JP4894958B2 - Water-soluble drug sustained release technology - Google Patents

Description

  The present invention relates to sustained release compositions for oral administration for the delivery of active substances (eg drugs), in particular readily water-soluble drugs. In particular, the present invention relates to novel compositions containing at least one polymer having an opposite charge to a charged micelle-forming drug.

  Conventional oral and intravenous drug administration greatly limits the effectiveness of many drugs. These administration methods do not maintain the drug concentration within the therapeutically effective range, but rapidly increase the blood concentration at the beginning of administration, and then rapidly decrease to below the therapeutic concentration range because the drug is metabolized by the living body. End up. Therefore, in order to achieve a therapeutic effect, frequent administration over a long period is required to maintain the drug concentration within the therapeutically effective range. To overcome this problem, many sustained release formulations have been developed that avoid an initial burst of drug and achieve a constant level of drug release.

  Compositions composed of macromolecules are generally used to achieve sustained drug release (see Langer et al. Nature 392: 6679 supp. (1998)). A variety of successful polymeric sustained release formulations have been developed for drug release with different physical properties. Such formulations are extremely effective in extending the release time of relatively hydrophobic and water-insoluble drugs.

  However, due to rapid drug diffusion from the polymer matrix, it has been difficult to achieve sustained release of easily water-soluble drugs using existing sustained release techniques. Accordingly, new compositions and methods that can suppress drug diffusion and the burst effect of easily water-soluble drugs are desired. The present invention fulfills these and other needs.

(Summary of the Invention)
The present invention provides, inter alia, an oral sustained release formulation containing a polymer having a charge opposite to that of the micelle-forming drug. Although the micelle concept is well known in the field of surfactants or drug carriers, the application of micelle-forming drugs to sustained release compositions is not known at all. Furthermore, very surprisingly, the composition is very effective for the sustained release of active substances, especially water-soluble drugs. As a further advantage, the composition can provide sustained release even when the composition contains a large amount of drug.

  The present invention provides an oral sustained-release pharmaceutical composition comprising at least one polymer having a charge opposite to that of a charged micelle-forming drug, and optionally a hydrogel-forming polymer substance and a hydrophilic base. provide. A micelle-forming drug may have a positive or negative charge at physiological pH.

  In another embodiment, the present invention provides a method for modulating the dissolution behavior of a micelle-forming drug, which involves changing the molar ratio of a charged micelle-forming drug to at least one macromolecule having an opposite charge. A method of adjusting the dissolution behavior of a micelle-forming drug by, or by changing the loading of a polymer having an opposite charge. Suitable micelle forming drugs include, for example, such as antidepressants, adrenergic beta receptor antagonists, anesthetics, antihistamines. Preferably, the micelle forming drug is a water soluble drug.

  In other embodiments, the present invention provides a method for the sustained release of micelle-forming drugs. This includes a pharmaceutical composition for oral administration containing at least one polymer having an opposite charge to a charged micelle-forming drug, whereby the micelle-forming drug is released slowly.

  In other embodiments, the present invention provides methods for the sustained release of micelle-forming drugs. This includes a pharmaceutical composition for oral administration containing at least one polymer having a charge opposite to that of a charged micelle-forming drug, and optionally a hydrogel-forming polymer and a hydrophilic base. Slow release of micelle-forming drug.

Further, the objects and advantages of the present invention will become clearer after reading the following drawings and specification.

(Definition of terms)
The term “active substance” means any drug that can be contained in a physiologically acceptable tablet for oral administration. Preferred active materials include micelle-forming active materials that can form electrically charged colloidal particles.

  The term “cps” or “centipoise” is a unit of viscosity, in millipascal seconds. Viscosity is measured with a Broolfield or other viscometer. For example, Wanget al. Clin. Hemorheol. Microcirc. 19: 25-31 (1998); Wang et al. J. Biochem. Biophys. Methods 28: 251-61 (1994); Cooke et al. J. Clin. Pathol. 41 : 1213-1216 (1998).

  The term “carrageenan” in the present invention means all water-soluble extracts obtained from carrageenan, Irish moss, seaweed from the Atlantic coast of Europe and North America. This includes GP-911, GP-812, GP-379, GP-109, GP-209, commercially available from FMC, eg Viscarin® 109, Gelcarin® including. Carrageenan is a high molecular weight, linear molecule with a highly sulfated galactose skeleton. They are composed of sulfated and unsulfated repeating units of galactose and 3,6 anhydrous galactose, which are linked to each other by α- (1-3) and β- (1-4) glycosidic bonds Are combined. Other commercial sources of carrageenan are Sigma and Hercules.

  The term “polyacrylic acid” or “PAA” used in the present invention includes all modes and molecular weights of polyacrylic polymers. This includes, for example, Carbopol 971 from B.F. Goodrich.

  The term “polyethylene oxide polymer” or “PEO” as used in the present invention includes all modes and molecular weights of polyethylene side polymers. For example, Polyox WSR-303a (average molecular weight 7 million, viscosity 7500-10000 cps, 1% aqueous solution, 25 ° C.), Polyox WSR Coagulanta (average molecular weight 5 million, Viscosity 5500-7500cps under the same conditions as above, Polyox WSR-301a (average molecular weight 4 million, viscosity 1650-5500 cps under the same conditions as above), Polyox WSR-N-60Ka (average molecular weight 2 million, 2000-4000cps, 2 % Aqueous solution, 25 ° C.). See WO 94/06414 described in the present invention as reference material.

  The term “polyethylene glycol” or “PEG” as used herein includes all modes and molecular weights of polyethylene glycol polymers. This includes Macrogol 400, Macrogol 1500, Macrogol 4000, Macrogol 6000, and Macrogol 20000, all of which are registered trademarks of Nippon Oil & Fats.

The terms “hydroxypropylmethylcellulose”, “carboxymethylcellulose sodium”, “hydroxyethylcellulose” and “carboxyvinyl polymer” used in the present invention include those conventionally used. Hydroxypropyl methylcellulose (HPMC) includes, for example, both the registered trademark of Shin-Etsu Chemical Co., Ltd. 20 ° C). Sodium carboxymethylcellulose (CMC-Na) includes, for example, Sunrose F-150MCa (average molecular weight 200,000, viscosity 1200-1800 cps, 1% aqueous solution, 25 ° C.) -1000MCa (average molecular weight 42000, viscosity 8000-12000 cps under the same conditions as described above), and SANLOUS F-300MCa (average molecular weight 300,000, viscosity 2500-3000 cps under the same conditions as described above). For example, HECDaicel SE850a (average molecular weight 1.48 x 10 ⁶ , viscosity 2400-3000 cps, 1% aqueous solution, 25 ° C), HECDaicel SE900a (average) Including a molecular weight of 1.56 × 10 ⁶ and a viscosity of 4000-5000 cps under the same conditions as above. Carboxyvinyl polymer includes Carbopol 940a with an average molecular weight of about 25 × 10 ⁵ from BF Goodrich.

  As used herein, the term “therapeutic agent” refers to any drug that is orally administered in a physiologically acceptable tablet.

  The term “micelle formation” as used in this invention refers to the formation of electrically charged colloidal particles, ions of oriented molecules, or aggregates of many compounds / molecules loosely assembled by secondary bonds. Any compound that can be made.

FIG. 1 represents the release of water-soluble drug (10% by weight) from 400 mg PAA / PEO (polyacrylic acid / polyethylene oxide) matrix in artificial intestinal fluid (SIF). FIG. 2 shows the correlation between T50 and logP of a basic water-soluble drug released from a 400 mg PAA / PEO (polyacrylic acid / polyethylene oxide) (1: 1.5) tablet. FIG. 3 shows the correlation between critical micelle concentration (CMC) and logP. FIG. 4 shows an example of a charged drug (positive or negative charge) suitable for use in a release experiment. FIG. 5 represents the release of negatively charged drug from a PAA / PEO (polyacrylic acid / polyethylene oxide) matrix. FIG. 6 represents the release of diltiazem hydrochloride from PAA (polyacrylic acid) / polysaccharide matrix tablets (400 mg) in artificial gastric fluid (SGF, FIG. 6a) and artificial intestinal fluid (SIF, FIG. 6b). FIG. 7 represents the release of diltiazem hydrochloride from PAA (polyacrylic acid) / sulfated polymer matrix tablets (400 mg) in artificial gastric fluid (SGF, FIG. 7a) and artificial intestinal fluid (SIF, FIG. 7b). FIG. 8 represents the release of diltiazem hydrochloride from various matrix tablets in artificial gastric fluid (SGF, FIG. 8a) and artificial intestinal fluid (SIF, FIG. 8b). FIG. 9 represents the release of diltiazem hydrochloride (25 wt%) from PAA (polyacrylic acid) / carrageenan matrix tablets in artificial gastric fluid (SGF) and artificial intestinal fluid (SIF). FIG. 10 represents the optimization of the PAA (polyacrylic acid) / carrageenan ratio in a composition containing 25% by weight diltiazem hydrochloride. FIG. 11 represents the release of diltiazem hydrochloride (60 wt%) from matrix tablets with different PAA (polyacrylic acid) / carrageenan ratios in artificial gastric fluid (SGF, FIG. 11a) and artificial intestinal fluid (SIF, FIG. 11b). FIG. 12 represents the release of diltiazem hydrochloride from PAA (polyacrylic acid) / Viscarin 109 matrix with different drug content in artificial gastric fluid (SGF, FIG. 12a) and artificial intestinal fluid (SIF, FIG. 12b). FIG. 13 represents the release of diltiazem hydrochloride (25 wt%) from a carrageenan-based competitive system in artificial gastric fluid (SGF, FIG. 13a) and artificial intestinal fluid (SIF, FIG. 13b). FIG. 14 represents the release of diltiazem hydrochloride (25 wt%) from a competitive system based on PAA (polyacrylic acid) in artificial gastric juice. FIG. 15 represents the release of diltiazem hydrochloride (60% by weight) from the competitive system in artificial gastric fluid (FIG. 15a) and artificial intestinal fluid (FIG. 15b). FIG. 16 shows the influence of the amount of PAA (polyacrylic acid) added on the release of diltiazem hydrochloride (50 wt%) in JP 2nd fluid (Japanese Pharmacopoeia Disintegration Test Method 2nd liquid). FIG. 17 shows the effect of the addition amount of PAA (polyacrylic acid) / carrageenan on the release of diltiazem hydrochloride (50 wt%) in JP 2nd fluid (Japanese Pharmacopoeia Disintegration Test Method 2nd liquid).

Detailed Description of Preferred Embodiments
The present invention provides, inter alia, an oral sustained release formulation containing an active substance that forms micelles (ie, a drug) and a polymer that has an opposite charge and forms a hydrogel matrix. This composition is generally produced by directly compressing a drug and a polymer excipient.

  Advantageously, this composition provides a very slow release rate of the active substance. In a preferred embodiment, rapid drug diffusion is suppressed by a hydrogen bond complex between a polymer having opposite charge and a drug micelle. Without being bound by any other particular theory, it is likely that the drug is released by the polymer charge being neutralized by hydroxide ions at the matrix / elution interface and the breakage of these bonds.

  In one embodiment, the number of administrations of the composition can be reduced, thereby improving patient compliance. In addition, side effects of drugs can be reduced by inhibiting rapid increases in drug blood levels (as seen in standard compositions). A further advantage of the composition is that the release rate from the composition is not significantly affected even when the drug is encapsulated at a high dose.

  Factors and events that form the rationale for the embodiments of the present invention will now be discussed. However, this discussion should not be construed as limiting or limiting the present invention. Those skilled in the art will appreciate that various embodiments of the present invention can be implemented regardless of the model used to describe the theoretical basis of the present invention.

(Active substance in the present invention)
The active substance in the present invention is not particularly limited as long as it is a drug that forms micelles. Micelle formation has been observed in antidepressants, adrenergic beta-receptor antagonists, anesthetics, antihistamines, phenothiazines, antiacetylcholine drugs, tranquilizers, antibacterials and antibiotics (Attwood et al., J. Pharm. Pharmac., 30, 176-180 (1978); Attwood etal., J. Pharm. Pharmac., 31, 392-395 (1979); Attwood et al., J. Pharm. Pharmac., 38, 494- 498 (1986); Attwood J. Pharm. Pharmac., 24, 751-752 (1972); Attwood et al. J. Pharm. Sci. V. 63, no. 6, 988993 (1974); Attwood, J. Phar Pharmacol., 28, 407-409 (1976)). Exemplary antidepressants that form micelles include imipramine hydrochloride, omipramol hydrochloride, amitriptyline hydrochloride. Representative adrenergic β receptor antagonists that form micelles include oxprenolol hydrochloride, acebutolol hydrochloride, and solutol hydrochloride. Representative anesthetics that form micelles include procaine hydrochloride, lidocaine hydrochloride, and amesokine hydrochloride. Representative antihistamines that form micelles include diphenhydramine hydrochloride, chlorcyclidine hydrochloride, diphenylpyraline, promethazine hydrochloride, bromdiphenhydramine hydrochloride, tripelenamine hydrochloride, mepyramine maleate. Representative phenothiazines that form micelles include chlorpromazine hydrochloride and promethazine hydrochloride. Other micelle-forming drugs include tranquilizers, antibacterial agents, and antibiotics.

  In certain embodiments, the active substance includes, but is not limited to, betacaine sulfate, synchrocaine hydrochloride BP and lignocaine hydrochloride (Sigma), prilocaine hydrochloride BP and bupivacaine hydrochloride (Astra Pharmaceuticals), mepivacaine hydrochloride (Leo), proparacaine hydrochloride ( Squibb) and Amesokine BP (Smithand Nephew Pharmaceuticals). In other embodiments, the following active agents are useful in the present invention. These include, but are not limited to, 4 '-(1-hydroxy-2-isopropyl-aminoethyl) methane sulphonanifide (Duncan, Flockhart), rabetrol [5- (1-hydroxy-2- (1 -Methyl-3-phenyl-propylamino) ethyl) salicylamide] (Allen and Hanburys), acebutolol ((±) -3'-acetyl-4 '-(2-hydroxy-3-isopropylaminopropoxy) -butyranide) (May andBaker), propranolol {(±) -1-isopropylamino-3-naphth-1'-yloxypropan-2-ol} (ICI), oxyprenolol {(±) -1- (o-allyloxyphenoxy ) -3-Isopropylaminopropan-2-ol}} (Ciba), timolol maleate {(-)-1-butylamino-3 (4-morpholino-1,2,5-thiazol-3-yl-maleate)- Oxy) propan-2-ol} (Merck, Sharp and Dohme), metroprolol raltrale (tartaric acid (±) -1- Isopropylamino 3-p- (2-methoxyethyl) phenoxypropan-2-ol) (Geigy Pharmaceuticals). As other specific examples, the active ingredient includes, but is not limited to, adiphenine hydrochloride (Ciba), methylporzine sulfate BP (Beecham Research), racecino chloride BPC (Vestric), chlorphenoxamine hydrochloride (Evans Medical), piperiodrate hydrochloride , Pipenzolate bromide (MCPPharmaceuticals), Orphenadrine hydrochloride BP (Brocades, Gt Britain), Benztropine mesylate BP (MerckSharp and Dohme), Cridinium bromide (Roche), Ambutonium bromide (Wyeth), Benzironitum bromide ( Parke-Davis). Diphenhydramine hydrochloride BP (2-diphenylmotooxy-NN-dimethylethylamine hydrochloride) and chlorcyclidine BP [1- (p-chlorodiphenylmethyl) -4-methylpiperazine hydrochloride] were obtained from Park Davis and Blowelcome, respectively. obtained. Diphenhydramine hydrochloride [2- (α-p-bromophenyl-α-phenylmethoxy) -NN-dimethylethylamine hydrochloride] and diphenylpyraline hydrochloride (4-diphenyl-methoxy-1-methylpiperidine hydrochloride) were obtained respectively. Those skilled in the art will also be aware of other active ingredients applicable to the present invention.

  In a preferred embodiment, the active substance of the present invention is a readily water-soluble drug. In a more preferred embodiment, the active ingredient of the present invention is a basic drug. The present invention is particularly useful for drugs that exhibit large bursts due to rapid diffusion from the polymeric matrix. Easily water-soluble drugs have inorganic and organic acid salts (which have a positive charge due to noncovalent bonding of protons), molecules which have a permanent positive charge (or negative charge), and negative charges (which are weak acids and strong acid salts). Containing molecules. For example, a readily water-soluble drug means a drug having a solubility in water of 10 mg / mL or more, more preferably 100 mg / mL or more.

  Specific active substances suitable for use in the compositions of the present invention are charged micelle-forming drugs, selected on the basis of closely related critical micelle concentration (CMC) and / or log P (See Example 3). LogP, the octanol-water partition coefficient, reflects the hydrophobic properties of non-dissociated drugs. CMC, a measure of the concentration at which a compound forms micelles, represents a hydrophobic function as well as the stereochemical properties of a molecule, the ability to rotate functional groups, and counterions. The presence of charged micelle-like drug aggregates in a hydrogel matrix containing a polymer with opposite charge results in a cooperative interaction. It is this cooperative interaction that controls the rate of drug release from the polymeric matrix. Thus, CMC and logP can be used to predict drug release rates and identify drugs that can exhibit sustained release by the compositions of the present invention. Low CMC and / or high log P drugs are slowly released from the compositions of the invention, while drugs that are less likely to form micelles behave similarly to drug release from standard oral compositions. Released at.

  Accordingly, release of the drug by any standard method known to those skilled in the art to adjust the stated critical micelle concentration and / or the degree of cooperative interaction between the micelle-forming drug and the oppositely charged polymer. The behavior can be adjusted. Methods for adjusting the critical micelle concentration and / or the degree of cooperative interaction include changing the hydrophobicity of the drug by introducing functional groups, and changing the electrostatic interaction between the drug and the polymeric excipient. Including any other way to let you. In certain embodiments, the present invention provides a method of sustaining the release behavior of a micelle-forming drug. That is, the critical micelle concentration of the micelle-forming drug is decreased, thereby sustaining the release behavior of the micelle-forming drug.

  In other aspects, the present invention provides additional methods of sustaining the release behavior of micelle-forming drugs. These include, for example, changing the composition of the polymer, changing the ratio of polymer to drug, changing the amount of polymer with opposite charge, and changing the tablet size and shape as well. Including.

  One way to determine the presence of micelles is to measure the change in light scattering at an angle of 90 degrees, i.e., measure S90 as a function of the concentration of a solution. Thereafter, the scattering graph is analyzed. When scattering increases continuously with increasing concentration, it indicates that micelles are not formed. If S90 shows a graph refracted against the plotted concentration, it represents micelle formation. The critical micelle concentration is determined from S90 as a function of molarity, that is, the inflection point of the graph measuring scattering at an angle of 90 degrees with the incident beam. Other methods for measuring micelle formation are also known to those skilled in the art.

  Beneficially, the drug content of the composition of the present invention is very high. Furthermore, increasing the drug content (eg up to 60% by weight) does not significantly increase the release rate in the artificial gastric fluid (SGF), and indeed in the artificial intestinal fluid (SIF), the drug content increases. The release rate decreases (see Example 8).

  In certain preferred embodiments, the micelle-forming drug has a positive or negative charge at physiological pH. As used herein, physiological pH is about 0.5 to about 8, more preferably about 0.5 to about 5.5. A positive or negative charge at physiological pH refers to the overall charge of the molecule. That is, as long as the overall charge is positive or negative, it can have one or more functional groups that contribute to the charge.

  One method for evaluating whether a micelle-forming drug or polymer has a positive or negative charge at physiological pH is a method of experimentally measuring the charge of the molecule. For example, a suitable buffer or gel at a certain pH is prepared and the cathode and anode are placed in the buffer or an alternative electrophoresis gel. If positively charged, the micelle-forming drug moves to the cathode. If the micelle-forming drug is negatively charged, the drug moves to the anode. The polymer with the opposite charge in the pharmaceutical composition moves towards the opposite electrode. For example, if the micelle-forming drug is positively charged, it moves to the cathode. The oppositely charged polymer moves to the anode.

  As another evaluation method, the charge of the micelle-forming drug and / or polymer can be evaluated using the Henderson-Hesselbeck equation. The Henderson-Hasselbeck equation is a mathematical description that defines the pH of a solution of acid-base pairs in terms of the dissociation constant of a weak acid and the equilibrium concentration of the acid and its conjugate base. When pK is equal to pH, [Ha] is equal to [A]. The pK value gives quantitative information about the strength of the acid, strong acids are characterized by undefined pK values (e.g. pK = -log 0 like hydrochloric acid), quasi-strong acids are small pK Characterized by value, weak acids are characterized by large pK values. By using the Henderson-Hasselbeck equation, the charge of a micelle-forming drug and / or polymer can be evaluated.

(I. Charged polymer excipient in the present invention)
The composition of the present invention also contains at least one polymeric excipient or polymer having a charge opposite to that of the micelle-forming drug. In a preferred embodiment, the cooperative interaction between the charged excipient and the micelle-forming drug is the basis for the sustained release characteristics of the present invention.

  The composition can contain a negatively charged polymer such as a carboxyl group or a sulfate group. These include, but are not limited to, sulfuric polymers, polyacrylic acid, polymethacrylic acid, methylmethacrylic-methacrylic acid copolymer, alginic acid, xanthan gum, gellan gum, guar gum, carboxymethylcellulose, locust bean gum and hyaluronic acid including.

  Particularly preferred negatively charged polymers include polyacrylic acid and sulfuric acid polymers. Sulfate-based polymers include carrageenan (eg, Biscalin® and / or Gelcalin®) and dextran sulfate. More preferably, when polyacrylic acid is selected as one polymer, a sulfuric acid-based polymer can be selected as another polymer.

  Preferably, the composition may also contain a hydrogel-forming polymer having physical properties that exhibit high viscosity when gelled, whereby the formulation of the present invention can be digested with meal digestion. It can withstand the contraction movement of the tube and can retain its shape more or less until it reaches the lower digestive tract, ie the colon. For example, a polymer having a viscosity of 1000 cps or more in a 1% aqueous solution (at 25 ° C.) is particularly preferable.

  The properties of a polymer depend on its molecular weight. The hydrogel-forming polymer used in the present invention is preferably a relatively high molecular weight substance, that is, an average molecular weight of 2 million, more preferably 4 million or more. Furthermore, the polymer may be branched, linear, cross-linked, or a combination thereof.

Examples of these polymers include Polyox (registered trademark) WSR303 (viscosity average molecular weight: 7 million, viscosity: 7500-10000 cps (1% aqueous solution, 25 ° C.)), Polyox ( (Registered trademark) WSRCoagulant (viscosity average molecular weight: 5 million, viscosity: 5500-7500cps (1% aqueous solution, 25 ° C)), Polyox (registered trademark) WSR301 (viscosity average molecular weight: 4 million, viscosity: 1650-55000cps (1% aqueous solution, 25 ° C)), Polyox (registered trademark) WSR N-60K (viscosity average molecular weight: 2 million, viscosity: 2000-4000cps (2% Aqueous solution, 25 ° C.), both of which are manufactured by Meisei Chemical Co., Ltd. Alcox (registered trademark) E-75 (viscosity average molecular weight: 2 to 2.5 million, viscosity: 40-70 cps (0.5% aqueous solution, 25 ° C.)), Alcox (registered trademark) E-100 (viscosity average molecular weight: 2.5-3 million, viscosity: 90-110 cps (0.5% aqueous solution, 25 ° C.)), Alcox (registered trademark) E-130 (viscosity average molecular weight: 3 to 3.5 million, viscosity: 130-140 cps (0.5% aqueous solution, 25 ° C.)), Alcox (registered trademark) E-160 (viscosity average molecular weight: 3.6 to 4 million, viscosity: 150-160 cps (0.5% aqueous solution, 25 ° C)), Alcox (registered trademark) E-240 (viscosity average molecular weight: 4-5 million, viscosity: 200-240 cps (0.5% aqueous solution, 25 ° C.)), all PEO-8 (viscosity average molecular weight: 1.7-2 million, viscosity) : 20-70 cps (0.5% aqueous solution, 25 ° C)), PEO-15 (viscosity average molecular weight: 3.3-3.8 million, viscosity: 130-250cps (0.5% aqueous solution, 25 ° C)), PEO-18 (viscosity average molecular weight) : 4.3 to 4.8 million, viscosity: 250-480 cps (0.5% aqueous solution, 25 ° C.)) and the like.

  In order to provide a hydrogel-type formulation suitable for sustained release, the formulation generally comprises from about 10 to about 95%, more preferably from about 15 to about 90%, by weight of the formulation weighing less than 600 mg. It preferably contains a gel-forming polymer. Preferably, the formulation contains 70 mg or more, more preferably 100 mg or more of the hydrogel-forming polymer per formulation. The above amounts are such that the composition can withstand erosion in the gastrointestinal tract for a significant amount of time in order to achieve sufficient sustained release.

  The hydrogel-forming polymer may be used alone or in combination of two or more of the hydrogel-forming polymers.

  Preferably, the release rate can be slowed down in a pH-independent manner in both gastric and small intestine conditions, depending on the particular combination and the proportion of polymeric excipients. The optimal combination and ratio may vary depending on the particular active substance and its content.

  Preferred excipient combinations include PAA (polyacrylic acid) / PEO (polyethylene oxide), PAA (polyacrylic acid) / carrageenan, PAA (polyacrylic acid) / dextran sulfate. Preferably, the polymer ratio is 1: 0.5, 1: 1 or 1: 5, most preferably 1: 1.5.

  Preferred excipient combinations also include PAA (polyacrylic acid) / carrageenan / PEO (polyethylene oxide). Preferably, the ratio of PAA (polyacrylic acid) to carrageenan is 1: 0.5, 1: 1 or 1: 5, most preferably 1: 1.5. Preferably, the ratio of PAA (polyacrylic acid) with added carrageenan to polyethylene oxide is 1: 0.5, 1: 1 or 1: 2, most preferably 1: 1.5.

  In order to achieve sustained drug release in the lower gastrointestinal tract as well as in the upper gastrointestinal tract in humans, the formulation gels at least 2 hours after administration, and the tablet erodes while moving to the lower gastrointestinal tract, resulting in Released.

  The term “gelation rate of the composition” used in the present invention means the ratio of tablets that have been gelated when the tablets once compressed are soaked for a certain period of time. 2). The formulation absorbs water when it remains in the upper digestive tract. As a result, the gel is almost completely gelled (that is, the gelation rate is 70% or more, preferably 75% or more, more preferably 80% or more). In order to migrate, the drug is sustained and completely released and absorbed. As a result, sustained release is achieved even in the lower part of the digestive tract where there is almost no water. In particular, when the gelation rate is less than about 70%, sufficient drug release cannot be obtained, and the bioavailability of the drug may decrease (EP No. 1,205, 190A1).

  In the present invention, the term “upper gastrointestinal tract” means from the stomach to the duodenum and jejunum, and the term “lower gastrointestinal tract” means from the ileum to the colon.

  The composition can also contain a hydrophilic base to achieve a higher gelation rate. The hydrophilic base is not particularly limited as long as the above-described hydrogel-forming polymer substance is dissolved before gelation. For example, the amount of water required to dissolve 1 g of this hydrophilic base is preferably 5 mL or less (20 ± 5 ° C.), more preferably 4 mL or less (under the same conditions).

  Examples of this hydrophilic base include polyethylene glycol (eg, Macrogol 4000, Macrogol 6000, Macrogol 20,000, which are trade names of Nippon Oil & Fats), polyvinylpyrrolidone (eg, trade name of BASF) PVP (registered trademark) K30), sugar alcohols such as D-sorbitol, xylitol, sucrose, maltose, lactulose, D-fructose, dextran (for example, dextran 40), saccharides such as glucose, polyoxyethylene hydrogenated castor oil (for example, Cremophor (registered trademark) RH40 manufactured by BASF, HCO-40, HCO-60 manufactured by Nikko Chemical Co., Ltd., polyoxyethylene polyoxypropylene glycol (for example, Pluronic (registered trademark) F68 which is a trade name of Asahi Denka Kogyo Co., Ltd.) Water-soluble polymers such as surfactants). Polyethylene glycol, sucrose and lactulose are preferred, and polyethylene glycol (particularly Macrogol 6000) is more preferred. The above hydrophilic bases can be used singly or as a mixture of plural kinds.

  When a hydrophilic base is added in the present invention, the ratio used is preferably about 5 to about 80% by weight, more preferably 5 to 60% by weight, based on the total preparation.

  Preferred excipient combinations include PAA (polyacrylic acid) / PEO (polyethylene oxide) / PEG (polyethylene glycol). Preferably, the ratio of PAA (polyacrylic acid) to PEO (polyethylene oxide) is 1: 0.5, 1: 1 or 1: 5. More preferably, the amount of PEG (polyethylene glycol) is 5% to 60% by weight relative to the total formulation.

  Preferred excipient combinations also include PAA (polyacrylic acid) / carrageenan / PEO (polyethylene oxide) / PEG (polyethylene glycol). Preferably, the ratio of PAA (polyacrylic acid) to carrageenan is 1: 0.5, 1: 1 or 1: 5. Preferably, the ratio of PAA (polyacrylic acid) plus carrageenan to PEO (polyethylene oxide) is 1: 0.5, 1: 1 or 1: 2. More preferably, the amount of PEG (polyethylene glycol) is 5% to 60% by weight of the total formulation.

  The composition may contain one positively charged polymer or a combination of such polymers including, but not limited to, polyethyleneimine, chitosan, polyvinylpyridinium bromide, polydimethylaminoethyl methacrylate. it can.

  Depending on the viscosity of the polymer, the polymer material can form a matrix containing the active ingredient. For example, a polymer in which the viscosity of a 1% aqueous solution has a viscosity of 1000 cps or more is particularly preferable from the viewpoint of matrix forming ability.

  Sustained release of micelle-forming drug can be achieved by the method of oral administration composition of the present invention.

(II. Other tablet improvements)
Improvement of drug release from the tablet matrix of the present invention can also be achieved by any known method such as, for example, various coatings such as ion exchange complexes with Amberlite IRP-69. The tablet of the present invention may contain a drug that reduces gastrointestinal motility or may be co-administered. The active agent can also be modified to produce a prodrug that is chemically modified from a biologically active compound, which releases the active compound in vivo, such as by enzyme or hydrolysis. The auxiliary layer or coating can serve as a diffusion barrier that provides an additional means of controlling the rate and timing of drug release.

(IV. Composition additive)
If desired, the formulations of the present invention may contain appropriate amounts of other pharmaceutically acceptable excipients (eg, lactose, mannitol, potato starch, wheat starch, rice starch, corn starch and crystalline cellulose), binders ( For example, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose and gum arabic), swelling agents (eg, carboxymethylcellulose and carboxymethylcellulose calcium), lubricants (eg, stearic acid, calcium stearate, magnesium stearate, talc, aluminum metasilicate) Magnesium, calcium hydrogen phosphate, and anhydrous calcium hydrogen phosphate), fluidizing agents (eg, hydrous silica, light anhydrous silicic acid, dry aluminum hydroxide gel), colorants (eg, yellow tridioic acid) Iron and iron sesquioxide), surfactants (eg sodium lauryl sulfate, fatty acid sucrose ester), coating agents (eg zein, hydroxypropylmethylcellulose and hydroxypropylcellulose), buffers (eg sodium chloride, magnesium chloride, citric acid) Acids, tartaric acid, disodium hydrogen phosphate, sodium dihydrogen phosphate, calcium hydrogen phosphate, ascorbic acid), fragrances (eg, 1-menthol, peppermint oil, and fennel oil), preservatives (eg, sodium sorbate) , Potassium sorbate, methyl p-benzoate, and ethyl benzoate).

(V. Manufacturing method)
The preparation of the present invention is a solid preparation having a certain shape, and can be produced by any ordinary production method. Exemplary manufacturing methods include, for example, compressed tablet manufacturing methods. These manufacturing methods include mixing and granulating the active substance and optionally a charged polymer, and optionally another additive, and compression molding of these components / compositions. Other manufacturing methods include, for example, a capsule compression filling method, an extrusion method in which a molding process is performed by melting and pouring the mixture, an injection molding method, and other similar methods. Further, for example, any coating treatment such as sugar coating may be performed.

  The following examples are illustrated, but the present invention is not limited to these examples.

(Test method 1)
This test method describes the preparation of the basic formulation of the present invention and the measurement of drug release.

  Several compositions containing various drugs were made. The drug was manually mixed with the excipients in a mortar and compressed into 400 mg tablets using a culver press or oil press with a tableting pressure of 1000 pounds. An 11 mm round flat was used.

(Substance used)
Carbopol 971 (BFGoodrich); Polyox 303 (Union Carbide); Two types of carrageenan, Biscarin (registered trademark) 109 and Gelcalin (FMC); Santural ^™ 180 (Monsanto Pharmaceutical Ingredients), Kelton (a registered trademark) LVCR (MonsantoPharmaceutical Ingredients), xanthan gum, sodium chitosan alginate (MW International, Inc.); Macrogol 6000 (Japanese fats and oils); K100M (Dow Chemical); hydroxypropyl methylcellulose (HPMC); gum cellulose 12M31P TP (Hercules); carboxymethylcellulose (CMC) sodium; and dextran sulfate (Sigma).

(Method)
In vitro drug release was measured by in vitro dissolution test. In these experiments, Examples 1 to 10 were carried out using US Pharmacopoeia Second Method, paddle rotation speed of 100 rpm, and 1000 mL of test solution. Drug release was prepared according to the US Pharmacopoeia, none of which added enzyme and was evaluated using artificial gastric fluid (SGF) at pH 1.2 or artificial intestinal fluid (SIF) at pH 7.5. The sinker was used in all experiments. Samples were taken from the containers at predetermined intervals and quantified by an ultraviolet-visible absorption spectrometer with a wavelength of 240 nm.

(Example 1)
This example illustrates that drug release rate does not correlate with drug solubility and that specific interactions affect its release rate.

  Release from matrix tablets directly tableted with a mixture of polyacrylic acid / polyethylene oxide (PAA / PEO) ratio of 1: 1.5 as additive for many basic water-soluble drugs (10 wt.% Of drug) The behavior was examined under artificial intestinal fluid conditions. Release rate (time to release 50% of drug from matrix to solution) was assessed by T50 (Figure 1). The test results summarizing the drug properties and release rate are shown in Table 1.

  Drugs with similar charges show significantly different release behavior in modified SIF and do not correlate with drug solubility (Figure 1, Table 1). Therefore, it can be concluded that a simple electrostatic interaction alone does not release the water-soluble drug slowly.

(Example 2)
This example illustrates that the drug log P can be used to predict whether sustained release will be achieved by the composition of the present invention. The ability to predict drug release behavior based on log P characteristics is one of the important advantages of the present invention.

  The ability of a drug to bind to a specific polyelectrolyte depends on its critical micelle concentration (CMC). However, since CMC values are rarely available for drugs, attempts have been made to relate the release rate to the drug physical properties used for general drug characteristics. Regarding the drugs used in the release experiments described above (Table 1), various parameters such as molecular weight, solubility, PKa, logP, log D and surface tension were analyzed from the viewpoint of correlation with release time. It was found that log P (which is the octanol / water partition coefficient of non-dissociated drug) has a substantially linear relationship with T50 (FIG. 2). logP showed a close correlation with CMC. In fact, a linear relationship was established between log P and CMC (Figure 3). The log P and CMC values for various drugs were quoted from Attwood publications.

（実施例3）
この実施例は、PAA（ポリアクリル酸）／PEO（ポリエチレンオキサイド）の比率が1:1.5の添加剤混合物を用いることにより、恒久的な正電荷を有する分子の徐放が達成できることを説明している。

(Example 3)
This example illustrates that by using an additive mixture with a PAA (polyacrylic acid) / PEO (polyethylene oxide) ratio of 1: 1.5, sustained release of molecules with a permanent positive charge can be achieved. Yes.

  The following positively charged substances were tested: monovalent positively charged benzethonium chloride and betanechol, divalent positively charged thiamine nitrate and thiamine hydrochloride, and dipole betaine (FIG. 4).

  Although thiamine hydrochloride showed slightly faster release, all drugs showed sustained release with different release rates (Table 2). These results show that even when the drug does not have a strong hydrophobic group, as long as the drug is permanently positively charged, specific interactions with charged polymer additives (See example for Bethanechol chloride). In contrast, drug structure and charge configuration play an important role in the degree of interaction with the polymeric additive (see thiamine hydrochloride). Thiamine molecules may influence micelle formation by placing a charge in the center of the molecule (Figure 4).

(Example 4)
This example illustrates that drugs with opposite charges and polymeric additives are important for sustained drug release. As shown in Fig. 5, cefazolin sodium and cefmetazole sodium, which are easily water-soluble negatively-charged drugs, escape from the negatively charged PAA (polyacrylic acid) / PEO (polyethylene oxide) matrix by diffusion and gradually. Without achieving release, its T50 is about 5 hours.

(Example 5)
This example illustrates the effect of the liquid environment on drug release from a matrix with a PAA (polyacrylic acid) / PEO (polyethylene oxide) ratio of 1: 1.5. The initial experiment described in Example 1-4 was performed in an artificial intestinal fluid (SIF) in which polyacrylic acid was ionized. In order to evaluate the release kinetics in the gastric environment, the dissolution of various water-soluble drugs was performed in a modified artificial gastric juice (SGF). Table 3 compares the T50 values in SGF and SIF for various drugs.

表3に示すように、人工腸液中における放出時間は、人工胃液中よりも有意に長い。明らかなように、低pHの液中において、PAA（ポリアクリル酸）のイオン化の大部分は抑制される。これにより、PAA（ポリアクリル酸）／PEO（ポリエチレンオキサイド）と薬物間の協力的な結合の形成が妨げられるかもしれない。人工胃液中における短い放出時間の他の考えられる理由として、低pH条件において、PEO（ポリエチレンオキサイド）の負に帯電した酸素原子とPAA（ポリアクリル酸）のカルボキシル基間の水素結合により高分子複合体が形成され、これによりカルボキシル基と薬物との相互作用が妨害されることが挙げられる。

As shown in Table 3, the release time in the artificial intestinal fluid is significantly longer than in the artificial gastric fluid. As is apparent, most of the ionization of PAA (polyacrylic acid) is suppressed in the low pH solution. This may prevent the formation of cooperative bonds between PAA (polyacrylic acid) / PEO (polyethylene oxide) and the drug. Another possible reason for the short release time in artificial gastric fluid is a polymer composite due to hydrogen bonding between the negatively charged oxygen atom of PEO (polyethylene oxide) and the carboxyl group of PAA (polyacrylic acid) at low pH conditions A body is formed, which interferes with the interaction between the carboxyl group and the drug.

(Example 6)
This example describes a combination of polymeric additives that provide sustained release under both SGF (artificial gastric fluid) and SIF (artificial intestinal fluid) conditions.

(Evaluation of multiple polysaccharides)
Seven types of polysaccharides (carrageenan, xanthan gum, sodium alginate, chitosan, HPMC (hydroxypropylmethylcellulose), CMC-Na (carboxymethylcellulose) containing 25% by weight diltiazem hydrochloride (DI) and combined with PAA (polyacrylic acid) Sodium release) was tested for drug release rate (Figure 6). The combination of PAA (polyacrylic acid) and carrageenan has been shown to provide the slowest drug release in SGF (in artificial gastric juice). This effect is probably due to the strong acidity of the carrageenan functional group (—SO 4 —), which has a negative charge even at low pH and allows interaction between the carrageenan and the drug.

(Evaluation of other sulfuric polymers)
As with the different types of carrageenan, dextran sulfate is used in combination with a PAA (polyacrylic acid) / PEO (polyethylene oxide) ratio of 1: 1 and diltiazem hydrochloride (25% by weight), and its release rate is SGF (artificial gastric fluid) and Measurements were made in SIF (artificial intestinal fluid). Sustained release was observed for all combinations containing sulfate polymers (FIG. 7).

(Further analysis of the effect of replacing PAA (polyacrylic acid) with PEO (polyethylene oxide))
PAA (polyacrylic acid) / carrageenan (1: 1) When replacing PAA (polyacrylic acid) in the composition with high molecular weight PEO (polyethylene oxide), PAA (polyacrylic acid) / carrageenan (1: 1) ) And PEO (polyethylene oxide) / carrageenan (1: 1) composition overlap in SGF (artificial gastric fluid) over about 6 hours (FIG. 8, a). After this, rapid drug release occurs due to fast erosion of the PEO (polyethylene oxide) / carrageenan matrix. In contrast, in SIF (artificial intestinal fluid), the PAA (polyacrylic acid) / carrageenan composition exhibits slower drug release over time than the PEO (polyethylene oxide) / carrageenan composition (FIG. 8, b). . Thus, the combination of PAA (polyacrylic acid) and carrageenan can provide the best in vitro drug release properties in both SGF (artificial gastric fluid) and SIF (artificial intestinal fluid).

(Comparison of release rate of PAA (polyacrylic acid) / carrageenan in SIF (artificial intestinal fluid) and SGF (artificial gastric fluid))
Figure 9 shows that the release of diltiazem hydrochloride (25 wt%) from a PAA (polyacrylic acid) / carrageenan (1: 1) matrix is linear in both SGF (artificial gastric fluid) and SIF (artificial intestinal fluid) And that the release rates of the two liquids are the same. The dissolution test of the sample with the test solution replaced after 2 hours showed a linear release behavior very similar to the behavior of FIG.

(Example 7)
This example illustrates that the optimal polymer additive composition is test solution dependent (FIG. 10).

  For compositions containing 25% by weight diltiazem hydrochloride, a composition with a 1: 1 PAA (polyacrylic acid) / carrageenan ratio achieved the slowest release rate in SGF (artificial gastric juice). The release rate in artificial intestinal fluid decreased with increasing PAA (polyacrylic acid) content in the composition.

  Interestingly, various optimal compositions with high doses of diltiazem hydrochloride (60% by weight) were observed. In SGF (artificial gastric juice), the drug release rate decreased with increasing carrageenan content, and the release rate in SIF (artificial intestinal fluid) was almost independent of the additive ratio (FIG. 11).

  Based on these observations, the release behavior is thought to be largely governed by the stoichiometry of the drug / additive complex in different test solutions.

(Example 8)
This example illustrates that to the extent that the drug content is increased to 60% by weight, the drug content has little effect on the release rate in SIF (artificial intestinal fluid). In the range where the drug content is increased to 50% by weight, the increase in release rate in SGF (artificial gastric juice) is relatively small (FIG. 12).

(Example 9)
This example illustrates that the composition of the present invention is excellent for sustained drug release.

  Release of diltiazem hydrochloride (25%) from a PAA (polyacrylic acid) / carrageenan (1: 1) matrix was compared to a known composition containing PAA (polyacrylic acid) and carrageenan (Bonferoni et al., AAPS Pharm. Sci. Tech, 1 (2) article 15 (2000); Bubnis etal., Proceed. Int'l. Symp. Control. Rel. Bioact. Mater., 25, p. 820 (1998); Devi et al ., Pharm. Res., V.6, No 4, 313-317 (1989); Randa Rao et al., J. Contr. Rel., 12, 133-141 (1990); Baveja et al., Int. J. Pharm., 39, 39-45 (1987); Stockwel et al., J. Contr. Rel. 3, 167-175 (1986); Perez-Marcos et al., J. Pharm. Sci., V. 85, No. 3 (1996); Perez-Marcos et al., Int. J. Pharm. 111,251-259 (1994); Dabbagh et al., Pharm. Dev. Tech., 4 (3), 313-324 ( 1999); Bonferoni et al., J. Contr. Rel. 25, 119-127 (1993); Bonferoni et al., J. Contr. Rel. 30, 175-182 (1994); Bonferoni et al., J. Contr. Rel. 51, 231-239 (1998); US Patent 4,777,033; EU Patent 0 205 336 B1).

  Carrageenan-containing systems described in the literature include carrageenan / HPMC (hydroxypropylmethylcellulose) and carrageenan / CMC (carboxymethylcellulose). All matrices were prepared in the same manner as the matrix mixed with Biscalin 109 / second polymer (1: 1). The composition consisting of PAA (polyacrylic acid) / carrageenan (1: 1) matrix showed significantly slower release of diltiazem hydrochloride in both SGF (artificial gastric fluid) and SIF (artificial intestinal fluid) (FIG. 13).

  Sustained release with PAA (polyacrylic acid) / HPMC (hydroxypropylmethylcellulose) has already been reported (US Patent 4,777,033; EU Patent 0 205 336 B1).

  Although all formulations showed sustained release in SIF (artificial intestinal fluid) with a T50 of 20 hours or more, a composition comprising a PAA (polyacrylic acid) / carrageenan (1: 1 and 3: 2) matrix was (Artificial gastric juice) showed significantly slower release of diltiazem hydrochloride than the control PAA (polyacrylic acid) / HPMC (hydroxypropylmethylcellulose) (FIG. 14).

  Even when the drug content in the composition is increased to 60% by weight, the PAA (polyacrylic acid) / carrageenan system maintains the slowest release rate compared to all other competing systems (FIG. 15).

(Example 10)
This example compares the release rates of various drugs from the initial composition (PAA (polyacrylic acid) / PEO (polyethylene oxide)) and the new composition consisting of PAA (polyacrylic acid) / carrageenan.

  The release rate of various drugs that have been shown to interact with PAA (polyacrylic acid) / PEO (polyethylene oxide) matrix is the rate of release from PAA (polyacrylic acid) / carrageenan (1: 1) matrix. Compared with. Most drugs showed sustained release close to zero order release from the PAA (polyacrylic acid) / carrageenan matrix. In general, but not all drugs, drug release from PAA (polyacrylic acid) / carrageenan matrix is higher than that from PAA (polyacrylic acid) / PEO (polyethylene oxide) matrix. ) And SIF (artificial intestinal fluid).

  To illustrate, Table 4 below shows T50 values (release time) in SIF (artificial intestinal fluid). In this study, PAA (polyacrylic acid) / PEO (polyethylene oxide) (1: 1.5) composition is 10% active substance, PAA (polyacrylic acid) / carrageenan (1: 1) is 25% active substance Was included.

（試験法2）
（溶出試験）
in vitro薬物放出はinvitro溶出試験により測定した。これらの実験は日本薬局方第14改正（以降、日局とする）溶出試験第2法（パドル法）、パドル回転速度200rpm、900mLの試験液を用いて実施した。薬物放出は、pH1.2の日局崩壊試験第1液（以降、日局第1液とする）、あるいは、pH6.8の日局崩壊試験第2液（以降、日局第2液とする）を用いて評価した。シンカーは全ての実験で使用しなかった。予め決められた間隔で、サンプルを容器より採取し、波長250nmの紫外−可視吸収分光計を用いて定量した。

(Test method 2)
(Dissolution test)
In vitro drug release was measured by in vitro dissolution test. These experiments were carried out using the Japanese Pharmacopoeia 14th revision (hereinafter referred to as the Japanese Pharmacopoeia) dissolution test method 2 (paddle method), paddle rotation speed 200 rpm, and 900 mL of test solution. Drug release is pH 1.2 JP disintegration test 1st liquid (hereinafter referred to as JP 1st liquid) or pH 6.8 JP disintegration test 2nd liquid (hereinafter referred to as JP 2nd liquid). ). The sinker was not used in all experiments. Samples were taken from the containers at predetermined intervals and quantified using an ultraviolet-visible absorption spectrometer with a wavelength of 250 nm.

(Gelation test)
Using the JP 1st liquid and JP 2nd liquid, a gelation test was conducted as follows. Immerse the test tablet in the test solution at 37 ° C for 2 hours, remove the gel layer, take out the core part where the gel is not formed, then dry it at 40 ° C for 5 days with a dryer, and measure the weight of the dried core (W _obs ). The gelation rate of the composition is calculated from Equation 1. The value obtained by subtracting the core weight from the _initial tablet weight (W _initial ) was divided by the initial tablet weight and multiplied by 100 to calculate the gelation rate (G).

  As used herein, “gelation rate” represents the proportion of the gelled tablet portion. The method for calculating the gelation rate is not particularly limited, and examples thereof include the following methods.

  That is, the test tablet is soaked for a predetermined time, the volume (or weight) of the part not forming the gel is measured, and the result is subtracted from the tablet volume (or weight) before the start of the test.

Gelation rate (G,%) = (1− (W _obs −W _initial )) × 100 (Formula 1)
W _obs : Weight of the non-gelled part after the start of the test W _initial : Formulation weight before the start of the test (Example 11)
This example illustrates the effect of the addition of a polymer having an opposite charge to the micelle-forming drug on the drug release behavior.

  Contains 50% by weight diltiazem hydrochloride and different amounts of PAA (polyacrylic acid) with PEO (polyethylene oxide) / PEG (polyethylene glycol) (1: 1) mixture and 1: 0 (polyacrylic acid relative to the total weight) 50% by weight), 1: 1 (25% polyacrylic acid based on total weight), 3: 1 (37.5% polyacrylic acid based on total weight), 1: 3 (based on total weight) The polyacrylic acid was used in combination at a ratio of 12.5% by weight) or 1: 9 (5% by weight of polyacrylic acid based on the total weight). A composition comprising polyethylene oxide / polyethylene glycol (1: 1) containing 50% by weight diltiazem hydrochloride and no PAA (polyacrylic acid) was prepared as a control. According to the method described in Test Method 2, the drug release rate in JP 2nd liquid was evaluated (FIG. 16). Even in the case of containing a small amount of PAA (polyacrylic acid) such as 5% by weight with respect to the total formulation, sustained drug release was achieved in all formulations containing PAA (polyacrylic acid). The results also revealed that the drug release rate decreased as the amount of PAA (polyacrylic acid) was increased instead of the polyethylene oxide / polyethylene glycol (1: 1) mixture.

  The effect of the addition amount of PAA (polyacrylic acid) and carrageenan on drug release behavior was also investigated. The ratios of PAA (polyacrylic acid) and carrageenan, and polyethylene oxide and polyethylene glycol were fixed at 1: 1, respectively. Contains 50% by weight diltiazem hydrochloride and different amounts of PAA (polyacrylic acid) / carrageenan (1: 1) with PEO (polyethylene oxide) / PEG (polyethylene glycol) (1: 1) mixture 1: 0 (total PAA (polyacrylic acid) and carrageenan are 25% by weight and 25% by weight, respectively, 3: 1 (PAA (polyacrylic acid) and carrageenan are 18.75% and 18.75% by weight, respectively, based on the total weight) 1: 1 (PAA (polyacrylic acid) and carrageenan are 12.5% and 12.5% by weight, respectively) or 1: 3 (PAA (polyacrylic acid) and carrageenan are 6.25% each by weight) % And 6.25% by weight were used in combination (FIG. 17).

  A composition comprising a PEO (polyethylene oxide) / PEG (polyethylene glycol) ratio of 1: 1 containing 50% by weight of diltiazem hydrochloride and not containing PAA (polyacrylic acid) / carrageenan was prepared as a control. The results also revealed that the drug release rate decreased as the amount of PAA (polyacrylic acid) / carrageenan mixture added increased. Therefore, the drug release rate can be controlled by changing the amount of polymer having a charge opposite to that of the micelle-forming drug.

(Example 12)
This example illustrates that the composition of the present invention is excellent in gelation.

  Contains 50% by weight diltiazem hydrochloride, and the ratio of PAA (polyacrylic acid) / carrageenan / PEO (polyethylene oxide) / PEG (polyethylene glycol) is 1: 1: 0: 0, 1: 1: 1: 1 or 1 The gelation test of the preparation consisting of: 1: 3: 3 was performed according to the method described in Test Method 2. The gelation ratios of these compositions in JP 1st liquid were 75.0%, 80.8% and 80.7%, respectively.

  In the case of a preparation having a ratio of PAA (polyacrylic acid) / PEO (polyethylene oxide) / PEG (polyethylene glycol) of 1: 9: 9, the gelation rate in JP 1st liquid and JP 2nd liquid is They were 78.0% and 76.9%, respectively.

(Test method 3)
(Pharmacokinetic study in beagle dogs)
Nine male beagle dogs weighing 9.3 to 13.4 kg were fasted for 18 hours before administration. After oral administration of test tablets containing 200 mg of diltiazem hydrochloride together with 30 mL of water, water was ad libitum, but no food was given until the end of the final blood collection. Blood was collected at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours after administration. Thereafter, plasma was separated by centrifugation and used for quantitative analysis by high-performance liquid chromatography with ultraviolet detection.

(Example 13)
This example illustrates the effect of the gelation rate of the formulation on the sustained drug release in vivo.

  Two preparations containing 200 mg of diltiazem hydrochloride and having different amounts of PAA (polyacrylic acid) / PEO (polyethylene oxide) / PEG (polyethylene glycol) (gelation rate in JP 1st liquid, preparation A: 63.4%, preparation B : 77.6%) was used for pharmacokinetic studies in beagle dogs. Formulation A released almost no drug in the lower gastrointestinal tract, but formulation B was shown to show sustained drug release in the lower gastrointestinal tract as well as in the upper gastrointestinal tract.

  To compare in vivo drug release between the two formulations in detail, the area under the plasma drug concentration curve (AUC) from 0 to 24 hours was calculated as a function of drug absorption in vivo. The AUC of formulation B (7541.2 ± 2153.7 ng h / mL) is significantly greater than the AUC of formulation A (4346.1 ± 1811.6 ng h / mL), and therefore the drug release in vivo for formulations with low gelation rate is not It was confirmed to be complete.

  All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference in their entirety for all purposes. Although the invention has been described with reference to preferred embodiments and examples, the purpose of the invention is not limited only to the described embodiments. It will be apparent to those skilled in the art that modifications and adaptations may be made to the invention described above without departing from the spirit and scope of the invention, and thus are defined and limited by the appended claims. The

Claims (5)

(I) a water-soluble micelle forming drug having a positive electrostatic load at physiological pH,
(II) at least one polymer having an opposite charge that is polyacrylic acid, and (III) carrageenan or dextran sulfate.
Oral sustained release pharmaceutical composition characterized by containing.   The oral sustained-release pharmaceutical composition according to claim 1, wherein the micelle-forming drug is a basic drug.   The micelle-forming drug consists of antidepressant, adrenergic β receptor antagonist, anesthetic, antihistamine, phenothiazine, tranquilizer, antibacterial, antibiotic, anti-inflammatory, analgesic, antipyretic and diuretic The oral sustained-release pharmaceutical composition according to claim 1, which is selected from the group. It said drug 75 wt% to 10 wt%, polyacrylic acid is 50% by weight 5, oral sustained release pharmaceutical composition according to claim 1 or et 3. 75 wt% said drug from 10% by weight, polyacrylic acid from 5 to 50 wt%, and 50 wt% carrageenan or dextran sulfate is from 5% by weight, orally according to claim 1 or et 4 Sustained release pharmaceutical composition.

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