JP2001010951A - Sustained release preparation of hydrogel - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject preparation capable of also utilizing the colon as a site for absorbing a medicine, providing a stable concentration in the blood, and capable of extremely extending the absorbing time of the medicine by using the medicine, a specific additive and a high molecular material forming a hydrogel. SOLUTION: The objective preparation having the ability for nearly completely gelatinizing the preparation during the retention in the stomach and the small intestine at the upper part of the digestive tract, and having releasing ability of the medicine even at the colon at the lower part of the digestive tract comprises (A) one or more kinds of medicines (e.g. nicardipine hydrochloride), (B) one or more kinds of additives requiring >=5 ml water for dissolving 1 g and for allowing the water to penetrate into the interior, (e.g. a polyethylene glycol, a polyvinylpyrrolidone and a D-sorbitol) and (C) a high molecular material capable of forming a hydrogel [capable of providing a high viscosity at the time of gelatinization, especially providing 1% aqueous solution having >=1,000 cPs viscosity (at 25 deg.C), e.g. a polyethylene oxide having >=2,000,000 molecular weight].

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a sustained-release preparation capable of releasing a drug for a long period of time. More specifically, the present invention relates to a sustained-release hydrogel preparation capable of excellently releasing a drug not only in the upper gastrointestinal tract but also in the colon in the lower gastrointestinal tract.

[0002]

2. Description of the Related Art Conventionally, various hydrogel preparations have been proposed for the purpose of sustained release of drugs. As an example of these, for example, Japanese Patent Application Laid-Open No. Sho 62-120315 discloses that a drug, a water-soluble polymer capable of forming a hydrogel, and an enteric coating base are formed and compressed.
No. 0 discloses a hydrogel preparation comprising a core composed of a drug and a water-soluble polymer substance and an outer layer based on the water-soluble polymer substance, and Japanese Patent Publication No. 40-2053 discloses a drug and ethylene oxide Long-acting preparations and the like containing a polymer and, if necessary, a hydrophilic substance and the like are known.

[0003]

However, these drugs are intended to continuously release the drug while staying in the upper gastrointestinal tract such as the stomach and the small intestine. It is not intended for drug release in the lower gastrointestinal tract. That is, in a sustained-release preparation in which the drug is released and absorbed while descending in the gastrointestinal tract, the absorption and release of the drug in the upper gastrointestinal tract greatly affect the bioavailability, but in the colon, In the past, drug release was considered to be difficult due to the effects of low water content, waste contents, etc., and research on drug release properties was scarcely conducted (Abstracts of the 6th Annual Meeting of the Pharmaceutical Society of Japan ( 1990), p. 30, Pharm.Tech, Japan 8 (1),
(1992), p. 41). Furthermore, the biological half-life of the drug itself is also an important factor when studying a sustained-release preparation, but it is considered that it is difficult to achieve a sufficient sustained-release for a drug having a short half-life of the drug itself. Ta (Monthly Pharmaceutical Affairs 25 (11), (19
83), p. 29).

[0004]

Means for Solving the Problems In the study of sustained release of a drug, the present inventors have found that a drug is absorbed into the inside of the preparation and stays in a completely gelled state while staying in the upper gastrointestinal tract such as the stomach and the small intestine. The present inventors have found that the drug can be released even in the colon having low water content by transferring the drug to the lower gastrointestinal tract, and completed the present invention. That is, the present invention relates to the present invention, wherein the amount of water necessary for dissolving at least (1) one or more drugs and (2) 1 g is 5
One or two or more preparations exhibiting a solubility of less than 1 ml, and an additive for infiltrating water into the inside of the preparation, and (3) a polymer substance that forms a hydrogel, It is a hydrogel sustained-release preparation which has the ability to gel almost completely and has the ability to release drugs even in the colon in the lower gastrointestinal tract. In the present invention, the state where the preparation is almost completely gelled means that about 70% of the preparation
%, Preferably about 80% or more gelled. The sustained-release preparation of the present invention can achieve a stable drug blood concentration because the absorption time of the drug can be greatly extended by using the colon as an absorption site. That is, the formulation of the present invention absorbs water while staying in the upper gastrointestinal tract, gels almost completely, and migrates to the lower gastrointestinal tract while the surface of the formulation undergoes erosion, and further releases the drug due to further erosion. Therefore, good and sustained drug absorption can be achieved even in a colon having little water.

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION The sustained-release preparation of the present invention is described in more detail below. The one or more drugs applied to the preparation of the present invention are not particularly limited as long as they are drugs intended for sustained release. Representative drugs include indomethacin, diclofenac, diclofenac Na, codeine, ibuprofen, phenylbutazone, oxyfenbutazone, mepyrizole, aspirin, etensamide, acetaminophen, aminopyrine, phenacetin, butylscopolamine bromide, morphine, etomidrin, Anti-inflammatory, antipyretic, antispasmodic or analgesic drugs such as pentazocine and fenoprofen calcium, antituberculous drugs such as isoniazid, ethambutol hydrochloride, isosorbide dinitrate, nitroglycerin, nifedipine, barnidipine hydrochloride, nicardipine hydrochloride, dipyridamole, amrinone, indenolol hydrochloride, hydralazine hydrochloride Drugs for circulatory organs, such as, methyldopa, furosemide, spironolactone, guanethidine nitrate, reserpine, amosulalol hydrochloride, Antipsychotics such as lupromazine, amitriptyline hydrochloride, nemonapride, haloperidol, moperone hydrochloride, perphenazine, diazepam, lorazepam, chlordiazepoxide, antihistamines such as chlorpheniramine maleate, diphenhydramine hydrochloride, thiamine nitrate, tocopherol acetate, sicotiamine, phosphate Vitamin drugs such as pyridoxal, cobamamide, ascorbic acid, nicotinamide, gout drugs such as allopurinol, colchicine, probenedide, hypnotics such as amobarbital, bromvalerylurea, midazolam, chloral hydrate, fluorouracil, carmofur, aclarubicin hydrochloride, cyclo Antineoplastic drugs such as phosphamide and thiotepa, antidepressant drugs such as phenylpropanolamine and ephedrine, acetohexamide, Diabetic drugs such as shulin and tolbutamide; diuretics such as hydrochlorothiazide, polythiazide and triamterene; bronchodilators such as aminophylline, formoterol fumarate and theophylline; antitussives such as codeine phosphate, noscapine, dimemorphan phosphate and dextromethorphan. , Quinidine nitrate, dichitoxin,
Antiarrhythmic drugs such as propafenone hydrochloride and procainamide; surface anesthetics such as ethyl aminobenzoate, lidocaine and dibucaine hydrochloride; antiepileptic drugs such as phenytoin, etosuximide, primidone; synthetic adrenal glands such as hydrocortisone, prednisolone, triamcinolone and betamethasone Corticosteroids, famotidine, ranitidine hydrochloride,
Drugs for digestive organs such as cimetidine, sucralfate, sulpiride, teprenone, praunitol, indeloxazine, idebenone, tiapride hydrochloride, bifemelane hydrochloride,
Central nervous system drugs such as calcium hopatenate, therapeutic agents for hyperlipidemia such as pravastatin sodium, and antibiotics such as ampicillin phthalidyl hydrochloride, cefotetan, and josamycin. Particularly representative of these drugs is nicardipine hydrochloride. In addition, a drug having a short biological half-life may be used. The amount of the drug may be any amount as long as it exhibits a medicinal effect, but is usually 85% by weight of the whole preparation.
Or less, preferably 80% by weight or less.

[0006] In order to facilitate the absorption of these drugs even in the colon with low water content, it is preferable to improve their solubility. As a method for improving solubility (solubilizing treatment), known methods applicable to hydrogel preparations, for example, surfactants (polyoxyethylene hydrogenated castor oils, polyoxyethylene sorbitan higher fatty acid esters, polyoxyethylene poly) Oxypropylene glycols, sucrose fatty acid esters, etc.)
Drugs and solubilizers such as polymers (water-soluble polymers such as hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), and carboxymethylethylcellulose (CM
Solid dispersion with EC), hydroxypropyl methylcellulose phthalate (HPMCP), methyl methacrylate-methacrylic acid copolymer (Eudragit L, S, trade name; manufactured by Rohm and Haas Co.) A method of forming a body is included. When the drug is a basic substance, a method of adding an organic acid such as citric acid or tartaric acid can also be used. If necessary, a method of forming a soluble salt,
A method of forming an inclusion compound using cyclodextrin or the like can also be adopted. The means of solubilization can be changed as appropriate depending on the target drug ["Recent formulation technology and its application I", Isamu Utsumi, Pharmaceutical Journal 157-159 (1983) and "Pharmaceutical Monograph No. 1, Biological Science Utilization ”, Tsuneji Nagai et al., Soft Science, 78-82 (1988)]. Of these, a method of improving the solubility by forming a solid dispersion of the drug and the solubilizing agent is preferably employed (Japanese Patent Application Laid-Open No. 56-493).
No. 14, FR2460667).

[0007] Next, as an additive for allowing water to penetrate into the preparation of the preparation of the present invention (hereinafter, an additive for allowing water to penetrate into the preparation is referred to as a hydrophilic base), the hydrophilic base The amount of water required to dissolve 1 g of the agent is 20 ± 5
5 ml or less, preferably 4 ml or less at 0 ° C,
The higher the solubility in water, the higher the effect of infiltrating water into the formulation. Examples of such a hydrophilic base include polyethylene glycol (PEG; for example, trade names PEG400, PEG15
00, PEG4000, PEG6000, PEG20000 manufactured by NOF Corporation, polyvinylpyrrolidone (PVP; for example, trade name PVP K30 BASF)
Water-soluble polymers such as D-sorbitol and xylitol, sucrose, anhydrous maltose, D-fructose, dextran (eg, dextran 40), saccharides such as glucose, and polyoxyethylene curing. Castor oil (HCO; for example CremophorRH40 manufactured by BASF, HCO-
40, HCO-60 Nikko Chemicals, Inc., polyoxyethylene polyoxypropylene glycol (for example, Pluronic F68 Asahi Denka Co., Ltd.) or polyoxyethylene sorbitan higher fatty acid ester (Tween; for example, Tween80, manufactured by Kanto Chemical Co., Ltd.) Agents, salts such as sodium chloride and magnesium chloride or organic acids such as citric acid and tartaric acid,
Amino acids such as glycine, β-alanine, lysine hydrochloride,
It is an amino sugar such as meglumine. Particularly preferred are PEG6000, PVP, D-sorbitol and the like.

The ratio of the hydrophilic base depends on the properties (solubility, therapeutic effect, etc.) and content of the drug, the solubility of the hydrophilic base, the properties of the polymer forming the hydrogel, or the Although it depends on various factors such as the condition of the patient, the ratio is preferably such that the preparation can be almost completely gelled while staying in the upper gastrointestinal tract. The time the drug stays in the upper gastrointestinal tract depends on the species, and there are individual differences,
Approximately 2 hours after administration in dogs, approximately 4-5 hours after administration in humans (Br. J. Clin. Pharmac., (1988) 26, 435-44).
3). In the case of humans, the ratio is preferably such that the preparation can be almost completely gelled in 4 to 5 hours after administration. Generally, 5 to 80% by weight, preferably 5 to 60% by weight, based on the whole preparation
% By weight. If the content of the hydrophilic base is low, the gelation does not proceed to the inside and the release in the colon is not sufficient. On the other hand, if the content is too large, gelation proceeds in a short time, but the gel is easily broken, the elution of the drug is accelerated, there is a possibility that sufficient sustained release may not be achieved, and the amount of the base also increases, Each of the formulations has disadvantages such as an increase in the size of the preparation itself.

Next, as the polymer substance which forms a hydrogel, the preparation of the present invention is almost completely gelled,
It can withstand the contraction movement of the digestive tract due to food digestion and can move to the colon at the lower part of the digestive tract while maintaining a certain shape,
It is necessary to have properties such as viscosity at the time of gelation. As the polymer substance forming a hydrogel applicable to the preparation of the present invention, a substance having a high viscosity at the time of gelation is preferable. For example, a 1% aqueous solution (25 ° C.) having a viscosity of 1000 cps or more is particularly preferable. Further, the properties of the polymer substance depend on its molecular weight, the polymer substance forming a hydrogel applicable to the preparation of the present invention is preferably a higher molecular weight substance, more preferably an average molecular weight of 2,000,000 or more, more preferably an average molecular weight of 4 or more.
One million or more. Examples of such a polymer substance include polyethylene oxide (PEO) having a molecular weight of 2,000,000 or more (for example, Polyox WSR-303 (trade name) (average molecular weight: 7,000,000, viscosity: 7500-10000cps (1% aqueous solution 25
° C)), Polyox WSR Coagulant (average molecular weight 5 million, viscosity: 5500-7500 cps (same)), Polyox WSR-301 (average molecular weight: 4 million, viscosity: 1650-5500 cps (same)), Polyox WSR-
N-60K (average molecular weight: 2,000,000, viscosity: 2000-4000cps (2%
Aqueous solution (25 ° C)), manufactured by Union Carbide Co., Ltd.), hydroxypropyl methylcellulose (HPMC) (for example, Metrolose 90SH100000 (trade name: 4100-5600cps (1
% Aqueous solution 20 ° C)), Metrolose 90SH50000 (viscosity: 2900-
3900cps (same as above), Metroz 90SH30000 (viscosity: 25000-
35000cps (2% aqueous solution at 20 ℃)) All manufactured by Shin-Etsu Chemical Co., Ltd.), sodium carboxymethylcellulose (CMC-N
a) (for example, trade name Sunrose F-150MC (average molecular weight:
200,000, viscosity 1200-1800cps (1% aqueous solution 25 ° C), Sunrose F-1000MC (average molecular weight: 420,000, viscosity 8000-12000cps
Sunrose F-300MC (average molecular weight: 300,000, viscosity 2500-3000 cps (same)) manufactured by Nippon Paper Industries), hydroxyethyl cellulose (HEC) (for example, trade name: HEC Daicel SE850 (average molecular weight: 1.48 million) , Viscosity 2400-3000CPS (1%
Aqueous solution 25 ° C), HEC Daicel SE900 (average molecular weight: 156)
10,000, viscosity 4000-5000 cps (same), manufactured by Daicel Chemical Industries) or carboxyvinyl polymer (for example, Carbopol 940 (average molecular weight: about 2.5 million) BF Goodrich Che
mical). Preferably average molecular weight 200
More than 10,000 PEOs. When a sustained release of a long period, for example, 12 hours or more is required, a higher polymer, preferably having an average molecular weight of 4,000,000 or more or having a higher viscosity, preferably a 1% aqueous solution having a viscosity at 25 ° C of 3000 cps or more. Molecules are mentioned as suitable. These polymer substances that form a hydrogel can be used alone or in combination of two or more. Also, a mixture comprising two or more kinds of polymer substances and having the properties suitable for the present invention as a whole can be suitably used as the polymer substance forming the hydrogel of the present invention.

In humans, to have the ability to release drugs in the colon, at least 6 to 8 hours after administration,
More preferably, a part of the gelled preparation must remain in the colon after 12 hours or more.
In order to form a hydrogel preparation having such properties, the size of the preparation, the type of polymer substance, the nature of the drug and the additive for infiltrating water into the tablet, the content, etc., vary, Generally, in a tablet of 600 mg or less, the proportion of the polymer substance forming a hydrogel to the whole preparation is 10 to 95% by weight, preferably 15 to 95% by weight.
90% by weight, and the amount of the preparation per tablet is preferably 70 mg or more, more preferably 100 mg or more per tablet. If the amount is less than this, it may not be able to withstand erosion in the digestive tract for a long period of time, and sufficient sustained release may not be achieved. The usefulness of the hydrophilic base and the hydrogel-forming polymer substance (hereinafter referred to as a hydrogel-forming base) of the preparation of the present invention was confirmed by the following experiments.

Experimental Examples (Regarding Types and Amounts of Hydrophilic Base and Hydrogel-Forming Base) (1) Gel formation rate over time of the sustained-release hydrogel preparation of the present invention Sample Hydrogel-forming base Polyox WSR- 303 (hereinafter POLYOX303
100 parts by weight) and 150 parts by weight of hydrophilic base PEG6000.
Parts by weight, mixed in a mortar, and compressed with an oil press using a tableting pressure of 1 ton / punch.
mg tablets were obtained. Gel formation test Japanese Pharmacopoeia 12 revision (hereinafter JP)
armacopoeia of JapanXII) Using paddle rotation speed 2 by dissolution test method 2 and JP method 2 (paddle method)
The test was performed at 5 rpm. The tablet was taken out at each time, and after the gel layer was peeled off, the diameter (D obs) of the non-gelled portion was measured. The gelation rate (G) was calculated from D obs (Table
1, Figure 1, Equation 1). Here, the gelation ratio indicates a ratio of a portion of the tablet where a gel is formed. The method for calculating the gelation ratio is not particularly limited, and examples thereof include the following calculation method. The calculation method is a method of measuring the volume (or weight) of the non-gelled portion after wetting the tablet for a certain period of time, and subtracting it from the volume (or weight) of the tablet before the start of the test. Specifically, the gel layer of the tablet moistened for a certain time is peeled off, and the diameter (or thickness) of the non-gelled portion
Is measured and calculated using Equation 1.
Similarly, it may be obtained from Expression 2 below. Further, using the difference in strength between the gel layer and the portion where no gel is formed, the diameter (or thickness) when a certain pressure is applied is regarded as the diameter (or thickness) of the non-gel portion, and It can be calculated from 1.

[0012]

[Table 1]

[0013]

(Equation 1)

Test Results Hydrogel tablets containing PEG 6000 as a hydrophilic base are:
The inner diameter was reduced at a substantially constant speed, and gelation proceeded. Almost completely (80% or more) gelled 2 hours after the start of the test.

(2) Content of Hydrophilic Base Sample Hydrogel-forming base POLYOX303 100 parts by weight based on 100 parts by weight
A hydrophilic base material PEG6000 is blended in a ratio of 0 to 150 parts by weight or less, mixed in a mortar, and compressed with an oil press at a compression pressure of 1 ton / punch to obtain a tablet with a diameter of 8.0 mm and a weight of one tablet. 200 mg tablets were obtained. Gel formation test Using the Japanese Pharmacopoeia Disintegration Test Solution 2 as a test solution, a test was conducted at a paddle rotation speed of 25 rpm according to the Japanese Pharmacopoeia Dissolution Test Method 2 (paddle method). The tablet was taken out at each time, and after the gel layer was peeled off, the diameter (D obs) of the non-gelled portion was measured. The gelation rate (G) was calculated from D obs (Table 2, Figure
2).

[0016]

[Table 2]

Test Results It was shown that, by blending 15 parts by weight (13.0% of the tablet weight) of the hydrophilic base PEG6000, 80% or more of the gel was formed in 2 hours. In addition, it was shown that when 10 parts by weight (9.1% of the tablet weight) of the hydrophilic base PEG6000 was added, 80% or more of the gel was formed in 4 hours.

(3) Screening of hydrophilic base Sample hydrogel forming base POLYOX303 100 parts by weight,
Mix 100 parts by weight of various hydrophilic bases, mix in a mortar,
Using an oil press, press with a tableting pressure of 1 ton / punch and press
8.0 mm tablets weighing 200 mg per tablet were obtained. Gel formation test Using the Japanese Pharmacopoeia Disintegration Test Solution 2 as a test solution, a test was conducted at a paddle rotation speed of 25 rpm according to the Japanese Pharmacopoeia Dissolution Test Method 2 (paddle method). Two hours after the start of the test, the tablets were taken out, the gel layer was peeled off, and the diameter (D obs) of the non-gelled portion was measured. The gelation rate (G) was calculated from D obs (Table
3, Figure 3).

[0019]

[Table 3]

Test results When D-mannitol and lactose, each having a solubility of 6 ml or 8 ml, respectively, required for dissolving 1 g of the additive, were added, the gelation was almost equivalent to that of POLYOX303 alone. Rate, indicating that the effect of gelling to the inside of the tablet was small. Hydrophilic bases for gelation of 80% or more in 2 hours include glycine, PVP K30, PEG6000, D-sorbitol and other highly soluble bases (at least the amount of water required to dissolve 5 ml or less, preferably 4 ml or less) has been found to be suitable.

(4) Investigation of Hydrogel-Forming Base Using acetaminophen and nicardipine hydrochloride (Pd) as model drugs, the amount and molecular weight of the hydrogel-forming base required as a sustained-release preparation were examined. Part 1. Investigation on suitable blending amount The relationship between the blending amount of the gel-forming base and the dissolution behavior was examined. Acetaminophen

[0022]

[Table 4]

The components shown in Table 4 were mixed in a mortar and tabletted with an oil press at a tableting pressure of 1 ton / punch to obtain a tablet (containing 50 mg of acetaminophen). Nicardipine hydrochloride (Pd) 1 part by weight of Pd1, 0.2 parts by weight of HCO-60, 0.4 parts by weight of hydroxypropyl methylcellulose (TC-5E, manufactured by Shin-Etsu Chemical Co., Ltd.)
-Dissolve in methanol mixture (1: 9) and spray-dry using a spray drier.
And

[0024]

[Table 5]

The components shown in Table 5 were mixed in a mortar, and the mixture was tableted with an oil press at a tableting pressure of 1 ton / punch to give a tablet (Pd 8
0 mg). Dissolution test Using JP Disintegration Test Solution 1 or 2 as the test solution, conduct a test on model formulations of acetaminophen and nicardipine hydrochloride (Pd) by JP Dissolution Test Method 2 (Paddle Method). Was. Sampling was performed at each time, and the amount of drug in the solution was measured by the UV method (FIGS. 4 and 5). Test results The elution rate could be controlled by the content of the hydrogel-forming base POLYOX303. When using 50 mg of acetaminophen as the main drug, POLYOX303 content 1
By blending 00 mg (50% of the tablet weight) or more, it was possible to sustain release for 12 hours or more even under high stirring (paddle rotation speed 200 rpm, pH 6.8). Similarly, when using Pd 80 mg as the main drug, the POLYOX303 content 96 mg
(37.5% of tablet weight) or more, it was possible to sustain release for 12 hours or more even under high stirring (paddle rotation speed 200 rpm, pH 1.2). The preferred content ratio of the hydrogel-forming base varies depending on the type and amount of the drug and the hydrophilic base, the required dissolution rate, and the like, but it was shown that the larger the content ratio, the slower the release. Also,
When it was expected that the release was continued for 12 hours or more, it was shown that it is necessary to contain about 70 mg or more, preferably 100 mg or more, of the hydrogel-forming base per tablet.

Part 2. The relationship between the molecular weight of the gel-forming base and the duration of release was studied. Acetaminophen

[0027]

[Table 6]

Polyethylene oxide (PEO) having an average molecular weight of 900,000, 1,000,000, 2,000,000, 4,000,000, 5,000,000 or 7,000,000 was used. The mixture was mixed in a mortar and compressed with an oil press at a compression pressure of 1 ton / punch to obtain a diameter of 9.0 mm and a tablet weight of 350 mg. Nicardipine hydrochloride (Pd) Dissolve 1 part by weight of PdL, 0.4 part by weight of HCO-40, and 0.8 part by weight of hydroxypropyl methylcellulose (TC-5E, manufactured by Shin-Etsu Chemical Co., Ltd.) in a mixture of water and methanol (1: 9), and use a spray dryer. Spray-dried and spray-dried 2
And

[0029]

[Table 7]

As polyethylene oxide (PEO), the molecular weight is 900,000, 1,000,000, 2,000,000, 4,000,000, 5,000,000 or 70,000,000.
100,000 was used. The mixture was mixed in a mortar and compressed with an oil press at a compression pressure of 1 ton / punch to obtain a tablet having a diameter of 11.0 mm and a tablet weight of 568 mg (containing 80 mg of Pd). Dissolution test The acetaminophen formulation and the nicardipine hydrochloride formulation were treated in the same manner as in the dissolution test performed in the study of the above-mentioned 1 suitable amount (FIGS. 6 and 7). Test results Hydrogel-forming base polyethylene oxide (PEO)
The elution rate changed depending on the average molecular weight of. When 50 mg of acetaminophen is used as the main drug, the average molecular weight of PEO is 4
By using a grade of at least 1,000,000, it was possible to sustain release for 12 hours or more even under high stirring (paddle rotation speed 200 rpm, pH 6.8). Similarly, when Pd 80 mg was used as the main drug, it was possible to sustain release for 12 hours or more by using a grade of PEO having an average molecular weight of 2,000,000 or more.

(5) Confirmation of gel formation in vivo A sample obtained by adding a hydrophilic base (PEG6000, PVP K30, D-sorbitol) to a sample hydrogel forming base (POLYOX303) in the following mixing ratio. Each was mixed in a mortar, and compressed with an oil press using a tableting pressure of 1 ton / punch.
A tablet weighing 200 mg was obtained. POLYOX303: PEG6000 = 100: 10,25,50,100 POLYOX303: PVP K30 = 100: 10,25,100 POLYOX303: D-sorbitol = 100: 10,25,100 Dog dissection test Male beagle dog fasted for about 20 hours ( DOG A, B) were orally administered with various formulations together with 30 ml of water. Two hours later, after pentobarbital sodium anesthesia, the blood was removed and the abdomen was opened. From inside the digestive tract,
The tablets were collected and Dobs were measured. The gelation rate (G) was calculated from D obs (Table 8).

[0032]

[Table 8]

Test Results In Dog A, the tablet had already moved to the colon 2 hours after administration, and the residence time of the tablet in the upper gastrointestinal tract was 2 hours or less. However, except for tablets containing 10 parts of PEG6000,
All were gelled at 80% or more, almost corresponding to the in vitro results. In Dog B, the tablets stayed in the stomach 2 hours after administration, and all tablets had gelled by 80% or more.
Based on the above results, the hydrogel tablets containing an appropriate amount of a hydrophilic base (PVP K30, PEG6000, D-sorbitol) capable of gelling by 80% or more in vitro allow water to penetrate into the tablets even in vivo. It was found that the gelation was easy.

If necessary, other pharmaceutically acceptable additives such as excipients such as lactose, mannitol, potato starch, wheat starch, rice starch, corn starch, crystalline cellulose, hydroxypropyl, etc. Binders such as methylcellulose, hydroxypropylcellulose, methylcellulose and gum arabic, swelling agents such as carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, stearic acid, calcium stearate,
Lubricants such as magnesium stearate, curk, magnesium metasilicate aluminate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, fluidizing agents such as hydrous silicon dioxide, light anhydrous silicic acid, and dried aluminum hydroxide gel,
Coloring agents such as yellow iron sesquioxide and iron sesquioxide, surfactants such as sodium lauryl sulfate and sucrose fatty acid ester, coating agents such as zein, hydroxypropylmethylcellulose and hydroxypropylcellulose, l-menthol, peppermint oil, fennel oil And a preservative such as sodium sorbate, potassium sorbate, methyl rosebenzoate and ethyl parabenzoate.

The preparation of the present invention is a solid preparation having a certain shape and a hydrogel-forming ability, and may be produced by any method as long as it can be applied to ordinary hydrogel preparations. For example, a tableting method in which a drug, a hydrophilic base material and a high molecular substance forming a hydrogel, and further, if necessary, other additives are added and mixed, compression molding, a capsule compression filling method, or solidification after melting and melting the mixture Extrusion molding, injection molding, and the like.
Further, after the molding, a usual coating treatment such as sugar coating or film coating can be performed. Alternatively, the capsule may be filled after molding.

When solubilizing the drug applied to the preparation of the present invention, it can be performed before the above-mentioned preparation. When solubilization is performed using a solubilizing agent, the hydrophilic base of the present invention may also serve as the solubilizing agent.For example, the hydrophilic base is solubilized by a hydrophilic base and other additives as necessary. It can also be produced by a method of tableting by adding a polymer substance which forms a hydrogel with the drug and, if necessary, other additives. The sustained-release preparation of the present invention may further have an immediate release part, if necessary. For example, the preparation of the present invention can be coated with the immediate-release part. Further, depending on the purpose, a dry coated tablet can be obtained. For example, if a higher blood concentration is required after a certain period of time, a faster drug elution rate (eg, higher drug content, lower hydrogel-forming base content, and / or lower hydrophilic base content) Core tablets in the formulation, and the outer layer part slows down the drug dissolution rate (reduces the drug content, increases the hydrogel-forming base content and / or
Alternatively, the drug dissolution rate can be increased after a certain period of time by reducing the content of the hydrophilic base).

[0037]

EXAMPLES The preparation of the present invention will be described below in more detail. The present invention is not limited by these examples. Example 1 AAP 100 (parts by weight) PEG6000 400 POLYOX303 300 Acetaminophen (AAP) and PEG6000 were melted at 80 ° C., cooled, solidified, and pulverized. The pulverized product and POLYOX303 were mixed in a mortar and compressed with an oil press at a compression pressure of 1 ton / punch to obtain a tablet having a diameter of 9 mm and a tablet weight of 400 mg (containing 50 mg of AAP). Comparative Formulation 1 AAP 100 (parts by weight) POLYOX303 200 AAP and POLYOX303 were mixed in a mortar and compressed with an oil press using a tableting pressure of 1 ton / punch to obtain a tablet with a diameter of 8.5 mm and a tablet weight of 300.
A tablet (containing 100 mg of AAP) was obtained. The following tests were performed on Example 1 and Comparative Formulation 1 obtained above. (1) Dissolution test 1 Using the Japanese Pharmacopoeia Disintegration Test Method 2 as the test solution, the test was performed according to the Japanese Pharmacokinetic Dissolution Test Method 2 (paddle method). Sampling was performed at each time, and AAP in the solution was measured by a UV method (Table 9, FIG. 8).

[0038]

[Table 9]

(2) Gel formation test The test was carried out at a paddle rotation speed of 25 rpm by the Japanese Dissolution Test Method 2 (paddle method) using JP Disintegration Test Method 2 as a test liquid. The tablet was taken out at each time, and the diameter (D obs) of the non-gelled portion was measured. The gelation rate (G) was calculated from D obs (Table 10, Fig. 9)

[0040]

[Table 10]

(3) Dog Administration Test 1 Male beagle dogs (n = 4) fasted for about 20 hours were given the tablets of Example 1 × 2 tablets (AAP 100 mg) and Comparative Formulation 1 (AAP 100 mg)
Was orally administered with 30 ml of water. Blood was collected over time and the drug concentration in plasma was measured by HPLC / UV method (Table 11, FIG. 10). The absorption rate was calculated by the Deconvolution method using the drug concentration data in plasma at the time of iv administration of a 100 mg aqueous solution of AAP as a weight function. The absorptivity 24 hours after the tablet administration in the example was set to 100 (Table 12).

[0042]

[Table 11]

[0043]

[Table 12]

Test Results In the in vitro dissolution test, Comparative Formulation 1 and Example 1 showed almost the same dissolution behavior (FIG. 8, Table 9), but the water penetration rate (gelation rate) was significantly different. (Figure 9, Table 10). As a result of oral administration of these preparations to dogs, the change in plasma drug concentration upon administration of Example 1 was clearly persistent as compared with that upon administration of Comparative Formulation 1 (FIG. 10). In addition, the area under the plasma drug concentration-time curve (AUC) and mean residence time in the body (MRT) at the time of administration of Comparative Formulation 1 showed large variations, which is presumed to be due to individual differences in the gastrointestinal transit time (Table 1). 11). On the other hand, AUC and MRT at the time of administration of Example 1 had small variations, suggesting that they were not easily affected by the gastrointestinal transit speed. Furthermore, since the absorption time was maintained, the maximum plasma drug concentration (C max) at the time of administration of Example 1 was almost equal to that at the time of administration of Comparative Formulation 1, but the AUC increased about 1.8 times. Deconv
The absorption behavior by olution and the dissolution test result were compared. In the case of administration of Comparative Formula 1, the drug stays in the upper gastrointestinal tract for about 2 hours.
The absorption was similar to the in vitro elution result, but the absorption was significantly suppressed after 2 hours (FIG. 11, Table 12). The retention time of the preparation in the upper gastrointestinal tract under dog fasting conditions was about 2 hours, indicating that the drug was less likely to be eluted and absorbed in the lower gastrointestinal tract. In contrast, the administration of Example 1 showed almost the same absorption as the result of the in vitro dissolution test. In other words, it is clear that the drug is well eluted and absorbed in the lower gastrointestinal tract as well as in the upper gastrointestinal tract (FIG. 12, Table 12). (4) Dog dissection test Three male beagle dogs fasted for about 20 hours were used. Dissect
Each formulation was orally administered 2, 4 and 6 hours before with 30 ml of water. Dissection was performed under blood anesthesia under pentobarbital Na anesthesia and laparotomy was performed to examine the position of the preparation in the digestive tract (Table 13). In addition, the small intestine was divided into five equal parts, and the small intestines were 1, 2, 3, 4, and 5 from the top, respectively. Test results:

[0045]

[Table 13]

Example 1 in which the gelation ratio was improved by blending Comparative Formulation 1 with a low gelation ratio and a hydrophilic base,
In vivo, it was found that the same gastrointestinal motility was exhibited. Two hours after administration, one case of both preparations was retained in the stomach, but the rest was present in the small intestine 5 and the colon. Therefore, it was shown that the retention time of the preparation in the upper gastrointestinal tract was about 2 hours under canine fasting conditions, as previously known. That is, at the time of administration of Example 1, the high blood concentration shown after 2 hours indicates that the drug was well eluted and sufficiently absorbed from the preparation despite the fact that the preparation was present in the lower gastrointestinal tract. It was confirmed that it was caused by

Example 2 Pd 160 (parts by weight) HCO-60 80 TC-5E 160 PEG 6000 400 POLYOX 303 240 Nicardipine hydrochloride (Pd), HCO-60, TC-5E and PEG 6000
Is dissolved in a mixed solvent (dichloromethane / methanol),
Spray drying was performed using a spray drier. With dried goods
Mix POLYOX303 in a mortar and use an oil press to
Tableting pressure: 1 ton / Punched with a pestle, diameter 9.0 mm, tablet weight 346.7 mg
A tablet (containing 53.3 mg of Pd) was obtained. Comparative Formulation 2 Pd130 (parts by weight) Tween80 26 Sustained release part (SR) CMEC 130 POLYOX303 57.2 Pd30 Quick release part (QR) TC-5E15 Nicardipine hydrochloride (Pd), Tween80 and CMEC as a mixed solvent (dichloromethane. Methanol) and spray dried using a spray drier. Dried product and POLYOX30
The tablets were mixed with an oil press and tableted with a tableting pressure of 0.8 ton / punch to give a tablet (SR) having a diameter of 8.0 mm and a weight of 171.6 mg (containing 65 mg of Pd) per tablet. Separately, Pd and TC-5E are dissolved in a mixed solvent (dichloromethane / methanol), and the solution is quickly released (QR, Pd 15m) into SR (Pd 65mg) using a high coater.
g), one tablet weighs 194.1 mg, comparative formula 2 (Pd 80m
g) was obtained.

The following tests were conducted on Example 2 and Comparative Formulation 2 obtained above. (1) Dissolution test The dissolution test was carried out at a paddle rotation speed of 200 rpm according to the dissolution test method 2 (paddle method), using JP Disintegration Test Method 1 as a test solution. Sampling was performed at each time, and Pd in the solution was measured by a UV method (Table 14).

[0049]

[Table 14]

(2) Gel formation test Using the Japanese Pharmacopoeia Disintegration Test Method No. 1 as a test solution, a test was performed at a paddle rotation speed of 25 rpm by the Japanese Pharmacopoeia Dissolution Test Method No. 2 (paddle method). Two hours later, the tablets were taken out, and the diameter (D obs) of the non-gelled portion was measured. The gelation rate (G) was calculated from D obs (Table 15).

[0051]

[Table 15]

(3) Dog Administration Test Male beagle dogs (n = 6) fasted for about 20 hours were given the tablets of Example 2 × 3 tablets (Pd 160 mg) and the comparative formulation 2 tablets × 2 tablets (Pd
160 mg) was orally administered together with 30 ml of water. Blood was collected over time, and the drug concentration in plasma was measured by HPLC / UV method (Table 16, FIG.
13).

[0053]

[Table 16]

Test Results In the in vitro dissolution test, Comparative Formulation 2 (SR) and Example 2 showed almost the same dissolution behavior (Table 14), but the penetration rate of water (gelation rate) was significantly different (Table 14). Table 15). As a result of oral administration of these preparations to dogs, the change in plasma drug concentration upon administration of Example 2 was clearly persistent as compared with the administration of Comparative Formulation 2. After administration of Comparative Formulation 2, administration of the drug to the lower gastrointestinal tract resulted in a marked decrease in plasma drug concentration after 2 hours, indicating that the drug was less likely to be eluted and absorbed in the lower gastrointestinal tract. On the other hand, at the time of administration of Example 2, the drug concentration in plasma persisted even after 2 hours of translocation to the lower gastrointestinal tract, and it is clear that the drug was well dissolved and absorbed in the lower gastrointestinal tract. . Furthermore, since the absorption time was maintained, the Cmax at the time of administration of Example 2 was almost the same as that at the time of administration of Comparative Formulation 2, but the AUC was increased by about 3.0 times.

Example 3 Pd 65 (parts by weight) Tween 80 13 Sustained release part (SR) CMEC 65 PEG6000 65 POLYOX303 65 Pd 15 Quick release part (QR) Nicardipine hydrochloride (Pd), Tween 80 and CMEC are mixed solvents (dichloromethane / methanol) ) And spray dried using a spray drier. Dried product and PEG6000
And POLYOX303 are mixed and compressed with an oil press using a tableting pressure of 1.0 ton / punch to produce a tablet with a diameter of 8.5 mm and a tablet weight of 273 mg.
A tablet (SR) containing (QR, containing 65 mg of Pd) was obtained. In addition, a tablet containing 15 mg of Pd separately as a quick release part (QR) was obtained. Comparative Formulation 3 Pd 65 (parts by weight) Tween80 13 Sustained release part (SR) CMEC 65 POLYOX303 28.6 Pd 15 Quick release part (QR) TC-5E 7.5 Nicardipine hydrochloride (Pd), Tween80 and CMEC Dichloromethane / methanol) and spray dried using a spray drier. Dried product and POLYOX303
And tableting with an oil press at a tableting pressure of 0.8 ton / punch to a diameter of 8.0 mm and a tablet weight of 171.6 mg (containing 65 mg of Pd)
Tablets (SR) were obtained. Separately, Pd and TC-5E were dissolved in a mixed solvent (dichloromethane / methanol), and SR (Pd 65 mg) was coated with a quick release part (QR, Pd 15 mg) using a high coater. A tablet (Pd 80 mg) was obtained.

(1) Dissolution test The dissolution test was carried out at a paddle rotation speed of 200 rpm according to the Japanese Dissolution Test Method 2 (paddle method) using JP Dissolution Test Method 2 as the test liquid. Sampling was performed at each time, and Pd in the solution was measured by a UV method. Comparative Prescription 3 (SR) and Example 3
FIG. 14 shows the results of the dissolution test of (SR). (2) Gel formation test Using the Japanese Pharmacopoeia Disintegration Test Method 1 as a test liquid, a test was conducted at a paddle rotation speed of 25 rpm by the Japanese Pharmacopoeia Dissolution Test Method 2 (paddle method). Two hours later, the tablet was taken out, the gel layer was peeled off, and the weight (Wobs) of the non-gelled portion was measured. The gelation rate (G) was calculated from W obs using the following formula 2 (Table 17).

[0057]

[Table 17]

[0058]

(Equation 2)

(3) Dog Administration Test Example 3 SR was performed on male beagle dogs (n = 6) fasted for about 20 hours.
And 2 tablets each of QR (Pd 160 mg) and 2 tablets of comparative prescription (Pd 16
0 mg) was orally administered together with 30 ml of water. Blood was collected over time, and the drug concentration in plasma was measured by HPLC / UV method (Fig. 15, Table
18).

[0060]

[Table 18]

(4) Dog dissection test Three male beagle dogs fasted for about 20 hours were used. Dissect
Each of the formulations was orally administered together with 30 ml of water 2, 4, and 6 hours before. Dissection was performed under blood anesthesia under pentobarbital Na anesthesia, and laparotomy was performed to examine the position of the preparation in the digestive tract (Table 19). In addition, the small intestine was divided into five equal parts, and the small intestine was designated as 1, 2, 3, 4, or 5 from the upper part, respectively.

[0062]

[Table 19]

Test Results In the in vitro dissolution test, Comparative Formulation 3 (SR) and Example 3 (SR)
Showed almost the same elution behavior (FIG. 14), but the gelation rate was significantly different (Table 17). Results of dissection experiment, Example 3
And Comparative Formulation 3 showed almost the same gastrointestinal transit (Table 1).
9). As a result of oral administration of these preparations to dogs, the change in drug concentration in plasma upon administration of Example 3 was clearly persistent as compared with Comparative Formulation 3. After administration of Comparative Formulation 3, the plasma drug concentration was significantly reduced from 2 hours after the preparation was transferred to the lower gastrointestinal tract, indicating that the drug was less likely to be eluted and absorbed in the lower gastrointestinal tract. On the other hand, at the time of administration of Example 3, the drug concentration in plasma persisted even after 2 hours of translocation to the lower gastrointestinal tract, and it is clear that the drug was well dissolved and absorbed in the lower gastrointestinal tract. (Figure 15). Furthermore, since the absorption time was maintained, CmaX at the time of administration of Example 3 was almost equivalent to that at the time of administration of Comparative Formulation 3, but AUC was increased by about 4.4 times (Table 1).
8).

Example 4 Pd 80 (mg) PVP K30 32 HCO-60 16 POLYOX303 240 Lubricant 4 Nicardipine hydrochloride (Pd), PVP K30 and HCO-60 were dissolved in methanol. The solution was spray-granulated into POLYOX303 using a fluidized bed granulator. A lubricant was added to the granulated product, mixed and tableted to obtain a tablet having a diameter of 9.5 mm and a tablet weight of 372 mg (containing 80 mg of Pd).

Example 5 Pd 80 (mg) TC-5E 32 HCO-60 16 PEG6000 32 POLYOX 303 240 Lubricant 8 Superplasticizer 4 Nicardipine hydrochloride (Pd), TC-5E and HCO-60 were mixed with water and methanol ( 1: 9), and the solution was spray-dried. POLYOX303 and a lubricant equivalent to 4 mg were added to the spray-dried product, followed by dry granulation. Add 4mg of lubricant and fluidizer to the granulated product, mix and tablet, 9.5mm in diameter, weight per tablet 4
A tablet of 12 mg (containing 80 mg of Pd) was obtained.

Example 6 Pd 80 (mg) TC-5E 32 HCO-60 32 PEG6000 32 POLYOX303 384 Lubricant 11.2 Superplasticizer 5.6 Nicardipine hydrochloride (Pd), TC-5E, HCO-60 and PEG6000
Was dissolved in a mixture of water and methanol (1: 9), and the resulting solution was spray-dried. POLYOX303 and a lubricant equivalent to 5.6 mg were added to the spray-dried product, followed by dry granulation. Add 5.6 mg of lubricant and fluidizer to the granulated product, mix and compress, tablet 11 mm in diameter,
A tablet weighing 576.8 mg (containing 80 mg of Pd) was obtained.

Example 7 Pd 80 (mg) TC-5E 64 Tween80 32 PEG6000 32 POLYOX303 360 Lubricant 11.4 Glidant 5.7 Nicardipine hydrochloride (Pd), TC-5E and Tween80 were mixed with water / methanol ( 1: 9). The lysate was spray dried. PEG6000, POLYOX303, and a lubricant equivalent to 5.7 mg were added to the spray-dried product, followed by dry granulation. Add 5.7 mg of lubricant and fluidizer to the granulated product, mix and compress, tablet 11 mm in diameter,
A tablet weighing 585.1 mg (containing 80 mg of Pd) was obtained.

Example 8 Pd and TC-5E were dissolved in a mixed solution of water and methanol (1: 9), and Example 7 (Pd 80 mg) was coated with a quick release part (Pd 20 mg) using a high coater. A tablet weighing 625.1 mg (Pd
100 mg).

Example 9 Pd and HPC-SL were dissolved in methanol, and Example 7 (80 mg of Pd) was coated with a quick release portion (20 mg of Pd) using a high coater. 100 mg).

Example 10 Pd 80 (mg) TC-5E 64 HCO-40 32 PEG6000 48 POLYOX303 344 Lubricant 11.4 Superplasticizer 5.7 Pd, TC-5E and HCO-40 were mixed with water and methanol ( 1: 9)
did. The lysate was spray dried. PEG6000, P for spray-dried products
OLYOX303 and a lubricant equivalent to 5.7 mg were added, followed by dry granulation.
An amount equivalent to 5.7 mg of a lubricant and a fluidizing agent were added to the granulated product, mixed, and tableted to obtain a tablet having a diameter of 11 mm and a tablet weight of 585.1 mg (containing 80 mg of Pd).

Example 11 Pd 100 (mg) TC-5E 80 HCO-40 40 PEG6000 48 POLYOX 303 300 Lubricant 11.4 Superplasticizer 5.7 Pd, TC-5E and HCO-40 were mixed with water and methanol ( 1: 9)
Was dissolved. The lysate was spray dried. PEG6 for spray-dried products
000, POLYOX303, and a lubricant equivalent to 5.7 mg were added, followed by dry granulation. Add 5.7 mg of lubricant and fluidizer to the granulated product, mix and compress, tablet 11 mm in diameter, 585.1 mg per tablet (Pd
(Containing 100 mg).

(1) Dissolution test The first solution of JP Disintegration Test was used as a test solution, and a test was conducted at a paddle rotation speed of 200 rpm according to the second dissolution test of JP Method (paddle method). Sampling was performed at each time, and Pd in the solution was measured by a UV method. FIG. 16 shows the dissolution test results of Example 4 and Example 5. FIG. 17 shows the dissolution test results of Example 6, Example 7, and Example 10. (2) Dog administration test Example 5 2 tablets or Example 62 in male beagle dogs (n = 6)
The tablets were administered once a day for 4 consecutive days. Blood was collected over time and the drug concentration in plasma was measured by HPLC / UV method. Test results Both Examples 5 and 6 showed high C24h in once-daily administration
Values (blood concentration 24 hours after administration) and high bioavailability.

Example 12 DF 37.5 (mg) PEG6000 37.5 POLYOX303 75.0 Diclofenac Na (DF), PEG6000 and POLYOX303 were mixed in a mortar, and a tableting pressure of 1 ton /
The tablets were pressed with a pestle to obtain tablets having a diameter of 7 mm and a weight of one tablet of 150 mg (DF 37.5 mg). Comparative Formulation 4 DF 37.5 (mg) POLYOX 75.0 DF and POLYOX303 were mixed in a mortar and compressed with an oil press using a tableting pressure of 1 ton / punch to obtain a tablet with a diameter of 6.0 mm and a tablet weight of 11.
A tablet of 2.5 mg (containing 37.5 mg of DF) was obtained. (1) Dissolution test The dissolution test was carried out in accordance with JP Dissolution Test Method 2 (paddle method) using JP Disintegration Test Solution 2 as a test solution. Sampling was performed at each time, and DF in the solution was measured by a UV method (FIG. 18). (2) Gel formation test Using the Japanese Pharmacopoeia Disintegration Test Method 2 solution as a test solution, a test was conducted at a paddle rotation speed of 25 rpm according to the Japanese Pharmacopoeia Dissolution Test Method 2 (paddle method). The tablet was taken out every two hours, and the diameter (D obs) of the non-gelled portion was measured. The gelation rate (G) was calculated from D obs (Table 20).

[0074]

[Table 20]

(3) Dog Administration Test Example 12 (DF) was performed on male beagle dogs (n = 5) fasted for about 20 hours.
37.5 mg) and Comparative Formulation 4 (DF 37.5 mg) were orally administered together with 30 ml of water. Blood is collected over time and the drug concentration in plasma
It was measured by the HPLC / UV method (Table 21, FIG. 19).

[0076]

[Table 21]

Experimental Results In the in vitro dissolution test, Example 12 and Comparative Formulation 4 showed almost the same dissolution behavior (FIG. 18), but the penetration rate of water (gelation rate) was significantly different (Table 20). ). As a result of oral administration of these preparations to dogs, the change in blood concentration at the time of administration of Example 12 was clearly longer than that at the time of administration of Comparative Formulation 4 (FIG. 19). Furthermore, the AUC at the time of administration of Example 12 was increased by about 1.7 times as compared with Comparative Formulation 4 (Table 21). That is, by applying the present invention also to diclofenac Na, which is an acidic drug, the drug is well eluted in the lower gastrointestinal tract.
It was confirmed that it was absorbed.

Example 13 DF 75 (mg) PEG 6000 75 POLYOX 303 150 Diclofenac Na (DF), PEG 6000 and POLYOX 303 were mixed in a mortar, and a tableting pressure of 1 ton /
The tablets were punched with a pestle to obtain tablets having a diameter of 8.5 mm and a tablet weight of 300 mg (containing DF 75 mg).

Example 14 DF 75 (mg) PEG 6000 75 POLYOX 303 300 Diclofenac Na (DF), PEG 6000 and POLYOX 303 were mixed in a mortar, and a tableting pressure of 1 ton /
The tablets were punched with a punch to obtain tablets having a diameter of 9.5 mm and a weight of 450 mg (containing 75 mg of DF).

Example 15 Famotidine 40 (mg) PEG6000 30 POLYOX303 150 Lubricant 2 After mixing famotidine, PEG6000, POLYOX303 and a lubricant, tableting was performed, and the tablet was 8.0 mm in diameter and 222 mg in tablet weight (famotidine).
(Containing 40 mg).

Example 16 Barnidipine hydrochloride 15 (mg) TC-5E 30 HCO-405 PEG 20000 40 POLYOX 303 207 Lubricant 3 Barnidipine hydrochloride, TC-5E and HCO-40 were dissolved in a water / methanol mixture (1: 9). did. Separately PEG20000 and POLYOX
303 was mixed. The solution was spray-granulated on the mixture using a fluid bed granulator. After drying the granulated product, mix the lubricant,
Tablets, 9.0 mm in diameter, 300 mg per tablet (barnidipine hydrochloride)
(Containing 15 mg).

Example 17 Amosulalol hydrochloride 40 (mg) Pluronic F68 40 POLYOX303 196 Lubricant 4 Amosulalol hydrochloride, Pluronic F68, POLYOX303 and a lubricant were mixed and pulverized, followed by dry granulation. The granulated product is compressed into tablets having a diameter of 8.5 mm and a tablet weight of 280 mg (Amosulalol Hydrochloride 40).
mg containing tablets).

Example 18 Tamsulosin hydrochloride 0.2 (mg) D-sorbitol 17.8 POLYOX WSR N-60K 180 Lubricant 2 Tamsulosin hydrochloride, D-sorbitol and PEO (POLYOX
WSR N-60K) was wet-granulated with ethanol and dried. Add lubricant to the dried product, mix and compress, 8m in diameter
m, a tablet weighing 200 mg (containing 0.2 mg of tamsulosin hydrochloride) was obtained.

Example 19 Indeloxazine hydrochloride 60 (mg) Sucrose 37 HPMC (90SH30000) 180 Lubricant 3 Indeloxazine hydrochloride, sucrose, HPMC and a lubricant were mixed, followed by dry granulation. The granulated product was compressed into tablets having a diameter of 9 mm and a tablet weight of 280 mg (containing 60 mg of indeloxazine hydrochloride).

Example 20 Formoterol Fumarate 0.16 (mg) Anhydromaltose 47.84 Carbopol 940 100 Lubricant 2 After mixing formoterol fumarate, anhydrous maltose, Carbopol 940 and a lubricant, tableting Then, a tablet having a diameter of 7 mm and a weight of one tablet of 150 mg (containing 0.2 mg of formoterol fumarate) was obtained.

Example 21 AAP 100 (mg) PEG6000 200 PEO (POLYOX WSR N-60K) 300 Acetaminophen (AAP), PEG6000 and PEO (POLYO)
X WSR N-60K average molecular weight: 2 million) in a mortar,
Using an oil press, press with a tableting pressure of 1 ton / punch and press
11 mm tablets weighing 600 mg per tablet (containing 100 mg of AAP) were obtained.

Comparative Example 5 AAP 100 (mg) PEO (POLYOX WSR N-60K) 300 AAP and PEO (POLYOX WSR N-60K) were mixed in a mortar,
Using an oil press, press with a tableting pressure of 1 ton / punch and press
9 mm tablets having a tablet weight of 400 mg (containing 100 mg of AAP) were obtained.

(1) Dissolution test 1 The disintegration test method No. 2 of JP was used as a test solution, and a test was performed at a paddle rotation speed of 200 rpm by the dissolution test method 2 (paddle method) of JP. Sampling was performed at each time, and AAP in the solution was measured by a UV method. (2) Gel formation test Using the Japanese Pharmacopoeia Disintegration Test Method 2 solution as a test solution, a test was conducted at a paddle rotation speed of 25 rpm according to the Japanese Pharmacopoeia Dissolution Test Method 2 (paddle method). Two hours later, the tablets were taken out, and the diameter (D obs) of the non-gelled portion was measured. The gelation rate (G) was calculated from D obs. (3) Dog administration test 1 Comparative example 5 (AAP) was performed on male beagle dogs (n = 6) fasted for about 20 hours.
100 mg) and Example 21 (AAP 100 mg) were orally administered together with 30 ml of water. Blood is collected over time and the drug concentration in plasma is HP
It was measured by the LC / UV method.

Test Results In the in vitro dissolution test, Comparative Example 5 and Example 21 showed almost the same dissolution behavior, but the results of Example 21 containing a hydrophilic base were added.
Showed a larger gelation ratio than Comparative Example 5. As a result of oral administration of these preparations to dogs, the change in drug concentration in plasma upon administration of Example 21 was clearly longer than that upon administration of Comparative Example 5. Example 21 Maximum Plasma Drug Concentration at Administration (C
max) was almost equivalent to that of Comparative Example 5, but AUC, MRT
Has increased. The blood concentration at the time of administration of Example 21 was 12
The blood concentration was high until after the time.

[0090]

According to the preparation of the present invention, the preparation absorbs moisture while staying in the upper gastrointestinal tract, gels almost completely, and migrates to the lower gastrointestinal tract while the surface of the preparation is eroded. Continue to release. Therefore, even in a colon with little water, a good and continuous release of the drug is performed, and the release of the drug for a long time of about 6 to 18 hours (about 12 to 24 hours including the release time of the upper gastrointestinal tract) is achieved. It is possible to achieve a stable blood concentration of the drug. Conventional sustained-release products release the drug only in the upper gastrointestinal tract, so the release time is at most about 6 hours, after which the blood concentration is prolonged due to the length of the biological half-life of the drug itself It was what was allowed. In the preparation of the present invention, the drug release time itself is prolonged, so that it is possible to achieve a continuous blood drug concentration of more than 12 hours even for a drug having a short biological half-life, which has been conventionally difficult. It is. Therefore, the preparation of the present invention has the advantages that the efficacy of the drug can be maintained and the number of administrations can be reduced, side effects can be reduced by suppressing the rapid rise of the blood drug concentration, and a constant blood drug concentration can be maintained. Have As described in the above examples, the present invention extends the absorption duration of any drug such as acetaminophen which is a neutral drug, nicardipine hydrochloride which is a basic drug, and diclofenac Na which is an acidic drug. It was confirmed that it was possible. Therefore, it is a highly versatile formulation technology regardless of the physical properties of the drug.

[Brief description of the drawings]

FIG. 1 shows the results of a gel formation test of a PEG6000-containing hydrogel sustained-release preparation.

FIG. 2 shows the results of a gel formation test when the content of PEG6000 was changed.

FIG. 3 shows the results of the gelation ratio of various hydrophilic bases after 2 hours.

FIG. 4 shows the relationship between the amount of POLYOX303 and the dissolution behavior (drug: acetaminophen).

FIG. 5 shows the relationship between the amount of POLYOX303 and the dissolution behavior (drug: nicardipine hydrochloride).

FIG. 6 shows the relationship between PEO molecular weight and elution behavior (drug:
Acetaminophen).

FIG. 7 shows the relationship between PEO molecular weight and elution behavior (drug:
Nicardipine hydrochloride).

FIG. 8 shows the dissolution test results of Example 1 and Comparative Formulation 1 by the paddle method.

FIG. 9 shows the gel formation test results of Example 1 and Comparative Formulation 1.

FIG. 10 shows the results of changes in drug concentration in dog plasma in Example 1 and Comparative Formulation 1.

FIG. 11 shows the results of the dissolution test of Comparative Formulation 1 and Deconvo.
The comparison of the absorption behavior by the lutlon method is shown.

FIG. 12 shows the results of the dissolution test of Example 1 and the results of Deconvolu.
2 shows a comparison of absorption behavior by the tion method.

FIG. 13 shows the change in drug concentration in dog plasma in Example 2 and Comparative Formulation 2.

FIG. 14 shows Example 3 (SR) and Comparative Formulation 3 (SR)
3 shows the results of the dissolution test by the paddle method.

FIG. 15 shows the change in drug concentration in dog plasma in Example 3 and Comparative Formulation 3.

FIG. 16 shows the results of the dissolution test by the paddle method of Examples 4 and 5.

FIG. 17 shows the dissolution test results of Examples 6, 7 and 10 by the paddle method.

FIG. 18 shows the dissolution test results of Example 12 and Comparative Formulation 4 by the paddle method.

FIG. 19 shows the change in drug concentration in dog plasma in Example 12 and Comparative Formulation 4.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 47/26 A61K 47/26 47/32 47/32 47/34 47/34 47/38 47/38 A61P 29/00 A61P 29/00 (72) Inventor Muneo Fukui 5- 13-14 Minamisurugadai, Fujieda-shi, Shizuoka Prefecture

Claims (4)

[Claims] (1) at least one or more drugs, (2)
The amount of water required for dissolving 1 g is 5 ml or less. One or more kinds of preparations exhibiting solubility of water and an additive for infiltrating water into the inside of the preparation, and (3) a polymer substance forming a hydrogel A method for producing a sustained-release hydrogel preparation, which has the ability to gel almost completely during stomach and small intestine retention in the upper gastrointestinal tract and has the ability to release drugs also in the colon in the lower gastrointestinal tract. 2. An additive for infiltrating water into the inside of the preparation is polyethylene glycol, polyvinylpyrrolidone,
D-sorbitol, xylitol, sucrose, anhydrous maltose, D-fructose, dextran, glucose, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, polyoxyethylene sorbitan higher fatty acid ester, sodium chloride, magnesium chloride, citric acid 2. The method for producing a sustained-release hydrogel preparation according to claim 1, wherein the preparation is one or more selected from the group consisting of tartaric acid, glycine, β-alanine, lysine hydrochloride, and meglumine. 3. The polymer substance forming a hydrogel has an average molecular weight of 2,000,000 or more or a 1% aqueous solution (2%).
3. The method for producing a sustained-release hydrogel preparation according to claim 1, comprising a polymer substance having a viscosity at 5 ° C.) of 1000 cps or more, which may be one kind or a mixture of two or more kinds. 4. The method for producing a sustained-release hydrogel preparation according to claim 1, which is a dry-coated tablet.