmaceutical preparations according to the present invention further comprise additives such as pharmaceutically acceptable excipients, binders, disintegrants, lubricants and the like for preparing tablets.

Microcrystalline cellulose, lactose, calcium phosphate, pregelatinized starch, mannitol, etc. may be used as the excipient, and further, pharmaceutically acceptable ingredients may be further included.

As the binder, hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone and the like may be used, and in addition, other pharmaceutically acceptable ingredients may be further included.

As the disintegrant, croscarmellose sodium, crospovidone, sodium starch glycolate, pregelatinized starch, microcrystalline cellulose, mannitol and the like can be used, and further, pharmaceutically acceptable ingredients may be further included.

As the lubricant, magnesium stearate, calcium stearate, stearic acid, talc, colloidal silicon dioxide, sodium stearyl fumarate and the like may be used, and further, pharmaceutically acceptable ingredients may be further included.

The present invention also relates to a method for producing a tablets comprising an active ingredient of a polyfrenzin having the above-mentioned particle size distribution according to the present invention, wherein the ingredients to be added are microcrystalline cellulose and crospovidone (more preferably microcrystalline cellulose, crospovidone, Magnesium stearate) is more preferable in view of various purposes of the present invention, that is, in terms of dissolution rate, bioavailability, storage stability, ease of mass production, and the like.

In the case where the particle size of the polyfrenzin is not in the range according to the present invention, the influence of other additives is small, but when the particle size of the polar prezink is in the range of the present invention, the microcrystalline cellulose and crospovidone Microcrystalline cellulose, crospovidone, and magnesium stearate) were very preferable.

Accordingly, the present invention provides a tablets (straight-tablets) characterized by being prepared by uniformly mixing and then compressing a polyfrenzine, microcrystalline cellulose, crospovidone and optionally magnesium stearate having a particle size distribution according to the present invention .

The polypregnancy tablets according to the present invention were prepared by using 900 mL of pH 4.0 buffer as the elution medium and having a dissolution rate of 85% or more at 15 minutes using paddles at a rotation speed of 50 rpm. The dissolution rate was packed in a high density polyethylene container It can be kept for 6 months when stored at 40 ℃ and 75% relative humidity.

In addition, when the tablets are prepared by direct mixing with the components constituting the polar foreskin tablets according to the present invention, problems such as mixing unevenness and poor fluidity do not occur, and it is preferable that the tablet contains about 10,000 tablets (preferably 50,000 tablets, more preferably, There is no problem of mass production such as sticking during the production of tablets of 100,000 tablets.

Further, the polypregnancy tablets according to the present invention are geometric mean values of pharmacokinetic parameters calculated using zinc blood concentration corrected for baseline values after administration to humans, Cmax is within the range of 0.8-1.0 μg / mL, and AUC is 2.7 To 3.3 μg · hr / mL.

The present invention provides a tablet formulation containing polyprepinke that is superior in stability during storage and distribution, is easy to mass-produce, and is comparable to granule formulations having different dissolution rates and bioavailability.

FIG. 1 shows the results of a comparative dissolution test of tablets and commercial granules according to one embodiment of the present invention.

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.

Example  One: Paula Prezink  Preparation of tablets containing

75 g of a polarizing powder having a particle size d90 of about 290 μm, 63 g of microcrystalline cellulose, 10 g of crospovidone, and 2 g of magnesium stearate were uniformly mixed. The mixture was compressed using a suitable tablet machine to prepare tablets containing the polyfrenzin.

Example  2: Comparative dissolution test of tablet and commercial product

A comparative dissolution test of tablets prepared according to Example 1 and commercially available granules was carried out. 900 mL of pH 4.0 buffer was used as an eluent, and a paddle method with a rotation speed of 50 rpm was used as an elution method. The results of the comparative dissolution test were as shown in Fig. 1 below, and reached a dissolution rate equivalent to that of the granule preparation within 15 minutes.

Example  3: Paula Prezink In size  Change over time of tablet elution rate

Example  3-1: Time-dependent change of refining dissolution rate during storage of accelerated conditions

A tablet containing polyfrenzin was prepared according to the same composition and manufacturing method as in Example 1, using a polarized prism having a particle size d90 of about 580 μm.

The prepared tablets and the tablets of Example 1 were packed in a high-density polyethylene container and stored at 40 DEG C and 75% relative humidity. The stored tablets were taken out one month, two months, three months, and six months after the storage, and the dissolution test was carried out in the same manner as in Example 2, and the results were as shown in Table 1 below.

Tablets prepared using polylazinc with a particle size d90 of about 580 μm showed a very large decrease in dissolution rate when stored at 40 ° C and 75% relative humidity, which corresponds to the accelerated conditions. The 15-minute dissolution rate in the pH 4.0 buffer is a dissolution test standard for testing the stability of commercially available polofinke preparations. The dissolution rate during the storage of the accelerated conditions for 6 months is usually set at the recommended level 80%, it is thought that the constant effect of the drug can not be expected during the storage period.

Paula Prezink In size  Results of refining dissolution test during storage of accelerated conditions Paula Prezink
D90 of particle size pH 4.0, 15 minute dissolution rate (%) Early 1 month 2 months 3 months 6 months 290 μm 97.9 99.1 96.2 92.4 88.1 580 μm 89.2 92.1 85.0 81.3 70.4

Example  3-2: Time-dependent change of refining dissolution rate during storage of harsh conditions

Tablets containing polyfrenzin were prepared according to the same composition and manufacturing method as in Example 1 using polylactic acid having a particle size d90 of about 110 μm, 210 μm, 320 μm and 580 μm.

The prepared tablets and the tablets of Example 1 were placed in glass vials and stored at 60 DEG C and 75% relative humidity without being capped. A part of the stored tablets was taken out after one week, two weeks, and four weeks after storage, and a dissolution test was carried out in the same manner as in Example 2. The results are shown in Table 2 below.

The tablets stored under harsh conditions showed a significant difference in the time course of the dissolution rate according to the particle size of the polarized zinc. Since the results of the severe condition 4 were similar to those of the accelerated condition 6 months, when the stability of the tablet was predicted based on the results of the severe condition 4, it was found that when the particle size of the polar prinks was about 300 μm or less, And the expression of TGF - β1 was thought to be expected.

Paula Prezink In size  Results of refinement dissolution test during storage under severe conditions Paula Prezink
D90 of particle size pH 4.0, 15 minute dissolution rate (%) Early 1 week 2 weeks 4 weeks 110 μm 97.7 97.5 95.2 94.4 210 μm 97.0 96.7 92.1 91.3 290 μm 96.5 95.2 92.6 90.5 320 μm 94.5 91.4 88.7 84.2 580 μm 87.0 83.2 77.6 72.3

Example  4: Paula Prezink In size  Manufacturing Fairness

Example  4-1: Sticking ( sticking ) Test on occurrence

The tablets containing the polar prinx were prepared according to the same constituents and manufacturing method as in Example 1 using a polarizing plate having a particle size d90 of about 21 μm, 290 μm and 580 μm.

In the case of using a polarized pre-zink having a particle size of about 290 μm and 580 μm, there was no problem during the production of 100,000 tablets. However, when using a polar pre-zink having a particle size d 90 of about 21 μm, Sticking which is a phenomenon that a part of the tablet is attached to the engraved portion of the punch for the tablets has occurred from the time of manufacture.

Example  4-2: Mixed Unevenness  Test of occurrence

Polar flexure having a particle size d90 of about 7 [mu] m, 37 [mu] m and 290 [mu] m was mixed with the same constituents as in Example 1. [ A small amount of specimens were collected from 6 different sites of the mixture and weighed 150 mg separately and the contents were measured. The results were as shown in Table 3 below.

As a result of the content test of the mixture using the polarized zinc powder having d90 of 7 μm in particle size, the variation coefficient of the measured values was not more than 5% and the content uniformity was not suitable for the production, and between the polar prepreg and other additives The reason for this is the occurrence of classification due to the difference in particle size. The coefficient of variation of the content values was less than 1% when the polarized zink having a particle size d90 of 37 μm and 290 μm was used. Therefore, it was considered that mixing unevenness would not occur in the manufacturing process of the tablets using a polarized zinc powder having a particle diameter d90 of 30 μm or more.

Paula Prezink In size  Test results of the content of mixture according to content(%) D90 of Paula prezink particle size 7 μm 37 μm 290 μm Measured value -1 104.9 99.1 100.0 Measure -2 104.7 100.3 101.4 Measure -3 113.4 99.7 101.6 Measured value -4 96.7 98.8 99.4 Measure -5 97.1 100.6 102.2 Measure-6 107.9 99.7 101.2 Average 104.1 99.7 101.0 Standard Deviation 6.4 0.7 1.1 Coefficient of variation 6.2% 0.7% 1.0%

Example  4-3: Test for fluidity of mixture

Polar flexure having a particle size d90 of about 7 [mu] m, 37 [mu] m and 290 [mu] m was mixed with the same constituents as in Example 1. [ As a result of measuring the fluidity of the mixtures with a 15 mm funnel mounted on a fluidity measuring instrument, the mixture using the polar prinks having a particle size d90 of 37 μm and 290 μm smoothly passed through the funnel, The mixture with zinc did not pass through the funnel. Therefore, it was considered that the use of the polarized prinks having a particle diameter d90 of 30 μm or more would not cause problems due to poor fluidity during the production of tablets.

Example  5: Bioequivalence study of tablets and commercial products

In 63 healthy adult men, the tablets prepared in the same manner as in Example 1 were used as a test drug, and a commercially available granular preparation was used as a reference drug for randomization, single administration, and 2 × 2 cross test Was carried out.

The bioequivalence was determined according to the statistical evaluation method based on the drug equivalence test standard based on the values of the pharmacokinetic parameters calculated through the blood zinc concentration after administration. Zinc, an indicator component of the equivalence determination, is an endogenous substance, and pharmacokinetic parameters should be calculated using the blood concentration corrected for baseline according to the bioequivalence study standard. Therefore, in order to measure the basal value of zinc concentration in the blood, the blood was collected in the same manner as the blood collection schedule after the administration on the day before the administration.

The two preparations were orally administered on the day of dosing, and blood samples were collected for 8 hours to measure changes in the zinc blood concentration over time. Inductively Coupled Plasma - Mass Spectrometry (ICP - MS) was used to analyze zinc in blood. Precision, accuracy, and stability tests were performed on the zinc component for one day and one day.

The AUC (blood concentration curve backward), Cmax (maximum blood concentration) and Tmax (maximum blood concentration reaching time) after the baseline correction were calculated from the zinc concentration analysis results of the blood samples, The bioequivalence of the drug was determined, and Tmax was used as a reference value. The geometric mean values of the pharmacokinetic parameters calculated using the Zinc Blood Concentration after the baseline correction of the reference drug and the test drug and the 90% confidence interval of the test drug / control drug geometric mean ratio and geometric mean ratio were as shown in Table 2 below. Both the Cmax and AUC of the 90% confidence interval were included within the range of 0.80 to 1.25, which is the criterion for bioequivalence, and it was expected that the tablets produced had the same level of drug efficacy as the commercial granules.

Basal  Results of statistical treatment using zinc concentration after correction Treaty Test drug Geometric mean ratio 90% confidence interval of mean ratio Cmax (μg / mL) 0.921 0.918 0.996 0.960 to 1.034 AUC (μg · hr / mL) 2.995 3.046 1.015 0.975 to 1.058

Claims (11)

A tablet made by the direct method, characterized in that it contains a polarizing agent having a particle size (d90) of not more than 500 μm corresponding to 90% of the maximum particle size in the cumulative distribution of the particles as an active ingredient. The tablet according to claim 1, wherein d90 of the particle size of the polarized zinc is 300 m or less. The tablet according to claim 1, wherein d90 of the particle size of the polarized zinc is 30 to 300 m. The tablet of claim 1, wherein the tablet further comprises microcrystalline cellulose and crospovidone. The tablet of claim 4, wherein the tablet further comprises magnesium stearate. The tablet according to claim 4, wherein the tablet is prepared by uniformly mixing and then compressing the polyphenzin, microcrystalline cellulose and crospovidone. The tablet according to claim 5, wherein the tablet is prepared by uniformly mixing and then compressing the polyphenzin, microcrystalline cellulose, crospovidone, and magnesium stearate. delete The tablet according to claim 1, wherein the tablets do not suffer from sticking, mixing irregularities, and poor flowability during manufacture by the direct method. 4. The method according to any one of claims 1 to 3, wherein 900 mL of pH 4.0 buffer is used as the elution medium of the tablet, the dissolution rate at 15 minutes is 85% or more when paddles at a rotation speed of 50 rpm are used, Wherein the dissolution rate is kept in a high-density polyethylene container for 6 months when stored at 40 DEG C and 75% relative humidity. 4. The method according to any one of claims 1 to 3, wherein the geometric mean value of the pharmacokinetic parameters calculated using the zinc blood concentration corrected for baseline after administration to the human of the tablet is in the range of 0.8 to 1.0 μg / mL And wherein the AUC is contained in the range of 2.7 to 3.3 μg · hr / mL.

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