KR20000059684A - A process for the preparation of extended release formulation containing a dihydropyridine derivative - Google Patents

Abstract

PURPOSE: A method for producing sustained release preparation containing dihydropyridin derivative is provided for improving convenience in use and reducing the frequency of administration. CONSTITUTION: The method for producing sustained release preparation containing dihydropyridin derivatives in particular, felodipine of formula (1) having antagonism against calcium, comprises the steps of: dissolving dihydropyridine derivative felodipine into an organic solvent; dissolving polyvinylpyrolidine into the organic solvent to produce binder solution; adding the binder solution to diluent mixture containing cellulose polymer and mixing them to produce sustained release preparation, in which the organic solvent is methanol, ethanol, acetone, methylene chloride, or the mixture thereof and cellulose polymer is hydroxypropylmethyl cellulose. The preparation contains 1 wt.% of felodipine, 1 to 50 wt.% of organic solvent, 0.5 to 5 wt.% of polyvinylpyrolidine, and 5 to 100 wt.% of cellulose polymer.

Description

A process for the preparation of extended release formulation containing a dihydropyridine derivative}

The present invention relates to a process for preparing a sustained preparation comprising a dihydropyridine derivative and to a sustained preparation prepared by the method.

Dihydropyridine derivative of Formula 1, namely, felodipine (Felodipine) is a drug useful in the treatment of circulatory diseases with calcium antagonism, solubility in water is very low 0.5mg / L.

In orally administrable preparations, poorly soluble substances, such as felodipine, play an important role in the absorption process and bioavailability. Therefore, Korean Patent Publication No. 95-2147 discloses a method for increasing bioavailability by adding a solubilizer as a method for increasing bioavailability of poorly soluble materials.

On the other hand, a method of using a solid dispersion is known as a method of increasing the dissolution rate of poorly soluble materials, which has the advantage of not using a solubilizer such as a surfactant. The solid dispersion is mainly composed of a melting method and a solvent method, and the double melting method is a method in which a poorly soluble drug and a carrier are melted by heating and then cooled to prepare a solid dispersion. The physical properties of the can vary. The solvent method is a method of preparing a solid dispersion by dissolving a poorly soluble drug and a carrier in a solvent which can be solubilized at the same time, and then drying the solvent to affect the physical and chemical stability of the solid dispersion due to the residual solvent.

In particular, in the case of preparing a solid dispersion by a solvent method using polyvinylpyrrolidone as a carrier, since it has a high viscosity property during the drying process, it is difficult to stir and because the strong viscosity is difficult to completely remove the organic solvent, residual solvent In case of using a solid dispersion prepared in the formulation, when the single dose of the main drug such as felodipine is small, the ubiquity of the drug occurs during the mixing of the excipients, resulting in poor content uniformity. In addition, due to the viscosity may delay the dissolution, there are many difficulties in industrial mass production.

On the other hand, in general, the drug for treating a disease is preferable because the drug is released at a constant rate to maintain a therapeutic concentration in the blood, thereby reducing the number of administration of the drug and increasing the convenience of the patient as well as reducing side effects. Therefore, a long-acting formulation is widely used as a drug for the treatment of diseases, and various methods of such a persistent formulation technology are currently known. For example, Korean Patent Publication No. 90-5009 discloses a method using pH-dependent binders to take advantage of the pH difference in the gastrointestinal tract.

The present inventors have conducted a lot of research to develop a sustained preparation containing felodipine, in particular, a ferrodipine-containing long-acting formulation that effectively solves the problems caused by using a solid dispersion by a solvent method without adding a solubilizer such as a surfactant. As a result of the efforts with the results, the present inventors have found that the preparation of a sustained preparation effectively improving the problem of content non-uniformity due to residual organic solvent and high viscosity has been completed.

It is therefore an object of the present invention to provide a process for the preparation of a sustained preparation comprising a dihydropyridine derivative, ie felodipine.

It is also an object of the present invention to provide a long-acting formulation prepared by the above production method.

1 is a view showing the mean blood concentration change when a persistent formulation containing felodipine is administered to a human body.

The present invention provides a sustained preparation comprising dissolving felodipine in an organic solvent and then dissolving polyvinylpyrrolidone to prepare a binder solution, and then adding and binding the binder solution to an excipient mixture containing a cellulose polymer. It is about a method.

Polyvinylpyrrolidone used in the production method of the present invention is a component used to increase the solubility of water in the crystalline structure of felodipine, the content is preferably 0.5 to 5 parts by weight based on 1 part by weight of felodipine. Do. According to the preparation method of the present invention, it is possible to prepare the pelodipine, which is a crystalline structure, in polyvinylpyrrolidone, which is an amorphous structure, in the form of a solid dispersion having increased solubility in water.

As the organic solvent usable in the production method of the present invention, an organic solvent capable of dissolving felodipine and polyvinylpyrrolidone may be used. Examples thereof include methanol, ethanol, acetone, methylene chloride or a mixture thereof. The amount is preferably used in an amount suitable for use as the binder liquid, for example, 1 to 50 parts by weight based on 1 part by weight of felodipine.

Cellulose polymers usable in the production process of the present invention are components added to prepare a long-acting formulation, preferably hydroxypropylmethylcellulose (e.g., Metolose 60SH-4000, Metolose 60SH-50, etc.) may be used, it is preferable to use 5 to 100 parts by weight based on 1 part by weight of felodipine.

The production method of the present invention may be prepared by including additives that are commonly added in the preparation of a sustained preparation, for example, by adding excipients such as anhydrous lactose and microcrystalline cellulose, and lubricants such as synthetic aluminum silicate and magnesium stearate. It may include.

The present invention encompasses long-acting formulations prepared according to the above methods, and particularly preferably the formulation is a tablet.

In the preparation method according to the present invention, since the felodipine is first dissolved in an organic solvent and then polyvinylpyrrolidone is used as a binder without a separate drying process, a solid dispersion is prepared separately using a medicine and a carrier. In other words, it can effectively solve problems such as residual organic solvent, difficulty in stirring due to high viscosity at the end of drying, and content nonuniformity. In the manufacturing method of the present invention, by uniformly mixing the liquid binder solution in which the pelodipine is dissolved with the excipient, the content is uniform, and the drying efficiency is increased, thereby easily removing the organic solvent, thereby improving the residual organic solvent and the content uniformity. In the general tablet granulation process without the additional process, the solid dispersion is produced, and the bioavailability is excellent without the addition of solubilizers such as surfactant.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, these examples do not limit the scope of the invention.

Example 1

Persistent tablets with the following compositions were made by the following method.

Pelodipine 0.5g

Polyvinylpyrrolidone K30 1.5 g

Lactose free 3.0g

Metolose 60SH-4000 3.5g

Metolose 60SH-50 12.0g

0.3g of microcrystalline cellulose

0.5 g magnesium stearate

Pelodipine was completely dissolved in 13 ml of ethanol, and then polyvinylpyrrolidone K30 was dissolved therein to prepare a binding solution. Lactose free, Metolose 60SH-4000, Metolose 60SH-50 and microcrystalline cellulose were mixed, and then, a binder solution prepared in advance was added thereto, then combined and granulated, and dried. After the dried product was established, magnesium stearate was added thereto as a lubricant, and the mixture was remixed, and a sustained tablet containing 5 mg of felodipine per tablet was obtained by a tablet press.

Example 2

A persistent tablet having the following composition was prepared in the same manner as in Example 1 except that synthetic aluminum silicate was added as a lubricant.

Pelodipine 0.5g

Polyvinylpyrrolidone K90 1.8g

Lactose free 2.0g

Metolose 60SH-4000 3.5g

Metolose 60SH-50 11.5g

0.3g of microcrystalline cellulose

Synthetic Aluminum Silicate 2.5g

0.2 g magnesium stearate

Example 3

A persistent tablet was prepared in the same manner as in Example 1 with the following composition.

Pelodipine 0.5g

Polyvinylpyrrolidone K90 1.8g

Lactose free 3.5g

Metolose 60SH-4000 3.5g

Metolose 60SH-50 12.0g

0.3g of microcrystalline cellulose

0.5 g magnesium stearate

Example 4

A persistent tablet was prepared in the same manner as in Example 1, except that 0.25 g of polyvinylpyrrolidone K90 was used.

Example 5

A persistent tablet was prepared in the same manner as in Example 1, except that 1 g of polyvinylpyrrolidone K90 was used.

Example 6

Except for using 2.5g of polyvinylpyrrolidone K30, the sustained tablet was prepared in the same manner as in Example 1.

Experimental Example 1

The total area under the peak blood concentration (Cmax), peak blood concentration reaching time (Tmax), and blood concentration / time curves after administration of the sustained tablet containing 5 mg of felodipine prepared in Example 3 in 16 healthy males As a result of measuring the pharmacokinetic parameters such as (AUC), Cmax was 1.50 ng / ml, Tmax was 6.2 hours, AUC was 19.60 ng · hr / ml, and the change in blood concentration was shown in FIG. 1.

As can be seen from the above pharmacokinetic parameters and Figure 1 it can be seen that the formulation according to the present invention exhibits a sufficient sustained effect.

The production method of the present invention can exhibit excellent bioavailability and sustainability effect without the addition of solubilizers such as surfactants, and can effectively solve the problems associated with the use of solid dispersions.

Claims (8)

A process for producing a sustained preparation comprising dissolving felodipine in an organic solvent and then dissolving polyvinylpyrrolidone to prepare a binder solution, and then adding the binder solution to an excipient mixture containing a cellulose polymer to associate the binder solution. The method of claim 1, wherein the organic solvent is methanol, ethanol, acetone, methylene chloride or a mixture thereof. The method of claim 2, wherein the content of the organic solvent is 1 to 50 parts by weight based on 1 part by weight of felodipine. The method of claim 1, wherein the content of the polyvinylpyrrolidone is 0.5 to 5 parts by weight based on 1 part by weight of felodipine. The method of claim 1, wherein the cellulose polymer is hydroxypropylmethylcellulose. The method of claim 1, wherein the content of the cellulose polymer is 5 to 100 parts by weight based on 1 part by weight of felodipine. A sustained preparation prepared by the process according to any one of claims 1 to 6. 8. The long-acting formulation of claim 7, wherein the formulation is a tablet.