KR20070012205A - Controlled Release Pellets Containing Tolterodine With Stability Over Time - Google Patents

Abstract

The present invention relates to a novel pharmaceutical composition that can improve the stability over time during the storage and distribution of pellets controlling the release of the drug, and in particular, the drug is tolterodine, tolterodine-based compound or a pharmaceutically acceptable thereof. Controlled-release pellets containing possible salts, in particular sustained-release pellets, are soluble in dimethylaminoethyl methacrylate, methyl methacrylate copolymer (dimethylaminoethyl methacrylate copolymer; E ”) or polyvinylacetal diethylaminoacetate (hereinafter referred to as AEA), which relates to a novel pharmaceutical composition capable of preventing changes in dissolution rate for water during storage and distribution.

Description

Controlled-release pellet containing tolterodine with stability over time

Figure 1 shows the dissolution rate of the conventional controlled release pellets (Example 1) and those coated with Eudragit E of the present invention (Example 3) and coated with AEA (Example 4). .

Figure 2 shows the dissolution rate of the novel controlled release pellet (Example 2) of the present invention and coated with Eudragit E of the present invention (Example 5) and coated with AEA (Example 6) To show.

3 shows the results of evaluation of stability of Examples 1 and 3 over time.

4 shows the results of evaluation of stability of Examples 2 and 5 over time.

5 shows the results of evaluation of stability of Examples 1 and 4 over time.

6 shows the results of evaluation of stability of Examples 2 and 6 over time.

7 shows the results of evaluation of stability of Examples 7 and 8 over time.

The present invention relates to a novel pharmaceutical composition that can improve the stability over time during the storage and distribution of pellets for controlling the release of the drug, and in detail, the drug is a tolterodine, a tolterodine-based compound, or a pharmaceutical composition thereof. Controlled-release pellets, including sustained-release salts, specifically sustained-release pellets, are insoluble substances Eudragit E or polyvinylacetal diethylaminoacetate (hereinafter referred to as "AEA") at pH 5.5 or above. It is related with the novel pharmaceutical composition which can prevent the dissolution rate change with respect to moisture during storage and distribution.

Korean Patent No. 10-0467384 discloses pellets with controlled release (i) a core unit of an inert material that is substantially water soluble or water swellable; (ii) a first layer of substantially water-insoluble polymer on the core unit, which is suitable for controlling the permeation of water into the core; (iii) a second layer covering the first layer and containing the active ingredient; And (iv) a third layer of a polymer effective to control the release of the active ingredient on the second layer. The present inventors have found a problem that the dissolution rate of the pellets thus prepared is accelerated (40 ° C., R.H. 75%), and changes drastically depending on the storage period. Intensive research has been conducted to solve the problem of extreme drug deviation caused by the change of dissolution rate. As a result, satisfactory to invent a new composition coated with Eudragit E or AEA which is insoluble at pH above 5.5 Achievement was achieved. The controlled release pellets thus prepared were confirmed to significantly prevent the dissolution rate change over time under accelerated conditions due to improved stability to moisture, and completed the present invention.

In addition, the inventors of the present invention provide controlled pellets separate from the above patents in the course of research, which include: (i) a core unit of substantially insoluble material or water swellable inert material or waxes; (ii) a first layer covering the core unit and containing the active ingredient; And (iii) a second controlled release composition comprising a second layer of polymer on the first layer that is effective for controlling the release of the active ingredient, i.e. without a layer that controls the permeation of water into the core. . By coating the pellets with Eudragit E or AEA, it was possible to overcome the problem of changes in the dissolution rate over time during storage and distribution without involving the dissolution rate according to the coating.

Controlled-release, or sustained-release, formulations for drugs are well known in the art, and especially when developed in pellet form, drug dissolution is caused by in vivo factors such as gastrointestinal motility in patients as compared to matrix-type tablets. Since it can be minimized, it is known to be advantageous in reducing drug deviations between and within patients. Although many studies and inventions on such sustained-release preparations have been reported, there are few studies and inventions aimed at improving the stability of sustained-release preparations.

In general formulations that are not sustained-release, since the active ingredient shows sufficient dissolution within 4 hours, the increase and decrease of dissolution rate over time after manufacture may have little effect on the treatment and toxic expression of the patient. However, in sustained-release formulations designed to progressively elute the drug over 8 hours, changes in dissolution over time are not only significant to the treatment, but also severe. May cause toxicity. As such, it is true that such studies have not been fully carried out, although it is very important to secure the stability over time in designing sustained-release formulations.

In general, the material used for the moisture-proof coating affects the dissolution of the drug to some extent, so in the sustained-release formulations for finely controlling the dissolution rate, the selection of the material to be added for moisture-proof may be a key technology. In the present invention, by controlling the controlled release pellet containing tolterodine using Eudragit E or AEA used to mask the bitterness in the prior art, the stability during storage and distribution can be remarkably improved without affecting the dissolution rate. Could.

In the design of controlled-release, especially sustained-release formulations, the pellet form has less variation in drug dissolution due to in vivo factors such as gastrointestinal motility in the patient than in the tablet form of the matrix. It is known to be advantageous for reducing the deviation. However, the pellet form not only has a wider surface area in contact with external factors such as moisture and light than the matrix form manufactured by tablets, but also hydrophobic polymers alone or mixed with hydrophilic polymers rather than gelation of hydrophilic polymers. Since the release control layer is often used, there is a high risk of changing the dissolution rate over time according to storage conditions. Nevertheless, the conventional techniques for controlled release pellets are mostly related to the method of controlling the release of the active ingredient, and there is insufficient interest in the techniques related to securing stability over time. Controlled-release, especially sustained-release formulations contain a large amount of drugs compared to general formulations, so if the dissolution rate changes over time according to storage conditions, serious toxicity is caused to the patient, so securing stability over time is a very important task.

In the present invention, it is to ensure the stability over time for the pellet-type controlled release formulation having a significant advantage due to the small drug deviation in and between the patients compared to the tablet in the matrix form. Controlled release pellets include (i) a core unit of an inert material that is substantially water soluble or water swellable as known from Korean Patent No. 10-0467384; (ii) a first layer of substantially water-insoluble polymer on the core unit, which is suitable for controlling the permeation of water into the core; (iii) a second layer covering the first layer and containing the active ingredient; And (iv) a third layer of polymer on the second layer effective to control the release of the active ingredient, and (i) substantially water-soluble or water-swellable inerts or waxes developed by the inventors independently. Core unit; (ii) a first layer covering the core unit and containing the active ingredient; And (iii) a novel controlled release composition comprising a second layer of polymer on the first layer that is effective to control the release of the active ingredient, ie, a layer that does not control the permeation of water into the core.

Eudragit E or AEA was selected to prevent changes in dissolution rates over time during storage and distribution without affecting the dissolution rate of the controlled release composition. Since the pH of the stomach in vivo is typically considered to be pH 1.2, the added layer may quickly dissipate from the stomach for stability over time when taking the composition achieved in the present invention. That is, it is possible to ensure the same dissolution rate as that of the controlled release pellets containing no moisture barrier layer by rapidly dissipating from above the layer after taking it for the purpose of moisture barrier.

The present invention is characterized by coating with indra material Eudragit E or AEA at pH 5.5 or more in order to ensure the stability of the controlled release pellet, it is known in the Republic of Korea Patent Registration 10-0467384 One (i) a core unit of inert material that is substantially water soluble or water swellable; (ii) a first layer of substantially water-insoluble polymer on the core unit, which is suitable for controlling the permeation of water into the core; (iii) a second layer covering the first layer and containing the active ingredient; And (iv) a third layer of polymer on the second layer effective to control the release of the active ingredient, or (i) substantially water-soluble or water-swellable inerts or waxes developed by the inventors independently Core unit; (ii) a first layer covering the core unit and containing the active ingredient; And (iii) a novel controlled release composition consisting of a second layer of polymer effective on controlling drug release, ie, not comprising a layer that controls the permeation of water into the core.

Therefore, the first object of the present invention

(i) a core unit of inert material or waxes that is substantially water soluble or water swellable;

(ii) a first layer covering the core unit and containing tolterodine, a tolterodine-based compound or a pharmaceutically acceptable salt thereof as a drug; And

(iii) a second layer of polymer effective to control drug release on the first layer

It provides a novel controlled release pellet consisting of.

The controlled release pellet of the present invention is characterized in that the dissolution rate of the drug on the first layer is 80% or more after 18 hours in the dissolution test using the USP apparatus 1 at 900 mL of pH 6.8 phosphate buffer, temperature 37 ° C. and 100 rpm. Doing.

A second object of the present invention is to control-release pellets containing tolterodine, tolterodine-based compounds or pharmaceutically acceptable salts thereof Eudragit E or polyvinyl acetal diechyl insoluble at pH 5.5 or higher It is to provide a controlled release pellet having stability over time, characterized in that the coating coating with amino acetate (polyvinylacetal diethylaminoacetate).

Controlled-release pellets with stability over time of the present invention is characterized in that the dissolution rate of the drug in the dissolution test using the USP apparatus 1 at 900 mL pH 6.8 phosphate buffer, temperature 37 ℃ and 100 rpm conditions 60% or less after 24 hours. .

First, the novel controlled-release composition developed by the present inventors prepared a first layer by mixing a drug with a water-soluble polymer using inert beads composed of water-soluble or water-swellable substances or waxes as a core, and then preparing a water-insoluble polymer, A composition containing a second layer that controls drug release of the first layer by alone or by mixing a polymer having a pH-dependent solubility and a water-soluble polymer. That is, it is a novel pellet composition capable of achieving good drug dissolution without a layer controlling the permeation of water into the core among the compositions known from the conventional Korean Patent 10-0467384.

In the present invention, USP apparatus 1 containing tolterodine, a tolterodine-based compound, or a pharmaceutically acceptable salt thereof as a drug, and the temperature of 37 ° C. and 100 rpm using 900 mL of the first liquid of the 8th amendment of KP For 2 hours, and the sample was transferred to 900 mL of pH 6.8 phosphate buffer for 16 hours, for a total of 18 hours including the first solution, from 10 to 40% in 2 hours and 80% in the last 18 hours. Pharmaceutical formulations exhibiting the above dissolution rates are defined as controlled release formulations. It also includes semi-finished products that may appear in the intermediate process of preparing pharmaceutical formulations.

Materials that can be used as cores are known to those skilled in the art as sucrose / starch spheres (Sugar Spheres NF), sucrose crystals, or extruded and dried spheres consisting of typical excipients such as microcrystalline cellulose and lactose. Any pharmaceutically acceptable seed can be used without limitation, and preferably, a particle size in the range of 0.3 to 1.7 mm is used.

Examples of the core unit of the water-soluble or water-swellable inert substance usable in the present invention include sugars such as sucrose, mannitol, sorbitol and lactose, starch such as potato starch and corn starch, cellulose such as hydroxyethyl cellulose and microcrystalline cellulose. You can use more than 1 type.

In addition, white wax, Carnauba wax, and microcrystalline wax, which are commonly used pharmaceutically, may be used as a seed, and preferably, it contains carnauba wax. Seeds in the 0.3 to 1.7 mm size range are most suitable as cores.

Drugs constituting the first layer include tolterodine, tolterodine-based compound or a pharmaceutically acceptable salt thereof. Polymers used in admixture with drugs include polyvinylpyrrolidone (PVP), polyalkylene glycols such as polyethylene glycol, gelatin, polyvinyl alcohol, starch and derivatives thereof, cellulose derivatives such as hydroxypropyl Methyl cellulose (HPMC), hydroxypropyl cellulose, carboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, carboxyethyl cellulose and carboxymethyl hydroxyethyl cellulose, acrylic acid polymers, methacrylic acid or methacrylate Polymers (Eudragit L100-55, L30 D-55, L12.5, L100, S12.5, S100, FS 30D), hydroxypropylmethylcellulose phthalate and any other pharmaceutically acceptable polymer It includes. The ratio of drug and polymer is in the range of 1: 0.01-20 (mass / mass), and the mass ratio of the first layer to the core is in the range of 2 to 100%.

The second layer is a layer for controlling drug release alone or through addition of a water-soluble polymer so as to be suitable for the controlled release formulation defined in the present invention. Specific examples of water-insoluble polymers that can be used include hydroxyethylcellulose, methylcellulose, ethylcellulose, methacrylic acid and methacrylate polymers (Eudragit RS 12.5, RS 100, RS PO, RS). 30D, RL 12.5, RL 100, RL PO, RL 30D, NE 30D, NE 40D, L100-55, L30D-55, L12.5, L100, S12.5, S100, FS 30D, E12.5, E100, E PO), Polyethylene, Polyamide, Poly (Ethylene-Vinylacetate), Cellulose Nitrate, Silicone, Poly-Lactide-Co-Gly Water-insoluble materials commonly used as polylactic acid (poly [lactide-co-glycolide]), and specific examples of water-soluble polymers added for controlled release include polyethylene glycol and polyethylene oxide. ), Carboxymethylcellulose , Polyvinylpyrrolidone (PVP), hydroxypropylmethylcellulose (Hydroxypropylmethylcellulose), polyvinyl alcohol (Polyvinylalcohol), and the like, and includes a water-soluble polymer commonly used in the pharmaceutical field and sucrose (Sucrose), lactose Sugars such as Lactose, Mannitol, Sorbitol, etc. The second layer may comprise plasticizers commonly used in the pharmaceutical field for the integrity of the membrane. The amount and the ratio of the water-soluble polymer to be added may be used in various ways depending on the type and properties of the polymer in order to meet the conditions of the controlled release formulation prescribed in the present invention.

The controlled release pellets prepared as described above are coated with Eudragit E or AEA, which is an insoluble substance, at a pH of 5.5 or higher to significantly improve the stability over time. Methods to ensure sufficient target stability over time include drug coated on the first layer for 24 hours using USP Apparatus 1 at 900 mL of phosphate buffer at pH 6.8, temperature 37 ° C. and 100 rpm with coated pellets. When measuring the dissolution rate with respect to, the amount of coating that can maintain the dissolution rate of 60% or less is set. That is, since it is so natural to vary the amount of Eudragit E or AEA to be coated according to the size of the pellet, the coating amount may not be a feature of the present invention. In addition, a water-soluble polymer, a plasticizer, and a pigment may be added to improve the process and quality, but in any case, the dissolution rate is about 60% or less in the dissolution test, thereby improving stability over time for the controlled release pellet. The composition is characterized by the present invention. Such dissolution patterns include semi-finished products produced during the preparation of controlled release formulations containing tolterodine, tolterodine-based compounds or pharmaceutically acceptable salts thereof.

Example 1

800 g of 20 to 25 mesh billiard bodies were placed in a fluidized bed granulator, 523 g of Surelease (Colorcon Inc.) was suspended in 375 g of purified water to prepare a primary coating solution, and the coating was carried out at 36 to 40 ° C. 23.3 g of tolterodine L-tartrate and 4.4 g of hydroxypropylmethylcellulose (5 cps) were dissolved in 1.46 kg of purified water, followed by secondary coating. Dissolve 19.3 g of hydroxypropylmethylcellulose (5 cps) in 250 g of purified water, suspend 463 g of Sureia, and then carry out a third coating.

Example 2

Put 745.5 g of the billiard bodies corresponding to 18-20 mesh in the fluidized bed granulator and coat a solution of 24.0 g of tolterodine L-tartrate and 36.0 g of hydroxypropylmethylcellulose (5 cps) in 2.0 kg of 50% ethanol solution. 75.6 g of ethyl cellulose (20 cps) and 18.9 g of polyethylene glycol 6000 are dissolved in 90% ethanol solution, followed by secondary coating and drying.

Example 3

The pellet of Example 1 is coated by dissolving 1.09 kg of Eudragit E in 10.0 kg of 80% ethanol.

Example 4

The pellet of Example 1 is coated by dissolving 219 g of AEA in 1.5 kg of 80% ethanol.

Example 5

The pellet of Example 2 is coated by dissolving 900 g of Eudragit E in 6.0 kg of 80% ethanol.

Example 6

The pellet of Example 2 was coated by dissolving 180.0 g of AEA in 1.5 kg of 80% ethanol.

Example 7

745.5 g of Carnauba wax beads corresponding to 18 to 20 mesh were added to the fluidized bed granulator, and 22.0 g of tolterodine L-tartrate and 36.0 g of hydroxypropylmethylcellulose (5 cps) were dissolved in 2.0 kg of 50% ethanol solution. Coating. 75.6 g of ethyl cellulose (20 cps) and 18.9 g of polyethylene glycol 6000 are dissolved in 90% ethanol solution, followed by secondary coating and drying.

Example 8

The pellet of Example 7 was coated by dissolving 180.0 g of AEA in 1.5 kg of 80% ethanol.

Experimental Example

Dissolution Test Method

Precisely take an amount of pellets equivalent to 4.0 mg as tolterodine and fill it into an appropriate capsule, and then use USP Apparatus 1 at a temperature of 37 ° C. and 100 rpm using 900 mL of the first liquid of the 8th Amendment. Elution is carried out, and the sample is transferred to 900 mL of pH 6.8 phosphate buffer for 16 hours, including the first solution, for a total of 18 hours, and then the dissolution rate is calculated at each time point.

Figure 1 shows the dissolution rate of the conventional controlled release pellets (Example 1) and those coated with Eudragit E of the present invention (Example 3) and coated with AEA (Example 4) ,

Figure 2 shows the dissolution rate of the novel controlled release pellet (Example 2) of the present invention and coated with Eudragit E of the present invention (Example 5) and coated with AEA (Example 6) To show.

[Stability test method over time]

Evaluation for the prediction of the stability of the pellet over time was performed by dissolution test for 24 hours using USP apparatus 1 at a temperature of 37 ℃ and 100 rpm using a pH 6.8 phosphate buffer 900 mL.

  Stability Prediction Results Characteristic 24-hour dissolution rate Example 1  Conventional Controlled Release Pellets 91.0% Example 2  Novel controlled release pellets of the present invention 90.6% Example 3  Conventional controlled release pellets coated with Eudragit E 45.2% Example 4  Conventional controlled release pellets coated with AEA 14.7% Example 5  Novel controlled release pellets of the present invention coated with Eudragit E 41.6% Example 6  Novel controlled release pellets of the present invention coated with AEA 10.1% Example 7  Controlled Release Pellets Made from Carnauba Wax Beads 94.5% Example 8  Controlled-Release Pellets of Example 7 Coated with AEA 52.0%

[Stability evaluation method over time]

To evaluate the stabilization potential of pellets prepared with Eudragit E or AEA, 40 ° C., R.H. Dissolution test was performed after storing for 6 months at 75%.

3 shows the results of evaluation of stability of Examples 1 and 3 over time.

4 shows the results of evaluation of stability of Examples 2 and 5 over time.

5 is a result of the stability evaluation of Example 1 and Example 4 over time,

6 shows the results of evaluation of stability of Examples 2 and 6 over time.

7 shows the results of evaluation of stability of Examples 7 and 8 over time.

The present invention relates to a novel pharmaceutical composition that can improve the stability over time during the storage and distribution of pellets controlling the release of the drug, and in particular, the drug is tolterodine, tolterodine-based compound or a pharmaceutically acceptable thereof. Controlled-release pellets containing possible salts are coated and coated with insoluble substances Eudragit E or polyvinylacetal diethylaminoacetate (AEA) at pH 5.5 and above, thereby preventing moisture during storage and distribution. It is possible to prevent the dissolution rate change for the.

Claims (11)

Controlled-release pellets containing tolterodine, tolterodine-based compounds or pharmaceutically acceptable salts thereof are insoluble substances of dimethylaminoethyl methacrylate and methyl methacrylate copolymer, which are insoluble at a pH of 5.5 or higher. (Trade name: Eudragit E) or controlled release type pellets having stability over time, characterized in that the coating coating with polyvinylacetal diethylaminoacetate (polyvinylacetal diethylaminoacetate). The method of claim 1, wherein the controlled release pellet comprising the tolterodine, tolterodine-based compound or a pharmaceutically acceptable salt thereof (i) a core unit of inert material or waxes that is substantially water soluble or water swellable; (ii) a first layer covering the core unit and containing tolterodine, a tolterodine-based compound or a pharmaceutically acceptable salt thereof as a drug; And (iii) a second layer of polymer effective to control drug release on the first layer Controlled-release pellet having stability over time, characterized in that consisting of. The controlled release pellet comprising the tolterodine, tolterodine-based compound or a pharmaceutically acceptable salt thereof is prepared using USP Apparatus 1 at 900 mL pH 6.8 phosphate buffer, temperature 37 ° C. and 100 rpm. Controlled-release pellet having stability over time, characterized in that the dissolution rate for the drug on the first layer in the dissolution test is 80% or more after 18 hours. The method of claim 1, wherein the controlled release pellet comprising the tolterodine, tolterodine-based compound or a pharmaceutically acceptable salt thereof (i) a core unit of inert material or waxes that is water soluble or water swellable; (ii) a first layer of water insoluble polymer on the core unit; (iii) a second layer covering the first layer and containing the active ingredient; And (iv) controlled release pellets having stability over time, comprising a third layer of polymer effective to control the release of the active ingredient on the second layer. The method according to any one of claims 1 to 4, Coated with dimethylaminoethyl methacrylate-methyl methacrylate copolymer (trade name: Eudragit E) or polyvinylacetal diethylaminoacetate, which is an insoluble substance above pH 5.5. The controlled release pellets coated with controlled release with stability over time characterized in that the dissolution rate of the drug was 60% or less after 24 hours in the dissolution test using USP apparatus 1 at 900 mL of pH 6.8 phosphate buffer, temperature 37 ° C. and 100 rpm. Mold pellets. A pharmaceutical composition comprising a controlled release pellet having a stability over time according to claim 2. (i) a core unit of inert material or waxes that is substantially water soluble or water swellable; (ii) a first layer covering the core unit and containing tolterodine, a tolterodine-based compound or a pharmaceutically acceptable salt thereof as a drug; And (iii) consisting of a second layer of polymer effective to control drug release on the first layer, in a dissolution test using USP Apparatus 1 at 900 mL pH 6.8 phosphate buffer, temperature 37 ° C. and 100 rpm. Controlled-release pellet, characterized in that the dissolution rate for the drug is more than 80% after 18 hours. The method according to any one of claims 2, 4 or 7, The core unit of a water-soluble or water-swelling inert substance is one of cellulose selected from sucrose, mannitol, sorbitol, sugar selected from lactose, potato starch, corn starch, hydroxyethyl cellulose and microcrystalline cellulose. Controlled-release pellet having time-lapse stability, characterized in that it comprises more than one species. The method according to any one of claims 2, 4 or 7, A controlled release pellet having light stability according to claim 1, wherein the wax core unit is carnauba wax. The method according to any one of claims 2, 4 or 7, Controlled release with time-lapse stability, characterized in that the polymer effective to control the release of the drug comprises at least one of the cellulose, methyl cellulose, methacrylic acid and methacrylic polymers (Eudragit), hydroxyethyl cellulose Mold pellets. The method of claim 4, wherein A water-insoluble polymer, characterized in that it comprises one or more of ethyl cellulose, methyl cellulose, methacrylic acid and methacrylic acid polymers (Eudragit), hydroxyethyl cellulose pellets having a time-lapse stability characterized in that.

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