JPH08333259A - Pharmaceutical preparation composition containing sucralfate - Google Patents

Abstract

PURPOSE: To obtain the subject composition having guaranteed bioavailability of the drug without causing the adsorption and trapping of the drug to sucralfate in spite of the formulation of the preparation to compound the drug and sucralfate at the same time. CONSTITUTION: (A) Sucralfate and (B) other drug are compounded in the same preparation to effect the rapid dissolution of the component B without being adsorbed or trapped to the component A. Preferably, the compound A is compounded together with the component B in the same preparation in separated state, the preparation is composed of a quick acting part containing the component B and a slow acting part containing the component A and the component B is a drug liable to be adsorbed or trapped by the component A to cause the absorption inhibition, concretely an H2 receptor antagonist selected from methidine, ranitidine, famotidine, nizatidine and acetic acid roxatidine acetate.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a preparation in which a drug is blended with sucralfate at the same time, while maintaining the original absorption characteristics without the drug being adsorbed and trapped by sucralfate.

[0002]

2. Description of the Related Art Sucralfate is used in the digestive tract,
Gastric acid forms a bioadhesive gel that attaches to the gastrointestinal mucosa and provides a local protective barrier. At the site of inflammation or ulcer, this protective barrier exerts a healing effect by protecting the gastrointestinal mucosa from excess gastric acid and the like and promoting the body's own gastric mucosa repair action. In the medical field, various drugs are administered at the same time with the expectation that sucralfate will protect the gastric mucosa.

However, the bioadhesive gel composition formed by sucralfate adsorbs the drug, traps it in the gel composition, or forms a complex depending on the drug to be co-administered. It has been reported that the absorption of the drug itself is hindered or delayed due to the effect of the drug. If one example is listed, for example, 1990
Year, Brouwers et al., Tma of ciprofloxacin
x, Cmax, AUC, and bioavailability were significantly reduced by the combined use with sucralfate (Drug Invest., 2 (3): 197, 1).
990). In the same year, Lafontaine et al. Reported a delay in absorption of naproxen by sucralfate (Clin. Ph.
arm. , 9 (10): 773, 1990) by Can.
tral and the like are A by theophylline sucralfate
Decrease in UC (Clin. Pharm., 7 (1): 5
8, 1988) to the absorption delay of ibuprofen of Ana et al. By sucralfate (Biopharm. D).
rug Dispos. , 7 (5): 443, 198.
6), Maconochie et al. Showed a decrease in AUC and Cmax due to simultaneous administration of ranitidine sucralfate (C
lin. Pharmacol. Ther. , 41
(2): 205, 1987) and Yoshida et al. Reported a decrease in AUC due to coadministration of cimetidine sucralfate (Japanese Journal of Gastroenterological Diseases, 84 (5): 1025, 1987).

Further, Japanese Patent Application No. 4-500445 of Beecham Group Public Limited Company expects a local sustained-release action of H2 antagonist by reversely utilizing the adsorption action of sucralfate.

As described above, although it is known that by combining or administering sucralfate and other drugs at the same time, the absorption of the drug may be adversely affected by the action of adsorption or trap of the drug. Most effective methodologies and means for avoiding this have not been proposed. In the actual medical field, it is necessary to avoid concomitant use of sucralfate with other drugs or to administer them sequentially with a time lag, etc. Guaranteeing bioavailability has been difficult.

[0006]

The object of the present invention is to eliminate the action of a drug by sucralfate in a preparation in which sucralfate and another drug are mixed at the same time, and to guarantee the original bioavailability of the drug.

[0007]

[Means and Actions for Solving the Problems] In such a situation, the present inventors provide a formulation in which sucralfate and another drug are simultaneously mixed to avoid the absorption inhibitory action of the drug by sucralfate. As a result of intensive studies, the drug product is composed of an immediate-release part and a delayed-release part, and sucralfate is incorporated in the delayed-release part, and the compounded drug is adsorbed or trapped in sucralfate by the drug containing the drug simultaneously mixed in the immediate-release part. It was found that the conventional absorption characteristics are maintained without being affected by.

That is, according to the present invention, after the drug contained in the immediate release part of the preparation containing sucralfate and other drug is rapidly disintegrated and eluted, the sucralfate contained in the delayed release part is delayed after this. It provides a disintegrating and releasing formulation. The drug that was previously disintegrated and dissolved by this formulation is immediately dissolved or dispersed in the living body secretory fluid such as gastric juice, so it is absorbed without being affected by adsorption or trap by sucralfate, which disintegrates later and gels with gastric acid. Transfer to the site is possible.

The present invention limits the components contained in the delayed release part to sucralfate, and is used in the technology / additive for delaying disintegration used in the delayed release part, or in the immediate release part. Formulation technology for accelerating disintegration ・ Types and amounts of additives are not limited.

For example, as a formulation technique for obtaining a delayed release part, an oily base such as hardened oil and wax typified by fatty acid, and a water-soluble typified by cellulose derivative such as methylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose. A method of adding a gel-forming base such as a polymer, a matrix base typified by a hydrophobic base such as ethyl cellulose and an acrylic acid copolymer, a method of film coating of the above water-soluble polymer, etc. is there. In order to obtain an immediate release part, addition of a foaming base typified by baking soda, citric acid, partially pregelatinized starch,
Addition of disintegrants such as starch derivatives such as sodium carboxymethyl starch and hydroxypropyl starch, or cellulose derivatives such as carmellose, carmellose calcium, croscarmellose sodium and low-substituted hydroxypropyl cellulose. , A fluidized bed granulation method, etc. can be considered. Further, the constitution or dosage form of these quick release part and delayed release part is not limited.

The drug used in the present invention is a drug that is adsorbed and trapped by sucralfate and is inhibited in absorption. For example, antiepileptic drugs diazepam and phenytoin; antipyretic and analgesic drugs acetaminophen, aspirin, ibuprofen, ketoprofen, Naproxen,
Indomethacin; psychrotic drugs chlorpromazine hydrochloride, imipramine hydrochloride, sulpiride; anticonvulsant methylbenactidium bromide; cardiotonic drug digoxin; antiarrhythmic drugs procainamide hydrochloride, indenolol hydrochloride, verapamil hydrochloride; diuresis Drug furosemide; antihypertensive drug nicardipine hydrochloride; coronary vasodilator diltiazem hydrochloride, dipyridamole, nifedipine; bronchodilator theophylline; H2 receptor antagonists cimetidine, ranitidine, famotidine, nizatidine, roxatidine acetate Acetate; hormone drugs prednisolone, ethinyl estradiol, warfarin potassium; diabetes drug chlorpropamide; antibacterial calcium aluminoparaaminosalicylate, erythrium Mycin, hydrochloric Shipurofurokisan is norfloxacin, etc., cimetidine preferably, H2 receptor antagonists, ranitidine,
Examples include famotidine, nizatidine, and roxatidine acetate acetate. Further, two or more of these drugs may be used in an appropriate combination.

Examples of dosage forms that can carry out the present invention include the following, but any other structure can be used as long as the dosage form can carry out the present invention.

A mixed preparation of two granules or a mixed preparation of two particles, which is produced by mixing an immediate release granule and a delayed release granule, and two or three layers consisting of a layer of immediate release part and a layer of delayed release part Tablets, inner core tablet is slow release, outer layer tablet is immediate release tablet, tablet consisting of immediate release matrix containing delayed release granules in a dispersed state, delayed release core tablet Tablets coated with immediate release film containing, granule preparation coated with immediate release film containing drug around delayed release core granules, coated with immediate release drug powder around delayed release core granules Granule preparation, slow release tablet, capsule filled with a mixture of granule or powder and immediate release tablet, granule or powder, slow release particles dispersed in an aqueous solution or jelly containing drug Liquid or jelly.

In the present invention, the amount of sucralfate contained in the delayed release part is not particularly limited, but the usual dose of sucralfate is 300 mg to 12
00 mg, preferably 500 mg to 1080 mg is desirable. The amount of the drug contained in the immediate release part is not particularly limited, and an amount that can expect a usual drug effect is desirable.

[0015]

EXAMPLES The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these preparations.

[Example 1] (Two-granule mixed preparation) Slow-release granules Sucralfate 1500 g D-mannitol 130 g Hydroxypropylmethylcellulose 60 g Sucralfate and D-mannitol were weighed and mixed,
After kneading with 10% ethanol, the mixture was granulated by an extrusion granulation method, dried and then coated with hydroxypropylmethyl cellulose.

Immediate-release granules Cimetidine 400 g Lactose 800 g Cimetidine and lactose were weighed and mixed, kneaded with water, granulated by an extrusion granulation method, and dried.

Each granule was weighed and mixed according to the prescribed amount to prepare a two-granule preparation.

[Example 2] (Double-layer tablet) Slow-release part powder Sucralfate 1000 g Polyethylene glycol 6000 1000 g Magnesium stearate 2 g Hydrous silicon dioxide 4 g Fast-release part powder Famotidine 10 g Crystalline cellulose 300 g Polyethylene glycol 6000 25 g Slow-release part, The powder of each quick-release part is weighed and mixed, and a two-layer tablet is manufactured by a direct compression method.

[Example 3] (Double layer tablet) Slow release part Sucralfate 1500 g D-mannitol 187 g Hardened oil 300 g Calcium silicate 8 g Calcium stearate 5 g Quick release part Ranitidine hydrochloride 84 g Carboxymethyl starch sodium 240 g Anhydrous calcium phosphate 669 g Hardened oil 3 g Stea Calcium phosphate 4 g Powders of the slow-release part and the quick-release part were weighed and mixed to prepare a double-layer tablet by the direct compression method.

[Example 4] (Nucleated tablets) Inner core tablets Sucralfate 1000 g Sucrose fatty acid ester (HLP 15) 460 g Magnesium stearate 10 g Hydroxypropylmethyl cellulose 30 g Outer kernel tablets Nizatidine 150 g Lactose 4675 g Carmellose calcium 100 g Hydroxypropyl cellulose 50 g Magnesium stearate 25 g Inner core tablet: Sucralfate, sucrose fatty acid ester, and magnesium stearate powder are weighed and mixed, and 1 tablet 147 mg tablet is prepared by direct compression method, and hydroxypropyl methylcellulose is coated to prepare inner core tablet.

Outer core tablet: The mixed powder was granulated using a 70% ethanol solution of hydroxypropyl cellulose, dried, and then mixed with magnesium stearate, and one tablet containing an inner core tablet of 650 mg was prepared using a coreless tablet machine. Make a core tablet.

[Example 5] (Coated tablet) Inner core tablet Sucralfate 1000 g Polyethylene glycol 6000 583 g Light anhydrous silicic acid 10 g Magnesium stearate 7 g Coating layer Roxazine acetate 75 g Hydroxypropylmethyl cellulose 80 g Propylene glycol 20 g Titanium oxide 5 g Inner core tablet One tablet of 320 mg was prepared by direct compression method, and the coating layer components were dissolved and dispersed in isopropanol for coating, and it was confirmed that the required amount of loxazin hydrochloride hydrochloride was coated.

Example 6 (Spherical Coated Granules) Inner Core Granules Sucralfate 1000 g Spherical Granules (Nonpareil) 900 g Hydroxypropyl Cellulose 100 g Coating Layer Famotidine 10 g D-Mannitol 200 g Hydroxypropylmethyl Cellulose 15 g Propylene Glycol 5 g Centrifugal Fluid Coating Granulator While spraying hydroxypropylcellulose aqueous solution on spherical granules quantitatively, sucralfate is quantitatively sprayed from an automatic powder spraying device,
After the drying is repeated and the spraying of sucralfate is completed, a 50% alcohol solution of hydroxypropylmethylcellulose and propylene glycol in the coating layer is quantitatively sprayed, a mixed powder of famotidine and D-mannitol is quantitatively sprayed, and drying is repeated to produce spherical coated granules.

[Example 7] (Double-layer tablet) Slow release part Sucralfate 2000 g Hydroxymethyl cellulose 180 g Magnesium stearate 20 g Fast release part Methyl benactidium bromide 40 g Hydroxypropyl starch 100 g Calcium citrate 2040 g Magnesium stearate 20 g Slow release part The powder of each quick-release part is weighed and mixed, and a two-layer tablet is manufactured by a direct compression method.

[Comparative Example 1] (Granule) Blended granules Sucralfate 1500 g Cimetidine 400 g Mannitol 237.5 g Lactose 237.5 g The above powders were weighed and mixed and kneaded with 10% ethanol, and then granulated by an extrusion granulation method. Then, a granule was manufactured through a drying process.

[Comparative Example 2] (Tablets) Compounded tablets Sucralfate 1000 g Famotidine 10 g Crystalline cellulose 600 g Polyethylene glycol 6000 460 g Magnesium stearate 2 g Hydrous silicon dioxide 4 g The above powders are weighed and mixed to prepare tablets by a direct compression method.

[Test Example] Granules of Example 1 1927 mg
(A two-granule mixed preparation of 800 mg of an immediate release part and 1127 mg of a delayed release part) and 1583 mg of the granules of Comparative Example 1 were subjected to a Japanese Pharmacopoeia dissolution test using a Japanese Pharmacopoeia liquid 1 (900 ml) and a rotating basket method. The drug of the example, cimetidine, was rapidly released, and 5 to 10 minutes after that, sucralfate formed a paste and adhesiveness occurred. In contrast, in the comparative example, sucralfate paste was immediately formed, and cimetidine was eluted at 50% at 50% elution time.
A delay of more than a minute was observed (Fig. 9), and it was confirmed quantitatively that the drug remained in the paste. The results of the disintegration test with water are shown in the table.

One tablet (585.3 mg) of Example 2 and one tablet (519 mg) of Comparative Example 2 were placed in a beaker with 200 ml of Japanese Pharmacopoeia liquid 1 at 37 ° C. under stirring.
The supernatant was sampled with time, filtered, and then the absorbance was measured with a spectrophotometer. The drug of the Example, famotidine, was rapidly released, and thereafter sucralfate formed a paste, and adhesion was generated. On the other hand, in the comparative example, sucralfate paste was immediately formed and the elution of famotidine was observed to be delayed by 10 minutes or more at the elution time of 75% (Fig. 10), indicating that the drug remained in the paste. It was confirmed quantitatively. The results of the Japanese Pharmacopoeia disintegration test are shown in the table.

Further, the same tests were conducted for the formulations of Examples 3 to 7. The results of the Japanese Pharmacopoeia disintegration test for these formulations are also shown in the table below.

Table: Disintegration test results with water Formulation Disintegration (dissolution) time Example 1 5 seconds (immediate release granules) 8 minutes (slow release granules) Comparative example 1 12 seconds Example 2 11 minutes (immediate release layer) 25 minutes (Slow release layer) Comparative Example 2 9 minutes Example 3 2 minutes (rapid release layer) 14 minutes (slow release layer) Example 4 1 minute (outer layer tablet) 16 minutes (inner core tablet) Example 5 3 minutes (coating layer Dissolution) 14 minutes ( inner core tablet) Example 6 4 minutes (coating layer dissolution) 15 minutes (inner core granules) Example 7 2 minutes (immediate release layer) 15 minutes (slow release layer)

[0032]

As described above, according to the present invention, it is possible to guarantee the original bioavailability of a drug without being adsorbed and trapped by the sucralfate, despite the formulation in which the drug and sucralfate are simultaneously mixed. I can expect it.

[Brief description of drawings]

FIG. 1 is a two-particle mixed preparation or a two-particle mixed preparation of the present invention, which is obtained by mixing immediate release granules and delayed release granules.

FIG. 2 is a bilayer or trilayer tablet of the present invention comprising an immediate release layer and a delayed release layer.

FIG. 3 is a tablet of the present invention in which the inner core tablet is slow-release and the outer layer tablet is fast-release.

FIG. 4 is a tablet of the present invention comprising an immediate release matrix containing delayed release granules in a dispersed state.

FIG. 5: Tablets coated around the delayed release core tablet with an immediate release film containing the drug.

FIG. 6 is a granule preparation in which an immediate release film containing a drug is coated around a delayed release core granule.

FIG. 7: Granule preparation in which delayed-release core granules are coated with immediate-release drug powder around the granules.

FIG. 8: Capsules filled with a mixture of a slow release tablet, granules or powder and an immediate release tablet, granules or powder.

FIG. 9 is a graph showing an elution curve of cimetidine in the granular preparations of Examples and Comparative Examples.

FIG. 10 is a graph showing famotidine dissolution curves in tablets of Examples and Comparative Examples.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI technical display location A61K 31:34) (A61K 31/70 31: 425) (A61K 31/70 31: 445)

Claims (5)

[Claims] 1. A preparation in which sucralfate and another drug are mixed in the same preparation, and the drug is rapidly eluted without being adsorbed or trapped by sucralfate. 2. The preparation according to claim 1, wherein sucralfate is separately blended in the same preparation as another drug, and is composed of an immediate-release part containing the other drug and a delayed-release part containing sucralfate. 3. The drug according to claim 1, wherein the drug is adsorbed and trapped by sucralfate to be inhibited in absorption.
Or the preparation according to 2. 4. The drug is an antiepileptic drug, diazepam, phenytoin; antipyretic analgesics, acetaminophen, aspirin, ibuprofen, ketoprofen, naproxen, indomethacin; psychotropic drugs chlorpromazine hydrochloride, imipramine hydrochloride, sulpiride; Methylbenactidium bromide, an anticonvulsant; digoxin, a cardiotonic drug; procainamide hydrochloride, an antiarrhythmic drug,
Indenolol hydrochloride, verapamil hydrochloride; furosemide, a diuretic; nicardipine hydrochloride, a hypotensive drug; diltiazem hydrochloride, dipyridamole, nifedipine, a coronary vasodilator; theophylline, a bronchodilator; cimetidine, ranitidine, H2 receptor antagonists
Famotidine, nizatidine, roxatidine acetate acetate; hormone drugs prednisolone, ethinyl estradiol, warfarin potassium; diabetes drug chlorpropamide; antibacterial calcium aluminoparaaminosalicylate, erythromycin, ciprofloxan hydrochloride, norfloxacin; The formulation according to claim 1, 2 or 3, which is a combination of any of the above. 5. The formulation according to claim 4, wherein said drug is an H2 receptor antagonist selected from cimetidine, ranitidine, famotidine, nizatidine or roxatidine acetate acetate.