JP4224866B2 - Base with controlled dissolution time - Google Patents

Description

[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a base capable of delaying the dissolution time in the digestive tract and a preparation using the same.
[0002]
[Prior art]
In recent years, various drug delivery methods (drug delivery systems) have been proposed in order to cause a drug to directly act on a disease site. Known oral preparations include time-release preparations and sustained-release preparations. A time-release preparation is a preparation that releases a drug after a certain lag time, and is a preparation that releases a drug after a certain time has elapsed after oral administration.
[0003]
As a time-release preparation, a preparation in which a drug and a swelling agent are coated with a water-insoluble substance, and the swelling agent that has absorbed moisture with time elapses ruptures the tablet from the inside to release the drug is disclosed in JP-A-62-30709 It is described in.
[0004]
Advantages of timed-release preparations include diseases that cause abnormal blood pressure and heart rate with constant periodicity, asthma and low back pain that require high drug blood levels when waking up or early in the morning It is effective in the treatment of diseases such as hypotension.
[0005]
In recent years, attempts have been made to deliver drugs to the large intestine with a system in which an enteric coating is applied to these granules and the system has a lag time corresponding to a transit time of 3 to 4 hours. Oral administration of drugs (peptides, etc.) that are decomposed and inactivated by acid or enzyme through the gastro-gastrointestinal route even if they are conventionally administered orally by delivering drugs to the large intestine with relatively few digestive enzymes It is useful in that it can be made possible. For delivery of drugs to the large intestine, a method has been proposed in which tablets or granules are coated with a polymer having an azo group that can be decomposed only in the large intestine. However, a polymer containing an azo group is not always safe. I can't say. In addition, a system for delivering a drug by utilizing the pH fluctuation (pH increase) of in-vivo digestive juice has been proposed, but the certainty of specific drug delivery to the large intestine is poor.
[0006]
On the other hand, various sustained-release preparations that continue to release the drug for a certain period of time are known, but conventionally known ones have problems such as complicated manufacturing operations and restrictions on the drugs that can be used. .
[0007]
[Problems to be solved by the invention]
Here, if a slow-dissolving substance layer is provided on the outer shell of the drug layer, and the time-release preparation is developed, the slowly-dissolving substance gradually dissolves from the outside of the tablet and the drug is released at once when reaching the drug layer. Although useful as a new drug delivery method, such a method is not known to date.
[0008]
Moreover, if there is no restriction | limiting in the chemical | medical agent which can be used and the sustained release formulation which can be manufactured simply is made, usefulness is high as a pharmaceutical formulation.
[0009]
An object of the present invention is to provide a base capable of obtaining a new time-release preparation and sustained-release preparation.
[0010]
[Means for Solving the Problems]
As a result of intensive studies for solving the above-mentioned problems, the present inventors have found one or more selected from the group consisting of alkali metal salts of carboxymethyl cellulose, alkali metal salts of carboxymethyl starch and alkali metal salts of cross carboxymethyl cellulose. In addition, a base compounded with a water-soluble alkaline substance containing magnesium takes time to dissolve in the digestive tract, and the dissolution time can be adjusted by the composition and ratio of the base, so that it is a time-release type preparation. The present invention was completed by finding that it is preferable as a base for sustained-release preparations.
[0011]
That is, the present invention includes (A) one or more selected from the group consisting of an alkali metal salt of carboxymethyl cellulose, an alkali metal salt of carboxymethyl starch and an alkali metal salt of cross carboxymethyl cellulose, and (B) containing magnesium It is a base made of a water-soluble alkaline substance.
[0012]
DETAILED DESCRIPTION OF THE INVENTION
In the present invention, “water-soluble alkaline substance containing magnesium” is an alkaline substance soluble in water containing magnesium that can be used as a pharmaceutical additive. Mention may be made of magnesium, magnesium hydroxide and magnesium carbonate. Two or more of them can be used in combination.
[0013]
The alkali metal salt of the present invention is a salt with an alkali metal such as sodium, lithium and potassium, and the most preferable one is a sodium salt.
[0014]
The compounding amount of each component in the present invention is one or two or more selected from the group consisting of an alkali metal salt of carboxymethyl cellulose, an alkali metal salt of carboxymethyl starch, and an alkali metal salt of cross carboxymethyl cellulose, based on 1 part by weight. Thus, it is preferable to add an amount of 0.2 to 5 parts by weight of the water-soluble alkaline substance containing magnesium.
[0015]
The drug release pattern can be controlled by a combination of the amount of the base added, the composition, the ratio thereof, etc. As a specific method, for use in a time-release preparation, the periphery of the central tablet containing the drug is used. May be coated with the base of the present invention to provide an outer shell layer. As a manufacturing method, it was obtained by mixing a drug, an excipient, a disintegrant, a binder, etc., and adding a lubricant to a granulated product obtained by granulation and sizing by a conventional method. The base of the present invention is compression coated with the base of the present invention, or the central granule or tablet containing the drug produced by a conventional method is dissolved or dissolved in water or the like. A time-release preparation can be obtained by spray coating the suspension.
[0016]
In order to use the base of the present invention as a sustained-release preparation, the drug and the base of the present invention are mixed and granulated. The sustained-release preparation keeps releasing the drug for a long time together with the gradually dissolving base. The production method can be obtained by mixing the base of the present invention and a drug, and if necessary, usually necessary substances such as excipients, disintegrants, binders, etc., and granulating and sizing by a conventional method. However, not only using the granulated product as it is, but also adding a suitable lubricant, excipient, drug immediate release granule, etc., it can be packed into capsules or compressed to form tablets. You can also
[0017]
In the time-release preparation using the base of the present invention, the drug layer and the outer shell layer can be repeated to obtain the same effect as if the drug was administered several times in a single dose. Is possible. Moreover, if the outer shell of the sustained-release preparation using the base of the present invention is further coated with the base of the present invention, the drug can be gradually administered only to a specific site (such as the large intestine). The preparation using the base of the present invention is not particularly limited with respect to the production method and production order, and can be produced using production equipment and methods generally used as pharmaceutical production methods.
[0018]
Preparations using the base of the present invention include anti-inflammatory agents, vasodilators, central nervous system drugs, psychotropic agents, antidepressants, antihistamines, laxatives, analgesics, vitamins, antacids, antihypertensives, antihypertensives Can be used for orally administrable drugs such as platelet aggregating agents, antipyretics, antitussives, antiseptics, antispasmodic drugs, diuretics, asthma drugs, nutritional additives, anticancer drugs, peptide drugs, anthelmintic drugs, antibiotics, etc. .
[0019]
When a preparation is made using the base of the present invention, other bases, excipients, lubricants, corrigents, coating agents, sugar coatings that can be used as pharmaceutical additives within a range that does not impair the effect. Commonly used components such as binders (hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), etc.) can be used.
[0020]
Add additives that can generally be used as pharmaceutical additives such as excipients and disintegrants in order to improve production efficiency such as controlling disintegration of the preparation, improving granule strength, and improving powder flowability. If necessary, an enteric film, a film coat, a hydrophobic film, a sugar coating layer, or the like can be applied for the purpose of adjusting the drug release, masking the bitter taste of the drug, or preventing the decomposition by light.
[0021]
【Example】
Hereinafter, the present invention will be described in detail by way of examples and test examples.
[0022]
Example 1: Timed-release preparation Sodium carboxymethylcellulose (CMC-Na) 150 g, magnesium oxide light (Kyowa Kagaku) 150 g, Nuto 200 g, corn starch 50 g, crystalline cellulose 100 g, light anhydrous silicic acid 30 g, hydroxypropylcellulose 65 g Were mixed with a plastic bag, pulverized with a sample mill, and then mixed with a plastic bag to obtain a mixture. This mixture was granulated with water using a vertical granulator, the granulated product was dried, then coarsely crushed and sieved with a speed mill, and 5 g of magnesium stearate was added to obtain an outer shell layer composition.
[0023]
A 6 mm diameter tablet (tablet weight 85 mg) containing 50 mg of theophylline was used as a central tablet, and about 280 mg of the outer shell layer composition obtained above was compression-coated with a 9 mm diameter ordinary face to obtain a time-release tablet.
[0024]
Example 2 Timed Release Formulation CMC-Na Low Viscosity 200g, Magnesium Oxide Light 200g, Neutral 16g, Corn Starch 20g, Crystalline Cellulose 80g, Light Silicic Anhydride 24g, Hydroxypropyl Cellulose 56g And then mixed with a plastic bag to obtain a mixture. This mixture was granulated with a vertical granulator using water. After drying the granulated product, it was coarsely crushed with a speed mill and sieved, and 4 g of magnesium stearate was added to obtain an outer shell layer composition.
[0025]
A 6 mm diameter tablet (tablet weight 85 mg) containing 50 mg of theophylline was used as a central tablet, and about 280 mg of the outer shell layer composition obtained above was compression-coated with a 9 mm diameter ordinary face to obtain a time-release tablet.
[0026]
Control Example 1
A control tablet was obtained in the same manner as in Example 1 except that the composition was changed to “magnesium oxide light” in Example 1 and the amount of “corn starch” increased (corn starch 200 g).
[0027]
Example 3: Time-release preparation Cross sodium carboxymethylcellulose 120 g, magnesium oxide light 120 g, nut sugar 100 g, corn starch 100 g, crystalline cellulose 80 g, light anhydrous silicic acid 24 g, hydroxypropylcellulose 52 g were mixed in a plastic bag, and sample mill After pulverization, the mixture was obtained by mixing with a plastic bag. This mixture was granulated with a vertical granulator using water. The granulated product was dried, then roughly crushed with a speed mill and sieved, and 5 g of magnesium stearate was added to obtain an outer shell layer composition.
[0028]
A 6 mm diameter tablet (tablet weight 85 mg) containing 50 mg of theophylline was used as a central tablet, and about 280 mg of the outer shell layer composition obtained above was compression-coated with a 9 mm diameter ordinary face to obtain a time-release tablet.
[0029]
Control Example 2
A control tablet was obtained in the same manner as in Example 3, except that the formulation was changed to “magnesium oxide light” in Example 3 to increase “Neutou” and “corn starch” by 60 g each (Neutto 160 g, corn starch 160 g).
[0030]
Example 4: Sustained-release preparation Acidic drug ibuprofen 200 g, CMC-Na low viscosity 150 g, magnesium oxide light 150 g, corn starch 50 g, crystalline cellulose 100 g, light silicic anhydride 30 g, hydroxypropylcellulose 65 g were mixed in a plastic bag. After pulverizing with a sample mill, the mixture was obtained by mixing with a plastic bag. This mixture was granulated with a vertical granulator using water. After the granulated product is dried, it is coarsely crushed and sieved with a speed mill, 5 g of magnesium stearate is added, and then 150 mg of powder is used on a collect 12 tableting machine (Kikusui Seisakusho) using a 7 mm-diameter ordinary surface. The tablet was obtained by compression molding at a pressure of 1.0 ton / cm ² .
[0031]
Control 3
A control tablet was obtained in the same manner as in Example 4 except that “magnesium oxide light” in Example 4 was changed to “sodium bicarbonate”.
[0032]
Control Example 4
A control tablet was obtained in the same manner as in Example 4 except that “magnesium oxide light” in Example 4 was changed to “Nutou”.
[0033]
Example 5: Sustained-release preparation Acidic drug ibuprofen 200 g, croscarmellose sodium 150 g, magnesium oxide light 75 g, sodium hydrogen carbonate 75 g, corn starch 50 g, crystalline cellulose 100 g, light anhydrous silicic acid 30 g hydroxypropylcellulose 65 g And then pulverized with a sample mill and mixed again with a plastic bag to obtain a mixture. This mixture is granulated with water in a vertical granulator, dried, sieved with a speed mill, added with 5 g of magnesium stearate, and then collected with a collect 12 tableting machine (Kikusui Seisakusho) with a 7 mm diameter plain surface. Tablets were obtained by compression molding at a pressure of 1.0 ton / cm ² using a scissors.
[0034]
Control 5
160 g of acidic drug ibuprofen, 120 g of croscarmellose sodium, 60 g of nuts, 100 g of corn starch, 80 g of crystalline cellulose, 24 g of light anhydrous silicic acid, and 52 g of hydroxypropylcellulose were mixed in a plastic bag, ground in a sample mill, and then in a plastic bag. The mixture was obtained by mixing. This mixture was granulated with a vertical granulator using water. After the granulated product is dried, it is coarsely crushed and sieved with a speed mill, 4 g of magnesium stearate is added, and then 150 mg of powder is used on a collect 12 tableting machine (Kikusui Seisakusho) using a 7 mm diameter plain punch. The tablet was obtained by compression molding at a pressure of 1.0 ton / cm ² .
[0035]
Example 6: Sustained Release Formulation Basic Drug Metoclopramide 5g, Sodium Carboxymethyl Starch (Kimura Sangyo) 150g, Magnesium Oxide Light (Kyowa Chemical) 150g, D-Mannitol 100g, Corn Starch 100g, Crystalline Cellulose 100g, Light Anhydrous Silicone 30 g of acid and 65 g of hydroxypropylcellulose were mixed in a plastic bag, pulverized with a sample mill, and then mixed again in a plastic bag to obtain a mixture. This mixture is granulated with water in a vertical granulator, dried, sieved with a speed mill, added with 5 g of magnesium stearate, and then collected with a collect 12 tableting machine (Kikusui Seisakusho) with a 7 mm diameter plain surface. Tablets were obtained by compression molding at a pressure of 1.0 ton / cm ² using a scissors.
[0036]
Example 7: Sustained-release preparation Basic drug metoclopramide 5 g, CMC-Na 150 g, magnesium oxide light 150 g, D-mannitol 100 g, corn starch 100 g, crystalline cellulose 100 g, light anhydrous silicic acid 30 g, hydroxypropyl cellulose 65 g After mixing with a bag and pulverizing with a sample mill, the mixture was again mixed with a plastic bag to obtain a mixture. This mixture is granulated with water in a vertical granulator, dried, sieved with a speed mill, added with 5 g of magnesium stearate, and then collected with a collect 12 tableting machine (Kikusui Seisakusho) with a 7 mm diameter plain surface. Tablets were obtained by compression molding at a pressure of 1.0 ton / cm ² using a scissors.
[0037]
Example 8: Sustained-release preparation Basic drug metoclopramide 5 g, CMC-Na 150 g, synthetic hydrotalcite (Kyowa Chemical Industry) 150 g, D-mannitol 100 g, corn starch 100 g, crystalline cellulose 100 g, light anhydrous silicic acid 30 g, 65 g of hydroxypropylcellulose was mixed in a plastic bag, pulverized with a sample mill, and then mixed again in a plastic bag to obtain a mixture. This mixture is granulated with water in a vertical granulator, dried, sieved with a speed mill, added with 5 g of magnesium stearate, and then collected with a collect 12 tableting machine (Kikusui Seisakusho) with a 7 mm diameter plain surface. Tablets were obtained by compression molding at a pressure of 1.0 ton / cm ² using a scissors.
[0038]
Example 9: Sustained-release preparation Basic drug metoclopramide 5 g, CMC-Na 150 g, magnesium hydroxide 150 g, D-mannitol 100 g, corn starch 100 g, crystalline cellulose 100 g, light anhydrous silicic acid 30 g, hydroxypropyl cellulose 65 g After mixing with a bag and pulverizing with a sample mill, the mixture was again mixed with a plastic bag to obtain a mixture. This mixture is granulated with water in a vertical granulator, dried, sieved with a speed mill, added with 5 g of magnesium stearate, and then collected with a collect 12 tableting machine (Kikusui Seisakusho) with a 7 mm diameter plain surface. Tablets were obtained by compression molding at a pressure of 1.0 ton / cm ² using a scissors.
[0039]
Example 10: Sustained release preparation Basic drug metoclopramide 5 g, CMC-Na 150 g, magnesium carbonate 150 g, D-mannitol 100 g, corn starch 100 g, crystalline cellulose 100 g, light anhydrous silicic acid 30 g, hydroxypropyl cellulose 65 g And then pulverized with a sample mill and mixed again with a plastic bag to obtain a mixture. This mixture is granulated with water in a vertical granulator, dried, sieved with a speed mill, added with 5 g of magnesium stearate, and then collected with a collect 12 tableting machine (Kikusui Seisakusho) with a 7 mm diameter plain surface. Tablets were obtained by compression molding at a pressure of 1.0 ton / cm ² using a scissors.
[0040]
Example 11: Sustained-release preparation Basic drug metoclopramide 5 g, CMC-Na 150 g, magnesium aluminate metasilicate 150 g, D-mannitol 100 g, corn starch 100 g, crystalline cellulose 100 g, light anhydrous silicic acid 30 g, hydroxypropylcellulose 65 g Were mixed with a plastic bag, pulverized with a sample mill, and mixed again with a plastic bag to obtain a mixture. This mixture is granulated with water in a vertical granulator, dried, sieved with a speed mill, added with 5 g of magnesium stearate, and then collected with a collect 12 tableting machine (Kikusui Seisakusho) with a 7 mm diameter plain surface. Tablets were obtained by compression molding at a pressure of 1.0 ton / cm ² using a scissors.
[0041]
Control 6
A control tablet was prepared in the same manner as in Example 6 except that “D-mannitol” and “corn starch” were increased by 75 g each in place of “magnesium oxide light” in Example 6 (175 g of D-mannitol and 175 g of corn starch). Obtained.
[0042]
Control Example 7
A control tablet was prepared in the same manner as in Example 7, except that “D-mannitol” and “corn starch” were increased by 75 g each in place of “magnesium oxide light” in Example 7 (175 g of D-mannitol and 175 g of corn starch). Obtained.
[0043]
Test example 1
The tablets of Example 1 and Control Example 1 were subjected to the 12th revised Japanese Pharmacopoeia Dissolution Test Method 2 (soaked in the 1st Pharmacopoeia pH 1.2 solution as the test solution, and the amount of theophylline dissolved by taking timely samples. Was measured by the HPLC method), and the theophylline elution amount was measured. The results of the drug elution amount over time are shown in FIG.
[0044]
Test example 2
For the tablets of Example 2 and Control Example 1, the 12th revised Japanese Pharmacopoeia Dissolution Test Method 2 (using a phosphate buffer of pH 6.5 as the test solution, taking a timely sample, The elution amount of theophylline was measured by measuring the elution amount by the HPLC method. The results of the drug elution amount over time are shown in FIG.
Test example 3
The theophylline elution amount of the tablets of Example 3 and Control Example 2 was measured by the same test as in Test Example 2. The results of the drug elution amount over time are shown in FIG.
[0045]
Test example 4
For the tablets of Example 4 and Control Examples 3 and 4, the 12th revised Japanese Pharmacopoeia Dissolution Test Method 2 (using a Japanese Pharmacopoeia 1 solution at pH 1.2 as the test solution, taking a timely sample to dissolve ibuprofen The elution property of ibuprofen was examined by measuring the amount by HPLC method). The results of the drug elution amount over time are shown in FIG.
[0046]
Test Example 5
For the tablets of Example 5 and Control Example 5, the 12th revised Japanese Pharmacopoeia Dissolution Test Method 2 (using a phosphate buffer of pH 7.2 as the test solution, taking a timely sample and taking ibuprofen The elution property of ibuprofen was examined by measuring the elution amount by HPLC method). The results of drug elution amount over time are shown in FIG.
[0047]
Test Example 6
For tablets of Example 6 and Control Example 6, the 12th revised Japanese Pharmacopoeia Dissolution Test Method 2 (using a phosphate buffer solution of pH 6.5 as the test solution, taking a timely sample and taking metoclopramide The elution properties of metoclopramide were examined by measuring the elution amount. The results of drug elution amount over time are shown in FIG.
[0048]
Test Example 7
For the tablets of Examples 7 to 11 and Control Example 7, the twelfth revised Japanese Pharmacopoeia Dissolution Test Method Method 2 (using a phosphate buffer solution of pH 6.5 as the test solution, timely samples were collected) The elution of metoclopramide was examined by measuring the elution amount of metoclopramide by the HPLC method). The results of the drug elution amount over time are shown in FIG.
[0049]
【The invention's effect】
The present invention makes it possible to provide time-release preparations, sustained-release preparations and the like that are easy to manufacture and have a completely new concept.
[Brief description of the drawings]
1 is a graph showing the time course of theophylline elution amount at pH 1.2 in Example 1 and Control Example 1. FIG.
FIG. 2 is a graph showing changes with time in the elution amount of theophylline at pH 6.5 in Example 2 and Control Example 1.
FIG. 3 is a graph showing changes with time in the elution amount of theophylline at pH 6.5 in Example 3 and Control Example 2.
FIG. 4 is a graph showing changes over time in the elution amount of ibuprofen at pH 1.2 in Example 4, Control Example 3 and Control Example 4.
FIG. 5 is a time-dependent change in the elution amount of ibuprofen at pH 7.2 in Example 5 and Control Example 5.
6 is a graph showing changes over time in the elution amount of metoclopramide at pH 6.5 in Example 6 and Control Example 6. FIG.
7 is a graph showing changes over time in the elution amount of metoclopramide at pH 6.5 in Examples 7 to 11 and Control Example 7. FIG.

Claims (3)

In the outer shell layer of the central tablet containing the drug, (A) one or more selected from the group consisting of an alkali metal salt of carboxymethyl cellulose, an alkali metal salt of carboxymethyl starch and an alkali metal salt of cross carboxymethyl cellulose, and (B) A time-release preparation characterized by coating a base composed of a water-soluble alkaline substance containing magnesium. The time-release preparation according to claim 1, wherein the water-soluble alkaline substance containing magnesium is one or more selected from the group consisting of magnesium oxide, magnesium hydroxide and magnesium carbonate. Water-soluble alkali containing magnesium with respect to one or two or more parts by weight selected from the group consisting of alkali metal salts of carboxymethyl cellulose, alkali metal salts of carboxymethyl starch and alkali metal salts of cross-carboxymethylmethyl cellulose The time-release preparation according to claim 1 or 2, wherein the compounding amount of the substance is 0.2 to 5 parts by weight.

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