JP2638604B2 - Sustained release formulation - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION INDUSTRIAL APPLICATIONS Some of the currently useful and removed medicinal substances have a short biological half-life and may need to be taken several times a day. However, if the number of doses can be reduced, not only the burden on the patient can be reduced, but also the compliance of the patient can be improved and the therapeutic effect can be improved.

For that purpose, it is necessary to release the drug slowly and maintain an effective blood concentration for a long time.

In addition, if a medicinal substance can be released after a certain period of time, for example, it becomes possible to release more medicinal substance at a specific site in the digestive tract, and the therapeutic effect can be enhanced.

TECHNICAL FIELD The present invention relates to a preparation in which a medicinal substance is sustainedly released and a preparation in which a medicinal substance is released after a certain period of time.

2. Description of the Related Art Various formulation techniques relating to sustained release formulations have been proposed to maintain the effective blood concentration of a drug for a long time. Many of these preparations use various polymer substances. For example, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, pullulan, gelatin, collagen, casein, agar, acacia, dextrin, ethylcellulose, methylcellulose, chitin, chitosan, mannan, carboxymethylethylcellulose, carboxymethylcellulose sodium, polyethylene glycol , Sodium alginate, polyvinyl alcohol, cellulose acetate, polyvinyl pyrrolidone,
Silicone, polyvinyl acetal diethylaminoacetate, albumin and the like. [Sustained and controlled Release Drug Delivery Systems
g Delivery Systems) (1978) MARCEL DEKKER, INC.,
Pharmacy Vol.35, No.2, 575-583 (1984), JP-A-59-62521
[Problems to be Solved by the Invention] There are some problems when a sustained-release preparation is produced using these polymer substances. Because many high molecular substances, especially water-soluble high molecular substances, themselves have a high water content, the compounded medicinal substances are susceptible to degradation such as hydrolysis and often do not withstand long-term storage. is there. Although a high molecular substance has a molecular weight distribution and certain criteria, the molecular weight distribution and the average molecular weight generally differ from lot to lot. Therefore, even if the production process is sufficiently controlled, the sustained-release preparation using such a polymer substance will not have a constant dissolution property and will have a large fluctuation range. When a preparation using a polymer substance is implanted and used in a living body, many of the polymer substances are not decomposed in the living body at all, or even if they are decomposed very little,
After release of the medicinal substance, it is necessary to remove it from the living body again.
In addition, even when a polymer substance is degraded in a living body, its decomposition often depends on the degrading enzyme, and the elution rate of the medicinal substance also depends on the degrading enzyme. Furthermore, although this degradation is not limited to all of the monomers and is partially degraded, it is conceivable that the polymer is absorbed into the tissue as a macromolecule, and these macromolecular substances become antigens and become anaphylactic. It cannot be said that there is no danger of causing a shock [Pharmaceutical Factory Vol. 3, No. 10, 552-557 (1983), Chemistry, Special Issue 134, 151-157 Nankodo]. Sustained-release preparations that release a medicinal substance through a matrix type or semipermeable membrane cannot be used particularly for poorly soluble drugs because their release depends on the solubility of the medicinal substance. It is impossible to release a medicinal substance after a certain period of time in a preparation coated with a water-insoluble polymer substance. In addition, since the water-soluble polymer substance immediately swells infinitely, the release of the drug cannot be suppressed for a long time. Furthermore, in the case of an enteric polymer substance, a medicinal substance cannot be released at a pH of 5.0 to 5.5 or less,
Above that, it is released immediately, so that control by pH change is possible, but release of medicinal substances cannot be controlled by time.

Means for Solving the Problems The present inventor has conducted intensive studies on a method for producing a sustained-release preparation to solve the above-mentioned problems, and surprisingly selected from the group consisting of adenine, cystine and tyrosine, which are low molecular substances. It has been found that by using one or more of the above, the medicinal substance is sustained-released over a long period of time, or that the medicinal substance can be released after a certain period of time.

It should be noted that cystine and tyrosine have isomers,
It may be any of a mold, an L-form and a DL-form, and is not particularly limited.

In the sustained-release preparation of the present invention, a prescribed amount of a medicinal substance and an excipient is weighed, and a prescribed amount of one or more of adenine, cystine and tyrosine is weighed and mixed by a usual method. The amount of the medicinal substance varies depending on the kind of the drug, the dosage form and the like, but is usually 90% or less, preferably 75% or less based on the total composition weight. The amount of adenine, cystine and tyrosine is usually at least 2%, preferably at least 5%, based on the total weight of the composition. Excipients may or may not be added here, but preferred excipients include lactose, mannitol, inositol, calcium citrate, calcium hydrogen phosphate, fumaric acid, hydrogenated oil, corn oil, sesame oil , Stearic acid and the like. The amount of the excipient added is 0 to 95 based on the total weight of the composition.
%, Preferably 0 to 80%.

Since the sustained-release preparation of the present invention can be used for most pharmaceuticals, it is not limited to the water-soluble and poorly soluble active substances as the main drug, and can be used as an antihypertensive agent, an antipyretic analgesic anti-inflammatory agent, an immunomodulator. Drugs, adrenal hormones, drugs for diabetes, vasodilators, cardiotonic agents, agents for arrhythmias, agents for arteriosclerosis, antidote, and various other medicinal products.

The poorly soluble drugs mentioned here are those whose solubility affects the absorption, and have a solubility in water of 0.1% or less ["Pharmaceutical Science" 1974.9.20 (Nanzando), Nakai, Hanano, p. 296]
In the case of the poorly soluble drug, an excellent sustained release effect can be obtained by pulverizing the average particle diameter to 10 μm or less and using low-substituted hydroxypropylcellulose and hydroxypropylcellulose as excipients.

Particles having an average particle diameter of 10 μm or less can be produced, for example, by using a jet pulverizer (FS-4 type: manufactured by Seishin Enterprise).

A lubricant, for example, magnesium stearate, calcium stearate, talc, or the like is added to the thus obtained mixed powder, and the mixture can be compression-molded to give a tablet. In some cases, it may be an implantable preparation.

Further, a troche can be prepared by adding sucrose, a fragrance, a coloring agent, and the like, and compression-molding the mixture into a predetermined shape. In some cases, it can be administered orally.

Further, by laminating the layer A containing the medicinal substance and the layer B not containing the medicinal substance and compression-molding, it is possible to obtain a laminated tablet in which the dissolution property of the medicinal substance after a certain period of time is enhanced.

In some cases, a sustained-release multilayer tablet obtained by compression-molding the composition layer of the present invention and the immediate-release layer containing a medicinal substance, or one or more of the composition layer of the present invention, adenine, cystine and tyrosine. A sustained-release multi-layer tablet obtained by compression-molding three layers, ie, a layer containing the active ingredient and an immediate-release layer containing the medicinal substance, can also be used.

Further, a binder, for example, an aqueous solution or an organic solvent solution such as hydroxypropylcellulose, hydroxypropylmethylcellulose, corn starch or the like is added and kneaded, and the mixture is granulated, dried, and sized to obtain granules. Can be.

Further, a sustained release granule comprising the above composition granules and immediate release granules containing a medicinal substance, an enteric base such as hydroxypropylmethylcellulose phthalate, a sustained release enteric granule coated with carboxymethylethylcellulose or the like. , A sustained-release granule comprising the above composition granules coated with a water-insoluble base, a granule formed by coating with a water-insoluble base, and a sustained-release granule comprising immediate-release granules containing a pharmaceutically active substance; Granules that release the drug after a certain period of time can be obtained by coating the immediate-release granules containing the substance with a layer composed of one or more of adenine, cystine and tyrosine.

Further, a sustained-release tablet obtained by compression-molding the above-mentioned sustained-release granule, a sustained-release tablet obtained by compression-molding a mixture of the above-mentioned sustained-release granule and a water-insoluble base, A sustained release tablet obtained by coating the release tablet with an enteric base or a water-insoluble base can also be used. Further, a sustained-release sugar-coated tablet comprising the above-mentioned sustained-release tablet as a central tablet and a periphery coated with a sugar-coating layer,
Sustained-release sugar-coated tablets coated with a sugar-containing tablet containing a medicinal substance, a sustained-release tablet coated with the above-mentioned sustained-release tablet as a core, and coated with a quick-release composition containing a medicinal substance, followed by compression molding. Release-coated dry-coated tablet, a quick-release composition containing the above-mentioned sustained-release tablet as a core, coated with one or more layers of adenine, cystine and tyrosine, and further containing a medicinal substance around the outside thereof And then press-molded to form a sustained-release dry-coated tablet. In addition, an immediate release tablet containing a medicinal substance is used as a central tablet, and one or two of adenine, cystine and tyrosine are used.
Tablets which are coated with an enteric base such as hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose or the like and which are coated with a layer comprising at least one or more species and which release a drug after a certain time can be obtained.

Capsules can also be prepared by filling the above composition granules into capsules.

Further, a sustained-release suppository comprising the above-mentioned sustained-release granules in a suppository base and a sustained-release suppository obtained by coating the above-mentioned sustained-release tablet with a suppository may be used.

Effects of the Invention Adenine, cystine and tyrosine contained in the sustained-release tablet of the present invention may be used alone or as a mixture of two or more at any ratio. Also, the addition of water-soluble substances such as lactose, mannitol and inositol, or calcium citrate or calcium hydrogen phosphate which is insoluble or well wetted with water, increases the dissolution rate, and conversely, corn oil, sesame oil, etc. The dissolution rate can be reduced by adding oils or hardened oils or waxes such as stearic acid. Further, by adding an enteric base such as hydroxypropylmethylcellulose phthalate and carboxymethylethylcellulose or an organic acid such as fumaric acid, the dissolution rate is changed depending on the pH of the dissolution solution, or almost the same regardless of the pH of the dissolution solution. Elution rates can also be used.

In addition, the sustained-release tablet of the present invention releases a medicinal substance with the slow disappearance of one or more of adenine, cystine and tyrosine, so that the medicinal substance may be a water-soluble substance or a poorly soluble substance, and No restrictions.

In carrying out the present invention, it goes without saying that a coloring agent, a flavoring agent, a stabilizer and the like may be added as necessary.

Hereinafter, the present invention will be described by way of examples, but the present invention is not limited thereto.

Example 1 Multilayer tablet (per one tablet) Lower layer (mg) Middle layer (mg) Upper layer (mg) Nicorandil 7-3 adenine 52.6 29.8-Lactose--16.8 Crystalline cellulose--10 Calcium stearate 0.4 0.2 0.2 Total 60 (mg) 30 (mg) 30 (mg) After weighing 7 g of nicorandil, 52.6 g of adenine and 0.4 g of calcium stearate, they were mixed well in a plastic bag. This mixed powder is referred to as a mixed powder.

After 29.8 g of adenine and 0.2 g of calcium stearate were weighed, they were mixed well in a plastic bag. This mixed powder is referred to as “b mixed powder”.

After weighing 3 g of nicorandil, 16.8 g of lactose, 10 g of crystalline cellulose and 0.2 g of calcium stearate, they were mixed well in a plastic bag. This mixed powder is referred to as C mixed powder.

A single-shot tableting machine with a 7 mm diameter die and flat punch set.
First, 60 mg of the mixed powder a was filled into the mortar, and lightly pre-pressed. Then, 30 mg of the mixed powder b was filled thereon, and lightly pre-pressed similarly. It was compression molded with 1 ton.

The dissolution state of the laminated tablet is as shown in FIG. First
The figure shows the laminated tablet of the present invention, using the tester of the eleventh revision, Japanese Pharmacopoeia, dissolution test method (rotating basket method), using 500 ml of the second solution (pH about 6.8) as the test solution, 3 shows the results of a dissolution test performed at 100 rpm.

Example 2 Tablets (in one tablet) Thiamazole 5 mg L-tyrosine 70 adenine 70.5 Corn starch 2.5 Magnesium stearate 2 total 150 mg L-tyrosine 70 g and adenine 70.5 g are taken in a mortar, mixed well, and then mixed with 12% corn starch paste. 20.8 g was added and kneaded well. The kneaded product was sieved and granulated with a 35-mesh sieve, dried at 50 ° C. for 5 hours with a shelf dryer, and then sized with a 32-mesh sieve. 5 g of thiamazole, 143 g of the granules obtained above and 2 g of magnesium stearate were each placed in a plastic bag and mixed well in the plastic bag.

One-shot tableting machine with 8mm diameter mortar and flat punch set
The tablets were compression molded at a total pressure of 1.2 tons to a tablet weight of 150 mg.

Comparative Example Tablets (per one tablet) Thiamazole 5 mg Lactose 121 Crystalline cellulose 20 Maize starch 2 Magnesium stearate 2 Total 150 mg Take lactose 121 g in a mortar and add 12% corn starch paste
16.7 g was added and kneaded well. The kneaded product was sieved and granulated with a 35-mesh sieve, dried at 50 ° C. for 5 hours with a shelf dryer, and then sized with a 32-mesh sieve. 5 g of thiamazole, 123 g of the granules obtained above, 20 g of crystalline cellulose and 2 g of magnesium stearate were each placed in a plastic bag and mixed well in the plastic bag.

One-shot tableting machine with 8mm diameter mortar and flat punch set
The tablets were compression molded at a total pressure of 1.2 tons to a tablet weight of 150 mg.

 The dissolution state of this tablet is as shown in FIG.

Fig. 2 shows a tablet of the present invention and a tablet of a comparative example, using a tester of the eleventh revision, the Japanese Pharmacopoeia, dissolution test method (paddle method), and 500 ml of the second liquid (pH about 6.8) as a test solution. FIG. 3 shows the results of a dissolution test performed at a paddle rotation speed of 100 rpm.

Example 3 Granules (500 mg) Theophylline 150 mg DL-cystine 330 Corn oil 10 Carboxymethylethylcellulose 10 Total 500 mg Theophylline 150 g and DL-cystine 330 g were placed in a mortar and mixed well.

A mixture of 100 g of a 10% ethanol solution of carboxymethylethylcellulose and 10 g of corn oil is added to the mixed powder and kneaded well. The kneaded product was granulated with a cylindrical granulator equipped with a net having a diameter of 1.2 mm, dried at 45 ° C. for 6 hours with a shelf dryer, and sized with a 10-mesh sieve to obtain granules.

The dissolution state of the granules is as shown in FIG. Fig. 3 shows the use of a dissolution test (rotating basket method) tester for 200 mg of the granules of the present invention in the 11th revision, Japanese Pharmacopoeia, and 500 ml of the first solution (pH about 1.2) as the test solution. 4 shows the results of a dissolution test performed at a basket rotation speed of 100 rpm.

Example 4 Coated tablets (in one tablet) Central tablet Bishibanil (lyophilized powder: 5KE) 14 mg Lactose 31.5 Low-substituted hydroxyprol cellulose 50 Hydroxyprol cellulose 4 Calcium stearate 0.5 Subtotal 100 mg Outer layer Adenine 100 mg L-cystine 50 Calcium hydrogen phosphate 45 Hydroxypromethylcellulose 4 Calcium stearate 1 Subtotal 200 mg Enteric coating layer Eudragit L30D / 55 (dry) 30 mg Triacetin 3 Talc 7 Subtotal 40 mg Total 340 mg Picibanil (lyophilized powder) 14 g, Lactose 31.5 g Low substitution degree Take 50 g of hydroxypropylcellulose in a mortar and mix well.
g was added and kneaded. The kneaded material is sieved and granulated with 16 mesh,
After leaving it to stand in a desiccator containing silica gel for one day and drying, it was sized with a 12-mesh sieve. 99.5 g of the granulated product and 0.5 g of calcium stearate were placed in a plastic bag and mixed well in the plastic bag.

A single tableting machine equipped with a die having a diameter of 7 mm and a punch having an R of 10 mm was compression-molded at a total pressure of 0.8 ton so that one tablet weighed 100 mg to obtain a central tablet.

Adenine (100 g), L-cystine (50 g) and calcium hydrogen phosphate (45 g) were placed in a mortar and mixed well, and then a 10% aqueous solution of hydroxypropyl methylcellulose (40 g) was added and kneaded well. The kneaded product was sieved and granulated with a 20-mesh sieve, dried at 50 ° C. for 5 hours with a shelf dryer, and then sized with a 16-mesh sieve. 1 g of calcium stearate is added to 199 g of the obtained granules.
Was added and mixed well in a plastic bag to obtain outer layer granules.

First, about 70 mg of the outer layer granules were filled into the mortar with a single-shot tableting machine in which a 10 mm diameter die and a R = 14 mm punch were set, then the central tablet was placed on the center thereof, and further 130 mg of the outer layer granules were filled. A double tablet was obtained by compression molding at a total pressure of about 1.5 tons.

After adding 3 g of triacetin and 7 g of talc to 140 g of water and stirring well, Eudragit L30D · 55 (30% dispersion) 10
0 g was added to prepare an enteric coating solution.

30 g of double tablets (about 100 tablets) and 200 g of pre-made dummy tablets (tablet: 9 mm in diameter, R = 13 mm, weight: 210 mg) are put into a fluidized bed coating machine (UNI-GLATT: manufactured by Okawara Seisakusho), and Double tablets with the prepared enteric coating solution according to the usual method, 1
The coating operation was performed until 40 mg was coated per tablet.

 The dissolution state of the coated tablet is as shown in Table 1.

Table 1 shows the coated tablets of the present invention, using a tester of the elution test method (paddle method) of the 11th revision of the Japanese Pharmacopoeia, and the test liquids are the first liquid (pH about 1.2) and the second liquid (pH about 1.2). 6.8) This figure shows the results of a bacterial cell release test performed at 500 rpm using a paddle at a rotation speed of 100 rpm.

For the release of the cells, the test solution was observed under a microscope, and the presence or absence thereof was examined.

Example 5 Phenacetin and L-tyrosine are pulverized with a jet pulverizer (manufactured by Seishin Enterprise: Model FS-4), and the average particle size is 2-3.
A jet crushed powder of μm was obtained (hereinafter, a sample crushed by a jet crusher is referred to as a jet crushed powder).

50 g of phenacetin (jet milled powder), 37 g of lactose and 10 g of low-substituted hydroxypropylcellulose were weighed and mixed well in a mortar. To this mixed powder, 20 g of a 10% aqueous solution of hydroxypropyl cellulose and 12 g of water were added and kneaded well. The kneaded product was sieved and granulated with a 14-mesh sieve, dried at 50 ° C. for 5 hours with a shelf dryer, and then sized with a 10-mesh sieve. 1 g of calcium stearate was added to 99 g of the obtained granules and mixed well in a plastic bag. This granulated material is referred to as a granulated material a.

100 g of phenacetin (jet milled powder) and 93 g of L-tyrosine (jet milled powder) were weighed and mixed well in a mortar. To this mixed powder, 50 g of a 10% aqueous solution of hydroxypropyl cellulose and 44 g of water were added and kneaded well. The kneaded product is sieved and granulated with a 14-mesh sieve, and is heated to 50 ° C. in a shelf dryer.
And dried for 5 hours, and then sized with a 10-mesh sieve. To 198 g of the obtained granules, 2 g of calcium stearate was added and mixed well in a plastic bag. This granulated product is referred to as a granulated product b.

A single-shot tableting machine with a 10 mm diameter die and flat punch set.
First, 200 mg of the granulated material b was filled in a die, and lightly pre-pressed. Then, 100 mg of the granulated material a was filled thereon, and compression-molded at a total pressure of about 2 tons.

 The dissolution state of the laminated tablet is as shown in FIG.

Fig. 4 shows the results of the eleventh revision, the Japanese Pharmacopoeia, the dissolution test method (paddle method) for the laminated tablet of the product of the present invention,
Use 900 ml of distilled water for the test solution, paddle rotation speed 100 rpm
3 shows the results of the dissolution test performed in Example 1.

Example 6 Tablet (1 tablet) Griseofulvin 125 mg L-Tyrosine 40 Fumaric acid 126 Hydroxypropylcellulose 6 Magnesium stearate 3 Total 300 mg Griseofulvin (jet crushed powder: average particle diameter 1 to 1)
2 g) 125 g, L-tyrosine (jet crushed powder: average particle size 2-3 μm) 40 g and fumaric acid (jet crushed powder:
126 g of each (average particle size of 4 to 5 μm) were weighed and mixed well in a mortar. To this mixed powder, 60 g of a 10% aqueous solution of hydroxypropyl cellulose and 62 g of water were added and kneaded well.
The kneaded material is sieved and granulated with a 14-mesh sieve, using a shelf dryer.
After drying at 60 ° C. for 3 hours, the particles were sized with a 10-mesh sieve.
To 297 g of the obtained granules, 3 g of magnesium stearate was added and mixed well in a plastic bag.

One-shot tableting machine with a 10 mm diameter die and flat punch set
Compression molding was performed with a total pressure of about 2 tons so that the tablet weight was 300 mg.

Comparative Example Tablets (per one tablet) Griseofulvin 125 mg Lactose 166 Pidroxypropylcellulose 6 Magnesium stearate 3 Total 300 mg Griseofulvin (jet-milled powder: average particle size 1-2)
μm) 125 g and lactose 166 g were weighed and mixed well in a mortar. To this mixed powder, 60 g of a 10% aqueous solution of hydroxypropyl cellulose and 14 g of water were added and kneaded well. The kneaded product is sieved and granulated with a 14-mesh sieve, and is heated to 60 ° C. in a shelf dryer.
And dried for 3 hours, and then sized with a 10-mesh sieve. 3 g of magnesium stearate was added to 297 g of the obtained granules,
Mix well in a plastic bag.

One-shot tableting machine with a 10 mm diameter die and flat punch set
Compression molding was performed with a total pressure of about 2 tons so that the tablet weight was 300 mg.

FIG. 5 shows the drug release state from this tablet (the dispersion state of the griseofulvin microparticles was evaluated by turbidity measurement because griseofulvin is insoluble in water).

FIG. 5 shows the results of a release test performed on the tablet of the present invention and the tablet of Comparative Example in the eleventh revision, using a disintegration tester of the Japanese Pharmacopoeia, test solution: distilled water, 1000 ml, upper and lower: 20 times / minute. It is shown.

Example 7 Tablet (1 tablet) Griseofulvin 125 mg L-Tyrosine 166 Hydroxypropylcellulose 6 Magnesium stearate 3 Total 300 mg Griseofulvin (jet crushed powder: average particle diameter 1 to 1)
125 g of L-tyrosine (2 μm) and 166 g of L-tyrosine (jet crushed powder: average particle diameter of 2 to 3 μm) were weighed and mixed well in a mortar. 60 g of a 10% aqueous solution of hydroxypropylcellulose and 58 g of water were added to the mixed powder and kneaded well. The kneaded product is sieved and granulated with a 14-mesh sieve, and is dried at
And dried for 3 hours, and then sized with a 10-mesh sieve. 3 g of magnesium stearate was added to 297 g of the obtained granules,
Mix well in a plastic bag.

One-shot tableting machine with a 10 mm diameter die and flat punch set
The tablets were compression molded at a total pressure of about 2 tons so that the tablet weight was 300 mg.

FIG. 6 shows the state of drug release from the tablet (the dispersion state of the griseofulvin fine particles was evaluated by turbidity measurement because griseofulvin is insoluble in water).

FIG. 6 shows the results of a release test performed on tablets of the present invention in the eleventh revision, using a disintegration tester of the Japanese Pharmacopoeia, with a test solution: 1000 ml of distilled water and up and down: 20 times / minute. It is.

Example 8 Tablets (in one tablet) Digoxin 0.25 mg Lactose 8.75 L-cystine 153 Low-substituted hydroxypropylcellulose 120 Pidroxypropylcellulose 15 Calcium stearate 3 Total 300 mg Digoxin 0.25 g was dissolved in ethanol 135 g, and then hydroxypropyl 15 g of cellulose was added and dissolved to prepare a binder (the particle size of digoxin in the film obtained by drying this solution is 1 μm or less).

8.75 g of lactose, 153 g of L-cystine and 120 g of low-substituted hydroxypropylcellulose were weighed and mixed well in a mortar. The binder was added to the mixed powder and kneaded well. The kneaded product was sieved and granulated with a 14-mesh sieve, dried at 50 ° C. for 5 hours with a shelf dryer, and then sized with a 10-mesh sieve. Calcium stearate is added to 297 g of the obtained granules.
3 g was added and mixed well in a plastic bag.

One-shot tableting machine with a 10 mm diameter mortar and flat scale set
Compression molding was performed with a total pressure of 2 tons so that the tablet weight was 300 mg.

The elution state of this solvent is as shown in FIG. Fig. 7 shows a tablet of the present invention, using a dissolution tester (paddle method) tester of the 11th revision, Japanese Pharmacopoeia, using 900 ml of distilled water as the test solution, and rotating the paddle at 100 rpm. 3 shows the results of the dissolution test.

Example 9 Tablets (per one tablet) Indomethacin 25 mg Low-substituted hydroxypropylcellulose 24 Hydroxypropylcellulose 3 L-cystine 92 Hardened castor oil 5 Calcium stearate 1 Total 150 mg Indomethacin (jet milled powder: average particle size 6-7)
μm) 25 g and low substituted hydroxypropylcellulose 2
4 g of each was weighed and mixed well in a mortar. To this mixed powder, 10 g of a 10% aqueous solution of hydroxypropyl cellulose and 10 g of water were added and kneaded well. The kneaded product was sieved and granulated with a 24 mesh sieve and dried at 60 ° C. for 3 hours with a shelf dryer.
It was sized with a 20 mesh sieve.

 This granulated material is referred to as a granulated material a.

92 g of L-cystine and 5 g of hydrogenated castor oil were weighed and mixed well in a mortar. 20 g of a 10% aqueous solution of hydroxypropylcellulose and 18 g of water were added to the mixed powder and kneaded well. The kneaded product was sieved and granulated with a 24 mesh sieve, dried at 60 ° C. for 3 hours with a shelf dryer, and then sized with a 20 mesh sieve.

 This granulated product is referred to as a granulated product b.

Granules a50g, granules b99g and calcium stearate
1 g was added and mixed well in a plastic bag. It was compression-molded with a single punching machine in which a die having a diameter of φ8 mm and a flat punch were set with a total pressure of about 1.6 tons so that one tablet weighed 150 mg.

The dissolution state of this tablet is as shown in FIG. 8. FIG. 8 shows a test solution of the tablet of the present invention, using a tester of the eleventh revision, Japanese Pharmacopoeia, dissolution test method (rotating basket method). 1 shows the results of a dissolution test performed using 900 ml of the second solution (pH about 6.8) at a basket rotation speed of 100 rpm.

Example 10 Capsules (in one capsule) Ketoprofen 75 mg L-cystine 49 L-tyrosine 50 Stearic acid 20 ethylcellulose 6 Total 200 mg Ketoprofen 75 g, L-cystine (jet milled powder: average particle diameter 3-4 μm) 49 g, L-tyrosine 50 g of (jet crushed powder: average particle diameter of 2 to 3 μm) and 20 g of stearic acid (jet crushed powder: average particle diameter of 5 to 6 μm) were weighed and mixed well in a mortar. At the end of this mixture
60 g of a 10% ethyl cellulose / ethanol solution was added and kneaded well. The kneaded product was granulated by a cylindrical granulator equipped with a net of 1.2 mm in diameter, dried at 50 ° C. for 6 hours with a shelf dryer, and then heated once to 80 ° C. and held for 15 minutes. After the obtained granules were sized with a 10-mesh sieve, capsules were filled with 200 mg per capsule to obtain capsules.

The elution state of the capsule is as shown in FIG. FIG. 9 shows a capsule of the present invention, using a tester of the eleventh revision, Japanese Pharmacopoeia, dissolution test method (rotating basket method), and using 900 ml of the second liquid (pH about 6.8) as a test solution. The rotation number of the basket shows the result of the dissolution test performed at 100 rpm.

Example 11 Capsules (in 1 capsule) (spherical granules) Theophylline 100 mg Lactose 7 Microcrystalline cellulose 40 Hydroxypropylmethylcellulose 3 Subtotal 150 mg (Coating layer) Ethyl cellulose 22.5 mg Triacetin 2.5 L-Tyrosine 25 Subtotal 50 mg Total 200 mg Theophylline 100 g, lactose 7 g and crystalline cellulose 40 g were weighed and mixed well in a mortar. To this mixed powder, 60 g of a 5% aqueous solution of hydroxypropylmethylcellulose was added and kneaded well. The kneaded product was granulated with a cylindrical granulator equipped with a 1.0 mm diameter net, and then subjected to a spheroidizing treatment with a marmellaizer (manufactured by Fuji Paudal: Model Q-236). The spherical granules were dried at 60 ° C. for 3 hours using a shelf dryer.

After adding and dissolving 22.5 g of ethyl cellulose and 2.5 g of triacetin in 200 g of ethanol, 25 g of L-tyrosine (jet crushed powder: average particle diameter of 2 to 3 μm) was added and dispersed well to prepare a coating liquid.

Add 150g of the spherical granules to Uniglat (Okawara Seisakusho: U
NI-GLATT) and sprayed with 250 g of a coating solution to perform coating.

Coated spherical granules into hard capsules per capsule
200 mg was filled to obtain a capsule.

The elution state of this capsule is as shown in FIG. No.
For capsules of the product of the present invention shown in FIG. 10, using a tester of the eleventh revision, Japanese Pharmacopoeia, dissolution test method (rotating basket method), using 500 ml of distilled water for the test solution, and rotating the basket at 100 rpm It shows the results of the dissolution test performed.

Example 12 Fine granules (in 1 g) Magnesium oxide 300 mg L-cystine 320 stearic acid 100 crystalline cellulose 280 total 1000 mg 60 g of magnesium oxide, 64 g of L-cystine, 20 g of stearic acid and 56 g of crystalline cellulose were weighed and placed in a mortar. Mix well. 80 g of water was added to the mixed powder and kneaded well. The kneaded product was sieved and granulated with a 24 mesh sieve, and the granulated product was subjected to a spheroidizing treatment with a marmellaizer (manufactured by Fuji Paudal: Q-234 type). This fine granule was dried at 60 ° C. for 3 hours using a shelf dryer.

The antacid test (Fuchs test) of this fine granule is as shown in FIG. FIG. 11 shows the results of an antacid test (Fuchs test) performed on the fine granules of the product of the present invention.

Example 13 Implant Formulation Erythropoietin 0.016 mg L-cystine 8.984 Stearic acid 1 10 mg Erythropoietin (lyophilized product) 0.16 mg, L-cystine 89.84 mg and stearic acid 10 mg were weighed and mixed well in a mortar.

10 mg of the mixed powder was filled in a mold having a diameter of 2 mm, and compression molded at a total pressure of 200 kg using a hydraulic machine. The change in reticulocyte count of this implant preparation is as shown in FIG.

FIG. 12 shows the ratio of reticulocytes to red blood cells in blood obtained by implanting the implanted preparation of the present invention subcutaneously in rats. In addition, physiological saline containing erythropoietin was similarly subcutaneously administered for comparison.

Example 14 Floating preparation (in one tablet) Oxesazein 10 mg L-cystine 80 Stearic acid 10 Total 100 mg Oxasezain 1 g, L-cystine 8 g, stearic acid 1 g
And 5 g of dl-menthol were weighed and mixed well in a mortar.

One-shot tableting machine with a 7mm diameter die and flat punch set
The tablets were compression molded at a total pressure of about 1.5 tons to a tablet weight of 150 mg.

This tablet was heated under reduced pressure at 50 ° C. for 30 minutes to sublimate dl-menthol. The temperature was further raised to 80 ° C., and the stearic acid was once melted and then cooled to obtain a floating preparation.

When the floating formulation of the present invention is put into water, it rises,
Floating for more than 8 hours.

Example 15 Lozenge (in one tablet) Scopolamine hydrobromide 0.2 mg L-cystine 35.8 DL-tryptophan 30 Hardened castor oil 10 Corn starch 3 Calcium stearate 1 total 80 mg Scopolamine hydrobromide 0.2 g, L-cystine ( Jet pulverized powder: average particle diameter 3-4 μm) 35.8 g, DL-tryptophan (jet pulverized powder: average particle diameter 2-3 μm) 30
g and hydrogenated castor oil (jet milled powder: average particle size 3 to
4 μm) were weighed and mixed well in a mortar. To this mixed powder, 30 g of 10% corn starch paste was added and kneaded well. The kneaded product was sieved and granulated with a 14-mesh sieve, dried at 50 ° C. for 5 hours with a shelf dryer, and then sized with a 10-mesh sieve. To 79 g of the obtained granules, 1 g of calcium stearate was added and mixed well in a plastic bag.

One-shot tableting machine with a 7mm diameter die and flat punch set
The tablets were compression-molded at a total pressure of about 1.5 tons to a tablet weight of 80 mg.

 The lozenges of the present invention were present in the mouth for more than 8 hours.

[Brief description of the drawings]

FIG. 1 shows the dissolution state of the laminated tablet obtained in Example 1. FIG. 2 shows the dissolution state of the tablet (-O-) obtained in Example 2 and the tablet (... O ...) of the comparative example. FIG. 3 shows the dissolution state of the granules obtained in Example 3. FIG. 4 shows the dissolution state of the laminated tablet obtained in Example 5. FIG. 5 shows the dissolution state of the tablet (-O-) obtained in Example 6 and the tablet (... O ...) of the comparative example. FIG. 6 shows the dissolution state of the tablet obtained in Example 7. FIG. 7 shows the dissolution state of the tablet obtained in Example 8. FIG. 8 shows the dissolution state of the tablet obtained in Example 9. FIG. 9 shows the dissolution state of the capsule obtained in Example 10. FIG. 10 shows the dissolution state of the capsule obtained in Example 11. FIG. 11 shows the results of an antacid test (Fuchs test) for only the fine granules (-) and magnesium oxide (...) obtained in Example 12. FIG. 12 shows the implant preparation obtained in Example 13 (-○-).
The figure also shows the ratio of reticulocytes to red blood cells in blood for physiological saline containing a drug (... ○ ...).

Claims (9)

(57) [Claims] 1. A sustained-release preparation containing one or more selected from the group consisting of adenine, cystine and tyrosine and one or more active substances. 2. The sustained-release preparation according to claim 1, wherein the medicinal substance is a poorly soluble drug having a solubility of 0.1% or less. 3. The sustained-release preparation according to claim 2, wherein the poorly soluble drug has an average particle size of 10 μm or less. 4. The sustained-release preparation according to claim 3, further comprising low-substituted hydroxypropylcellulose and hydroxypropylcellulose. 5. The sustained-release preparation according to claim 1, which is a laminated tablet comprising a layer containing a medicinal substance and a layer containing no medicinal substance. 6. The sustained-release preparation according to claim 1, wherein the preparation containing a medicinal substance is coated with a layer containing no medicinal substance. 7. The sustained-release preparation according to claim 1, which is a granule containing a pharmaceutically active substance. 8. The sustained-release preparation according to claim 1, which is an implantable preparation containing a pharmaceutically active substance. 9. The sustained-release preparation according to claim 1, wherein a preparation containing a medicinal substance is filled in a capsule.