KR100912680B1 - Controlled release formulation - Google Patents

Abstract

The present invention provides a weakly basic drug which exhibits pH dependent solubility as an active ingredient; Provided as a matrix supporting the active ingredient, a matrix layer comprising a swellable hydrophilic polymer, a pH dependent polymer and an organic acid.

The formulations of the present invention can be prepared simply and economically, and are pH independent of weak base drugs exhibiting pH dependent solubility such as doxazosin at the time of in vivo administration, and the release pattern of the drug is not affected by the digestive tract peristalsis and releases to zero order. It can maintain effective blood concentration continuously for 24 hours to exert a certain effect.

pH dependent solubility, doxazosin, zero order release, controlled release

Description

Controlled Release Formulations

1 shows the release of mesylic acid doxazosin in a comparative formulation that does not contain citric acid.

Figure 2 shows the release of mesylic acid doxazosin in the formulation of the present invention.

Figure 3 shows the release of mesylic acid doxazosin in the formulation of the present invention in an elution medium having various pHs.

Figures 4a, 4b, 4c, 4d show the release of mesylic acid doxazosin in the formulation of the present invention and KaduraXL in different elution media of pH 1.2, pH 4.0, pH 6.8, distilled water, respectively.

Figure 5 shows a comparison of the release of mesylic acid doxazosin in the formulation of the present invention containing fumaric acid and Kadura XL.

6 shows the effect of citric acid content on the release of mesylic acid doxazosin from the formulation of the present invention.

Figure 7 shows the effect of tableting pressure on the release of mesylic acid doxazosin from the formulation of the present invention.

Figure 8 shows the effect of the stirring rate on the release of mesylic acid doxazosin from the formulation of the present invention.

Figures 9a and 9b are shown by comparing the release of mesylic acid doxazosin in the formulation of the present invention and Kadura XL at the stirring speed of 50rpm, 100rpm, respectively.

The present invention relates to a controlled release formulation of a weakly basic drug exhibiting pH dependent solubility, such as doxazosin, in particular independent of the pH value of the entire digestive tract, regardless of the peristalsis of the digestive tract, for at least 8 to 24 hours. A controlled release formulation capable of releasing.

Sustained release formulations that can sustain drug efficacy with once or twice daily administration have been developed in terms of improving patient compliance. Sustained release of such drugs may be attempted at the synthetic stage of the compound itself, such as by altering the skeleton of the compound so that drug efficacy can be sustained with once or twice daily administration, or controlled by the design of controlled release formulations through changes in formulation. Many attempts are being made. Controlled release systems include, for example, controlled release by a controlled release coating layer or controlled diffusion of drug by a matrix, controlled release of drug by corrosion of the matrix, and time dependent release controlled by which the drug is released after a certain delay time. In order for sustained-release formulations to maintain effective blood levels continuously for 24 hours in vivo and to exhibit a certain effect, they exhibit zero release pattern in vitro, resulting in constant release and absorption in the digestive tract. Should happen.

Basic drugs such as doxazosin exhibit pH dependent solubility. For example, it is known that the solubility of mesylic acid doxazosin, which is used as a general administration active ingredient of doxazosin, is 237 ± 7.31 μg / ml at pH 1.2 and 13.87 ± 4.85 μg / ml at pH 6.8. Therefore, basic drugs exhibiting pH dependent solubility such as mesylic acid doxazosin exhibit different release patterns according to pH change in the digestive tract upon oral administration. That is, the contact rate with the high pH small intestine changes from the highly soluble ionized form to the less soluble base form, resulting in a lower release rate of the drug through the base, resulting in a faster release profile in the gastrointestinal pH of 2.0 to 4.0. In contrast, the small intestine, pH 5.0 to 7.5, exhibits a relatively slow release profile. Since the absorption of the drug generally depends on the rate of release of the drug, the difference in pH-dependent release profile in the digestive tract also reduces or irregularizes the absorption of the drug in the body and thus in terms of the bioavailability of the drug and also the blood level of the drug. It causes problems such as inducing a sudden fluctuation of. Sudden fluctuations in the blood levels of these drugs have the problem of having side effects such as orthostatic hypotension in the case of therapeutically active drugs such as doxazosin. If contained, its severity is higher.

As described above, in the case of drugs showing pH dependent solubility such as doxazosin, in vitro which can maintain effective blood concentration continuously for a certain time regardless of patient side variables such as pH difference depending on the organs of the digestive tract and the presence of food. There is a need for a controlled release formulation that exhibits a zero order release profile.

In response to this need, Alsa's U.S. Pat.Nos. 4,765,989 and 4,837,111 disclose two layers, a push layer comprising an osmotic agent and a swellable hydrophilic polymer, and an active drug layer comprising doxazosin and a swellable hydrophilic polymer. An osmotic tablet is disclosed, which is surrounded by a semipermeable membrane. The tablet is a small hole in the active drug layer with a laser drill to release the doxazosin. When the tablet is administered into the body, the push layer acts as a pump to push out the doxazosin through the orifice. In addition, Pfizer's U.S. Patent No. 5,612,059 discloses an osmotic system using an asymmetric membrane for controlled release of doxazosin, and marketed doxazosin-containing osmotic double tablets under the trademark Kadura XL. The osmotic preparations containing doxazosin use the pressure generated by osmotic pressure in the tablet to exhibit zero release pattern in the digestive tract through micropores of the correct size, enabling uniform release over a long period of time, pH independent, and gastrointestinal tract. The release pattern of the drug is not affected by the peristaltic movement, but the manufacturing process is more complicated than the matrix type, and the skilled manpower is required for manufacturing, so that the overall manufacturing cost is high and a lot of time is required for manufacturing. There is a problem. In addition, such an osmotic release modulating agent should be prepared constantly because the osmotic release control mechanism itself is released by a highly sophisticated mechanism of action. Otherwise, it may be released due to breakage in vivo or without reproducible release. There is a problem that may indicate a pattern.

In addition, as a controlled release formulation for the matrix type doxazosin, a formulation comprising a core layer comprising an active ingredient such as doxazosin and HPMC, an intermediate coating layer and a coating layer comprising an enteric polymer and hydrophilic silicon dioxide, and additionally PEO is disclosed. (US Pat. No. 6,368,628). However, the formulation can release the active ingredient without the effect of food, but 99% of the drug is released in 12 hours, it does not release for a sufficient time, and even in the release aspect does not exhibit a zero release pattern have.

The present invention is prepared by a simple process for a weak base drug showing pH dependent solubility such as doxazosin, is independent of the pH value of the entire digestive tract, irrelevant to the gastrointestinal peristalsis, and exhibits a zero-order release pattern for 24 hours It is an object of the present invention to provide a controlled release agent that can maintain a constant blood concentration and exert a certain effect.

In order to achieve the above object,

Weakly basic drugs which exhibit pH dependent solubility as active ingredient; Provided as a matrix supporting the active ingredient, a matrix layer comprising a swellable hydrophilic polymer, a pH dependent polymer and an organic acid.

Controlled release formulations of the present invention are suitable for swelling hydrophilic polymers such as organic acids, polyethylene oxide (PEO), and pH-dependent polymers in order to be able to release pH-dependent, active substances exhibiting pH-dependent solubility in a zero order pattern. It is characterized by using a matrix prepared in combination.

Hereinafter, the present invention will be described in detail.

The swellable hydrophilic polymer of the present invention uses a polymer such as polyethylene oxide (PEO), hydroxypropyl methyl cellulose acetate succinate (HPMCAS), methyl cellulose (Methylcellulose), hydroxypropyl methyl cellulose, and the like. . The swellable hydrophilic polymer plays an important role in the zero release of the active ingredient in the formulation of the present invention. The swellable hydrophilic polymer of the present invention forms a swelling layer, a diffusion layer, and an erosion layer when contacted with a digestive fluid such as gastric or intestinal fluid, and maintains the drug release rate at a constant rate through the swelling layer and the erosion layer. That is, when the controlled release agent is exposed in the body, the digestive fluid penetrates into the matrix, and the swelling of the matrix layer rapidly progresses to form a gel barrier to suppress drug release, and then the matrix layer gradually erodes the active ingredient. Will emit. This initial swelling process in the swelling / erosion process inhibits the early release of the active ingredient in the gastrointestinal tract, and the late erosion process offsets the decrease in release of the active ingredient in the small intestine. The swellable hydrophilic polymer is preferably used in an amount of 5 to 50 parts by weight, more preferably 20 to 50 parts by weight, based on 1 part by weight of the active ingredient.

As the swellable hydrophilic polymer of the present invention, polyethylene oxide (PEO) is particularly preferable. Polyethylene oxide (PEO) is a nonionic swellable hydrophilic polymer, in particular a linear form of unsubstituted ethylene oxide is preferred (e.g. Polyox WSR 303 (molecular weight: 7000000), Polyox WSR Coagulant (molecular weight: 5000000), Polyox WSR 301 (molecular weight: 4000000), Polyox WSR N-60K (molecular weight: 2000000), Polyox WSR N-12K (molecular weight: 1000000), and Polyox WSR 205 (molecular weight: 600000); manufactured by Dow Chemical Co., Ltd.) do). The polyethylene oxide is particularly preferably 1 × 10 ⁶ to 4 × 10 ⁶ Having molecular weight It is preferable that it is 1x10 <^6> -2 * 10 <^6> more preferably. If the molecular weight is 4 × 10 ⁶ or more, the gel is formed strongly, erosion is difficult, the swelling layer is thickened, the diffusion path in the matrix of the active ingredient is long, drug release is determined by swelling rather than erosion of the matrix layer drug release This irregularity has a problem, and when the molecular weight is 1 × 10 ⁶ or less, the reverse phenomenon is exhibited, there is a problem that the drug release is irregular. Therefore, when polyethylene oxide (PEO) having a molecular weight within the above range is used, the swelling / erosion process is well coordinated, and zero order release of the active ingredient is more possible.

The pH-dependent polymer is used as an auxiliary base for modifying an elution pattern, and is swelled but insoluble in a low pH solution such as gastric juice, and thus prevents burst release of the active ingredient in gastric juice. On the other hand, in high pH solutions such as small intestine, swelling and dissolution occur simultaneously, increasing the release rate of the active ingredient in the small intestine. The pH-dependent polymers are generally well known in the art, and for example, the following materials may be used. Alginic acid, sodium alginate, acrylic acid copolymers such as Eudragit, pectin, carrageenan, carboxymethylcellulose sodium, Kollidon  Vinyl acetate and vinyl pyrrolidone polymers, such as money and copolymers such as VA64 ^®, Methocel ^® and Aquacoat ^® and Tylose ^® and cellulose ethers, and cellulose ester, Keltro ^®, Rhodiel ^® and xanthan, chitosan, guar gum and arabic such as polyvinyl alcohol such as a polysaccharide or a modified polysaccharide, Mowiol ^®, such as gums, cellulose acetate phthalate, such as Aquateric ^®, mono, such as Cutina ^® -, di- and and triglycerides, mineral glycol waxes such as wax or shellac (Schellack) The same resin and the like, of which double alginic acid, sodium alginate, acrylic acid copolymer, pectin, carrageenan and carboxy methylcellulose sodium are preferred, and sodium alginate is particularly preferred. The pH-dependent polymer is used 3 to 15 parts by weight, more preferably 5 to 10 parts by weight based on 1 part by weight of the active ingredient.

The organic acid of the matrix layer modifies the pH-dependent release behavior of the active ingredient. That is, the micro pH environment in the matrix is kept acidic, increasing the solubility of the active ingredient even in high pH environments such as the small intestine, thereby increasing the release. The organic acid is selected from the group consisting of citric acid, fumaric acid, adipic acid, tartaric acid, succinic acid, ascorbic acid, maleic acid, malic acid, oxalic acid, malonic acid, benzoic acid and mandelic acid. Citric acid and fumaric acid are especially preferable, and citric acid is more preferable. The organic acid is used 1 to 30 parts by weight, more preferably 9 to 30 parts by weight based on 1 part by weight of the active ingredient.

As the active ingredient which can be used in the formulation of the present invention, a weakly basic drug having pH dependent solubility, doxazocin and its pharmaceutically acceptable salts are particularly suitable, and other tamsulosin And pharmaceutically acceptable salts thereof, paroxetine And pharmaceutically acceptable salts thereof, tolterodine and pharmaceutically acceptable salts thereof, venlafaxin and pharmaceutically acceptable salts thereof, and the like.

Doxazosin has the chemical name 4-amino-2- [4- (1,4-benzodioxane-2-carbonyl) piperazin-1-yl] -6,7-dimethoxyquinazoline as The preparation method and the like are described in US Pat. No. 4,188,390. Doxazosin or a pharmaceutically acceptable salt thereof is known as an alpha1-blocker that selectively antagonizes alpha1-adrenergic receptors to relax vascular smooth muscle and to treat hypertension and reduce urinary obstruction symptoms of benign prostatic hypertrophy.

[Formula 1]

Pharmaceutically acceptable salts of doxazosin include hydrochloride, bromate, iodide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartarate, bitartarate, succinate, maleate, gluconate Pharmaceutically acceptable acid addition salts thereof, such as acid salts, benzenesulfonate salts, P-toluenesulfonate salts and methanesulfonate salts, and the like, and are preferably methanesulfonate salts (mesylate salts).

The active materials may be in the form of physical mixtures dispersed directly in the matrix layer, or may be dispersed in the form of a solid solution, solid dispersion or granules.

The formulations of the invention can be formulated in a variety of forms by conventional methods. Tablets may be prepared by tableting, or may be formulated into powders, tablets, granules, etc. according to conventional methods, or filled into hard capsules in the form of powder or granules to prepare capsules. Although the formulation of the present invention will be described later, since the sustained release of the active ingredient is not disturbed according to the difference in the compression pressure, the preparation process can be easily produced by a simple direct method. These formulations may contain diluents (e.g. Avicel) in addition to the active ingredients.  Microcrystalline cellulose such as calcium phosphate, etc., lubricants for increasing fluidity (e.g. light silicic anhydride, talc, stearic acid and its metal salts), lubricants (stearic acid and its metal salts, hardened castor oil, non-wax) Waxes, such as these), etc. can be contained.

As described above, the formulation of the present invention exhibits a pH independent release pattern by using a combination of an organic acid, polyethylene oxide (PEO) and pH-dependent polymer as a matrix supporting the active ingredient. According to an embodiment of the present invention, the formulation of the present invention markedly improved the release rate of mesylic acid doxazosin even in the medium at pH 6.8, and exhibited a zero order release pattern over 8 to 16 hours regardless of the pH of the medium (experimental) Examples 1 and 2, see FIGS. 2 and 3).

In particular, the formulation of the present invention showed a similar release pattern in all pH ranges, compared with Kadura XL, which is a representative formulation of the controlled release formulation of doxazosin (see Experimental Example 3 and FIGS. 4A-4D), in particular It was confirmed that pH 6.8 exhibited a better zero-order release pattern than Kadura XL even at 16 to 24 hours (see FIG. 4c). Unlike the osmotic preparations such as Kadura XL, which has a complicated manufacturing process, it is simple and inexpensive to produce, but it is delayed time. It can be seen that the formulation is a zero release of the basic drug exhibiting pH dependent solubility over an interval of 16 to 24 hours.

It is common knowledge in the art that tableting pressure in the preparation of sustained-release tablets greatly affects the release pattern of the drug, but the dosage form of the present invention is almost different even if the tableting pressure in the manufacture of the tablet is different. Since it can not be produced (see Experimental Example 6 and Fig. 7), regardless of the tableting pressure, the intra-batch or inter-batch variation in the drug release rate (intra batch or inter batch variations) can be reduced to make the production very easy There is an advantage to this.

In addition, the formulation of the present invention was shown to have a small difference in the release rate according to the stirring speed in the same manner as the control formulation Kadura XL (see Experimental Example 7, 8 and 9), from which the formulation of the present invention is a gastrointestinal motility It can be seen that there is little difference in the release rate according to the present invention, which shows a constant and reproducible release pattern during the biological administration.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

<Example 1>

Mesyl acid doxazosin (manufactured by Sinoway, China) 4.85 mg per tablet, 130 mg of polyethylene oxide (manufactured by Dow, PEO WSR N12K), citric acid (manufactured by Sigma-Aldrich, Germany) 60 mg, sodium alginate (manufactured by Kibun, Japan ) 30 mg, Avicel PH 102 72.15 mg, and magnesium stearate 3 mg each were weighed, filled in a mixer, and mixed. The mixture was passed through a 500 μm mesh sieve and then compressed on a tablet press using normal pressure to prepare a doxazosin-containing sustained release tablet of the present invention.

Comparative Example 1

Comparative tablets were prepared in the same manner as in Example 1, except that Avicel PH 102 was 132.15 mg without adding citric acid.

<Example 2>

Doxazosin-containing sustained-release tablets were prepared in the same manner as in Example 1, except that citric acid and fumaric acid were used.

Experimental Example 1

The tablets prepared in Comparative Example 1 and the tablets prepared in Example 1 were subjected to a dissolution test according to the dissolution test method (paddle method, method 2) disclosed in the US Pharmacopoeia, and eluted for 24 hours at intervals of 2 hours. The amount of mesylic acid doxazosin thus obtained was measured according to the following analysis method and shown in FIGS. 1 (Comparative Example 1) and 2 (Example 1), respectively.

Elution device; Rotating paddle

volume; 900 ml

Elution medium: artificial gastric juice (pH 1.2), phosphate buffer (pH 6.8)

Eluent temperature: 37 ± 0.5 ℃

Speed: 75 rpm

Method: UV spectrometer (wavelength: 250 nm)

As shown in FIG. 1, the comparative tablet containing no organic acid citric acid shows a significant difference in the elution rate of the doxazosin in the medium at pH 1.2 and the medium at pH 6.8 and shows a pH-dependent release pattern. Can be. On the other hand, the formulation of the present invention, as can be seen in Figure 2, the dissolution rate is significantly improved even in the medium at pH 6.8, and exhibited a zero release pattern in both the medium of pH 1.2 and the medium of pH 6.8.

Experimental Example 2

In order to examine the pH effect of the medium on the release of the drug of the present formulation, for the preparation prepared in Example 1, the medium and distilled water of pH 1.2, pH 4.0, pH 6.8 to the method performed in Experimental Example 1 According to the dissolution test, the amount of mesylic acid doxazosin eluted for 24 hours at intervals of 2 hours was measured and shown in FIG.

Elution device; Rotating paddle

volume; 900 ml

Elution medium: distilled water, artificial gastric juice (pH 1.2), phosphate buffer (pH 4.0 and pH 6.8)

Eluent temperature: 37 ± 0.5 ℃

Speed: 75 rpm

Method: UV spectrometer (wavelength: 250 nm)

As shown in Figure 3, the release pattern of doxazosin was similar to each other in the medium of different pH, thereby confirming that the formulation of the present invention releases doxazosin independently of the pH of the medium.

Experimental Example 3

The release pattern of the formulation of the present invention was compared with Kadura XL, which is commercially available as a representative formulation of the controlled release formulation of doxazosin. The dissolution test was carried out according to the method carried out in Experiment 1 for the medium and distilled water of Kadura XL (containing 4 mg of doxazosin base) and pH 1.2, pH 4.0, and pH 6.8 for the preparation prepared in Example 1, The amount of mesylic acid doxazosin eluted for 24 hours at intervals of time was measured according to the following assay and shown in FIGS. 4A to 4D, respectively. In addition, the release pattern of doxazosin of the present formulation and the release pattern of doxazosin of Kadura XL were compared by calculating f _{2 according} to the following formula.

[Equation 1]

(Where n is the number of sampling and Rj and Tj are the percent elution of the reference and experimental drugs at j hours.)

f ₂ is It is calculated from 0 to 100. When f ₂ is 100, the reference drug and the test drug are used. Means that the emission profiles are exactly the same, and the more dissimilar they are, the more f ₂ Access to zero According to the Food and Drug Administration (FDA) and The European Agency for the Evaluation of Medicinal Products, f ₂ Indicative values of 50-100 indicate that the two emission profiles are similar. The f ₂ value calculated by Equation 1 was calculated as 64.23, 52.10, 56.27 and 68.40 in pH 1.2, pH 4.0, pH 6.8 and distilled water medium, respectively. It can be seen from Figure 4a to Figure 4d that the release of doxazosin from the formulation of the present invention indicates a zero-order release, from the f ₂ value (more than 50) calculated by the figure and the formula 1, Kadura XL of the present invention The release pattern of doxazosin from the formulation was found to be the same over 8-16 hours. In particular, as shown in Figure 4c, in the dissolution medium of pH 6.8 it was confirmed that the formulation of the present invention showed a better 0-order release form than Kadura XL in 16 to 24 hours. As a result, unlike osmotic preparations such as Kadura XL, which are difficult to manufacture, the formulations of the present invention are simple and inexpensive to produce, while zero-releasing basic drugs that exhibit pH dependent solubility over a delayed time interval, i.e. 16 to 24 hours. It can be seen that the formulation.

Experimental Example 4

Using the preparation prepared in Example 2, the dissolution test of artificial gastric juice (pH 1.2) was performed in the same manner as in Experimental Example 1, and the amount of eluted mesylic acid doxazosin was analyzed by HPLC (methanol 65 (mobile phase) v / v)%: acetate buffer 1M, pH 4.0: diethylamine = 90: 10: 0.03 mixed solution, flow rate: 0.9 ml / min, UV-detection: 250 nm, C8 column (Pinomenex, luna 5μ, 150 × 4.6 mm)) and the release pattern is shown in FIG. 5 using Kadura XL as a control formulation. As shown in FIG. 5, even when fumaric acid is used as the organic acid, it exhibits a similar release pattern to Kadura XL as a control formulation, and it can be seen that the doxazosin is constantly released at a zero-order reaction rate.

Experimental Example 5 Effect of Citric Acid Content

In order to examine the effect of the citric acid content in the formulation of the present invention, to prepare a tablet by weighing to have a component ratio of the following Table 1 (unit mg) by varying the content of citric acid, and for the elution medium of phosphate buffer (pH 6.8) The dissolution test was performed in the same manner as in Experimental Example 1, and the release pattern is shown in FIG. 6.

TABLE 1

<Unit: weight ratio> Mesyl Acid Doxazosin PEO Avicel PH-102 Citric acid Sodium alginate Magnesium stearate One One 26.8 27.25 0.00 6.19 0.62 2 One 26.8 26.22 1.03 6.19 0.62 3 One 26.8 24.15 3.09 6.19 0.62 4 One 26.8 21.06 6.19 6.19 0.62 5 One 26.8 17.97 9.28 6.19 0.62 6 One 26.8 14.88 12.37 6.19 0.62 7 One 26.8 8.69 18.56 6.19 0.62 8 One 26.8 2.51 24.74 6.19 0.62 9 One 26.8 0.00 30.93 2.51 0.62

As shown in FIG. 6, in the absence of citric acid, doxazosin is released at less than 20% even after 24 hours in a medium of pH 6.8, whereas the dissolution rate of doxazosin increases as the content of citric acid increases. In particular, in the case of 9 to 30 parts by weight with respect to 1 part by weight of the drug, after 24 hours, it was shown that the release of 90 to 100%, showing a typical zero-order release pattern.

Experimental Example 6 Influence of Tableting Pressure

In formulating the formulation of the present invention into a tablet, to examine the effect of tableting pressure, after weighing in the same component ratio as in Example 1, tablets were prepared by varying the tableting pressure to 70N, 90N, 110N, 130N, phosphate buffer The dissolution test of (pH 6.8) was carried out in the same manner as in Experimental Example 1, the release pattern is shown in FIG. As shown in Figure 7, it can be seen that the release of doxazosin from the formulation of the present invention is not affected by the tableting pressure during tablet manufacture.

<Experiment 7> Influence of the stirring speed

In Example 1, the dissolution test was performed by changing the rpm of the phosphate buffer (pH 6.8) to 50, 75, 100, and 150 rpm. The results are shown in FIG. 8, and the elution at 50 rpm and 100 rpm was performed. Aspects are compared in FIGS. 9A and 9B with KaduraXL as the control formulation. As shown in Figure 8, the formulation of the present invention was shown to have a low dissolution difference according to the stirring speed, from which the formulation of the present invention has a small difference in the dissolution rate according to the gastrointestinal motility, constant and reproducible release pattern in vivo administration It could be seen that. In addition, as shown in Figures 9a and 9b, the formulation and the control formulation of the present invention is similar in dissolution pattern (f ₂ 50 or less), the formulation of the present invention was confirmed that the release pattern of the drug is not affected by the gastrointestinal peristalsis as in Kadura XL.

As described above, the dosage form according to the present invention can be prepared simply and economically, and the pH-dependent weak basic drugs exhibiting pH dependent solubility such as doxazosin at the time of in vivo administration are not affected by the release pattern of the drug by peristalsis of the digestive tract. In this case, the elution pattern of the 0th order can be shown to maintain effective blood concentration continuously for 24 hours, thereby exhibiting a certain effect.

Claims (9)

Weakly basic drugs selected from the group consisting of doxazosin, tamsulosin, paroxetine, tolterodine, venlafaxine, and pharmaceutically acceptable salts of the above drugs, which exhibit pH dependent solubility as the active ingredient; Swellable hydrophilic polymers selected from the group consisting of polyethylene oxide, hydroxypropylmethylcellulose acetate succinate, methylcellulose and hydroxypropylmethylcellulose; Alginic acid, sodium alginate, acrylic acid copolymer, pectin, carrageenan, carboxymethylcellulose sodium, vinyl acetate, vinylpyrrolidone, cellulose ether, cellulose ester, xanthan, chitosan, guar gum, gum arabic, polyvinyl alcohol, cellulose acetate A matrix-type tablet comprising a monolayer comprising an organic acid and a pH dependent polymer selected from the group consisting of phthalates, mono-, di- and triglycerides, mineral glycol waxes and shellac. delete The method of claim 1, wherein the polyethylene oxide (PEO) is 1 × 10 ⁶ to 4 × 10 ⁶ Tablets having a molecular weight. delete The tablet of claim 1, wherein said pH dependent polymer is selected from the group consisting of alginic acid, sodium alginate, acrylic acid copolymers, pectin, carrageenan and sodium carboxymethylcellulose. The tablet according to claim 1, wherein the organic acid is selected from the group consisting of citric acid, fumaric acid, adipic acid, tartaric acid, succinic acid, ascorbic acid, maleic acid, malic acid, oxalic acid, malonic acid, benzoic acid and mandelic acid. delete The method according to any one of claims 1, 3, 5, and 6, wherein 5 to 50 parts by weight of the swellable hydrophilic polymer, 5 to 10 parts by weight of the pH dependent polymer, and organic acid 1 with respect to 1 part by weight of the active ingredient. To 30 parts by weight tablets. The method according to claim 1, wherein the active ingredient is doxazosin or a pharmaceutically acceptable salt thereof, and based on 1 part by weight of the active ingredient, 20 to 50 parts by weight of polyethylene oxide (PEO) as the swellable hydrophilic polymer, the pH dependent polymer 5 to 10 parts by weight of sodium alginate, and 9 to 30 parts by weight of citric acid as the organic acid.

Images