KR20080028365A - Manufacturing method of controlled-release tablet containing doxazocin mesylate - Google Patents

Abstract

A method for preparing a controlled-release tablet comprising doxazosin mesylate is provided to be simple and economical, and obtain the controlled-release tablet which releases doxazosin mesylate at zero-order rate for 12 hours and has reduced content variation and dissolution variation. A method for preparing a controlled-release tablet comprising doxazosin mesylate comprises the steps of: (a) mixing doxazosin mesylate, low- viscosity hydroxypropylmethylcellulose, at least one gum selected from the group consisting of xanthan gum, arabia gum, guar gum and locust bean gum, a diluent and a lubricant; (b) compacting the mixture to prepare dry granule; and (c) mixing the dry granule with a lubricant to make a final mixture and tabletting the final mixture, wherein the viscosity of the low-viscosity hydroxypropylmethylcellulose is between 80 and 120 cP when measured as 2 wt% aqueous solution at a temperature of 20 deg.C and the diluent is at least one selected from the group consisting of lactose, mannitol, microcrystalline cellulose and corn starch.

Description

MANUFACTURING METHOD OF CONTROLLED-RELEASE TABLET CONTAINING DOXAZOCIN MESYLATE}

The present invention relates to a method for producing mesylic acid doxazosin sustained-release tablets.

Mesylic acid doxazosin is an angiotensin II as the mesylate salt of 4-amino-2- [4- (1-4-benzodioxane-2-carbonyl) piperazin-1-yl] -6,7-dimethoxyquinazolin. It is a drug widely used as an antihypertensive agent classified as an antagonist.

In the treatment of hypertension, sustained-release preparations have been generally used which release the drug at a constant rate for a long time in order to maintain the drug efficacy and reduce the side effects caused by the drug. For this purpose, it is desirable that not only the drug is released at a constant rate, but also that the dissolution rate (pattern) remains unchanged in the external environment in terms of maintaining the drug efficacy and preventing side effects, and the dissolution rate is kept constant for each drug. Being also very important. This dissolution deviation is also a very important factor in ensuring the quality uniformity of the formulation. In addition, since the dissolution deviation is closely related to the absorption deviation in the body, it is desirable to reduce the dissolution as much as possible for the purpose of sustaining the efficacy and reducing side effects.

Kadura XEL sustained-release tablet ™ (Pfizer Pharmaceuticals, Korea) is currently available as a sustained-release tablet that releases mesylic acid doxazosin at a constant rate for more than 12 hours. However, Kadura XL sustained-release tablet ™ is an agent that uses osmotic pressure to release the drug at a constant speed. Therefore, it is complicated to manufacture because the micropore and the osmotic boundary membrane where the drug is released on the tablet surface are complicated, and the tablet surface can be punched for manufacturing. The disadvantage is that it requires a separate facility.

Technical challenge

Therefore, the technical problem to be achieved by the present invention is simple to manufacture, does not require a separate equipment for manufacturing, and can be released not only mesylateoxazosin at a zero-order (zero-order) for a certain time, eluting It is to provide a method for producing mesylic acid doxazosin sustained-release tablets in which the deviation (ie, body absorption deviation) is reduced.

Technical solution

In order to achieve the above technical problem, the present invention (S1) mesylic acid doxazosin; Low viscosity hydroxypropylmethylcellulose; Any one or more gums selected from the group consisting of xanthan gum, gum arabic, guar gum and locust bean gum; Excipients; And mixing the lubricant; (S2) compacting the mixture to prepare dry granules; And (S3) mixing the prepared dry granules with a glidant, and tableting. The method provides a method for preparing mesylic acid doxazosin sustained-release tablets, comprising: dissolution deviation, ie, absorption deviation in the body.

More preferably, the present invention has a viscosity of 80-120 cps when the low-viscosity hydroxypropylmethylcellulose is measured at 20 ° C. with a 2% aqueous solution in the method for preparing mesyl acid doxazosin sustained-release tablet. It provides a method of manufacturing.

Preferably, the present invention provides a method for preparing mesylic acid doxazosin sustained-release tablet, characterized in that the excipient is at least one selected from the group consisting of lactose, mannitol, microcrystalline cellulose and corn starch in the method for preparing mesylic acid doxazosin sustained-release tablet, More preferably, the present invention provides a method for producing mesylic acid doxazosin sustained-release tablet, characterized in that the excipient is lactose.

More preferably, the present invention provides a method for producing mesylic acid doxazosin sustained-release tablet, wherein the gum is xanthan gum in the method for producing mesyl acid-doxazosin sustained-release tablet.

More preferably, the present invention provides a method for preparing mesyl acid doxazosin sustained-release tablets with respect to the total weight of the sustained-release tablets with mesylic acid doxazosin 0.5 to 2% by weight; 40-50% by weight of low viscosity hydroxypropylmethylcellulose; Xanthan gum 4-10 wt%; And it provides a method for producing mesylic acid doxazosin sustained-release tablet characterized in that 25 to 35% by weight lactose is used.

Preferably, the present invention provides a method for preparing mesylic acid doxazosin sustained-release tablet, characterized in that further mixing the binder in the step (S1) in the method for producing a mesyl acid doxazosin sustained-release tablet, more preferably, the present invention It provides a method for producing mesylic acid doxazosin sustained-release tablet characterized in that the binder is a linear copolymer of 5 to 15% by weight of N-vinyl-2-pyrrolidone and vinyl acetate relative to the total weight of the sustained-release tablet.

Preferably, the present invention further comprises the step of coating the sustained-release tablet of the mesylic acid doxazosin sustained-release tablet in the method for producing the mesylic acid doxazosin sustained-release tablet (S4) with a coating liquid containing a release control polymer and a pore-forming agent. A method of producing the method, more preferably, the release controlling polymer is polyvinylacetate, and the pore-forming agent is polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate copolymer, or a mixture thereof. Provided are methods for preparing sustained-release tablets.

Hereinafter, the manufacturing method of the mesylic acid doxazosin sustained-release tablet of this invention is demonstrated more concretely.

The present invention (S1) mesylic acid doxazosin; Low viscosity hydroxypropylmethylcellulose; Any one or more gums selected from the group consisting of xanthan gum, gum arabic, guar gum and locust bean gum; Excipients; And mixing the lubricant; (S2) compacting the mixture to prepare dry granules; And (S3) mixing the prepared dry granules with an additional glidant and tableting. Finally, the method provides a method for preparing mesylic acid doxazosin sustained-release tablets, wherein the dissolution deviation (in the end, absorption in the body) is improved.

The present invention uses a mixture of low-viscosity hydroxypropylmethylcellulose and gum as a release control material to release mesylic acid doxazosin at a zero order rate for a period of time.

Unlike the general sustained-release tablet, the preparation method of the present invention uses low viscosity hydroxypropyl methyl cellulose to control the release of mesylic acid doxazosin. When the high viscosity polymer is used for the emission control, the content of the polymer may be relatively small, thereby increasing the dissolution deviation. The low viscosity hydroxypropyl methyl cellulose of the present invention means that the viscosity is less than 200 cp when measured at 20 ° C. with a 2% aqueous solution, but it is more preferable that the viscosity is 80 to 120 cP.

In addition, when only low viscosity hydroxypropyl methyl cellulose was used for the preparation of mesylic acid doxazosin sustained-release tablet, the dissolution deviation was very large. In order to improve this, the present inventors experimented by mixing several different polymers, and when the gums were contained in the sustained-release tablet containing mesylic acid doxazosin and low-viscosity hydroxypropylmethylcellulose, as well as the elution deviation (ie, absorption in the body) A surprising invention has been made that the deviation is very low. Although the physical properties of the gum serve to fix the overall shape of the sustained-release tablet against external physical forces, it is expected that such a dissolution deviation reduction effect occurs, but the present invention is not limited to this theory.

Xanthan gum, gum arabic, guar gum and locust bean gum can be used as the gum to play such a role. However, xanthan gum is most preferred in terms of controlling the sustained release of mesylic acid doxazosin by interacting with low viscosity hydroxypropylmethylcellulose.

As the excipient of the present invention, any one or more selected from the group consisting of lactose, mannitol, microcrystalline cellulose and corn starch may be used. However, microcrystalline cellulose and corn starch may sometimes act as a disintegrant, which may increase the absorption deviation in the body. In addition, the storage stability of mannitol is relatively poor compared to lactose, so the sustained release of mesylic acid doxazosin may be modified during storage. Therefore, lactose is the most preferred excipient for the purposes of the present invention.

Therefore, the most preferable components in the method for preparing mesylic acid doxazosin sustained-release tablet of the present invention are mesylic acid doxazosin, low viscosity hydroxypropylmethylcellulose, xanthan gum and lactose, each of which is 0.5 to 2 weight of mesylic acid doxazosin relative to the total weight of the sustained-release tablet. It is more preferable that they are 40 to 50 weight% of low viscosity hydroxypropylmethylcellulose, 4 to 10 weight% of xanthan gum, and 25 to 35 weight% of lactose. When the content of the low viscosity hydroxypropyl methyl cellulose is more than the above range, the release rate is too slow, and when less than the above range, the release rate is too fast to maintain the desired release rate. If the content of xanthan gum is outside the above range, it is difficult to induce a desired release rate similarly to hydroxypropylmethylcellulose, and the dissolution deviation is increased, making it unsuitable for commercially available formulations. In addition, even in the case of lactose used as a filler, it is difficult to meet the desired dissolution rate because the content of other release control polymers is inevitably reduced or increased when it is out of the content range.

In addition, the compression of mesylic acid doxazosin, low-viscosity hydroxypropylmethylcellulose, xanthan gum, lactose, etc. is not produced as dry granules. do. It is expected that the mixing uniformity of the above components is decreased due to the vibration generated during the transport and / or tableting of the tableting powder when it is directly stroked, thereby causing a large dissolution deviation, but the present invention is not limited to this theory.

The compression of the step (S2) of the present invention may be performed using a roller compactor, an extruder for compression, or a tableting machine for manufacturing dry granules, but is not limited thereto. Considering the mass production aspect, roller compactor is most preferred.

In another aspect, the present invention provides a method for producing mesylic acid doxazosin sustained-release tablet characterized in that the (S1) step of further mixing the binder. The binder increases the binding strength of dry granules to facilitate subsequent processes such as transporting and tableting, as well as maintaining the physical properties of mesylic acid doxazosin and the release control polymer uniformly, thereby controlling dissolution rate and dissolution deviation. It is thought to be.

In the present invention, a linear copolymer of polyvinylpyrrolidone, vinylpyrrolidone and vinyl acetate, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose may be used as the binder, but is not limited thereto. Preference is given to linear copolymers of vinylpyrrolidone and vinyl acetate (Copovidone ™, BASF, Germany) in terms of interacting with other components to control the dissolution rate. In this case, the content of the binder is preferably 5 to 15% by weight based on the total weight of the sustained-release tablet.

In the case of the sustained-release tablet of mesylic acid doxazosin according to the present invention, it is necessary to adjust the initial release rate in order to maintain an appropriate drug release pattern. Therefore, preferably, the present invention further comprises the step of coating the sustained-release tablet with a coating liquid containing (S4) a release control polymer and a pore-forming agent in the method for producing the mesylic acid doxazosin sustained-release tablet. Provided are methods for preparing sustained-release tablets. Coating of such tablets can be carried out by methods well known to those skilled in the art using conventional tablet coaters.

As the release controlling polymer, polyvinylacetate, hydroxypropylmethylcellulose phthalate, methacrylic acid copolymer, hydroxypropylmethylcellulose acetate succinate or a mixture thereof can be used, but polyvinylacetate is preferable in terms of initial release rate control. .

The coating liquid used in the present invention also includes a pore former. If only the release control polymer is coated, the release may be excessively delayed, and thus a pore-forming agent needs to be included. As the pore-forming agent, polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate copolymer, low viscosity hydroxypropylmethylcellulose, low viscosity hydroxypropyl cellulose or a mixture thereof can be used, and polyvinylpyrrolidone, vinyl Pyrrolidone-vinylacetate copolymers or mixtures thereof are preferred.

The coating liquid used in the present invention also includes a surfactant for coating as a substance which gives plasticity to the controlled release polymer. Dibutyl sebacate, triethyl citrate, propylene glycol, polyethylene glycol or a mixture thereof may be used as the coating surfactant, but is not limited thereto.

The coating liquid used in the present invention may further contain a lubricant (for example, talc), a light shielding agent (for example, titanium dioxide), and the like.

More preferably, the (S4) step is 0.5 to 5 parts by weight of polyvinylacetate; 0.5 to 3 parts by weight of a pore-forming agent selected from polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate copolymer, low viscosity hydroxypropylmethylcellulose, low viscosity hydroxypropylcellulose and mixtures thereof; 0.5 to 3.5 parts by weight of talc, titanium dioxide or a mixture thereof; And it provides a method for producing mesylic acid doxazosin sustained-release tablet characterized in that the coating solution containing 0.1 to 2 parts by weight of the coating for coating 3 to 9% by weight relative to the total weight of the sustained-release tablet.

If the coated weight is less than 3% by weight relative to the total weight of the sustained-release tablet, the initial release rate may be too fast. If the coated weight exceeds 9% by weight, the initial release rate may be too slow.

1 is a graph showing the average concentration of doxazosin in plasma with time after taking an embodiment according to the present invention and Kadura XEL sustained-release tablet ™ (Pfizer Korea).

Embodiment for Invention

Hereinafter, the present invention will be described in detail with reference to Examples. However, embodiments according to the present invention can be modified in many different forms, the scope of the present invention should not be construed as limited to the embodiments described below. The embodiments of the present invention are provided to more completely explain the present invention to those skilled in the art.

<Manufacture of Examples 1-4 and Comparative Examples 1-2>

To prepare the mesylic acid doxazosin sustained-release tablet with the ingredients and contents shown in Table 1 below. First, uniformly mix the amount corresponding to 1,000 times the content of ingredients 1 to 6, compress it using a roller compactor (TF-Mini, Freund, Japan), and then establish it by using 16 mesh sieves. Dry granules were prepared. Thereafter, the ingredients of No. 7 and No. 8 were uniformly mixed with dry granules according to the ratio of Table 1 below, and the tablets were weighed about 292 mg and hardness of 10 tablets using a tableting machine (KI-1300, Kisan Machinery, Korea). Tableting to ± 1 Kp.

Table 1

<Elution evaluation of Examples 1-4 and Comparative Examples 1-2>

The samples prepared in Examples 1 to 4 and Comparative Examples 1 and 2 were subjected to the dissolution test according to the paddle method (75 rpm, 900 ml) of the pharmacopeias dissolution test method. As an elution medium, pH 1.2 buffer (into 2.0 g of sodium chloride, 7.0 ml of hydrochloric acid was added and purified water was added to 1 L), and Kadura XL sustained-release tablet ™ (Pfizer Co., Ltd.) was used as a control. All 18 samples (6 × 3 times) were tested and their average values and deviations are shown in Table 2.

TABLE 2

As shown in Table 2, the mesyl acid doxazosin sustained-release tablet of the present invention not only releases the drug at the zero-order rate for 12 hours but also had very little dissolution deviation. As shown in the experimental results of Comparative Examples 1 and 2, when xanthan gum was not contained, the dissolution pattern was relatively inadequate and the dissolution deviation was also very large. In addition, the sustained-release tablet of mesylic acid doxazosin of the present invention not only exhibits a dissolution pattern with a rate ratio (tilt) similar to that of the commercially available Kadura XEL sustained-release tablet ™, but also has a relatively small dissolution deviation. Therefore, the sustained-release tablet of the present invention is very useful considering that the production is very simple and economical.

<Manufacture of Comparative Example 3 using the direct hit method>

Mesylic acid doxazosin sustained-release tablets having the same ingredients and contents as in Example 1 were prepared by simply mixing all the ingredients without preparing dry granules, followed by direct punching using the tableting machine of Example 1.

<Elution Evaluation of Comparative Example 3>

The dissolution test of Comparative Example 3 was performed in the same manner as the dissolution test method described above. The results are shown in Table 3.

TABLE 3

As shown in Table 3, the sample of Comparative Example 3 showed a dissolution pattern somewhat similar to that of Example 1, but the dissolution deviation was very large.

<Manufacture of Example 5>

The initial dissolution rate of the mesylic acid doxazosin sustained-release tablet prepared in Example 1 was so fast that the sustained-release tablet was coated with a coating solution containing a release controlling polymer and a pore-forming agent. 10 parts by weight of Kollicoat SR30D ™ (water suspension consisting of 27% polyvinylacetate, 2.7% povidone and 0.3% sodium lauryl sulfate, BASF Korea), 1.2 parts by weight polyvinylpyrrolidone K30, 0.9 parts by weight talc, 0.8 titanium dioxide The sustained-release tablet of Example 1 was coated by 6% by weight based on the weight of the sustained-release tablet with a coating liquid consisting of parts by weight, 0.3 part by weight of propylene glycol, and 11.5 parts by weight of purified water.

<Evaluation of in vivo absorption pattern of Example 5>

After administering two tablets of Mesylateoxazosin sustained-release tablet prepared in Example 5 and two commercially available Kadura XEL sustained-release tablet ™ to 26 healthy adult males, 1, 2, 3, 4, 6, 8, 10, 12, 14 Blood samples were collected immediately after 16, 24, 48, 72 and 96 hours, and the concentration of doxazosin in the blood was measured. Twenty-six subjects were randomly divided into two groups of 13 subjects, and commercially available formulations were administered to the first group, and the sustained-release tablet of Example 5 was administered to the second group on the same dosing day, and vice versa. In order to rule out the effects of the meal fasted for 12 hours or more before dosing was maintained until 4 hours after dosing. Ethyl acetate was used as an extraction solvent for doxazosin in blood, and the concentration of doxazosin was analyzed using HPLC. The results are summarized in FIG. 1.

As shown in Figure 1, the mesyl acid doxazosin sustained-release tablet according to the production method of the present invention is very small absorption deviation in the body despite the sustained-release matrix-type matrix using a polymer. In addition, the present invention can produce a sustained-release tablet showing an absorption pattern similar to that of commercially available OROS ™ formulations using osmotic pressure technology, even with a very simple and economical manufacturing method.

Not only is the manufacturing method of the mesylic acid doxazosin sustained-release tablet according to the present invention simple and economical, but the sustained-release tablet made by the production method of the present invention has good sustained release with low elution deviation for releasing mesylic acid doxazosin at a zero-order speed for more than 12 hours. Indicates. Therefore, the sustained-release tablet produced by the production method of the present invention has a very small absorption deviation in the body, so that the fluctuation range of the drug is small, and in the end, it is considered to be advantageous in reducing side effects.

Claims (13)

(S1) mesylic acid doxazosin; Low viscosity hydroxypropylmethylcellulose; Any one or more gums selected from the group consisting of xanthan gum, gum arabic, guar gum and locust bean gum; Excipients; And mixing the lubricant; (S2) compacting the mixture to prepare dry granules; And (S3) mixing the prepared dry granules and the lubricating agent and tableting; manufacturing method of mesylic acid doxazosin sustained-release tablet comprising a. The method of claim 1, wherein the low viscosity hydroxypropyl methyl cellulose has a viscosity of 80 to 120 cps when measured at 20 ° C. with a 2% aqueous solution. The method according to claim 1, wherein the excipient is any one or more selected from the group consisting of lactose, mannitol, microcrystalline cellulose and corn starch. The method of claim 3, wherein the excipient is lactose. The method according to claim 1, wherein the black xanthan gum is mesylic acid venom. According to claim 1, wherein the sustained-release tablet is mesylic acid doxazosin 0.5 to 2% by weight relative to the total weight of the sustained-release tablet; 40-50% by weight of low viscosity hydroxypropylmethylcellulose; Xanthan gum 4-10 wt%; And lactose 25-35% by weight. The method for preparing mesylic acid doxazosin sustained-release tablet according to claim 1, wherein the binder (S1) is further mixed. 8. The method of claim 7, wherein the binder is a linear copolymer of vinylpyrrolidone and vinyl acetate. The method of claim 8, wherein the binder is 5 to 15% by weight relative to the total weight of the sustained-release tablet. 10. The method according to any one of claims 1 to 9, wherein the manufacturing method further comprises the step of coating the sustained-release tablet with a coating liquid comprising (S4) a release controlling polymer and a pore-forming agent. Method of producing sustained-release tablets. The method of claim 10, wherein the controlled release polymer is polyvinylacetate. The method of claim 10, wherein the pore-forming agent is polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate copolymer, or a mixture thereof. The method of claim 10, wherein (S4) step is 0.5 to 5 parts by weight of polyvinylacetate; 0.5 to 3 parts by weight of a pore-forming agent selected from polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate copolymer, low viscosity hydroxypropylmethylcellulose, low viscosity hydroxypropylcellulose and mixtures thereof; 0.5 to 3.5 parts by weight of talc, titanium dioxide or a mixture thereof; And 3 to 9% by weight of the total weight of the sustained-release tablet with a coating solution containing 0.1 to 2 parts by weight of the surfactant for coating.

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