KR102254307B1 - Eperisone-containing pharmaceutical having improved storage-stability - Google Patents

Abstract

The present invention relates to a stable eperisone pharmaceutical composition comprising eperisone hydrochloride or a pharmaceutically acceptable salt thereof, and comprises a non-metal salt additive, and at the same time, it is characterized in that it does not contain a metal salt additive. The pharmaceutical composition of the present invention exhibits high stability even without the addition of a special acidifying agent, stabilizer, or preservative, and has an effect suitable for preparation into tablets by compression molding.

Description

Eperisone pharmaceutical composition with improved storage stability {EPERISONE-CONTAINING PHARMACEUTICAL HAVING IMPROVED STORAGE-STABILITY}

The present invention relates to a stable eperisone pharmaceutical composition 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 Formula 1 below. It is mainly used in the form of hydrochloride, but it is also used in the form of other salts available pharmaceutically.

Eperisone works on the spinal cord and upper central level to suppress short synapses and reflexes, so as to relieve muscle tone and relax muscles, and treat painful muscle spasms associated with musculoskeletal disorders and spastic paralysis caused by neurological disorders. It is being used to In particular, eperisone is widely used in the treatment of muscle spasms to alleviate muscle stiffness and spinal pain because it has little central inhibitory effect.

However, eperisone having the above chemical structure has a problem of generating related substances according to moisture or pH fluctuations.

That is, there is a problem in pH stability in an alkaline environment, and there is a problem in storage stability due to changes over time even when the drug is formulated and stored.

Therefore, in order to improve the pH stability and storage stability, the development of an eperisone composition has been progressed, and in particular, a sustained-release pharmaceutical composition in which an acidic pH modifier is added to eperisone has been disclosed.

As an example of the prior art for this, Korean Patent Registration No. 10-1156054'Stable Eperisone-Containing Sustained-Release Pharmaceutical Composition' (Patent Document 1) can be cited, and in the document, specific types of acidifying agents such as carbomer and citric acid By formulating the formulation in a pH range of 5 to 6 or less, it is possible to suppress the decomposition of the main component without changing the dissolution characteristics even in extreme environments such as pH change due to the long-term storage stability of the formulation and the characteristics of the sustained-release formulation that must stay in the gastrointestinal tract for a long time. Disclosed is an eperisone sustained-release pharmaceutical composition. Accordingly, all of the disclosed contents of Patent Document 1 are incorporated and cited as prior art contents in this specification.

KR10-1156054 B1 (2012.06.07.)

As described above, there was a prior art for increasing the stability by using an acidifying agent such as Patent Document 1, but the stability effect was not satisfactory with the acidifying agent alone, and there was always a concern about fluctuations in the dissolution characteristics in the gastrointestinal tract due to pH adjustment. In addition, there are other problems, such as the possibility that the pH may be uneven depending on the moisture content in the manufacturing process.

Accordingly, the present inventors generally use eperisone for ingredients other than the main ingredient used in the manufacture of pharmaceutical preparations such as tablets in the art, for example, excipients, disintegrants, lubricants, and other additives. As a result of extensive screening tests for its stability as a pharmaceutically acceptable salt, it was surprisingly discovered that whether it contains or does not contain metal salts has a profound effect on the stability of eperisone. The invention was completed.

The present invention is conceived to solve the above-described prior art,

As a pharmaceutical composition comprising eperisone or a pharmaceutically acceptable salt thereof as an active ingredient, it provides a non-metallic salt additive, and at the same time, eperisone pharmaceutical composition characterized in that it does not contain a metal salt additive.

In addition, in the present invention, there is provided an eperisone pharmaceutical composition, wherein the metal salt additive is magnesium stearate as a lubricant.

In addition, in the present invention, the non-metallic salt additive is at least one selected from sucrose fatty acid ester, stearic acid, fumaric acid, hydrogenated vegetable oil, glyceryl behenate, glyceryl palmitostearate, starch, and PEG 6000 as a lubricant. It provides a pharmaceutical composition of eperisone.

In addition, in the present invention, the lubricant, based on the total weight of the composition, provides an eperisone pharmaceutical composition comprising 0.01 to 15% by weight.

In addition, in the present invention, as a disintegrant, the non-metallic salt additive is at least one selected from crospovidone, low-substituted hydroxypropyl cellulose, alginic acid, and pregelatinized starch.

In addition, in the present invention, the disintegrant provides an eperisone pharmaceutical composition, characterized in that it contains 0.01 to 25% by weight, based on the total weight of the composition.

Further, in the present invention, there is provided an eperisone pharmaceutical composition, wherein the pharmaceutically acceptable salt of eperisone is hydrochloride.

In the present invention, there is also provided an eperisone pharmaceutical composition, which is in the form of a tablet by compression molding.

The pharmaceutical composition of the present invention exhibits high stability without the addition of a special acidifying agent, stabilizer, or preservative, and has an effect suitable for manufacturing into tablets through compression molding.

1 is a graph of the results of stability experiments of a mixture of eperisone and non-metallic additives.
2 is a graph of the results of stability experiments of a mixture of eperisone and sodium metal additives.
3 is a graph of the results of stability experiments of a mixture of eperisone and calcium/potassium metal additives.
4 is a graph of the results of stability experiments of a mixture of eperisone and magnesium metal additives.
5 is a graph showing the stability test results of a prescription containing a metal additive and a prescription not containing a metal additive.
6 is a graph showing the comparative dissolution results of the tablets of the examples of the present invention with the reference drug.

Terms used in the present invention claims and specification are defined as follows.

'Additive' refers to a substance other than the active ingredient contained in a formulation, which is used for the purpose of enhancing the usefulness of pharmaceuticals, facilitating formulation, stabilizing the formulation, and improving the appearance. Additives are solvents, solubilizers, solubilizers, stabilizers, buffers, flavoring agents, bases, binders, suspending agents, antioxidants, coating agents, sustained-release agents, flavoring agents, moisturizing agents, wetting agents, antifoaming agents, brightening agents, and coloring agents, depending on the purpose of mixing. , Light-shielding agent, opacifying agent, osmotic pressure adjusting agent, pH adjusting agent, softening agent, emulsifying agent, adhesive, thickening agent, foaming agent, excipient, dispersing agent, disintegrant, preservative, anti-sticking agent, absorbent, waterproofing agent, chelating agent, softening agent, cryoprotectant, film formation Agents, penetrating agents, surfactants, plasticizers, lubricants, sweeteners, adsorbents, release controlling agents, fillers, diluents, preservatives, gelling agents, acidifying agents, and the like.

'Excipient' refers to a substance that is safe and increases stability, unlike active pharmaceuticals, and is used especially for the purpose of increasing the amount in solid preparations.

'Disintegrant' is a component added to expand when wet in order to be decomposed in the digestive tract before solid agents are absorbed. It plays a role in helping the absorption of pharmacological ingredients by making the formulation into small particles.

'Lubricants' are substances that are used to provide slip and reduce friction in the manufacture of tablets or external preparations. The lubricant improves the flowability of the powder and granular material to increase the filling property in the die, reduces the friction between the powder and granular material and the friction between the die and the punch, and facilitates the compression and ejection of the tablet from the die. .

A “metal salt” generally refers to an element defined as a metal on the periodic table, such as an element corresponding to Group 1 or Group 2 of the periodic table, such as lithium, beryllium, sodium, potassium, magnesium, and calcium, and a transition metal.

'Nonmetallic salt' refers to a salt formed of an element or compound other than a metal forming the'metallic salt'.

Hereinafter, the present invention will be described in detail.

The present invention is a pharmaceutical composition comprising eperisone or a pharmaceutically acceptable salt thereof as an active ingredient, comprising a non-metal salt additive, and at the same time, it is characterized in that it does not contain a metal salt additive.

The present inventors have confirmed that the stability of eperisone or a pharmaceutically acceptable salt thereof varies depending on the additive used in the formulation, and after continuous research, it has been found that the metal salt additive significantly lowers the stability.

Accordingly, the composition of the present invention does not contain a metal salt additive, and in particular, excludes magnesium stearate, which is very widely used as a lubricant in the manufacture of tablets.

The "nonmetallic salt additive as a lubricant" according to the present invention means a lubricant that does not contain a metallic substance, and does not include metal salt lubricants such as calcium stearate, magnesium stearate, sodium stearyl fumarate, and zinc stearate. Examples of the non-metallic salt lubricant according to the present invention may include fatty acid esters, fatty acids, alcohols, oils, fumaric acid, starch, polyethylene glycol, poloxamer, or mixtures thereof, but are not limited thereto.

Specifically, in one aspect of the present invention, the non-metallic salt lubricant is preferably, fatty acid esters (eg, glyceryl behenate, glyceryl palmitostearate, glyceryl monostearate, glyceryl trimyristearate). Rate, glyceryl tristearate, or sucrose fatty acid ester, etc.); Fatty acids and alcohols (eg, palmitic acid, palmitoyl alcohol, stearic acid, stearyl alcohol, etc.); Oils (eg, hydrogenated castor oil, mineral oil, hydrogenated vegetable oil, etc.); Fumaric acid; Starch; Polyethylene glycol (eg, PEG 4000 or PEG 6000), polytetrafluoroethylene; Or talc, more preferably sucrose fatty acid ester, stearic acid, hydrogenated vegetable oil, talc, glyceryl behenate, glyceryl palmitostearate, starch, or PEG 6000, most preferably glyceryl Behenate, or PEG 6000. The nonmetallic salt lubricant may be used alone or in combination of two or more.

In one aspect of the present invention, the non-metallic salt lubricant may be used in an amount of 0.01 to 15% by weight, preferably 0.05 to 10% by weight, more preferably 0.1 to 7% by weight, based on the weight of the total composition.

If the amount of the non-metallic salt lubricant is less than 0.01% by weight, there may be a concern about problems such as sticking during tablet tableting in the compression die, and when the amount of the nonmetallic salt lubricant is more than 15% by weight, The lubricant having high water repellency may cause unintended problems such as delayed disintegration of the tablet and lowered dissolution, and there is a possibility that tablet capping or laminating of the tablet may occur during tablet tableting.

In addition, since the composition of the present invention does not contain a metal salt additive, a disintegrant also contains a "non-metal salt disintegrant".

'Non-metallic salt disintegrant' refers to a disintegrant that does not contain metallic substances, such as sodium alginate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, sodium croscarmellose, and sodium starch glycolate. Does not include. As usable examples of the nonmetallic salt disintegrant according to the present invention, crospovidone, low-substituted hydroxypropylcellulose, methylcellulose, microcrystalline cellulose, alginic acid, or pregelatinized starch may be exemplified, and such nonmetallic salt disintegrants It is possible to prepare the pharmaceutical composition of the present invention with improved storage stability by using.

In one aspect of the present invention, the non-metallic salt disintegrant is preferably crospovidone, low-substituted hydroxypropylcellulose, alginic acid, or pregelatinized starch, most preferably, crospovidone or low-substituted hydroxypropyl cellulose. , But is not limited thereto. The non-metallic salt disintegrant may be used alone or in combination of two or more.

In one aspect of the present invention, the non-metallic salt disintegrant may be used in an amount of 0.01 to 25% by weight, preferably 0.1 to 20% by weight, more preferably 1 to 15% by weight, based on the weight of the total composition.

When the amount of the non-metallic salt disintegrant is less than 0.01% by weight, disintegration does not occur rapidly when the tablet is wetted, and there is a possibility that problems such as sticking may occur during tablet tableting, and the amount of the non-metallic salt disintegrant is If it is more than 25% by weight, it may not be suitable for tableting, and there may be a possibility that hardness or abrasion may be lowered, or a change in the properties of the formulation due to moisture may occur.

Eperisone contained as an active ingredient of the composition of the present invention, or a pharmaceutically acceptable salt of eperisone, may be used in the form of a pharmaceutically acceptable salt derived from an inorganic acid or an organic acid, and preferably, may be a hydrochloride salt. . The active ingredient may be included in an amount of 10 to 80% by weight, preferably 10 to 50% by weight, based on the total weight of the composition, but is not limited thereto.

Furthermore, the composition of the present invention may contain additional pharmaceutically acceptable additives in addition to the above-described lubricant and disintegrant. As a non-limiting example of this, in the case of a formulation for oral administration, excipients, binders, etc. may be mentioned as additives. However, in the case of additional additives, it is required to be a non-metallic salt additive.

Non-limiting examples of the excipients include microcrystalline cellulose, lactose, mannitol, and the like, and non-limiting examples of binders include pregelatinized starch, povidone, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose ( HPMC), polyvinyl alcohol (PVA), and the like.

The excipient may be included in an amount of 0.1 to 80% by weight, based on the weight of the total composition, and the binder in an amount of 0.1 to 40% by weight, based on the total weight of the composition.

In addition, the composition of the present invention may be formulated into various formulations, and the pharmaceutical composition according to the present invention is preferably a formulation for oral administration (powder, tablet, pill, capsule, liquid, suspension, emulsion, syrup, Granules, etc.), more preferably in the form of tablets, but is not limited thereto. Various processes involved in the manufacture of the pharmaceutical composition according to the present invention may be carried out based on a conventional pharmaceutical preparation process.

Hereinafter, the present invention will be described in more detail with reference to Examples and Experimental Examples. However, it should be clarified that the following examples and experimental examples are only for the detailed description of the invention and are not intended to limit the scope of the rights thereby.

Example

Example 1 to 22

A mixture was prepared in the formulations shown in Tables 1 to 4 below. For reference, Table 1 shows non-metal additives, Table 2 shows sodium metal additives, and Table 3 shows calcium/potassium/magnesium metal additives.

Example 23

Example 22 of Table 4 was compressed by a direct tableting method to prepare a tablet containing 75 mg of eperisone hydrochloride.

Comparative example

Comparative example 1 to 2

100 mg of eperisone hydrochloride was taken and used as Comparative Example 1.

The control drug was stripped and made into powder, and 266 mg was taken as Comparative Example 2.

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Experimental example

<Contrary Treaty>

As a reference drug, Nerexon Seobangjeong (seller: Daewon Pharmaceutical, manufacturer: Ajou Pharm), which was notified by the KFDA as a reference drug, was used.

<Stability test>

After leaving Examples 1 to 22 at 80° C. and saturated moisture for 12 hours, it was confirmed by analyzing whether the content of the active ingredient was decreased and the amount of related substance A was increased by a liquid chromatography method.

The results were as shown in FIGS. 1 to 5. For reference, FIG. 1 is a graph of the stability test results of Examples 1 to 6 (non-metallic additives), FIG. 2 is a graph of the stability test results of Examples 7 to 12 (sodium metal additives), and FIG. 3 is Examples 13 to 16 (calcium/potassium metal additives) are a graph of the stability test results, and FIG. 4 is a graph of the stability test results of Examples 17 to 19 (magnesium metal additives).

As can be seen in FIG. 1, in the case of non-metallic additives, the amount of related substances and the level of reduction in the content were not large, and were equal to or higher than the commercially available control drug.

On the other hand, as can be seen in FIGS. 2 to 4, it was confirmed that most of the metal additives greatly reduced the stability of the active ingredient.

In addition, as can be seen in FIG. 5, the formulations containing no metal additives and the formulations using only non-metallic additives have significantly improved stability compared to the formulations containing metal additives, and are at a level equal to or higher than that of a commercially available control drug. It was confirmed that it was stable.

<Comparative dissolution test>

Each tablet of Example 23 and the control drug was put in a buffer solution at 37° C. and a pH of 1.2, and a comparative dissolution test was performed under the condition of a paddle method of 50 rpm, and the results are shown in Table 5 and FIG. 6. As a result of confirming the equivalence with the reference drug based on the drug equivalence test standard notified by the Ministry of Food and Drug Safety, the average dissolution rate of the reference drug when comparing the difference in the dissolution rate with the reference drug at three times when the dissolution rate of the reference drug is around 30%, 50% and 80% Since it was within ±10% of, the dissolution rate was equal to that of the reference drug.

Claims (8)

As a pharmaceutical composition comprising eperisone or a pharmaceutically acceptable salt thereof as an active ingredient,
A non-metal salt additive is included, and at the same time, a metal salt additive is not included,
Eperisone pharmaceutical composition, characterized in that the additive is a lubricant or disintegrant. The eperisone pharmaceutical composition according to claim 1, wherein the metal salt additive is magnesium stearate as a lubricant. The method according to claim 1, wherein the non-metallic salt additive is at least one selected from sucrose fatty acid ester, stearic acid, fumaric acid, hydrogenated vegetable oil, glyceryl behenate, glyceryl palmitostearate, starch, and PEG 6000 as a lubricant. Eperisone pharmaceutical composition. The pharmaceutical composition of claim 3, wherein the lubricant is contained in an amount of 0.01 to 15% by weight, based on the total weight of the composition. The eperisone pharmaceutical composition according to claim 1, wherein the non-metallic salt additive is at least one selected from crospovidone, low-substituted hydroxypropylcellulose, alginic acid, and pregelatinized starch as a disintegrant. The pharmaceutical composition of claim 5, wherein the disintegrant is contained in an amount of 0.01 to 25% by weight, based on the total weight of the composition. The eperisone pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable salt of eperisone is hydrochloride. The eperisone pharmaceutical composition according to claim 1, which is in the form of a tablet by compression molding.

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