KR100407519B1 - Sustained release tablet containing dried ferrous sulfate and L-glutamine as releasing controller - Google Patents

Abstract

The present invention relates to a sustained release tablet containing dry ferrous sulfate as an anemia treatment agent and a method for producing the same. Specifically, Eudragit S 100, a methacrylic acid copolymer, is used as a sustained-release matrix agent, calcium hydrogen phosphate is used as a matrix formation aid, and L-glutamine with gastric mucosal repair is used as a release control agent of dry ferrous sulfate. The present invention relates to a sustained-release tablet containing dry ferrous sulfate, which minimizes irritation to gastric mucosa of general sustained-release iron, and adjusts the mixing ratio of the water-soluble substance of L-glutamine and ferrous sulfate and the insoluble methacrylic acid copolymer. Is to optimize the dissolution.

Description

Sustained release tablet containing dried ferrous sulfate and L-glutamine as releasing controller

Iron agents used to treat anemia include iron for injection such as ferric chloride (FeCl ₃ ), reduced divalent iron salt preparations such as dry ferrous sulfate, trivalent iron complex preparations, and biological iron preparations, and have side effects such as constipation and gastric mucosal irritation. Nevertheless, oral administration of reduced bivalent iron preparations has become a mainstay of iron deficiency anemia treatment for economic and economic reasons.

Reduced divalent iron salts, such as ferrous sulfate, are ionized in the gastrointestinal tract and are easily absorbed, but some of them irritate the gastrointestinal mucosa and affect gastrointestinal mucosa cells, and some cause side effects such as nausea, vomiting and constipation. In order to reduce these side effects and to increase the compliance with the medication, a lot of slow-release formulations of dry ferrous sulfate have been developed to alleviate the side effects of iron to some extent, but it is difficult to fundamentally solve the side effects of iron powder caused by human constitution.

Sustained release formulations according to the conventional methods for preparing matrix tablets (The theory and practice of industrial pharmacy, 3rd ed., 1986, 143p) are methacrylic acid copolymers, matrix forming agents, insoluble materials and hydrophilic materials (hydrophilic). It is known to use a water-soluble polymer material (e.g. polyvinylpyrrolidone) as a release control agent in the case of sustained release iron, but the release of iron is controlled in the case of the controlled release iron Nevertheless, concerns about irritation to the gastric mucosa of iron are still not resolved.

In order to alleviate the irritation of the gastric mucosa of the iron agent, the present inventors experimented with a combination of the iron agent for many substances having a gastric mucosal protective action, and as a result, L-glutamine having gastric mucosal protective action The present invention was completed by finding that the dissolution of the drug can be optimized by controlling the blending ratio of the insoluble methacrylic acid copolymer and L-glutamine that can be used without changing the formulation and also used as a mattress in sustained-release tablets.

Calcium hydrogen phosphate used as matrix forming aid in the present invention is an insoluble matrix with Eudragit S 100 as a water insoluble substance and an amino acid having an amide which is a protein peptide component, and L-glutamine is added to the matrix formation as a water-soluble substance. By adjusting the mixing ratio, it was possible to optimize the elution of dry ferrous sulfate as a main component.

L-glutamine used in the present invention is one of the amino acids having an amide structure is an important energy source of small intestinal absorbent cells and helps the growth of intestinal epithelial cells. In addition, it proliferates and enhances the ability of immune cells to enter the mucosal mucosa, thus protecting the intestinal mucosa and restoring the damaged intestinal mucosa, and has been applied as a therapeutic agent for stomach and duodenal ulcers. (Encyclopedia of chemical technology Vol. KFDA Notification No. 2000-54, Japanese Medicine Collection 2001). L-Glutamine is also a very safe substance and is intended to be used as a food additive in CFR 172.320 of the US FDA.

L-glutamine has no compounding change with ferrous sulfate but can form a water-soluble ferro glutamine sulfate complex, similar to ferro glycine sulfate (US patent 2,877,253 and 2,957,806), depending on the pH of the water-soluble medium, such as glycine. However, ferro glycine sulfate is difficult to expect its own gastrointestinal repair. In contrast, a mixture of L-glutamine and dry ferrous sulfate can be expected to repair gastric mucosa. L-glutamine has been applied as a drug release modulator with gastric mucosal repair in sustained-release tablets of the present invention as a water-soluble substance.

The methacrylic acid copolymer used in the present invention is a copolymer of methacrylic acid and acrylic acid ester or methacrylic acid ester, and is divided into various kinds according to the ratio of structural unit materials and its physical properties also vary. Eudragit S 100 used in the present invention is a copolymer of methacrylic acid and methyl methacrylate (1: 2), which is insoluble in gastric fluid and soluble in enteric fluid with a pH of 7.0 or above, and is used in sustained-release preparations and enteric preparations. felled Substance(Hand book of pharmaceutical excipients 3th edition, Arthur H. Kibbe).

Although formulations using methacrylic acid copolymers have been developed for dry ferrous sulfate sustained-release tablets (eg Fero-grad , 500 Filmtab , Fero-gradumet , Filmtab , Iberet-500 , Filmtab , Abbort, Source: PDR 51th ed., 1997), preparations using methacrylic acid copolymers as matrixing agents and L-glutamine with gastrointestinal mucosal repair have not been reported. Table 2 below shows the composition of the dry ferric sulfate-containing formulation, which was harvested from Physicians desk reference (PDR) 51th ed., 1997.

Examples of compositional ingredients of dry ferrous sulfate-containing preparations in literature (PDR 51th, 1997) (unit; mg / 1 tablet) Name product name FEOSOL Tab. FERO-GRAD fct IBERET-500 fct SLOW-FE IROSPAN Dry ferrous sulfate 200 (65) 336 (105) 336 (105) 160 (50) 200 (65) Ascorbic acid 500 (Na Salt) 500 (Na Salt) 150 Niacinamide 30 Calcium Pantothenate 10 Nitrate Nitrate 6 Riboflavin 6 Pyridoxine hydrochloride 5 Vitamin b12 0.025 Folic acid 0.4 Methacrylic acid copolymer √ √ PVP K30 √ √ Potato starch √ √ Talc √ √ √ √ Magnesium stearate √ √ √ Titanium oxide √ √ √ √ Corn starch √ HPMC 2910 √ √ Calcium sulfate √ Glucose √ Stearic acid √ √ PEG √ √ √ Sod. laurylsulfate √ Mineral oil √

※ 1. All except FEOSOL Tab. Are controlled release or slow release tablets.

2. Values in () of dry ferrous sulfate column are converted into iron amounts.

3. √: Ingredient included in the drug substance in unknown quantity.

The present invention utilizes L-glutamine having gastrointestinal mucosal repair as a release control agent and releases ferrous sulfate slowly from the gastrointestinal tract using a water-insoluble matrix based on methacrylic acid polymer Eudragit S 100 to rapidly release iron salt. Reduce gastrointestinal side effects due to ionization, and take water-soluble iron preparations to reduce side effects such as ironic metallic fishy taste and discoloration of teeth, and reduce the number of doses of medication to improve patient compliance It is to provide a sustained release tablet that can be.

Figure 1 shows the iron dissolution curve of the present invention by the Food and Drug Administration Notice (1999-127) dissolution test method.

Figure 2 shows the iron dissolution curve of Example 1 by the US Pharmacopeia 24 revised dissolution test 3 method.

In order to control the elution of sustained-release tablets containing ferrous sulfate, and to minimize the irritation to the gastric mucosa of the sustained-release iron, L-glutamine as an essential ingredient is used as an essential component. In addition, dry ferrous sulfate: Eudragit S 100, a methacrylic acid copolymer used as a mattress, as a matrix forming aid, and the mixing ratio of calcium hydrogen phosphate: L-glutamine is 1: 0.04 to 0.20: 0.07 to 0.60: 0.07 to 0.32. By optimizing the dissolution pattern of the iron component.

The methacrylic acid copolymer used in the present invention is a copolymer of methacrylic acid and acrylic acid ester or methacrylic acid ester, and is divided into various kinds according to the ratio of structural unit materials and its physical properties also vary. Eudragit S 100 used in the present invention is a copolymer of methacrylic acid and methyl methacrylate (1: 2), which is insoluble in gastric juice and soluble in intestinal fluid of pH 7.0 or above, and is used in sustained-release preparations and enteric preparations. Hand book of pharmaceutical excipients 3th edition, Arthur H. Kibbe . However, controlling the iron dissolution rate with methacrylic acid alone has a large effect on the dissolution amplitude. Therefore, in order to obtain a consistent dissolution pattern and to obtain a desired dissolution pattern, the water-insoluble substance of the methacrylic acid copolymer and calcium hydrogen phosphate and the water-soluble substance L- It is necessary to select the blending ratio of glutamine and dry ferrous sulfate.

Although the present invention will be described in more detail with reference to the following examples, the present invention is not limited to the following examples.

Example 1

L-glutamine 30mg, calcium hydrogen phosphate 50mg, magnesium silicate, ascorbic acid, potato starch and 4/5 of dry ferrous sulfate were blended into 300 탆 apples into the v-type mixer in the formulation shown in Table 2 below. Methacrylic acid copolymer (Euradragit S 100) corresponding to 2/3 of the mixture is added to prepare a mixture. While stirring on a tank, isopropanol, dibutyl phthalate, purified water, and the remaining 1/3 of the methacrylic acid copolymer (Euradragit S 100) were added to dissolve and stirred to prepare a fed solution. The mixture and the mixture are mixed with stirring, and then granulated. The granules are evenly spread over a hot water dryer bart and terminated when the drying loss is about 3-4%. The dried granules are sieved to an oscillator with a mesh size of 1500 μm, and then polyvinylpyrrolidone, talc, magnesium stearate, hardened castor oil and the remaining 1/5 dry ferric sulfate are added and mixed with a v-stirrer.

Tableting was used as a rotary tableting machine and tablet diameter was 10.5 ± 0.1mm, thickness 4.26 ± 0.1mm, curvature radius 10mm, hardness 60 ~ 80N, tablet weight 480mg was prepared.

The coating process followed the ordinary sugar process and details are as follows. The tablets are first transferred to a dry coater and then coated with a solution of hydroxypropylmethylcellulose 2910 dissolved in an isopropanol-dichloromethane mixture. Subcoating with a subcoating solution containing talc, white sugar, gum arabic and corn starch, and then pigmented with a solution containing gelatin, white sugar, red No. 3, titanium oxide, white lead, carnauba wax in purified water-isopropanol mixture After the process, the tablets are transferred to a light pan and lighted using a light powder.

Example 2

In the non-oil formulation of Example 1, 50 mg of L-glutamine was combined and the calcium hydrogen phosphate was reduced to 30 mg to prepare the same method as in Example 1.

Comparative Example 1

In the non-oil formulation of Example 1, calcium hydrogen phosphate was prepared in the same manner as in Example 1, omitting 80 mg of L-glutamine.

Comparative Example 2

In the non-oil-free composition of Example 1, 80 mg of L-glutamine was blended and calcium hydrogen phosphate was omitted to prepare the same method as in Example 1.

Example 3

In the non-oil composition of Example 1, 50 mg of L-glutamine and 100 mg of calcium hydrogen phosphate were combined and prepared in the same manner as in Example 1.

Example 4

In the non-oil composition of Example 1, 80 mg of L-glutamine and 150 mg of calcium hydrogen phosphate were combined and prepared in the same manner as in Example 1.

Compositions and Contents of the Dry Ferrous Sulfate Sustained-Release Tablets of Examples 1-2 Ingredients (mg / 1 tablet) Example 1 Example 2 Medicine Dry Ferrous Sulfate (80mg as Fe) 256.0 256.0 Dissolution Adjuster L-Glutamine 30 50 Excipient Calcium hydrogen phosphate 50 30 Binder Methacrylic acid copolymer 20.84 20.84 Binder Povidone K30 4.0 4.0 Excipient Magnesium silicate 50.0 50.0 Excipient Potato starch 2.0 2.0 Antioxidant Ascorbic acid 30.0 30.0 Lubricant Magnesium Stearate 1.8 1.8 Lubricant Talc 18.0 18.0 Lubricant Cured Castor Oil 19.0 19.0 Agenda White sugar 197.0 197.0 Agenda Talc 79.0 79.0 Agenda Titanium oxide 0.58 0.58 Agenda Corn starch 14.4 14.4 Agenda Hydroxypropylmethylcellulose 2910 9.0 9.0 Agenda gelatin 1.2 1.2 Agenda Precipitated Calcium Carbonate 20.0 20.0 Agenda Gum arabic 4.3 4.3 coloring agent Red 3 Quantity Quantity Polish White lead Quantity Quantity Polish Carnauba Nap Quantity Quantity

Composition and Contents of the Dry Ferrous Sulfate Sustained-Release Tablet of Comparative Examples 1 and 2 Ingredients (mg / 1 tablet) Comparative Example 1 Comparative Example 2 Medicine Dry Ferrous Sulfate (80mg as Fe) 256.0 256.0 Dissolution Adjuster L-Glutamine 0 80 Excipient Calcium hydrogen phosphate 80 0 Binder Methacrylic acid copolymer 20.84 20.84 Binder Povidone K30 4.0 4.0 Excipient Magnesium silicate 50.0 50.0 Excipient Potato starch 2.0 2.0 Antioxidant Ascorbic acid 30.0 30.0 Lubricant Magnesium Stearate 1.8 1.8 Lubricant Talc 18.0 18.0 Lubricant Cured Castor Oil 19.0 19.0 Agenda White sugar 197.0 197.0 Agenda Talc 79.0 79.0 Agenda Titanium oxide 0.58 0.58 Agenda Corn starch 14.4 14.4 Agenda Hydroxypropylmethylcellulose 2910 9.0 9.0 Agenda gelatin 1.2 1.2 Agenda Precipitated Calcium Carbonate 20.0 20.0 Agenda Gum arabic 4.3 4.3 coloring agent Red 3 Quantity Quantity Polish White lead Quantity Quantity Polish Carnauba Nap Quantity Quantity

Composition and Contents of the Dry Ferrous Sulfate Sustained-Release Tablets of Examples 3 to 4 Ingredients (mg / 1 tablet) Example 3 Example 4 Medicine Dry Ferrous Sulfate (80mg as Fe) 256.0 256.0 Dissolution Adjuster L-Glutamine 50 80 Excipient Calcium hydrogen phosphate 100 150 Binder Methacrylic acid copolymer 20.84 20.84 Binder Povidone K30 4.0 4.0 Excipient Magnesium silicate 50.0 50.0 Excipient Potato starch 2.0 2.0 Antioxidant Ascorbic acid 30.0 30.0 Lubricant Magnesium Stearate 1.8 1.8 Lubricant Talc 18.0 18.0 Lubricant Cured Castor Oil 19.0 19.0 Agenda White sugar 197.0 197.0 Agenda Talc 79.0 79.0 Agenda Titanium oxide 0.58 0.58 Agenda Corn starch 14.4 14.4 Agenda Hydroxypropylmethylcellulose 2910 9.0 9.0 Agenda gelatin 1.2 1.2 Agenda Precipitated Calcium Carbonate 20.0 20.0 Agenda Gum arabic 4.3 4.3 coloring agent Red 3 Quantity Quantity Polish White lead Quantity Quantity Polish Carnauba Nap Quantity Quantity

[Test Example 1]

In the dissolution test method, the elution term of dried ferrous sulfate and mucoprotease sustained-release tablets of 1999-127 was used.

1) Test solution

a. Artificial gastric juice (pH 1.2): 2 g of NaCl and 80 ml of 1N-HCl are added to a 1 L flask, and distilled water is added to make 1000 ml.

b. Artificial gastrointestinal fluid (pH 4.5): 5 g NaCl and 6 g Glycerine 6 g 1N-HCl 6.5 mL are added to a 1 L flask, and distilled water is added to make 1000 mL.

c. Artificial intestine solution (pH 7.0): 1 g NaHCO _3, 1 g NaCl, NaH ₂ PO ₄ ㆍ 2H ₂ O, 5 g peptone powder (bactopeptone Difico 0118-10) is added to a 1L flask and distilled water is added to make 1000mL.

2) Apparatus: Dissolution test was carried out in accordance with the disintegration test apparatus of the Korean Pharmacopoeia General Test Methods. However, one glass tube with an outer diameter of about 23.5mm, a radius of 21.5 ± 0.5mm and a length of 77.5mm ± 2.5mm shall be used.

3) How to operate: Put 1 tablet of test tablet into the glass tube of the above figure, immerse in a measuring cylinder containing 60 ~ 70ml of artificial gastric juice, and perform vertical movement of amplitude of 50 ~ 60mm (28 ~ 32 times for 1 minute) in 37 ℃ water bath for 1 hour. do. Do not use an auxiliary plate. Elution for 6 hours in the order shown in Table 5 below (n = 6)

time Test solution pH 0 to 1 Artificial gastric juice pH 1.2 1 to 2 Artificial gastric juice pH 1.2 2-3 Artificial gastric juice pH 4.5 3 to 4 Artificial serous pH 7.0 4 to 5 Artificial serous pH 7.0 5 to 6 Artificial serous pH 7.0

The amount of iron ions (Fe ⁺⁺ ) eluted after 1 hour of vertical movement is quantified by the following test method.

4) Determination of iron ions (Fe ⁺⁺ )

Take up the total amount of the eluate, mix 20 mL of diluted sulfuric acid and 80 mL of freshly boiled and cooled water, and titrate this solution with 0.1 mol / L cerium sulfate solution to quantify iron ions (Fe ⁺⁺ ). (Indicator o -phenanthroline solution)

0.1M selium sulfate solution 1mL = 5.585mg Fe ⁺⁺

As a dissolution test method of the dry ferrous sulfate sustained-release tablet and the upper and lower limits on the dotted line shown in Figure 1, the elution term of the dry ferrous sulfate and mucoprotease sustained-release clause No. 1999-127 of the Food and Drug Safety Notice was used. If the elution is below the lower limit, the elution in the gastrointestinal tract is not good, so the iron is not absorbed properly in the duodenum and small intestine, which are the main absorption sites of iron. May cause According to FIG. 1 and Table 6, the most preferred elution of Example 1 using 30 mg of L-glutamine and 50 mg of calcium hydrogen phosphate was shown. When 80 mg or more of L-glutamine is used without using calcium hydrogen phosphate as in Comparative Example 2, dry ferrous sulfate is overdissolved, and when 80 mg of calcium hydrogen phosphate is used and L-glutamine is not used as in Comparative Example 1 The amount was much less than the standard. As a result of manufacturing and testing as in Example 3 and Example 4, the elution criteria were slightly deviated slightly at some time, but most of the elution criteria were satisfied, and Example 1 showed the most preferable dissolution rate.

[Test Example 2]

USP XXIV, 2000, p1994 The general test method was tested using the test method using "Reciprocating Cylinder" of "Drug release" clause <724>. Although it differs from the test equipment, 250 mL eluate is used instead of 70 mL of eluent specified in the Food and Drug Administration. The up and down reciprocation of the elution device was performed 30 times per minute, and diluted sulfuric acid was used to adjust the concentration of acid after elution. Use 33mL instead of 20mL, and 80mL of boiled and cooled water already has USP eluate of 250mL, so all operations and test methods are the same except that it is not used.

The result of testing the tablet produced by Example 1 by Test Example 2 is shown in Table 8 and FIG. According to Fig. 2, even with this test method, the standard of the cumulative amount of Fe ( ⁺⁺ ) dissolution according to the elution term of the dry ferrous sulfate / mucoprotease sustained-release clause of 1999-127 Came out to fit. Therefore, the preparation of sustained-release iron preparations according to the present invention The method is considered to be an excellent method.

time Elution amount of iron ion (mg) Reference (mg) Example 1 Example 2 Comparative Example 1 Comparative Example 2 Lower limit maximum 0 0.0 ± 0.0 0.0 ± 0.0 0.0 ± 0.0 0.0 ± 0.0 0 0 One 31.6 ± 0.4 42.1 ± 0.6 19.0 ± 0.5 47.6 ± 0.5 29.7 36.3 2 48.0 ± 0.5 59.5 ± 0.7 31.8 ± 1.0 66.3 ± 0.9 42.3 51.7 3 56.6 ± 0.6 69.0 ± 0.6 38.9 ± 1.2 79.7 ± 0.5 50.4 61.6 4 59.3 ± 0.6 71.2 ± 0.8 41.2 ± 1.2 83.2 ± 0.6 54.9 67.1 5 61.5 ± 0.5 74.2 ± 0.9 43.3 ± 1.2 85.8 ± 0.6 58.5 71.5 6 63.2 ± 0.4 76.1 ± 1.3 44.8 ± 1.2 88.0 ± 0.6 60.3 73.7

time Elution amount of iron ion (mg) Reference (mg) Example 3 Example 4 Lower limit maximum 0 0.0 ± 0.0 0.0 ± 0.0 0 0 One 27.6 ± 0.4 37.1 ± 0.8 29.7 36.3 2 43.5 ± 1.1 54.5 ± 0.9 42.3 51.7 3 52.3 ± 1.3 63.1 ± 1.1 50.4 61.6 4 54.9 ± 0.9 66.9 ± 1.3 54.9 67.1 5 57.5 ± 0.8 69.9 ± 1.2 58.5 71.5 6 58.2 ± 0.9 70.5 ± 1.1 60.3 73.7

time Elution amount of iron ion (mg) 0 0 One 33.4 2 50.6 3 58.3 4 61.5 5 65.1 6 69.0

The present invention relates to a sustained-release tablet containing dry ferrous sulfate as an anemia treatment agent. By using L-glutamine having gastric mucosal repair as a release regulator of dry ferrous sulfate, the irritation to the gastric mucosa of general sustained-release iron preparations is minimized. The dissolution of the drug can be optimized by adjusting the mixing ratio of the water-soluble substance of L-glutamine and dry ferrous sulfate and the methacrylic acid copolymer which is an insoluble substance.

Claims (4)

In sustained-release tablets containing dry ferrous sulfate, Eudragit S 100, a methacrylic acid copolymer, is used as a mattress, calcium hydrogen phosphate is used as a mattress formation aid, and L-glutamine is used as a gastric mucosa protection and release control agent. A sustained-release tablet containing dry ferrous sulfate, characterized in that. The dry ferrous sulfate-containing sustained-release tablet according to claim 1, wherein the mixing ratio of L-glutamine as a ferrous sulfate: release control agent is 1: 0.07 to 0.32. The method of claim 1 or claim 2, wherein the dry ferrous sulfate: Eudragit S 100, which is a methacrylic acid copolymer to be used as a mattress, and the proportion of calcium hydrogen phosphate to be used as a matrix forming aid are 1: 0.04 to 0.20: A sustained-release tablet containing dry ferrous sulfate, which is 0.07 to 0.60. A mixture was prepared by mixing L-glutamine, calcium hydrogen phosphate, magnesium silicate, ascorbic acid, potato starch and 4/5 of the dry ferrous sulfate and 2/3 of the methacrylic acid copolymer (Euragit S 100). While stirring on a tank, 1/3 of the amount of the organic solvent and purified water and Eudragit S 100 was added and dissolved to prepare a coalescing solution. The coalescing mixture was mixed with the coalescing solution while stirring, the granules were prepared, dried, and then poly Preparation of sustained-release tablets containing ferrous sulfate, characterized in that by adding 1/5 of the vinylpyrrolidone, talc, magnesium stearate, hardened castor oil and dry ferrous sulfate, mixing, tableting and coating sugar Way.