KR20080097787A - Controlled release multiple layer tablet comprising loratadine and pseudoephedrine - Google Patents

Abstract

A controlled release multiple layer tablet is provided to have an excellent medical treatment effect by containing a loratadine and a pseudoephedrine and eluting the loratadine component and the pseudoephedrine component effectively. A multilayer tablet for oral comprises an immediate-released layer and a slowly-released layer. The immediate-released layer has a loratadine and a pseudoephedrine having a therapeutic effective amount as an active component. The slowly-released layer contains an erupted controlling agent and uses the pseudoephedrine as an active component.

Description

Controlled release multiple layer tablet comprising loratadine and pseudoephedrine

FIG. 1 is a graph showing the comparative elution curve of pseudoephedrine sulfate in a multi-layered tablet prepared according to Example 1 and a snico S capsule commercially available as a reference drug.

FIG. 2 is a graph showing the comparative elution curve of loratadine in a multi-layered tablet prepared according to Example 1 and a snico S capsule sold as a reference drug.

FIG. 3 is a graph showing comparative elution curves of pseudoephedrine sulfate in a multi-layered tablet prepared according to Example 7 and Claritin-D for 24 hours as a reference drug. FIG.

Figure 4 is a graph showing the comparative elution curve of loratadine in the multi-layered tablet prepared according to Example 7 and Claritin-D 24 hours tablet as a reference drug.

Figure 5 shows the loratadine dissolution rate in the formulation of Example 1 and Comparative Example 1.

The present invention relates to oral multi-layered tablets containing loratadine and pseudoephedrine and whose elution is controlled.

Pseudoephedrine, a sympathetic neurostimulant, or a pharmaceutically usable salt thereof, is widely known as a decongestant, and loratadine is a non-sleeping antihistamine that is used for allergic rhinitis, allergic skin diseases, and acute hay fever. .

When the two drugs are prepared as a combination, it can have an excellent effect on colds and allergic rhinitis (US Pat. No. 5,314,697).

However, pseudoephedrine sulfate has a half-life of 5 to 7 hours in the blood, and loratadine to 12 to 15 hours, and in particular, loratadine has a very low solubility and a slow dissolution rate. Therefore, it is difficult to maintain effective blood concentrations when the two drugs are prepared as a simple fast-release complex preparation due to the characteristics such as solubility, absorption rate and half-life of the two drugs.

Techniques proposed to solve the above problems include the following.

U.S. Pat. No. 5,314,697 discloses sustained-release tablets consisting of suedephedrine sulfate with a hydrophilic gel in a slow-release matrix core and then a film coating layer containing loratadine thereon.

As described above, a composition prepared by forming a sustained-release matrix core with pseudoephedrine and film-coating loratadine thereon is released after the release of pseudoephedrine from the pseudoephedrine-containing matrix core layer after oral administration by dissolving and removing the loratadine film coating layer. It is difficult to achieve effective blood levels of early pseudoephedrine. In addition, since a small amount of loratadine is coated on a film, there is a difficulty in a process that is difficult to coat the correct amount of loratadine. In addition, loratadine is not easily dissolved and removed in the sustained-release matrix core because the solubility and dissolution rate are rapidly decreased at high pH. Since the release of the sustained-release matrix core is coated with such loratadine, dissolution of pseudodoephrine sulfate is delayed and the dissolution rate is varied. There is a problem that occurs. In addition, the sustained-release matrix core contains the entire amount of pseudoephedrine sulfate, which is not suitable for obtaining a therapeutically effective initial plasma concentration of pseudoephedrine.

Korean Patent No. 505899 discloses an oral capsule containing an immediate release pellet containing loratadine and pseudoephedrine sulfate and a sustained release pellet containing pseudoephedrine sulfate.

As described above, in the case of a capsule consisting of an immediate release pellet containing loratadine and pseudoephedrine sulfate and a sustained release pellet containing pseudoephedrine sulfate, the rapid release of loratadine and pseudoephedrine on an inert carrier (usually crystalline sucrose seed) Since it is manufactured by coating the pellet with sustained-release pellets, it is difficult to coat the pellet in the correct amount, and since the same amount of the immediate release pellet and the sustained-release pellet are difficult to fill, the exact amount of loratadine in each capsule And it is difficult to obtain a formulation containing sulfur pseudoephedrine. In addition, it has a disadvantage in that the manufacturing process is complicated because the coating solution must be prepared and a process such as spraying and drying must be performed.

Accordingly, the present inventors prepare an immediate release layer comprising loratadine and pseudoephedrine and sustained release layer granules using pseudoephedrine as active ingredients, and include the above-mentioned granules in different layers to prepare tablets for oral administration. To solve the problems in the above-described manufacturing method, a composite formulation showing a preferred dissolution pattern was developed.

Conventional forms of the combination of loratadine and pseudoephedrine are formulated by coating the loratadine component on the surface of a pellet or tablet. This is because there is a pharmacological problem in formulating the pseudoephedrine component and loratadine component into a single tablet. Loratadine is very low in unit dosages of 5 to 10 mg and has poor solubility. However, the half-life of blood concentration in vivo is very long, 12 to 15 hours, so that the sustained effect is achieved only once a day, so no sustained release is required. However, pseudoephedrine has a high solubility and a short half-life in vivo, so it is advantageous to prepare a sustained release formulation. Therefore, when loratadine is compressed into a single tablet simultaneously with the pseudoephedrine sustained release formulation, loratadine adheres to the sustained release matrix of pseudoephedrine and thus cannot exhibit the desired rapid release. Therefore, for the purpose of complete phase separation with pseudoephedrine so as not to affect the release of the two drugs, the prior art is a method for preparing by dissolving loratadine in a coating liquid or a capsule containing pellets. That is, for the purpose of phase separation so that the two drugs exhibit distinct patterns of dissolution. The limitations of the prior art are mentioned and thus will be omitted.

Since the combined formulation of pseudoephedrine and loratadine according to the present invention can be completely separated in one tablet through a new formulation called multi-layered tablet, the controlled release of the two formulations that should exhibit different release patterns without affecting the release of each other It is possible.

In addition, the multi-layered tablet according to the present invention distributes a portion of the pseudoephedrine component to the immediate release layer so as to quickly reach the therapeutically effective initial effective blood concentration of pseudoephedrine due to rapid dissolution, and then, the pseudoephedrine contained in the sustained release layer is gradually Because of the release, a sustained effective blood concentration can be maintained.

The loratadine present in the immediate release layer of the present invention has a poor solubility and has a low unit dose, so if it adheres to the sustained release matrix at the interface, a sufficient amount of a disintegrant is required to prevent the dissolution rate. In addition, a low unit dose of loratadine should be supplemented with a sufficient amount of diluent to show content uniformity. To this end, a diluent and a disintegrant are added respectively, and pseudoephedrine, which has a relatively high solubility, acts as a diluent and a disintegrant in the immediate release layer, thereby additionally overcoming such a problem.

In addition, the multi-layered tablet of the present invention improved the manufacturing problems of the prior art, it was possible to secure a uniform content of loratadine and pseudoephedrine and to maintain a constant dissolution pattern between each individual by a simple manufacturing method by general granule preparation and tableting .

Multi-layered tablets according to the present invention can be administered once or twice a day as a single tablet, unlike in the conventional method of administering pseudoephedrine three times a day and separately loratadine once or twice a day. You can expect the effect to improve.

Accordingly, the present invention provides oral-modulated oral lysate as a loratadine / pseudoephedrine complex having a uniform content of loratadine and pseudoephedrine per tablet, and having improved solubility of the two drugs having different solubility, absorption and half-life in the body. The purpose is to provide a multi-layer tablet for.

The present invention

An immediate release layer containing a therapeutically effective amount of loratadine and pseudoephedrine simultaneously as an active ingredient,

It is characterized by an oral multilayer tablet comprising a sustained release layer containing pseudoephedrine as an active ingredient and containing an elutability modifier.

Hereinafter, the oral multilayer tablet of the present invention will be described in detail.

The present invention is composed of an immediate release layer containing loratadine and pseudoephedrine as an active ingredient and a sustained release layer containing pseudoephedrine as an active ingredient, and by tableting them in a multi-layered tablet, a complex of loratadine and pseudoephedrine can be easily produced. It is easy to take the medicine on the schedule, and the rapid disintegration of the immediate release layer results in the rapid dissolution of loratadine, and the pseudoephedrine contained in the immediate release layer is also rapidly eluted to achieve a therapeutically effective amount of pseudoephedrine at an early stage. The present invention relates to oral multilayer tablets with controlled elution as loratadine / pseudophedrine complexes, in which the effective amount of pseudoephedrine can be maintained for a long period of time to maintain an effective amount thereof, and thus the two active active ingredients exhibit a desirable dissolution pattern.

Hereinafter, it will be described in detail for each component constituting the oral multilayer tablet of the present invention.

Oral multilayer tablet of the present invention

An immediate release layer containing a therapeutically effective amount of loratadine and pseudoephedrine simultaneously as an active ingredient,

Oral multilayer tablet consisting of a sustained release layer containing pseudoephedrine as an active ingredient and an elutability regulator.

As used throughout the specification of the present invention, "therapeutically effective amount" of loratadine and pseudoephedrine means an amount necessary to obtain a desired therapeutic effect upon oral administration, the content of which is easily determined by those skilled in the art in consideration of various factors. Can be determined. Therapeutically effective amounts of loratadine and pseudoephedrine used in the present invention are 5-15 mg / day and 200-300 mg / day, respectively, based on 70 kg of adult male.

The immediate release layer constituting the oral multilayer tablet of the present invention contains loratadine and pseudoephedrine or a pharmaceutically acceptable salt thereof as an active ingredient.

The amount of pseudoephedrine contained in the immediate release layer is an amount sufficient to obtain a therapeutically effective blood concentration, and is in the range of 1 to 50% by weight of the total amount of pseudoephedrine contained in the immediate release layer and the sustained release layer, preferably 15 to 35%. Weight percent range.

The loratadine contained in the immediate release layer can maintain a 24-hour effect by administering once a day as the half-life of blood concentration is about 12 hours to 15 hours. Therefore, the amount of loratadine is sufficient to obtain a therapeutically effective blood concentration, and may contain 2.5 to 15 mg, preferably 5.0 to 10.0 mg, regardless of the weight percent range of the total weight.

The immediate release layer of the oral multi-layered tablet of the present invention is disintegrated in the eluate in a short time to increase the dissolution rate of loratadine, the therapeutically effective amount of pseudoephedrine was configured to achieve the initial blood concentration.

In order to show a high disintegration rate, disintegrants are used in the immediate release layer, and as such disintegrants, low-substituted hydroxypropyl cellulose, crospovidone, sodium starch glycolate, croscarmellose sodium, carboxymethylcellulose calcium, pregelatinized One or a mixture of two or more selected from starch, microcrystalline cellulose, ion exchange resin, corn starch, lactose, and the like may be used. Particularly, crospovidone, sodium starch glycolate, croscarmellose sodium may be used alone, or Preference is given to using mixtures.

The content of these disintegrants necessary to obtain the desired elution phase of loratadine and pseudoephedrine is preferably in the range of 1 to 75% by weight, preferably 5 to 50% by weight, based on the total weight of the immediate release layer.

The immediate release layer constituting the oral multilayer tablet of the present invention may contain one or more pharmaceutically acceptable additives such as excipients, binders, glidants or glidants, in addition to the active ingredients and disintegrants described above. It can be selected by those skilled in the art within the range that does not impair the effect and dissolution of the active ingredient, it is apparent that their selection does not limit the scope of the present invention.

The sustained release layer constituting the oral multilayer tablet of the present invention contains pseudoephedrine or a pharmaceutically acceptable salt thereof as an active ingredient and includes an elutability modifier.

The elutability modifier forms a polymer matrix in the sustained release layer as a component used to maintain the long-term efficacy of pseudoephedrine or a pharmaceutically acceptable salt thereof having a short half-life in blood and good solubility.

The elutability modifiers include hydrophilic polymers including cellulose derivatives, gums, hydrophilic (meth) acrylate copolymers, hydrophilic polyvinyl derivatives, polyethylene derivatives, carboxyvinyl compounds, polysaccharides, and the like, and hydrophobic polyvinyl derivatives and hydrophobic (meth) s. Hydrophobic polymer etc. containing an acrylate copolymer etc. can be used.

Specifically, the dissolution modifier is hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, methylcellulose, ethylcellulose, carboxymethylcellulose sodium, cellulose acetate, cellulose acetate phthalate and methyl Hydroxyethyl cellulose; guar gum, locust bean gum, tragacanta, carrageenan, acacia gum, xanthan gum, and gum arabic; and the like as poly (butyl methacrylate) as a hydrophilic (meth) acrylate copolymer. , (2-dimethylaminoethyl) methacrylate, methyl methacrylate) copolymer, poly (methacrylic acid, methyl methacrylate) copolymer and poly (methacrylic acid, ethyl methacrylate) copolymer , Polyvinyl alcohol as hydrophilic polyvinyl derivative , Polyvinylpyrrolidone and polyvinylacetyldiethylaminoacetate, polyethylene glycol and polyethylene oxide as polyethylene derivatives, carbomer and the like as carboxyvinyl compound, dextrin, polydextrin, dextran, Pectin and pectin derivatives, alginates, polygalacturonic acid, xylan, arabinoxylan, arabinogalactan, starch, hydroxypropylstarch, amylose, amylopectin and the like can be used.

The hydrophobic polymer has a polyvinylacetate as a hydrophobic polyvinyl derivative, a poly (ethyl acrylate, methyl methacrylate) copolymer and a poly (ethyl acrylate, methyl methacrylate, trimethyl as a hydrophobic (meth) acrylate copolymer Aminoethyl methacrylate) copolymer and the like can be used.

The above-mentioned dissolution control agents may be used alone or in combination of two or more, the amount of these dissolution control agents to exhibit the desired dissolution pattern intended in the present invention is in the range of 10 to 90% by weight of the total weight of the sustained release layer, Preferably it is 50 to 80% by weight.

The sustained-release layer constituting the oral multilayer tablet of the present invention may contain one or more pharmaceutically acceptable additives such as excipients, binders, glidants or glidants, in addition to the active ingredients and dissolution modifiers described above, and their contents The silver can be selected by those skilled in the art within the range that does not inhibit the effect and the elution of the active ingredient, it is apparent that their selection does not limit the scope of the present invention.

In addition, the conditions of the tableting method applied in the production of multilayer tablets may be applied to various conditions known in the art, and the contents of loratadine and pseudoephedrine as active ingredients may be appropriately adjusted according to the number of administrations.

In addition, the multi-layered tablet of the present invention may include a suitable film coating layer, the additive and coating method for forming the coating layer is generally carried out.

Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited by the following Examples.

Example  1 to 6: Take twice a day Loratadine  And Preparation of Pseudo-Ephedrine Sulfate-Containing Multi-Layered Tablets

Example 1

The multilayer tablets of the ingredients and contents shown in the following Table 1 were prepared. In other words, pseudoephedrine sulfate, loratadine, hard silicic anhydride, cellulose, and croscarmellose sodium were weighed as a rapid release layer, sieved through a 35 mesh sieve, and each drug was mixed and mixed using a drum mixer for about 60 minutes. Separately, magnesium stearate was weighed, sieved through a 35 mesh sieve, placed in the mixture of the immediate release layer, and mixed using a drum mixer for about 3 minutes to prepare a mixture of the immediate release layer.

Separately from above, pseudoephedrine sulfate, hard silicic anhydride, and hydroxypropylmethylcellulose 2208 (Example 1) were weighed in a sustained release layer, sieved through a 35 mesh sieve, and each drug was mixed and mixed by a drum mixer for about 60 minutes. . Separately, magnesium stearate was weighed, sieved through a 35 mesh sieve, placed in a mixture of the sustained layer, and mixed using a drum mixer for about 3 minutes to prepare a mixture of the sustained layer. The mixture of the immediate release layer and the sustained release layer, respectively, were compressed using a multi-layer tablet press (MRC-37T: Sejong) to prepare a multi-layered tablet such as double or triple tablets. The multi-layered tablets were put in a pan coater (High-coater: Sejong) and then film-coated using Opadry.

Examples 2-6

Examples 2 to 6 were prepared in the same manner as in Example 1, except that the hydroxypropylmethylcellulose 2208 was prepared in the kind and amount of the composition shown in Table 1 below.

Examples 7 to 12: Preparation of loratadine and pseudoephedrine sulfate-containing multilayer tablets taken once daily

Example 7

The multilayer tablets of the ingredients and contents shown in the following Table 2 were prepared. In other words, pseudoephedrine sulfate, loratadine, hard silicic anhydride, cellulose, and croscarmellose sodium were weighed as a rapid release layer, sieved through a 35 mesh sieve, and each drug was mixed and mixed using a drum mixer for about 60 minutes. Separately, magnesium stearate was weighed, sieved through a 35 mesh sieve, placed in the mixture of the immediate release layer, and mixed using a drum mixer for about 3 minutes to prepare a mixture of the immediate release layer.

Separately from above, pseudoephedrine sulfate, hard silicic anhydride, and hydroxypropylmethylcellulose 2208 (Example 7) were weighed in a sustained-release layer, sieved through a 35 mesh sieve, and each drug was mixed and mixed using a drum mixer for about 60 minutes. . Separately, magnesium stearate was weighed, sieved through a 35 mesh sieve, placed in a mixture of the sustained layer, and mixed using a drum mixer for about 3 minutes to prepare a mixture of the sustained layer. The mixture of the immediate release layer and the sustained release layer, respectively, were compressed using a multi-layer tablet press (MRC-37T: Sejong) to prepare a multi-layered tablet such as double or triple tablets. The multi-layered tablets were put in a pan coater (High-coater: Sejong) and then film-coated using Opadry.

Examples 8-12

Examples 8 to 12 were prepared in the same manner as in Example 7, except that the hydroxypropylmethylcellulose 2208 was manufactured in the kind and amount of the composition shown in Table 1 below.

Comparative example  One

The immediate release layer granules and the sustained release layer granules of Example 1 were mixed and compressed into a single tablet.

Test Example 1: Dissolution Test

Two doses of loratadine and pseudoephedrine sulfate-containing multi-layered tablets prepared in Example 1 and the same dose of sneaker S capsules (Yuhan, Korea) were eluted under the following conditions, respectively. 1 and 2 are shown.

[Dissolution test condition]

Eluent: pH 1.2

Temperature: 37 ℃

Method: Paddle law (US Pharmacopoeia)

Paddle Speed: 50 rpm

1 is a graph showing 12 hours of elution of pseudoephedrine sulfate, and early dissolution of pseudoephedrine sulfate occurs rapidly due to rapid disintegration of the immediate release layer, so that the initial blood concentration of the therapeutically effective amount of pseudoephedrine sulfate can be quickly reached. It is judged that since the release of pseudoephedrine sulfate slowly for 12 hours, it can be confirmed that the therapeutically effective blood concentration of pseudoephedrine sulfate can be maintained continuously.

Figure 2 is a graph showing the dissolution of loratadine, it can be confirmed that the dissolution of loratadine was quickly completed by the rapid disintegration of the immediate release layer.

Figure 5 shows the loratadine dissolution rate in the formulation of Example 1 and Comparative Example 1. As can be seen from the graph, it was confirmed that the release of loratadine was delayed by the pseudoephedrine sustained release dissolution regulator in the single tablet form.

Test Example  2: Dissolution test

The same dose of Clarita-D 24 hour tablet (Sheringpura, USA) as a control drug and loratadine and pseudoephedrine sulfate-containing multilayer tablets prepared in Example 7 were eluted under the same conditions as in Test Example 1. The test was performed and the results are shown in FIGS. 3 and 4, respectively.

Figure 3 is a graph showing 24 hours of elution of pseudoephedrine sulfate, and early dissolution of pseudoephedrine sulfate occurs rapidly due to rapid disintegration of the immediate release layer, and thus it is determined that the initial blood concentration of the therapeutically effective amount of pseudoephedrine sulfate can be quickly reached. Since the release of pseudoephedrine is gradually released for 24 hours, it can be seen that the therapeutically effective blood concentration of pseudoephedrine sulfate can be continuously maintained, whereas the initial dissolution is relatively low in the 24 hours of clarithin-D. It can be seen that.

Figure 4 is a graph showing the dissolution of loratadine, it can be confirmed that the dissolution of loratadine was quickly completed by rapid disintegration of the immediate release layer.

Test Example 3: Dissolution Test

The dissolution test was performed by preparing three lots of loratadine and pseudoephedrine sulfate-containing multilayer tablets, which were taken twice a day and once a day, prepared in Examples 1 and 7, respectively.

According to Table 3, there was no significant difference between the dissolution rates of pseudoephedrine sulfate and loratadine in the multilayer tablet of each lot, and the same or superior dissolution patterns were shown in comparison with the respective model drugs. That is, the combination of pseudoephedrine and loratadine according to the present invention has a simple manufacturing method, little variation in preparation, and has a superior therapeutic effect.

Test Example 4 Content Uniformity Test

Three lots of loratadine and pseudoephedrine sulfate-containing multi-layered tablets, which were taken twice a day and once a day, prepared in Examples 1 and 7 were prepared, respectively, and the content uniformity test was conducted for each lot. The test was carried out according to the content uniformity test method of the Korean Pharmacopoeia 8 revisions, and the criterion is appropriate when the judgment is less than 15%. The content was analyzed using high performance liquid chromatography, and the results are shown in Table 4 below.

According to Table 4, it can be seen that the pseudoephedrine sulfate and loratadine sulfate of each lot is suitable for content uniformity and the variation is small. In particular, it was confirmed that the superiority compared to the model drug.

As described above, the present invention provides a method that can be prepared by simply tableting a complex preparation having a superior therapeutic effect due to a constant content and dissolution rate of loratadine and pseudoephedrine. The present invention effectively eluted the loratadine component and the pseudoephedrine component to produce a multi-layered tablet in combination with a uniform content as well as excellent therapeutic effect. In addition, a simple manufacturing method was able to reduce the time and economic cost of the manufacturer. Lastly, by taking only 1 or 2 times a day, it was possible to improve patient compliance and reduce economic burden.

Claims (8)

An immediate release layer containing a therapeutically effective amount of loratadine and pseudoephedrine as active ingredients, An oral multilayer tablet comprising a sustained release layer containing pseudoephedrine as an active ingredient and an eluting regulator. The multi-layered tablet according to claim 1, wherein the pseudoephedrine comprises pseudoephedrine or a pharmaceutically acceptable salt thereof. The multilayer tablet according to claim 1, wherein the pseudoephedrine of the immediate release layer is included in the range of 1 to 50% by weight of the total pseudoephedrine content of the multilayer tablet. The multi-layered tablet of claim 1, wherein the immediate release layer comprises a pharmaceutically acceptable disintegrant. The method of claim 4, wherein the disintegrant is sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose, corn starch, carboxymethyl cellulose calcium, pregelatinized starch, microcrystalline cellulose, ion exchange resin and croscarmellose A multi-layered tablet comprising one or two or more mixtures selected from sodium. The multi-layered tablet according to claim 4, wherein the disintegrant comprises 1 to 50 wt% of the total weight of the immediate release layer. The method of claim 1, wherein the elutability modifier is a hydrophilic polymer comprising a cellulose derivative, gum, hydrophilic (meth) acrylate copolymer, hydrophilic polyvinyl derivative, polyethylene derivative, carboxyvinyl compound, polysaccharide, hydrophobic polyvinyl derivative, A multi-layered tablet, characterized in that one or a mixture of two or more selected from hydrophobic polymers containing a hydrophobic (meth) acrylate copolymer. The multi-layered tablet according to claim 7, wherein the elutability modifier comprises 10 to 90 wt% of the total weight of the sustained release layer.

Images