KR101565505B1 - New drug delivery system comprising eperisone - Google Patents

Abstract

The present invention relates to a film-coated tablet comprising eperisone or a pharmaceutically acceptable salt thereof. A film-coated tablet of one embodiment of the present invention is prepared by mixing epelizone or a pharmaceutically acceptable salt thereof; Vinyl pyrrolidone-vinyl acetate copolymer; And hydroxypropyl methylcellulose. The film-coated tablet of the present invention contains hydroxypropylmethylcellulose and a vinylpyrrolidone vinyl acetate copolymer in a specific amount, and exhibits dissolution equivalent to that of the original drug, but has a small variation in dissolution rate. Further, the film-coated tablet of the present invention has a simple manufacturing method and an effect of reducing manufacturing cost.

Description

NEW DRUG DELIVERY SYSTEM COMPRISING EPERISONE < RTI ID = 0.0 >

The present invention relates to a film-coated tablet comprising eperisone or a pharmaceutically acceptable salt thereof.

Eperisone is a pharmacological substance having a central muscle relaxant action and has a structure as shown in the following formula (1). It is mainly used in the form of hydrochloride, but also in the form of other pharmaceutically acceptable salts.

Eperisson acts on the spinal cord and upper central level to suppress synapses and synaptic reflexes. It relieves muscle tension and muscle relaxation, and treats painful muscle spasms associated with musculoskeletal disorders and rigid paralysis caused by nervous system diseases . Especially, eperisone is widely used for treatment of muscular contraction to relieve muscle stiffness and spinal pain because of its low central inhibitory action.

For more detailed information on other ephedrins, reference can be made to those disclosed in Non-Patent Document 1 below, and a detailed description thereof will be omitted (in the following Non-Patent Document 1, Incorporated herein by reference in its entirety).

However, eferissone has the following disadvantages with respect to drug absorption and medication.

First, there is a disadvantage that the bioavailability is very low because the initial effect is large in the process of being absorbed in the gastrointestinal tract.

Second, because the absorption is unstable, there is a disadvantage that the difference in blood concentration of individual is large.

Third, the muscle relaxation effect of the absorbed eperisone is comparatively very short, so that it is troublesome to apply it relatively frequently.

Drug Delivery System (DDS) has been recently developed to compensate for the disadvantages of the above-mentioned eperisone, to increase the absorption effect of the drug, and to improve the homeostasis of drug plasma concentration.

Currently available formulations include injections, oral preparations, and transdermal preparations. Among these, attempts have been made to develop transdermal dosage forms in which drugs are administered into the body through the skin surface.

As a conventional prior art related to a transdermal preparation containing eperisone, the following Patent Document 1 (U.S. Patent No. 5,252,588) can be exemplified.

The following Patent Document 1 relates to an invention in which epirezone is formulated into a transdermal dosage form by using polyvinylpyrrolidone-introduced acrylate pressure-sensitive adhesive and cross-linked polyvinylpyrrolidone, wherein the transdermal dosage form , The more effective absorption of the drug through the skin is, the more effective the drug is, and the blood drug concentration is maintained for a long time.

US 5252588 A

 Martindale (35th ed.), P. 1736.

A first problem to be solved by the present invention is to provide an ephrisson film-coated tablet which is inexpensive to produce and easy to be punched.

As of February 22, 2011, about 40 eperisone-related medicines have been approved for domestic use in Korea, and all of the tablets containing eperisone are found to be sugar-covered.

The sugar coating is good in appearance and has an advantage of being able to block unpleasant smells and discoloration, but it takes longer time and process steps than general film coating because of addition of sugar coating process in production, resulting in higher production cost (Generally, the manufacture of sugar beet has a disadvantage in that it requires a long manufacturing period and a large number of additives, which leads to a high management cost).

In addition, the conventional epherison-containing products are produced by the wet granulation method, and the production time and process are added.

Therefore, the present invention is designed so that the direct method can be performed, and is manufactured by simple mixing, tableting, and film coating processes.

A second problem to be solved by the present invention is to provide an epherison-containing tablet having a low inter-subject dissolution rate.

The presently marketed eperisone is a sugar-coated tablet, which has a problem in that the elution deviation and weight deviation among the individual are severely observed. The large elution deviation of the drug entity means that the elution characteristics between the drug subjects are different, and thus, even though the same drug is prescribed at the same dose, the drug dose deviation between individuals may result in under or over dosage There is a danger.

Accordingly, the present invention provides an epherison-containing film-coated tablet which significantly reduces the drug release deviation between individuals.

A third problem to be solved by the present invention is to provide an epherison-containing tablet having bioequivalence with an original drug.

As described above, in the case of ephedrine-containing medicines, it is required to manufacture a film-coated tablet which can have a convenient and stable quality of operation and lower the manufacturing cost, rather than a sugar-coated tablet.

However, one problem here is the 'bioequivalence test' for specialty medicines. (In Korea, since 1988, the Ministry of Health and Welfare issued the "Guidelines for Approval of Manufacture and Manufacture of Pharmaceutical Products, etc." And a bioequivalence test is conducted when it is necessary to apply for permission to manufacture the same item and when necessary.

The Bioequivalence Test (BE Test) is a statistical method that tests whether a drug is equivalent to an original drug by administering it to a person before the drug is approved for generic drug sales. (Bioequivalence (BE) is an in vivo experiment conducted under similar conditions to demonstrate that two formulations of pharmaceutical equivalence or a pharmaceutically substitutable agent are statistically equivalent in bioavailability. Is the case where the amount and rate of absorption of each agent does not show a significant difference when the same dose is administered. "Equivalent in terms of formulation" means that the amount of the drug, the effective ingredient, the route of administration, The dosage and dosage should be the same, I say, if you create a different formulation).

In other words, in order for a generic drug to be marketed with permission, biological equivalence with the original drug should be recognized. For this purpose, it is necessary to delicately and specially control the drug elution characteristics.

In the case of Epery Son Jeong, the drug was firstly licensed as "Murex Tablets" in 1989, and "Murex Tablets" is the original drug. Only when the bioequivalence with the "Murex Tablets" You can get permission.

Thus, in the present invention, there is provided an epherrison-containing film-coated tablet specifically adjusted so as to have the same drug elution characteristics as the original drug.

The present invention provides film-coated tablets comprising epherison or a pharmaceutically acceptable salt thereof to solve the problems of the above-described prior art.

The film-coated tablet of the present invention contains hydroxypropylmethylcellulose and a vinylpyrrolidone vinyl acetate copolymer in a specific amount, and exhibits dissolution equivalent to that of the original drug, but has a small variation in dissolution rate. Further, the film-coated tablet of the present invention has a simple manufacturing method and an effect of reducing manufacturing cost.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a graph showing the dissolution rate and the dissolution rate deviation of the Epherisson hydrochloride film coated tablets prepared in the present invention (Example 1). FIG.
2 is a graph showing dissolution rates of Examples 2 to 5 of the present invention.
3 is a graph showing dissolution rates in Examples 7 to 9 of the present invention.
4 is a graph showing the dissolution rate and the dissolution rate deviation of commercially available eperisone hydrochloride glycoside (comparative example).

Hereinafter, the present invention will be described in detail.

The film-coated tablets of the present invention are characterized by comprising eperisone or a pharmaceutically acceptable salt thereof.

According to the present inventor's knowledge, only the sugar-containing tablets existed in the tablets containing the epherison, but there was no film-coated tablets. Thus, the film-coated tablet of the present invention is a novel pharmaceutical invention itself.

The film-coated tablets according to the present invention may be prepared as film-coated tablets, including the components of one embodiment described below, but are widely known to those skilled in the art (hereinafter referred to as " May also be prepared as known coating agents.

One embodiment of the film-

Eferissone or a pharmaceutically acceptable salt thereof;

Vinyl pyrrolidone-vinyl acetate copolymer; And

And hydroxypropyl methylcellulose.

One embodiment of the film-coated tablet of the present invention comprises a vinylpyrrolidone-vinyl acetate copolymer and a hydroxypropylmethylcellulose polymer in an appropriate ratio to control the dissolution rate of ephrisson or a pharmaceutically acceptable salt thereof.

In addition, by including vinylpyrrolidone-vinyl acetate copolymer and hydroxypropylmethylcellulose in place of conventional sugar-containing components, the release deviation is controlled to be smaller than that of sugar-coated tablets (the hydroxypropylmethylcellulose is dissolved in water and an organic solvent In addition, the vinylpyrrolidone-vinyl acetate copolymer has a characteristic of being gelled in both water and alcohol, and has a pH of not more than The two polymers are gelled irrespective of the pH so that the two polymers are gelled independently of the acidity in the gastrointestinal tract and thereby the drug elution deviation It is presumed that partial removal is possible).

In one embodiment of the film-coated tablet of the present invention, the vinylpyrrolidone-vinyl acetate copolymer is contained in an amount of 10 to 30% by weight based on the total weight of the tablet, and the hydroxypropylmethylcellulose is contained in an amount of 1 to 10% .

When the vinylpyrrolidone-vinyl acetate is contained in an amount less than 10% by weight based on the total weight, the initial elution amount is undesirably increased. When the vinylpyrrolidone-vinyl acetate content is more than 30% by weight, the dissolution rate is undesirably delayed.

If the content of hydroxypropylmethylcellulose is less than 1% by weight based on the total weight of the composition, the amount of initial elution may be excessively increased and the tablet may not be tableted. If the content exceeds 10% by weight, .

The vinylpyrrolidone-vinyl acetate copolymer may be of a suitable kind by a person skilled in the art without particular limitation, but vinylpyrrolidone: vinyl acetate = 6: 4 < / RTI > The vinylpyrrolidone-vinyl acetate copolymer having the vinylpyrrolidone: vinyl acetate = 6: 4 'was used to obtain dissolution characteristics as shown in the following Examples and Experimental Examples. Will be described later in Examples and Experimental Examples.

The hydroxypropyl cellulose may be of a kind suitable for a person skilled in the art without particular limitation, but it is preferably a 2208 type and has a viscosity of 80,000 to 120,000 cps in a 2% w / v aqueous solution at 20 ° C. 2208 type hydroxypropyl cellulose. As a result, dissolution characteristics similar to those of the following Examples and Experimental Examples were obtained, and detailed explanations thereof will be described in the following Examples and Experimental Examples.

In one embodiment of the film-coated tablet of the present invention, the epherison or pharmaceutically acceptable salt thereof is preferably contained in an amount of 20 to 50% by weight based on the total weight of the tablet.

In particular, when the vinylpyrrolidone-vinyl acetate, the hydroxypropylmethylcellulose, and the epherison or a pharmaceutically acceptable salt thereof fall within the respective preferred ranges mentioned above, the dissolution equivalence with the original sugar-containing drug .

One embodiment of the film-coated tablet of the present invention may further comprise one or more excipients selected from microcrystalline cellulose, and anhydrous lactose, for a direct process manufacturing process. The microcrystalline cellulose and the anhydrous lactose may be used in a suitable ratio by a person skilled in the art from a pharmaceutical point of view. The microcrystalline cellulose and the anhydrous lactose may further contain 10 to 30% by weight of microcrystalline cellulose and 10 to 30% by weight of total lactose, Is preferable in view of the mixing degree between the components of the drug.

One embodiment of the film-coated tablet of the present invention may further contain excipients such as colloidal silicon dioxide, magnesium stearate and the like, according to the consideration of those skilled in the art within the scope of not impairing the object of the present invention.

The preparation of one embodiment of the film-coated tablets of the present invention may be made by, but is not necessarily limited to, the method of making an epherison-containing film-coated tablet of the present invention.

A method of making a film-coated tablet of the present invention comprises mixing epherison or a pharmaceutically acceptable salt thereof, a vinylpyrrolidone-vinylacetate copolymer, hydroxypropylmethylcellulose, microcrystalline cellulose, and anhydrous lactose; And

And directly titrating the mixture.

The method for preparing a film-coated tablet of the present invention comprises mixing the excipient and the polymer in a pharmaceutically acceptable salt thereof, preparing a tablet through a direct tableting process, and coating the coated tablet with a film, The manufacturing process is much simpler. However, it is possible to secure a stable quality by reducing the deviation between the drug substances, and at the same time, the manufacturing cost can be greatly reduced and the mixing degree of each component of the drug can be also guaranteed. Particularly, there is an effect that the process time is shortened because there is no process of manufacturing granules.

Hereinafter, the present invention will be described in more detail by way of examples. It should be understood, however, that the following examples are for the purpose of illustration only and are not intended to limit the scope of the invention.

Example

Efferlon hydrochloride-containing film-coated tablets were prepared according to the following Examples 1 to 10.

Example  One

As in the prescription of Table 1 below, film-coated tablets containing ephedrine hydrochloride were prepared. Efferrison hydrochloride was sieved with a 20 mesh sieve, and microcrystalline cellulose and apple ephedrine hydrochloride were mixed and formulated as an excipient. The 20-mesh apple-free anhydrous lactose, vinylpyrrolidone-vinyl acetate copolymer (Kollidon VA64 ^TM ) and hydroxypropylmethylcellulose (HPMC 2208) were mixed. And the mixture was compressed into tablets using a mixture of lubricating agent and colloidal silicon dioxide (Aerosil ^TM, and magnesium stearate, and compressed tablet machine. Were then film-coated in a conventional manner using Opadry ^TM.

Example  2 to Example  6

A film-coated tablet of eperisone hydrochloride was prepared in the same manner as in Example 1, except that a film-coated tablet containing an eferrizone hydrochloride was prepared as shown in Table 2 below.

Example  7 to Example  10

The same procedure as in Example 1 was repeated except that a film-coated tablet containing efferisson hydrochloride was prepared as shown in Table 3 below.

Experimental Example

1. Evaluation of Hardness and Wear

Hardness was measured by a hardness tester (International Engineering KTF-25), and Mason's degree was measured by a Mason pottery (KIYA SEISAKUSHO 3880).

The results are shown in Table 4 below.

2. Evaluation of dissolution

(1) Comparative elution evaluation according to vinylpyrrolidone-vinyl acetate copolymer and hydroxypropylmethylcellulose content

The dissolution rate of the efferisson hydrochloride salt-containing film-coated tablet prepared in the above Example was evaluated. As the elution medium (900 ml), pH 1.2, 4.0, 6.8, and purified water maintained at about 37 ° C were used, and the rotational speed of the paddle at the elution test was 50 rpm.

The eluate was collected at 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, and 60 minutes after the start of the elution test, and the eluate was filtered using a 0.45 micrometer membrane filter. The absorbance was measured at 257 nm Respectively.

The dissolution rate results of Example 1 are shown in FIG. 1, the dissolution rate results of Examples 2 to 5 are shown in FIG. 2, and the results of Examples 7 to 9 are shown in FIG.

As shown in FIG. 1, in Example 1, it was found that elution was appropriate and uniform under various elution media.

As shown in FIG. 2, as the amount of the vinylpyrrolidone-vinyl acetate copolymer was increased, the hardness was weak and the disintegration was delayed. When the amount of vinylpyrrolidone-vinyl acetate copolymer was small, the initial dissolution rate was increased. That is, since the properties of the purified product are not improved, the amount of the vinylpyrrolidone-vinyl acetate copolymer to be used is preferably 10 to 30% by weight based on the total weight of the copolymer. In Example 6, tableting was possible, but the elution test was not performed because the hardness was low and the degree of grinding was high.

As shown in FIG. 3, disintegration tends to be delayed as the amount of hydroxypropylmethylcellulose used increases. If the amount of hydroxypropylmethylcellulose to be used is small, as shown in FIG. 3, if the dissolution rate is too fast and the amount of hydroxypropylmethylcellulose to be used is too large, even disintegration can not be achieved. Accordingly, the amount of hydroxypropylmethylcellulose is suitably about 1 to 10% by weight based on the total weight of the composition. In Example 10, the disintegration was too delayed and the elution test was not conducted separately.

(2) Comparative elution evaluation with Comparative Example

<Measurement of inter-individual dissolution deviation>

The comparative dissolution rate was evaluated in comparison with that in Example 1, using a commercial eperysone hydrochloride-containing sugar solution (Murex Stable ^TM ) as a comparative example. The experiment was conducted under the same conditions as in Example 1 above.

The results are shown in Table 5 and Fig.

As can be seen from Table 5 and FIG. 4, it was confirmed that the dissolution rate of the commercially available eperissone hydrochloride-containing sugar-coated diol was very high.

On the other hand, as shown in Fig. 1 and Table 6, it was found that the elution pattern of the Eperisson film-coated tablet of Example 1 showed good elution and uniformity even with little individual variation in dissolution rate.

&Lt; Evaluation of similarity of dissolution pattern &

In order to objectively evaluate the dissimilarity pattern of the dissolution pattern in the comparative example and the example 1, the similarity factor defined by the following equation (1) was calculated.

Where n is the number of time points, R _t is the average dissolution rate of the control (comparative) and T _t is the average dissolution rate of the test drug (Example 1). The comparison time points are 1/4, 2/4, 3/4, and 4/4.

When the dissolution rate after 30 minutes is 85% or more, the similarity factor f ₂ is 50 or more.

The results are shown in Tables 7 to 10 below.

As shown in Table 7 to Table 10, the reference product (comparative example) and the test product (Example 1), any image equivalent hayeotneun in the similarity factor rating, higher than both the similarity factor f ₂ 50 under a variety of elution medium Respectively.

Claims (2)

A main component comprising 20 to 50% by weight of eferrizone or a pharmaceutically acceptable salt thereof;
A vinylpyrrolidone-vinyl acetate copolymer in an amount of 10 to 30% by weight, a hydroxypropylmethylcellulose in an amount of more than 1 and less than 5% by weight, and an excipient selected from microcrystalline cellulose and lactose; And
Colloidal silicon dioxide, and magnesium stearate, wherein the lubricant is uniformly kneaded, and the compressed tablet is coated with a coating agent. delete

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