RU2322263C2 - System for prolonged release of soluble drug - Google Patents

Abstract

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to drugs and concerns sustained-release oral compositions. Agent comprises micelle-forming water-soluble main drug showing a positive charge at physiological pH value, polymer showing an opposite charge chosen from group consisting of polyacrylic acid, carboxymethylcellulose, xanthane gum, hellane gum, guara gum, dextran-sulfate and carragheenan, polyethylene oxide and if necessary a hydrophilic base. Also, invention proposes a method for sustained-release of micelle-forming drug.

EFFECT: improved and valuable medicinal and pharmaceutical properties of agent.

20 cl, 4 tbl, 24 dwg, 13 ex

Description

The application claims priority to US Patent Application No. 10/007877, filed November 13, 2001 and converted into provisional application US No.__, which is incorporated into this application in its entirety for all purposes by reference.

FIELD OF THE INVENTION

The present invention relates to new oral sustained release formulations for the delivery of an active agent (eg, a drug), especially a water-soluble drug. More specifically, the present invention relates to new compositions comprising a micelle-forming drug having a charge, and at least one polymer having an opposite charge.

State of the art

The introduction of drugs using traditional oral and intravenous methods severely limits the effectiveness of most drugs. Instead of maintaining drug levels within therapeutic ranges, these methods lead to a rapid initial increase in plasma concentration levels, followed by a rapid drop below therapeutic levels as the drugs are metabolized by the body. For this reason, repeated doses are required to maintain drug levels at therapeutic levels for a period of time sufficient to achieve a therapeutic effect. To solve this problem, in order to eliminate the initial effect of the "explosion" and ensure the release of drugs at constant levels, numerous sustained release preparations have been developed.

To achieve sustained drug release, polymer formulations are generally used (see Langer et al., Nature 392: 6679 supp. (1998)). For the release of drugs with different physical properties, a variety of successful, sustained release polymer formulations have been developed. Such formulations have proven extremely effective in increasing the release time in those cases where relatively hydrophobic and water-insoluble drugs are used.

However, due to the rapid diffusion of drugs through polymer matrices, it has proved difficult to achieve sustained release for well-soluble drugs using modern sustained release technologies. Thus, there is a need for new compositions and methods that could reduce the diffusion of drugs and eliminate the effect of "explosion" for well-soluble drugs in water. The present invention solves these and other problems.

Disclosure of invention

The present invention provides, inter alia, an oral sustained release formulation comprising a micelle forming drug and an oppositely charged polymer. Although the idea of micelles in the field of surfactants or drug carriers is well known, the use of a micelle-forming drug for sustained release formulations is not known at all. Moreover, the fact that such a composition is extremely effective for the sustained release of active agents, in particular water-soluble drugs, was in fact unexpected. Another advantage of the composition is its ability to provide a slow release, even when the composition contains large doses of the drug.

As such, the present invention provides an oral sustained release pharmaceutical composition comprising a micelle forming drug having a charge and at least one polymer having an opposite charge, and further comprising a hydrogel forming polymer material and a hydrophilic base. A micelle-forming drug can have either a positive or negative charge at physiological pH.

In another embodiment, the present invention provides a method for modulating the release profile of a micelle forming drug, comprising varying the molar ratio having a charge of a micelle forming drug and at least one polymer having an opposite charge, varying an additional amount of polymer bearing an opposite charge, thereby modulating the release profile of a micelle forming drug. Suitable micelle forming drugs include, for example, antidepressants, β-adrenergic blocking agents, anesthetics, antihistamines, and the like. Preferably, the micelle forming drug is a water soluble drug.

In yet another embodiment, the present invention provides a method for prolonging the release of a micelle forming drug, comprising: orally administering a pharmaceutical composition containing a micelle forming drug having a charge, and at least one polymer having an opposite charge, thereby increasing the release time of the micelle forming drug.

In yet another embodiment, the present invention provides a method for extending the release time of a micelle-forming drug, comprising: orally administering a pharmaceutical composition containing a micelle-forming drug having a charge, and at least one polymer having an opposite charge, and, in addition, optionally forming a hydrogel polymer substance and hydrophilic base, thereby prolonging the release of micelle-forming drugs.

Other objectives and advantages will become more apparent upon reading the following detailed description with drawings.

Brief Description of the Drawings

Figure 1 illustrates the release of a soluble drug (10 wt.%) From 400 mg of a PAA / PEO matrix in artificial intestinal medium (SIF).

Figure 2 illustrates the correlation between T ₅₀ and logP for alkaline readily soluble drugs released from a 400 mg PAA / PEO (1: 1.5) tablet.

Figure 3 illustrates the correlation between the critical micelle concentration (CMC) and logP.

Figure 4 illustrates examples of charged (positively or negatively) drugs suitable for use in release experiments.

5 illustrates the release of negatively charged drugs from a PAA / PEO matrix.

Figure 6 illustrates the release of Diltiazem HCl from tablets (400 mg) with a PAA / polysaccharide matrix in SGF (Figure 6a) and SIF (Figure 6b).

Fig. 7 illustrates the release of Diltiazem HCl from tablets (400 mg) with a PAA / sulfated polymer matrix in SGF (Fig. 7a) and SIF (Fig. 7b).

Fig. 8 illustrates the release of Diltiazem HCl from various matrix tablets in SGF (Fig. 8a) and SIF (Fig. 8b).

Figure 9 illustrates the release of Diltiazem HCl (25 wt.%) From the PAA / carrageenan (1: 1) matrix in SGF and SIF.

Figure 10 illustrates the optimization of the ratio of PAA / carrageenan for the composition with 25 wt.% Diltiazem HCl.

11 illustrates the release rate of Diltiazem HCl (60 wt.%) From tablets with matrices with different ratios of PAA / carrageenan in SGF (figa) and SIF (fig.11b).

Fig. 12 illustrates the release of Diltiazem HCl from the PAA / Viscarin 109 matrix with different drug contents in SGF (Fig. 12a) and SIF (Fig. 12b).

Fig. 13 illustrates the release of Diltiazem HCl (25 wt.%) From competing carrageenan-based systems in SGF (Fig. 13a) and SIF (Fig. 13b).

14 illustrates the release of Diltiazem HCl (25 wt.%) From competing PAA-based systems in SGF.

Fig. 15 illustrates the release of Diltiazem HCl (60% by weight) from competing systems in SGF (Fig. 15a) and SIF (Fig. 15b).

Figure 16 illustrates the effect of additional PAA on the release of Diltiazem HCl (50 wt%) in JP 2 ^nd fluid.

17 illustrates the effect of additional PAA / carrageenan on the release of Diltiazem HCl (50 wt%) in JP 2 ^nd fluid.

The implementation of the invention

Definitions

The term “active agent” means any drug that may be in a physiologically acceptable oral tablet. Preferred active agents include micelle forming active agents capable of forming electrically charged colloidal particles.

The term "centipoise", or "centipoise", is a unit of viscosity equal to MPa · s. Viscosity is measured on Brookfield viscometers or other viscometers. See, for example, Wang et al., Clin. Hemorheol. Microcirc. 19: 25-31 (1988); Wang et al., J. Biochem. Biophys. Methods 28: 251-61 (1994); Cooke et al., J. Clin. Pathol. 41: 1213-1216 (1998).

As used herein, the term “carrageenan” refers to all forms of a water-soluble extract of carrageenan, Irish moss, and seaweed from the Atlantic coast of Europe and North America. The sources are, for example, Viscarin ^® 109 and such as Gelcarin ^® GP-911, GP-812, GP-379, GP-109, GP-209 commercially available from FMC company. Carrageenans are high molecular weight, highly sulfated linear molecules with a galactose skeleton. They consist of sulfated and non-sulfated repeating units of galactose and 3,6-anhydrogalactose, interconnected by alternating α- (1-3) and β- (1-4) -glycoside bonds. Another commercial source of carrageenans is Sigma and Hercules Inc.

As used herein, the term “polyacrylic acid,” or “PAA,” includes all forms and molecular weights of PAA polymers. Sources include, for example, Carbopol 971 from B.F. Goodrich.

As used herein, the term “polyethylene oxide polymer,” or “PEO,” includes all forms and molecular weights of PEO polymers. Among the sources of PEO polymers are, for example, Polyox WSR-303 ™ (average MM: 7 · 10 ⁶ , viscosity 7500-10000 cPs, 1% in H ₂ O, 25 ° C); Polyox WSR Coagulant ™ (average MM: 5 · 10 ⁶ , viscosity 5500-7500 cps, under the same conditions as above); Polyox WSR-301 ™ (average MM: 4 · 10 ⁶ , viscosity 1650-5500 cps, under the same conditions as above); Polyox WSR-N-60K ™ (average MM: 2 · 10 ⁶ , viscosity 2000-4000 cPs, 2% in H ₂ O, 25 ° C), all of which are trade names of Union Carbide Co. See also WO 94/06414, which is incorporated herein by reference.

As used herein, the term "polyethylene glycol", or "PEG", includes all forms and molecular weights of PEG polymers. PEG sources include Macrogol 400, Macrogol 1500, Macrogol 4000, Macrogol 6000, Macrogol 20000, all of which are trademarks of Nippon Oil and Fats Co.

The terms “hydroxypropyl methylcellulose”, “sodium carboxymethyl cellulose”, “hydroxyethyl cellulose” and “carboxyvinyl polymer” include their usual uses. Sources include: for hydroxypropyl methylcellulose (HPMC), for example Metolose 90SH100000 ™ (viscosity 2900-3900 cps, under the same conditions as above); Metolose 90SH30000 ™ (viscosity 25000-35000 cps, 2% in H ₂ O, 20 ° C), all of which are trademarks of Shin-Etsu Chemicals Co. For sodium carboxymethyl cellulose (CMC-Na, or CMC-Na), for example Sanlose F-150MC ™ (average MM 2 × 10 ⁵ ; viscosity 1200-1800 cPs, 1% in Н ₂ О, 25 ° С), Sanlose F-1000MC ™ (average MM 4.2 × 10 ⁴ ; viscosity 8000-12000 cps, under the same conditions as above); Sanlose F-300MS ™ (average MM 3 × 10 ⁵ ; viscosity 2500-3000 cps, under the same conditions as above), all of which are trademarks of Nippon Seishi Co., Ltd. For hydroxyethyl cellulose (HEC), for example HEC Daicel SE850 ™ (average MM 1.48 × 10 ⁶ ; viscosity 2400-3000 cps, 1% in H ₂ O, 25 ° C); HEC Daicel SE900 ™ (average MM 1.56 × 10 ⁶ , viscosity 4000-5000 cps, under the same conditions as above), all of which are trademarks of Daicel Chemical Industries. For carboxyvinyl polymers, for example Carbopol 940 ™, the average MM is approximately 25 × 10 ⁵ , BF Goodrich Chemical Co.

As used herein, the term “therapeutic drug” means any drug that can be delivered in the form of an orally physiologically acceptable tablet.

The term "micelle formation" refers to any compound capable of forming electrically charged colloidal particles, ions consisting of oriented molecules or aggregates of a certain number of compounds (molecules) that are loosely held together by secondary bonds.

The present invention provides, inter alia, a sustained release oral preparation comprising a micelle forming active agent (i.e., a drug) and an oppositely charged polymer forming a hydrogel matrix. A composition is usually made by directly compressing a polymer-filled drug.

The composition advantageously provides an extremely low release rate of the active agent. In a preferred aspect, hydrogen bonded complexes between oppositely charged polymers and drug micelles inhibit rapid drug diffusion. Without being bound by any special theory, it is assumed that the release of the drug occurs when the polymer charge is neutralized by OH ions in the matrix / dissolution boundary zone and the bonds mentioned above break.

In one embodiment, the number of administrations of the composition can be reduced, thereby improving patient compliance with the prescribed regimen. Further, the side effects of the drug can be reduced by suppressing rapid increases in the concentration of the drug in the blood (as is the case with conventional formulations). Another advantage of the composition is that the content of large quantities of the drug does not significantly affect the rate of release.

This application discusses factors and events that create a theoretical basis for the implementation of the invention. However, the foregoing discussion should in no way be construed as binding or limiting on the present invention. Those skilled in the art will appreciate that various embodiments of the invention can be implemented regardless of the model used to describe the theoretical basis of the invention.

I. Active Agents of the Invention

The active agents of the invention can be any drugs that form micelles. Micelle formation has been observed previously for antidepressants, β-adrenergic blocking agents, anesthetics, antihistamines, phenothiazines, anti-acetylcholines, tranquilizers, antibacterial agents and antibiotics (see Attwood et al., J. Pharm. Pharmac., 30, 176-180 (1978) ); Attwood et al., 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, 6, 988993 (1974); Attwood, J. Pharm. Pharmacol. 28, 407-409 (1976) ) Representative micelle-forming drugs — antidepressants — include imipramine HCl, omipramol HCl, and amitriptyline HCl. Representative micelle-forming β-adrenergic receptor blockers include oxprenolol HCl, acebutolol HCl and solatol HCl. Representative micelle-forming anesthetics include procaine HCl, lidocaine HCl and amethocaine HCl. Representative micelle-forming antihistamines include diphenhydramine HCl, chlorocyclisine HCl, diphenylpyraline HCl, promethazine HCl, bromodiphenhydramine HCl, tripelaminamine HCl and mepiramine maleate. Representative micelle-forming phenothiazines include chlorpromazine HCl and promethazine HCl. Other micelle-forming drugs include tranquilizers, antibacterial drugs, and antibiotics.

In some aspects, active agents include, but are not limited to, betacaine hemisulfate, cincocaine hydrochloride BP, and lignocaine hydrochloride (Sigma); prilocaine hydrochloride BP, bupivacaine hydrochloride (Astra Pharmaceuticals), mepivacaine hydrochloride (Leo), propacaine hydrochloride (Squibb) and amethocaine hydrochloride BP (Smith and Nephew Pharmaceuticals). In a number of aspects, the following active ingredients are useful for the present invention. These include, but are not limited to, (4 '- (1-hydroxy-2-isopropyl-aminoethyl) methanesulfonanilide) (Duncan, Flockhart); labetolol [5- (1-hydroxy-2- (1-methyl-3-phenyl-propylamino) ethyl) salicylamide] (Allen and Hanburys); aceburtolol ((±) -3'-acetyl-4 '- (2-hydroxy-3-isopropylaminopropoxy) butyranyl)) (May and Baker); propranolol {(±) -1-isopropylamino-3-naphth-1'-yloxypropan-2-ol} (ICI) and oxprenolol {(±) -1- (o-allyloxyphenoxy) -3-isopropylaminopropan-2-ol)} (Ciba); thymolol maleate {maleate (-) - 1-butylamino-3- (4-morpholino-1,2,5-thiodiazol-3-yl-hydroxy) propan-2-ol} (Merck, Sharp and Dohme); metroproorol tartrate [tartrate (±) -1-isopropylamino-3-p- (2-methoxyethyl) phenoxypropan-2-ol] (Geigy Pharmaceuticals). In another embodiment, the active ingredients include, but are not limited to, adiphenin hydrochloride (Ciba); poldin methyl sulphate B.P. (Beecham Research); lahesino chloride V.R.S. (Vestric); chlorphenoxamine hydrochloride (Evans Medical); piperiodolate hydrochloride and pipenzolate bromide (M.C. Pharmaceutical); Orphenadrine hydrochloride B.R. (Brocades, Gt Britain); benztropine mesylate V.R. (Merck Sharp and Dohme); wedinium bromide (Roche); ambutonium bromide (Wyeth) and benzylonitum bromide (Parke Davis). Diphenylhydramine hydrochloride B.P. (2-diphenylmethoxy-NN-dimethylethylamine hydrochloride) and chlorocyclisine hydrochloride B.P. [1- (p-chlorodiphenylmethyl) -4-methylpiperazine hydrochloride] obtained from Parke-Davis and Company and Burroughs Welcome and Company, respectively. Bromodiphenhydramine hydrochloride [2- (α-p-bromophenyl-α-phenylmethoxy) -NN-dimethylamine hydrochloride] and diphenylpyraline hydrochloride (4-diphenylmethoxy-1-methylpiperidine hydrochloride), respectively. Other active ingredients suitable for use in the present invention are known to those skilled in the art.

In preferred embodiments, the active agents of the present invention are water-soluble drugs. In even more preferred embodiments, the active agents of the present invention are essential drugs. The invention is particularly well suited for drugs that exhibit a strong “explosion” effect due to rapid diffusion through polymer matrices. Well-water-soluble drugs include salts formed with inorganic and organic acids (positively charged by non-covalently bound protons), permanently positively (or negatively) charged molecules and negatively charged molecules (salts of weak and strong acids). A well-soluble drug in water means, for example, that its solubility exceeds 10 mg / ml, preferably above 100 mg / ml.

Specific active agents suitable for use in the compositions of the present invention, charged micelle-forming drugs, are selected based on the critical micelle concentration (CMC) and / or logP, which are closely related (see example 3). logP (drug distribution coefficient between octanol and water) characterizes the hydrophobic properties of the uncharged form of the drug. CMC, which is a measure of concentration at which a particular compound forms a micelle, is a function of hydrophobicity, as well as stereochemistry of the molecule, the ability of the groups and counterions to rotate. The presence of micelle-like charged drug aggregates inside a hydrogel matrix containing oppositely charged polymers leads to cooperative interaction. It is this cooperative interaction that determines the rate of release from the polymer matrix. Therefore, CMC and logP can be used to predict the rate of release of the drug and, thus, identify those drugs that will have a sustained release in the compositions of the present invention. Drugs with low CMC and / or high logP in the compositions of the present invention will be released slowly, while drugs with a lower tendency to form micelles will be released in accordance with profiles similar to those for standard oral formulations.

Accordingly, the drug release profile can be modulated using standard methods known to those skilled in the art for modulating the critical micelle concentration and / or degree of cooperative interaction between the micelle forming drug and oppositely charged polymers. Methods for modulating CMC and / or the degree of cooperative interaction include changing the hydrophobicity of the drug by introducing functional groups and any other methods of changing the electrostatic interaction between the drug and the polymer excipient. In some aspects, the present invention provides a method of broadening the release profile of a micelle forming drug, which comprises lowering a critical concentration of micelle formation of a micelle forming drug, thereby broadening the release profile of a micelle forming drug.

In some other aspects, the present invention provides further methods for broadening the release profile of a micelle forming drug. These methods include, for example, varying the polymer compositions, changing the polymer / drug ratio, varying the additional amount of polymer having the opposite charge, and also varying the size and shape of the tablet.

One way to establish the existence of micelles is to measure the change in light scattering at an angle of 90 °, i.e. S90 as a function of concentration in a suitable solution. The scattering plots thus obtained can then be analyzed. If the scattering monotonically increases with increasing concentration, no micelle formation occurs. If the plots show a distinct break in the concentration dependence of S90, it is attributed to the formation of micelles. The critical micelle concentration is determined by the break point on the scattering plots at an angle of 90 ° to the incident beam, S90, as a function of molar concentration. Other methods for establishing micelle formation are known to those skilled in the art.

An advantage is that the drug content in the compositions of the present invention can be extremely high. Moreover, the release rate does not increase significantly with increasing drug content (for example, up to 60 wt.%) In SGF and actually decreases with increasing drug content in SIF (see example 8).

In some preferred aspects, the micelle forming drug has a positive charge or negative charge at physiological pH. As used herein, a physiological pH is from about 0.5 to about 8, more preferably from about 0.5 to about 5.5. A positive charge or a negative charge at physiological pH means a total charge on the molecule. In other words, if the total charge is positive or negative, more than one functional group is possible that contributes to the charge.

One method of analysis to determine whether a micelle-forming drug or polymer has a positive or negative charge at physiological pH is to empirically determine the charge on the molecule. For example, a suitable buffer solution or gel having a specific pH is prepared. A cathode and anode are placed in a buffered solution or, alternatively, gel electrophoresis is used. In the case when the micelle-forming drug is positively charged, it migrates to the cathode. If the micelle-forming drug is negatively charged, it migrates to the anode. A polymer having an opposite charge in the pharmaceutical composition will migrate to the opposite electrode. For example, if a micelle-forming drug is positively charged, it will migrate to the cathode. The polymer having the opposite charge will migrate to the anode.

In another evaluation method, a charge on a micelle-forming drug and / or polymer is established using the Henderson-Hasselbach equation. The Henderson-Hasselbach equation is a mathematical formulation that determines the pH of a solution of a conjugated acid / base pair based on the dissociation constant of a weak acid and the equilibrium concentrations of acid and conjugated base. When pK = pH, [Na] is [A]. The pK values provide quantitative information regarding the strength of the acid, with very strong acids having undefined pK values (pK = -log0, HCl example), medium strength acids with low pK, and weak acids with high pK. When using the Henderson-Hasselbach equation, the charge of the micelle-forming drug and / or polymer is established in order to determine the charge located on them.

II. Charged polymer fillers of the invention

The composition of the present invention also includes at least one polymer filler or polymer with a charge opposite to that of the micelle-forming drug of the invention. In one preferred aspect, the cooperative interaction of a charged carrier with a micelle-forming drug is the basis for the sustained release properties of the present invention.

The composition may include negatively charged polymers, such as polymers with a carboxyl group or a sulfate group. These polymers include, but are not limited to, sulfated polymers, polyacrylic acid, polymethacrylic acid, a copolymer of methyl methacrylate with methacrylic acid, alginates, xanthan gum, gellan gum, guar gum, carboxymethyl cellulose, carob gum and hyaluronic acid.

Particularly preferred negative charge polymers include polyacrylic acid and sulfated polymers. Sulfated polymers include carrageenan (for example, Viscarin ^® and / or Gelcarin ^®), and dextran sulfate. If polyacrylic acid is selected as one polymer, it is preferred that sulfated polymers are other polymers.

Preferably, the composition may also include a hydrogel-forming polymer with physical characteristics such as high gelation viscosity, which allows the preparation of the present invention to be resistant to the contractile forces of the digestive tract arising from the digestion of food, and to some extent maintain its shape in the process advancement in the direction of the lower digestive tract, namely the colon. For example, a polymer having a viscosity of at least 1000 cPs in a 1% aqueous solution (25 ° C.) is particularly preferred.

The properties of the polymer depend on its molecular weight. The hydrogel-forming polymer that can be used in the present invention is preferably a substance with a relatively high molecular weight, namely a polymer having an average molecular weight of at least 2 · 10 ⁶ and more preferably not less than 4-10. In this case, the polymers can be branched chain, straight chain, be cross-linked or combine these features.

Examples of this polymer substance are polyethylene oxide, such as POLYOX ^® WSR 303 (medium viscosity molecular weight 7,000,000, viscosity from 7,500 to 10,000 cps (1% aqueous solution at 25 ° C)), POLYOX ^® WSR Coagulant (medium viscosity molecular weight 5,000,000, viscosity from 5500 to 7500 cps (1% aqueous solution at 25 ° C)), POLYOX ^® WSR 301 (medium viscosity molecular weight 4,000,000, viscosity 1650-5500 cps (1% aqueous solution at 25 ° C)), POLYOX ^® WSR N-60K (medium viscosity molecular weight 2,000,000, viscosity from 2,000 to 4,000 cps (2% aqueous solution at 25 ° C)) (all manufactured by Union Carbide); ALKOX ^® E-75 (medium viscosity molecular weight from 2,000,000 to 2,500,000, viscosity 40 to 70 cps (0.5% aqueous solution at 25 ° C)), ALKOX ^® E-100 (medium viscosity molecular weight from 2,500,000 to 3,000,000, viscosity from 90 to 110 centipoise (0.5% aqueous solution at 25 ° C)), ALKOX ^® E-130 (medium viscosity molecular weight from 3,000,000 to 3,500,000, viscosity 130 to 140 centipoise (0.5% aqueous solution at 25 ° C)), ALKOX ^® E-160 (medium viscosity molecular weight from 3,600,000 to 4,000,000, viscosity from 150 to 160 cps (0.5% aqueous solution at 25 ° C)), ALKOX ^® E-240 ( medium viscosity molecular weight from 4,000,000 to 5,000,000, viscosity from 200 to 240 cps (0.5% aqueous solution at 25 ° C)) (all manufactured by Meisei Cagaku Co., Ltd.); PEO-8 (medium viscosity molecular weight from 1,700,000 to 2,200,000, viscosity from 20 to 70 cPs (0.5% aqueous solution at 25 ° C)), REO-15 (medium viscosity molecular weight from 3,300,000 to 3,800,000, viscosity from 130 to 250 cps (0.5% aqueous solution at 25 ° C)), REO-18 (medium viscosity molecular weight from 4,300,000 to 4,800,000, viscosity 250 to 480 cps (0.5% aqueous solution at 25 ° C) ) (all manufactured by Seitetsu Cagaku Kogyo., Ltd.), etc.

In order to obtain a hydrogel type preparation suitable for sustained release, it is usually preferred that the preparation contains from about 10 to about 95% by weight, and more preferably from about 15 to about 90% by weight, of the hydrogel-forming polymer in a preparation weighing less than 600 mg Preferably, the preparation includes at least 70 and preferably at least 100 mg of a hydrogel-forming polymer per preparation. These levels will ensure that the composition withstands erosion in the digestive tract for a sufficiently long time to achieve a sufficient delayed release.

The above hydrogel-forming polymer may be used alone, or a mixture of two or more types of the hydrogel-forming polymers mentioned above may be used.

The particular combination and relative proportions of the polymer excipients are preferably such that they provide the lowest possible release rate under conditions of both the stomach and intestines, regardless of pH. The optimal combination and proportion may vary depending on the specific active agent and the percentage of active agent.

Preferred filler combinations include PAA / PEO, PAA / carrageenan and PAA / dextran sulfate. Preferably, the polymer ratio is 1: 0.5, 1: 1 or 1: 5, and most preferably the polymer ratio is 1: 1.5.

Preferred excipient combinations also include PAA / carrageenan / PEO. Preferably, the ratio of PAA to carrageenan is 1: 0.5, 1: 1 or 1: 5, and most preferably, the polymer ratio is 1: 1.5. Preferably, the ratio of the sum of PAA and carrageenan to PEO is 1: 0.5, 1: 1 or 1: 2, and most preferably, the polymer ratio is 1: 1.5.

To ensure slow release of the drug both in the lower part of the digestive tract and in the upper part of the human digestive tract, the drug must undergo gelation for at least 2 hours after administration, after which the tablet should erode when it moves through the lower part of the digestive tract, as a result what will be the release.

Used in the present invention, the term "degree of gelation of the composition" refers to the percentage of the tablet that underwent gelation after the compressed tablet was wetted for the prescribed time, and is determined by the method for determining the degree of gelation, which is described below (see Test method 2 ) Since when the drug is in the upper digestive tract, it absorbs water, thereby almost completely turning into gel (i.e., the degree of gelation is at least 70%, preferably not lower than 75% and most preferably not lower than 80%), and moves to the lower the digestive tract, during which the surface of the drug undergoes erosion and as the destruction continues, the drug is released, the drug is continuously and completely released and absorbed. As a result of this, a sustained release occurs, even in the lower part of the digestive tract, which contains a small amount of water. In a specific case, if the degree of gelation is below about 70%, a sufficient release of the drug will not be achieved and there is a chance of a decrease in the bioavailability of the drug (EP 1205190 A1).

As used herein, the term “upper digestive tract” refers to the portion from the stomach to the duodenum and jejunum, and “lower digestive tract” refers to the portion from the ileum to the colon.

In order to achieve a higher degree of gelation, the composition may also include a hydrophilic base. There are no particular restrictions on this hydrophilic base as long as it can dissolve before the hydrogel-forming polymer substance mentioned above forms a gel. In particular, the amount of water required to dissolve 1 g of this hydrophilic base is preferably 5 ml or less (at 20 ± 5 ° C), more preferably 4 ml or less (at the same temperature).

Examples of such a hydrophilic base are water-soluble polymers such as polyethylene glycol (e.g. Macrogol 4000, Macrogol 6000 and Macrogol 20000, all of which are trademarks of Nippon Oil and Fats Co.), polyvinylpyrrolidone (e.g. PVP ^® K30, which is a trade name of BASF ), sugar alcohols such as D-sorbitol, xylitol and the like, saccharides such as sucrose, maltose, lactulose, D-fructose, dextran (e.g. Dextran 40), glucose and the like, surfactants such as polyoxyethylene hydrogenated castor oil (e.g. Cremophor ^® RH40 (manufactured by we are BASF), HCO-40, HCO-60 (manufactured by Nikko Chemicals), polyoxyethylene-polyoxypropylene glycol (for example, Pluronic ^® F68, which is the trade name of Asahi Denka), etc. Polyethylene glycol, sucrose and lactulose are preferred. of which polyethylene glycol is most preferred (in particular Macrogol 6000.) This kind of hydrophilic base can be used alone, or a mixture of two or more types of the hydrophilic base can be used.

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

Preferred excipient combinations include PAA / PEO / PEG. The ratio of PAA to PEO is preferably 1: 0.5, 1: 1 or 1: 5. A more preferred amount of PEG is from 5 to 60% by weight, based on the total preparation.

Preferred excipient combinations also include PAA / carrageenan / PEO / PEG. The ratio of PAA to carrageenan is preferably 1: 0.5, 1: 1 or 1: 5. The ratio of the sum of PAA and carrageenan to PEO is preferably 1: 0.5, 1: 1 or 1: 2. A more preferred amount of PEG is from 5 to 60% by weight, based on the total preparation.

The composition may also include one positively charged polymer or combinations of such polymers, which include, but are not limited to, polyethyleneimine, chitosan, polyvinylpyridinium bromide and polydimethylaminoethyl methacrylate.

Depending on the viscosity of the polymer (s), the polymer material may form a matrix comprising the active ingredient. For example, a polymer having a viscosity of at least 1000 cps in a 1% aqueous solution is particularly preferred due to its ability to form a matrix.

By applying the method of oral administration of the composition of the present invention, a sustained release of a micelle-forming drug can be achieved.

III. Other tablet modifications

Modification of the drug release through the tablet matrix of the present invention can be carried out by any known method, such as, for example, applying various coatings, for example, ion-exchange complexes, for example, Amberlite IRP-69. The tablets of the invention may also include or be administered together with gastrointestinal motility (GI) reducing agents. The active agent can also be modified to produce a prodrug as a result of chemical modification of a biologically active compound that will release the active compound in vivo by enzymatic or hydrolytic cleavage, etc. Additional layers or coatings can act as diffusion barriers, providing additional means for controlling the speed and coordination over time of drug release.

IV. Additives to the composition

If desired, the preparation of the present invention may include suitable amounts of other pharmaceutically acceptable additives, such as indifferent excipients (e.g. lactose, mannitol, potato starch, rice starch, corn starch and crystalline cellulose), binding agents (e.g. hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose and methylcellulose) ), swelling agents (e.g., carboxymethyl cellulose and calcium carboxymethyl cellulose), lubricants (e.g., stearic acid, stearate lysium, magnesium stearate, talc, magnesium metasilicate-aluminate, calcium hydrogen phosphate and anhydrous calcium hydrogen phosphate), plasticizers (e.g., aqueous silica, light anhydrous silicic acid and dried aluminum hydroxide gel), dyes (e.g., yellow sesquioxide and sesquioxide ), Surfactants (e.g. sodium lauryl sulfate and sucrose fatty acid ester), coating agents (e.g. zein, hydroxypropyl methylcellulose and hydroxypropyl cellulose), buffering agents (e.g. sodium chloride, magnesium chloride, citric acid lots, tartaric acid, dibasic sodium phosphate, monobasic sodium phosphate, calcium hydrogen phosphate, ascorbic acid), perfumes (e.g. 1-menthol, peppermint oil and fennel oil) and preservatives (e.g. sodium sorbate, potassium sorbate, methyl ester p- benzoic acid and ethyl benzoate).

V. Fabrication

The preparation of the present invention is a solid preparation of a certain form, which can be made using any conventional methods. Typical methods include, for example, manufacturing methods using compression molding tablets. These methods include mixing and, if necessary, granulating the active agent, charged polymers and, if necessary, additional additives and pressing-molding the resulting composition (composition). Alternative methods include, for example, a capsule compression filling method, an extrusion molding method comprising melting the mixture and setting the molten mixture, an injection molding method, and the like. Any treatment may also be carried out to create a coating, for example sugar coating.

The following examples are intended to illustrate but not limit the present invention.

EXAMPLES

Test Method 1

This test method illustrates the basic method of manufacturing the compositions of the present invention, as well as measuring the release of drugs.

Several different formulations with various drugs were made. The drugs are manually mixed with excipients in a mortar and pressed into 400 mg tablets using a Carver press or an Oil press with an applied pressure of 70 kg / cm ² . A rounded tooling with a flat surface with a diameter of 11 mm was used.

Materials

Carbopol 971 (BF Goodrich); Polyox 303 (Union Carbide); two types of carrageenan, Viscarin P 109 and Gelcarin (FMC); Xantural ™ 180 (Monsanto Pharmaceutical Ingredients), Keltone LVCR Xanthan Gum (Monsanto Pharmaceutical Ingredients); Chitosan sodium alginate (M.W. International, Inc.); Macrogol 6000 (Nippon Oil and Fats Co.); Methocel K100M (The Dow Chemical Company); hydroxypropyl methylcellulose (HPMC); Cellulose Gum 12M31P TP (Hercules); sodium carboxymethyl cellulose (CMC); and dextran sulfate (Sigma).

Methods

In vitro drug release is measured in in vitro dissolution experiments. These studies were carried out using a USP (United State Pharmacopoeia) II device at a blade speed of 100 rpm in 1000 ml of solvent medium for Examples 1-10. Drug release is measured using either Artificial Gastric Medium (SGF), pH 1.2, or Artificial Gut Medium (SIF), pH 7.5, which are prepared according to the USP without enzyme addition. In all experiments, tablet weights were used. At certain intervals, the sample is taken from the container and analyzed on a UV-visible spectrophotometer at a wavelength of 240 nm.

Example 1

This example illustrates that the release rate of a drug is not correlated with the solubility of the drug, indicating that a specific interaction affects the release rate.

The behavior of the release of a large group of basic well-soluble drugs (10 wt.% Drugs) from matrix tablets obtained by direct compression using a mixture of polyacrylic acid / polyethylene oxide (PAA / PEO in a ratio of 1: 1.5) is studied under conditions of modified artificial intestinal environment (SIF). The release rate is characterized using t ₅₀ (time to release 50% of the drug from the matrix into the solution) (Fig. 1). The research results are presented in table 1, which summarizes the properties of the drug and the rate of release.

Table 1. Characteristics of Model Medicines Title Like Weight Solubility mg / ml T ₅₀ logP Pyridoxine HCl 205.64 222 four -1.9 Pseudoephedrine HCl 201.73 ~ 250 four 1,0 Zevimelin HCl 244.79 766 4,5 1,1 Ranitidine HCl 350.91 ~ 200 eleven 1.3 Diphenhydramine HCl 291.9 1000 fifteen 3.4 Diltiazem HCl 450.98 800 eighteen 3.6 Doxylamine succinate 388.8 1000 23 2,5 Tramadol HCl 299.8 > 1000 31 2,5 Amitriptyline HCl 313.9 500 57 4.8 Chlorpromazine HCl 354.4 400 56 5,4 Imipramine HCl 332.9 500 58 4,5 Benoxinate HCl 344.9 1000 22 4.0

Equally charged drugs have significantly different release profiles in the modified SIF, which do not correlate with drug solubility (FIG. 1, Table 1). Therefore, it can be concluded that electrostatic interaction alone does not in itself lead to a sustained release of soluble drugs.

Example 2

This example illustrates that the logP of a drug can be used to predict whether sustained release will be achieved using the composition of the present invention. The ability to predict drug release behavior based on its logP characteristic is one of the key advantages of the present invention.

The ability of a drug to bind to any polyelectrolyte depends on its critical micelle concentration (CMC). However, since the value of CMC is rarely known for drugs, an attempt was made to relate the rate of release to the properties of the drug, which are usually used to characterize it. For drugs that were used in the above release experiments (Table 1), various parameters are analyzed, in particular molecular weight, solubility, pKa, logP, logD and surface tension, from the point of view of their correlation with the time of release. It turned out that logP (distribution coefficient of the uncharged form of the drug between octanol and water) shows a close to linear relationship with T ₅₀ (figure 2). logP is closely related to CMC. Indeed, between logP and CMC was revealed almost linear relationship (figure 3). The logP and CMC values for different drugs were taken from Attwood publications.

Example 3

This example illustrates that sustained release for continuously positively charged molecules can be achieved using a mixture of PAA / PEO excipients (1: 1.5).

The following positively charged molecules are tested: benzethonium chloride and betanechol chloride having one positive charge each; thiamine mononitrate and thiamine hydrochloride, each having two positive charges; and betaine, which is a dipole (figure 4). Although thiamine HCl showed a relatively rapid release, all other drugs showed sustained release at different rates (Table 2).

Table 2. Characteristics of positively charged drugs and T ₅₀ Title Solubility mg / ml T ₅₀ h T ₁₀ h Comments Triamine mononitrate 300 fourteen one Two positive charges Thiamine HCl 1000 7.5 one Two positive charges Betaine 650 22 6 Dipole Betanechol chloride 1700 55 10 Forms an insoluble complex with PAA Benzetonium chloride 1000 25 Forms an insoluble complex with PAA

These results show that, even if the drug does not have strong hydrophobic groups, specific interaction with charged polymer excipients still remains possible (see, as an example, betanechol chloride), unless the drug carries a constant positive charge. On the other hand, the structure of the drug and the position of the charge (see thiamine HCl) can play an important role in the ability to interact with polymer carriers. The location in the thiamine charges in the center of the molecule (figure 4) can cause micelle formation.

Example 4

This example illustrates that oppositely charged drugs and polymer excipients are critical for prolonging drug release. As shown in FIG. 5, well-soluble negatively charged drugs, cefazolin sodium and cefmatazole sodium, diffuse from the negatively charged PAA / PEO matrix with a T ₅₀ of approximately 5 hours without achieving sustained release.

Example 5

This example demonstrates the effect of the fluid environment on drug release profiles for PAA / PEO mixtures (1: 1.5).

The previous experiments described in examples 1-4 were carried out under conditions of artificial intestinal medium (SIF) in which PAA was ionized. To assess the kinetics of release under gastric conditions, the dissolution of various types of soluble drugs is carried out in a modified artificial gastric medium (SGF). Table 3 compares the T ₅₀ values in SGF and SIF for different drugs.

Table 3. T ₅₀ values in SGF and SIF Drug name T ₅₀ to SGF, h T ₅₀ to SIF, h Diltiazem HCl 8 eighteen Tramadol HCl 8 31 Diphenhydramine citrate 12 25 Betanechol chloride 24 55 Betaine hydrochloride four 22 Thiamine mononitrate 3 fourteen

As shown in table 3, the release time in SIF is significantly longer than in SGF. It is obvious that in low pH environments, PAA ionization is largely suppressed. This can prevent the formation of cooperative bonds between PAA / PEO and the drug. Another possible reason for the short release times in SGF is that the formation of hydrogen-bonded polymer complex between the electronegative oxygen atom of PEO and the carboxyl group of PAA at low pH blocks the interaction of carboxyl groups with the drug.

Example 6

This example illustrates combinations of polymer excipients that provide sustained release under both SGF and SIF conditions.

Evaluation of many polysaccharides

Drug release rates were tested for seven different polysaccharides (carrageenan, xanthan gum, sodium alginate, chitosan, HPMC (hydroxypropyl methylcellulose), CMC-Na) in combination with PAA, at a content of 25 wt.% Diltiazem HCl (DI) (Fig. 6) . The results show that a combination of PAA with carrageenan can provide the slowest release of drug in SGF. This effect is probably due to the strongly acidic nature of the functional groups of carrageenan (SO ₄ ^- ), which remains negatively charged even at low pH and makes possible the interaction between carrageenan and the drug.

Assessment of other sulfated polymers

Various types of carrageenan are used, as well as dextran sulfate, in combination with PAA or PEO at a 1: 1 ratio and Diltiazem HCl (25 wt.%) And the release rate in SGF and SIF is measured. Sustained release was observed for all combinations containing sulfated polymers (Fig.7).

Additional analysis of the effects of PAA substitution on PEO

When PAAs in PAA / carrageenan (1: 1) are replaced by high molecular weight PEO, the release profiles for PAA / carrageenan (1: 1) and PEO / carrageenan (1: 1) in SGF overlap for approximately 6 hours (Fig. 8a ) After this period of time, matrix erosion causes a more rapid release of PEO / carrageenan from the matrix. In contrast, in SIF, the PAA / carrageenan composition exhibits a slower drug release compared to the PEO / carrageenan composition over the entire time period (Fig. 8b). Thus, the combination of PAA and carrageenan can provide the best in vitro drug release characteristics in both SGF and SIF.

Comparison of release rates for PAA / carrageenan in SGF and SIF.

Figure 9 shows that the release of DI (25 wt.%) From the PAA / carrageenan (1: 1) matrix is linear in both SGF and SIF and that the release rates are the same in both environments. The solubility test for samples with change of media after 2 hours found a linear release profile, very close to the profiles in Fig.9.

Example 7

This example illustrates that the optimal composition of the polymer filler depends on the environment (figure 10).

For a composition containing 25 wt.% DI (diltiazem HCl), the lowest release rate in SGF was achieved for the PAA / carrageenan composition (1: 1). In SIF, the release rate decreased as the amount of PAA in the composition increased.

Interestingly, other optimal compositions were observed for compositions with a high DI content of 60 wt.%. In SGF, the release rate of the drug decreased with increasing carrageenan content, and in SIF, the release rate of the drug was practically independent of the ratio of the components of the excipient (Fig. 11).

Based on these observations, we believe that the nature of the release is most likely determined by the stoichiometry of the drug-excipient complex in various media.

Example 8

This example illustrates that an increase in drug content has a negligible effect on the release rate in SIF for drug content up to 60% by weight. In SGF, the increase in release rate is relatively small when the drug content is up to 50 wt.% (Fig. 12).

Example 9

This example illustrates the excellent ability of the compositions of the present invention to extend the release of the drug.

The release of DI (25%) from the PAA / carrageenan matrix (1: 1) is compared with the previously described compositions containing PAA and carrageenan (Bonferoni et al., AAPS Pharm. Sci. Tech, 1 (2) article 15 (2000); Bubnis et al., Proceed. 1nt'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 4777033 ; EU Patent 0205336 B1).

Carrageenan-containing systems described in the literature include carrageenan / hydroxypropyl methyl cellulose (HPMC) and carrageenan / CMC. All matrices were prepared in the same way as the Viscarin 109 / second polymer mixture (1: 1). PAC / carrageenan (1: 1) matrix formulations showed significantly slower release of DI in both SGF and SIF (FIG. 13).

A PAK / HPMC (hydroxypropyl methyl cellulose) sustained release system is described (US Pat. No. 4,777,033, EU Patent No. 0205336 B1).

Compositions with a PAA / carrageenan matrix (1: 1 and 3: 2) showed a significantly slower release of DI compared to PAA / HPMC (1: 1) serving as a control in SGF (Fig. 14), although in SIG the drugs showed a prolonged release of the drug with a T ₅₀ above 20 hours

When the amount of drug in the system is increased to 60 wt.%, The rate of release from the PAA / carrageenan system remains the lowest compared to all other competing systems (Fig. 15).

Example 10

This example compares the release rates of various drugs for the parent formulation (PAA / PEO) and the novel PAA / carrageenan formulations.

The release rates of various drugs that previously showed interaction with the PAA / PEO matrix are compared with the release rates from the PAA / carrageenan matrix (1: 1). It turned out that most drugs exhibit prolonged, close to zero order kinetics, release from the PAA / carrageenan matrix. Drug release from the PAA / carrageenan matrix was generally slower in both SGF and SIF compared to release from the PAA / PEO matrix, although this was not observed for all drugs.

By way of illustration, Table 4 below represents T ₅₀ values (release time) in SIF. In this study, the composition of PAA / PEO (1: 1.5) contained 10% of the active substance, and the composition of PAA / carrageenan (1: 1) contained 25% of the active substance.

Table 4. T ₅₀ values in SIF Medicine PAK / PEO PAK / car logP Thiamine HCl 7.5 7.5 Ranitidine HCl eleven fifteen 1.3 Diphenhydramine HCl fifteen 8 3.4 Diltiazem HCl eighteen 21 3.6 Benoxinate HCl 22 23 5.2 Naratriptan HCl 22 25 1.8 Dioxylamine succinate 23 22 2,5 Tamsulosin HCl 26 25 2.24

Test Method 2

Dissolution test

In vitro drug release is measured in in vitro dissolution experiments. These studies are carried out using the Dissolution Test Method II (paddle method) in accordance with the Japanese Pharmacopoeia XIV (hereinafter referred to as “JP”) at a blade speed of 200 rpm in 900 ml of solvent medium. Drug release is evaluated using either JP disintegration analysis fluid 1 (hereinafter “JP 1 ^st fluid”), pH 1.2, or JP disintegration analysis fluid 2 (hereinafter “JP 2 ^nd fluid”), pH 6, 8. In the experiments do not use sinkers for tablets. At certain intervals, the sample is taken from the container and analyzed on a UV-visible spectrophotometer at a wavelength of 250 nm.

Gel test

A gel test is performed using JP 1 ^st fluid and JP 2 ^nd fluid as follows. The test tablet is moistened for 2 hours in an analysis medium at 37 ° C, the gel layer is removed and the core, non-gelled portion is taken, which is dried for 5 days at 40 ° C in a dryer and the dried core is weighed (W _obs ). The gelation degree of the compositions is calculated using equation 1. The value obtained by subtracting the core weight from the initial tablet weight (W _initial ) and dividing by the initial tablet weight is multiplied by 100 to calculate the gelation degree in% (G).

Used in this application, the term "degree of gelation" refers to the percentage of tablets that have undergone gelation. The choice of a method for calculating the degree of gelation is not particularly significant, and the method described below can be considered as an example.

Thus, the tablet is moistened for a predetermined time, after which the volume (or mass) of the non-gelled portion is measured and the obtained value is subtracted from the volume (or mass) of the tablet before starting the test.

The degree of gelation (G,%) = (1- (W _obs / W _initiai )) × 100 (equation 1)

W _obs is the mass of the part that has not undergone gelation after the start of the test,

W _initial - the mass of the drug before the test.

Example 11

This example illustrates the effect of an additional amount of polymers having a charge opposite to that of a micelle-forming drug on drug release profiles.

Use different amounts of PAA in combination with a mixture of PEO / PEG (1: 1) at a ratio of 1: 0 (wt.% PAA to the total amount is 50), 1: 1 (wt.% PAA to the total amount is 25), ratio 3: 1 (wt.% PAA to the total amount is 37.5), a ratio of 1: 3 (wt.% PAA to the total amount is 12.5) or 1: 9 ratio (wt.% PAA to the total amount is 5) , with contents of 50 wt.% Diltiazem HCl. A composition comprising PEO / PEG at a 1: 1 ratio without PAA containing 50 wt.% Diltiazem HCl was prepared as a control. The drug release rate was evaluated in JP 2 ^nd fluid in accordance with the method described in Test Method 2 (FIG. 16). Sustained release of the drug was achieved for all preparations containing PAA, even in the case of the content of such a small amount of PAA as 5 wt.% Of the total preparation. The results also showed that the drug release rate decreases with an increase in the amount of PAA due to the PEO / PEG mixture (1: 1).

The effects of additional PAA / carrageenan mixtures on drug release profiles are also being studied. The ratio of PAA and carrageenan and the ratio of PEO / PEG are fixed equal to 1: 1. Different amounts of PAA / carrageenan (1: 1) are used in combination with PEO / PEG (1: 1) at a ratio of 1: 0 (wt.% PAA and carrageenan to the total amount are 25 and 25, respectively), at a ratio of 3: 1 ( wt.% PAA and carrageenan to the total amount is 18.75 and 18.75, respectively), 1: 1 (wt.% PAA and carrageenan to the total amount is 12.5 and 12.5, respectively), with a ratio of 1: 3 ( wt.% PAA and carrageenan to the total amount is 6.25 and 6.25, respectively) with a content of 50 wt.% Diltiazem HCl (Fig.7). As a control, a composition is prepared containing PEO / PEG at a 1: 1 ratio without PAA / carrageenan with a content of 50 wt.% Diltiazem HCl. The results also showed that the release rate of the drug decreased with an increase in the amount of PAA / carrageenan mixture. Thus, the release rate of the drug can be controlled by varying the additional amount of polymer (s) having (their) charge opposite to the charge of the micelle-forming drug.

Example 12

This example illustrates the excellent gelling ability of the compositions of the present invention.

When conducting a gel test for preparations containing PAA / carrageenan / PEO / PEG at a ratio of 1: 1: 0: 0, 1: 1: 1: 1 or 1: 1: 3: 3, and containing 50 wt.% Diltiazem HCl , in accordance with the method described in Test Method 2, the degree of gelation of these compounds in JP 1 ^st fluid was 75.0, 80.8 and 80.7%, respectively.

In the case of a preparation containing PAA / PEO / PEG at a ratio of 1: 9: 9, the degree of gelation in JP 1 ^st fluid and in JP 2 ^nd fluid was 78.0 and 76.9%, respectively.

Example 13

Pharmacokinetic studies in beagle dogs

Nine male beagle dogs weighing 9.3 to 13.4 kg are deprived of food 18 hours before administration. After oral administration of a test tablet containing 200 mg of Diltiazem HCl with 30 ml of water, the dogs are allowed free access to water, but food is refused until the last blood sample has been taken. Blood samples are taken at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours after administration of the tablet. After that, the plasma is separated in a centrifuge and subjected to quantitative analysis in an HPLC system with UV detection.

Example 14

This example illustrates the effect of the degree of gelation of drugs on the sustained release of drugs in vivo.

Two preparations (Gelation degree in JP 1 ^st fluid: Preparation A: 63.4% and Preparation B: 77.6%) containing various amounts of PAA / PEO / PEG, as well as 200 mg of Diltiazem HCl, were used for pharmacokinetic studies on beagle dogs. The results showed that Preparation B gave a sustained release of the drug both in the lower digestive tract and in the upper digestive tract, while Preparation A released little drug in the lower digestive tract.

For a more detailed comparison of the in vivo drug release between the two drugs, the area under the plasma drug concentration versus time curve is calculated from 0 to 24 hours as a function of the amount of in vivo drug absorbed. The results showed that this area for Preparation B (7541.2 ± 2153.7 ng · h / ml) was significantly larger than the area for Preparation A (4346.1 ± 1811.6 ng · h / ml), which confirmed the insufficient release of the drug in vivo for a preparation with a lower degree of gelation.

All publications, patents and patent applications referred to in this application are included in the description by reference in their entirety and for all purposes. Although the invention has been described with reference to preferred embodiments and related examples, the scope of the present invention is not limited to these described embodiments. It should be apparent to those skilled in the art that modifications and adaptations of the invention described above can be made without departing from the spirit and scope of the invention, which is defined and described in the appended claims.

Claims (20)

1. An oral sustained release pharmaceutical composition comprising (I) a micelle-forming water-soluble drug, said drug being the main one and having a positive charge at physiological pH, and (II) at least one polymer having an opposite charge selected from the group consisting of polyacrylic acid, carboxymethyl cellulose, xanthan gum, gellan gum, guar gum, dextran sulfate and carrageenan; (Iii) polyethylene oxide; and if necessary including (Iv) a hydrophilic base. 2. The pharmaceutical composition according to claim 1, wherein said at least one polymer is polyacrylic acid, carrageenan, or a mixture thereof. 3. The pharmaceutical composition according to claim 1, in which the degree of gelation of the composition is at least 70%. 4. An oral sustained release pharmaceutical composition comprising (I) a micelle-forming drug, which is a water-soluble drug having a positive charge at physiological pH, (Ii) polyacrylic acid; (Iii) polyethylene oxide; and if necessary including (Iv) a hydrophilic base. 5. The pharmaceutical composition according to claim 4, in which the degree of gelation of the composition is at least 70%. 6. The pharmaceutical composition according to claim 4, in which the hydrophilic base mentioned above is represented by one, two or more species having such a solubility that 5 ml or less of water is required to dissolve 1 g of the base. 7. The pharmaceutical composition according to claim 6, in which the aforementioned hydrophilic base is represented by one, two or more species selected from the group consisting of polyethylene glycol, sucrose and lactulose. 8. The pharmaceutical composition according to claim 4, which further comprises (V) at least one polymer containing a sulfate group. 9. The pharmaceutical composition of claim 8, wherein said polymer is selected from the group consisting of carrageenan and dextran sulfate. 10. The pharmaceutical composition of claim 8, in which the degree of gelation of the composition is at least 70%. 11. The pharmaceutical composition of claim 8, wherein said hydrophilic base is represented by one, two, or more species having such a solubility that 5 ml or less of water is required to dissolve 1 g of the base. 12. The pharmaceutical composition according to claim 11, in which the hydrophilic base is represented by one, two, or more species selected from the group consisting of polyethylene glycol, sucrose and lactulose. 13. The pharmaceutical composition according to claim 4, which contains from about 10 to 75 wt.% The named medicinal product, from about 5 to about 50 wt.% Polyacrylic acid, from about 10 to about 90 wt.% Polyethylene oxide and from about 5 up to about 60 wt.% hydrophilic base. 14. The pharmaceutical composition of claim 8, which contains from about 10 to 75 wt.% The named medicinal product, from about 5 to about 50 wt.% Polyacrylic acid, from about 10 to about 90 wt.% Polyethylene oxide, from about 5 up to about 60 wt.% hydrophilic base and from about 5 to about 50 wt.% polymer having a sulfate group. 15. A method of prolonging the release of a micelle-forming drug, comprising oral administration of a pharmaceutical composition containing (I) a micelle-forming drug, which is a water-soluble basic drug having a positive charge at physiological pH, (Ii) polyacrylic acid; (Iii) polyethylene oxide, and further comprising (Iv) a hydrophilic base, thus prolonging the release of said micelle-forming drug. 16. The method according to clause 15, in which the above composition further comprises (V) at least one polymer containing a sulfate group; thus prolonging the release of said micelle-forming drug. 17. The pharmaceutical composition according to claim 1, additionally containing a hydrophilic base, in which the aforementioned hydrophilic base is represented by one, two or more species having such solubility that 5 ml or less of water is required to dissolve 1 g of the base. 18. The pharmaceutical composition according to claim 1 or 4, in which cooperative interactions between the specified oppositely charged polymer and the specified micelle-forming drug prevent the rapid diffusion of the drug from the composition. 19. The pharmaceutical composition of claim 18, wherein said cooperative interactions are hydrogen bonds. 20. An oral sustained release pharmaceutical composition comprising (I) a micelle-forming water-soluble drug, which is the main drug and has a positive charge at physiological pH, (II) a combination of two polymers having an opposite charge selected from the group consisting of polyacrylic acid, carboxymethyl cellulose, xanthan gum, gellan gum, guar gum, dextran sulfate and carrageenan, wherein one of the polymers is dextran sulfate or carrageenan; (Iii) polyethylene oxide; and if necessary including (Iv) a hydrophilic base.

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