KR100893727B1 - Sustained release solid formulations and methods of manufacturing the same - Google Patents

Abstract

The present invention includes a drug, such as tramadol or a pharmaceutically acceptable salt thereof, in a water-insoluble matrix of wax-like lipid excipients, wherein the drug is coated with a hydrophobic carrier and adsorbed with an adsorbent. A sustained release solid formulation and a method for preparing the same, wherein the void inside the matrix is filled with the excipient and has a reduced void fraction in the matrix. The formulation is able to reduce the side effects of the drug and maintain the effective blood concentration for a long time by uniformly releasing the drug over a long period of time, and it is an economical and convenient method because it does not require expensive equipment and the type and amount of excipients is low. It can manufacture.

Tramadol, tramadol hydrochloride, sustained release formulations, wax-like lipid excipients, matrices, voids, porosity

Description

Sustained release solid formulations and methods of manufacturing the same

1 is a graph showing the dissolution test results of tablets at pH 6.5 (○: Comparative Example 1; ●: Zitram XL sustained-release tablet; △: Example 1; ▲: Example 3; □: Example 4; Example 7);

2A is a SEM photograph of the internal cross section of a tablet according to Comparative Example 1;

2B is a SEM photograph of the internal cross section of the tablet according to Example 1. FIG.

FIELD OF THE INVENTION The present invention relates to sustained release solid formulations and methods for the preparation thereof, and more particularly, includes a drug in a water-insoluble matrix of a wax-like lipid excipient, the drug Is a sustained-release solid preparation and a method for preparing the same, which are coated with a hydrophobic carrier and adsorbed with an adsorbent, and the voids in the matrix are filled with the excipients and have a reduced void fraction in the matrix.

Tramadol is a non-narcotic analgesic that acts directly on opiate receptors, but has few side effects, such as respiratory depression, which is apt to occur in narcotic analgesics. It is used. Tramadol was initially formulated as a rapid release tablet containing 50 mg of tramadol. However, tramadol has a short half-life in the case of fast-acting tablets, which requires a lot of administration per day, and may cause side effects if the initial blood concentration is too high for immediate-release tablets. In order to solve this problem, studies have been conducted on sustained-release preparations in which tramadol is gradually released over a long time to maintain effective blood concentration for a long time.

Tramadol hydrochloride is a drug that dissolves very well in water, and as an example for controlling its dissolution, Korean Patent No. 354,702 discloses a hydrogenated vegetable oil in which tramadol hydrochloride is melted according to a melt-pelletisation method. And the mixture was mechanically processed in a high speed mixer to form agglomerates, and the aggregates were pulverized to obtain controlled release sustained-release particles having a constant diameter of 0.1 to 3.0 mm, followed by talc and magnesium stearate. A technique for controlling the dissolution rate of a drug for 24 hours is disclosed by adding a lubricant to make a tablet. However, the above-mentioned technique requires an expensive manufacturing facility for producing a sustained-release tablet, requires a very sophisticated work, and has a disadvantage in that the production process is complicated and the manufacturing cost is high. On the other hand, Korean Patent No. 325,494 discloses a matrix type tablet which sustains the release for 12 hours using hydroxypropylmethylcellulose having a viscosity of 10,000 to 150,000 mPas. In addition, Korean Patent No. 712,356 is a double granule obtained by primary granulation of a drug by melt granulation using glyceryl behenate and second granulation of the granules obtained by wet granulation with a hydrophobic wet granulation material. Sustained release formulations for controlling 24-hour dissolution characterized in that they are prepared using granules are disclosed. However, the formulations are not only manufactured through a multi-step process, but also have a large amount (high weight%) of additives, so that the expected effects can be achieved. have.

Accordingly, the present inventors conducted a continuous study to develop a formulation that is simple, economical and can effectively release a drug over a long time while having a small amount of additives (% by weight) based on the weight of a unit formulation. As a result, it was confirmed that a matrix solid formulation of a water-insoluble base was prepared, but the base was heated and melted to fill voids formed in the matrix to reduce voids in the matrix, thereby providing a formulation meeting the above objectives. Furthermore, it was confirmed that a better sustained release effect could be achieved by coating the surface of the drug with a hydrophobic carrier and then adsorbing the adsorbent, thus completing the present invention.

Accordingly, it is an object of the present invention to provide a solid preparation which is simple in production and economical and can effectively and slowly release a drug for a long time while having a small amount of an additive to the weight of a unit preparation.

Another object of the present invention is to provide a method for preparing the sustained release solid preparation.

The first aspect of the invention comprises a drug in a water-insoluble matrix of a wax-like lipid excipient, wherein the drug is coated with a hydrophobic carrier and adsorbed with an adsorbent, and voids in the matrix are filled with the excipient and reduced in the matrix. It relates to a sustained release solid preparation having a pore fraction.

The second aspect of the present invention

Iii) coating the drug with a hydrophobic carrier and adsorbing with an adsorbent;

Ii) mixing the drug of step iii) with a wax-like lipid excipient to prepare a solid formulation;

Iii) heating the formulation of step ii) at a temperature above the melting point of the wax-like lipid excipient so that the wax-like lipid excipient melts to fill the voids formed inside the matrix such that the void fraction is reduced;

Iii) cooling the solid formulation of step iii):

It relates to a method for producing a sustained release solid preparation comprising the step.

Hereinafter, the present invention will be described in detail.

One aspect of the invention relates to a matrix sustained release solid preparation, which has the effect of slowly releasing the drug through the mechanisms ⑴ and 아래 below:

⑴ The drug is mixed with the wax-like lipid excipient to prepare a solid formulation, and then heat-treated at an appropriate temperature to melt the wax-like lipid excipient and fill the pores in the tablet, thereby reducing the porosity in the matrix to infiltrate the dissolution medium and the drug. Delays the release of.

O Covering the drug with a hydrophobic carrier and adsorbing onto the adsorbent to delay elution of the drug.

In the present invention, the 'solid preparation' includes all the solid preparations commonly used in the pharmaceutical field, and includes, for example, tablets, granules, capsules, powders, and the like, and most preferably refers to tablets. It is not particularly limited to.

Water-insoluble matrix bases commonly used in the pharmaceutical field include gradumet type using porous plastics and wax matrix type using hardened castor oil. The drug dispersed in such a water-insoluble matrix is leached out of the drug as the surrounding elution medium enters through a passage connected internally to pores or capillaries in the matrix. If the drug is distributed in the polymer matrix, the dissolution rate of the drug can be described by Higuchi equation (1):

[Equation 1]

[Q: release rate, D: dissolution rate constant of drug, A: surface area, C _S : solubility of drug, t: dissolution time]

As shown in Equation 1, the discharge amount Q is proportional to the dissolution time t ^1/2 . In the case where the drug distributed inside the matrix of the water-insoluble base is leached through an interstitial channel or a pore, the Higuchi equation can be expressed by modifying it as shown in Equation 2 below.

[Equation 2]

Wherein Q, D, A, and C _S are as defined in Equation 1,

ε represents porosity,

τ represents tortuosity.

An increase in τ represents an increase in the diffusion path due to branching or bending of the pores, whereby the release of drug in a given time decreases as τ increases. ε represents the fraction present in the matrix as holes or gaps through which ambient elution media can penetrate. The matrix preparation of the water insoluble base is characterized by the fact that the drug is released through the pores from the inside of the matrix while there is no change in appearance during the long and slow release of the drug. Thus, good matrix excipient materials should have adequate flexibility and porosity.

Meanwhile, as shown in Equation 2, the release amount of the drug may be controlled by controlling ε, that is, porosity. When compressing granules or powders containing drugs, no matter how excellent the compressibility is, there are very fine pores between the particles. Accordingly, the present invention is to provide a matrix formulation in which the internal structure is rearranged by reducing the fraction of voids formed in the matrix of the solid formulation prepared primarily. In the present invention, a wax-like lipid excipient is used as the water-insoluble matrix base, and a uniform heat is applied to the compression-molded formulation to melt the wax-like lipid excipient to fill the fine pores around, thereby reducing the porosity of the matrix structure rearranged. Obtained matrix formulation. The preparation according to the present invention is preserved intact without any change in appearance such as disintegration for 24 hours, but has the characteristic that the drug can be released slowly and effectively through the controlled pore inside the preparation.

The present invention can be applied to any water-soluble or water-insoluble active ingredient suitable for use in formulated as a sustained release solid preparation, examples of the active ingredient to which the present invention can be applied are as follows:

 Analgesics such as hydromorphone, morphine, diamorphine, fentanyl, alpretanil, oxycodone, flurbiprofen, diclofenac, ketoprofen; Doxazosin, prazosin, alpreolol, athenol, metoproolol, bufranolol, fenbutolol, propranolol, esmolol, bisoprool, siriprolol, sotalol, metifranolol. Blood pressure lowering agents such as nadolol, oxprenol, captopril, ramipril, posinopril, silazapril, enalapril; Anti-allergic agents such as pheniramine, dimethindene, terpenadine, astemisol, tritoqualine, loratadine, doxylamine, mequitazine, dexchlorpheniramine, triprolidine, oxatomid; Amoxicillin, Ampicillin, Becampisillin, Piperacillin, Fib Ampicillin, Cloxacillin, Penicillin V, Flucloxacillin, Erythromycin, Metronidazole, Clindamycin, Trimethoprim, Neomycin, Sephachlor, Sepaderoxil Antibiotics such as cepicsim, seppodoxime, cepuroxine, cephalexin, and sepradine;

Bronchodilators / anti-asthmatic agents such as pyrubuterol, orciprelinin, terbutalin, phenoterol, clenbuterol, salbutamol, procaterol, theophylline, cholinetheophylate, theophylline-ethylenediamine; Antiarrhythmic agents such as biquidyl, procaineamide, mexyltin, tocainide, propaphenone, and efradiopium; Tranylcipromide, clomipramine, maprotilin, doxepin, opipramol, amitriptyline, decipramine, imipramine, fluoxamine, fluoxetine, paroxetine, trazodone, haloperidol, fifamferon, Pimozide, sulfide, phenethylin, methylphenyldart, trifluoroperazine, thiolidazine, oxazepam, lorazepam, bromozepam, alprazolam, devalprox, venlafaxine, bupropion, diazepam, clovazam, buspyrone Nerve central agent, such as piracetam; Melparan, cyclophosphamide, trophosphamide, chlorambucil, lomustine, busulfan prednisostin, fluorouracil, methotrecetate, mercaptopurine, thioguanine, hydroxycarbamide, altamine, Cell growth inhibitors and metastasis inhibitors such as procarbazine; Anti-migraine drugs such as risulide, methiserzid, dihydroergotamine, ergotamine, and pizotifen; Gastrointestinal agents such as cimetidine, pamotidine, ranitidine, roxatidine, pyrenjipine, omeprazole, misoprostol, proglumide, cisapride, bromopride, metoclopramide; Oral antidiabetic agents such as tubutamide, glybenclamide, glypizide, glyquidone, glyburide, tlazamide, acarbose, metformin;

Urinary incontinence medications such as tolterodine, oxybutynin, tropium, propiberine, darfenacin, and solifenacin

And pharmaceutically acceptable salts or esters of the aforementioned ingredients and combinations of two or more of the foregoing.

The present invention is preferably applicable for analgesics, in particular tramadol or pharmaceutically acceptable salts thereof.

In the manufacture of solid preparations, especially tablets, in order to more properly control the dissolution rate of the drug, the drug may be hydrophobic carriers such as vegetable oils, mineral oils, oils such as synthetic oils, and HLB (Hydrophilic Lipophlic Balance) values. It is preferred to coat with a surfactant, phospholipid lecithin or mixtures thereof having a lipophilic property of less than 6 and adsorb with an adsorbent. The amount of the hydrophobic carrier is preferably 10 parts by weight or less, for example, 1 to 10 parts by weight based on 100 parts by weight of the drug. When the amount of the hydrophobic carrier is used more than this, the fluidity of the mixture may be lowered and the hardness of the tablet may be lowered. Can be. As the adsorbent, colloidal silicon dioxide, metal salts of talc or stearic acid and the like can be used. The amount of the adsorbent is preferably 50 to 150 parts by weight based on 100 parts by weight of the hydrophobic carrier. When the amount of the adsorbent is less than this, the moldability of the tablet may be deteriorated. When the amount of the adsorbent is higher, the density of the mixture may be lowered, which may make it difficult to tablet, and the tablet may have a low hardness.

Wax-like lipid excipients usable in the present invention may be one or more selected from glyceryl fatty acid esters or fatty acid esters. Glyceryl fatty acid esters specifically include glyceryl palmitostearate, glyceryl behenate, glyceryl stearate, glyceryl oleate, and glyceryl myrister. Glyceryl myristate. Fatty acid esters may specifically be cetyl palmitate, cetyl caprate, stearyl palmitate, stearyl stearate, and the like. In the present invention, it is most preferable to use glyceryl palmitostearate. Precirol ATO 5 ^® (Gatteffose, France), a trade name for glyceryl palmitostearate, has a low melting point of 53-57 ° C., particularly 56 ° C., and a wax-like wax having an HLB value of 2 Lipid excipient. Precilol ATO 5 ^® is an excipient used in the preparation of sustained release formulations as well as acting as a glidant as a natural lubricant. In the present invention, the freshroll ATO 5 ^® mainly acts as a release control. In the present invention, the freshroll ATO 5 ^® may be used alone or in admixture with other wax-like lipid excipients. The wax-like lipid excipient preferably contains 10 to 80 parts by weight based on 100 parts by weight of the drug.

In the present invention, wax-like lipid excipients may be used in admixture with other waxes such as carnauba wax, beeswax, pewter, paraffin, microcrystalline wax, hardened oil and the like. The amount of the wax used is preferably 10 to 200 parts by weight based on 100 parts by weight of the wax-like lipid excipient.

Another aspect of the present invention provides a method for preparing the sustained-release solid preparation, the method for producing a sustained-release solid preparation according to the present invention

Iii) coating the drug with a hydrophobic carrier and adsorbing with an adsorbent;

Ii) mixing the drug of step iii) with a wax-like lipid excipient to prepare a solid formulation;

Iii) heating the formulation of step ii) at a temperature above the melting point of the wax-like lipid excipient so that the wax-like lipid excipient melts to fill the voids formed inside the matrix such that the void fraction is reduced;

Iii) cooling the solid formulation of step iii):

Steps.

In step iii), for more adequate release control, the drug may be used as an oil that is a liquid or semi-solid hydrophobic carrier, e.g. vegetable oil, mineral oil or synthetic oil, amphoteric with an lipophilic property of less than 6 HLB. It can be coated directly with a surfactant, phospholipid lecithin or mixtures thereof or mixed in a small amount of ethanol and then coated and the ethanol can be removed, for example at 50 ° C. It is then adsorbed with an adsorbent, for example colloidal silicon dioxide, talc or a mixture thereof.

In step ii), the coated and adsorbed drug is mixed with wax-like lipid excipients, for example by tableting to obtain tablets. A direct compression method is preferable for tableting, but a conventional method such as a wet granulation compression method or a dry granulation compression method can be used as necessary. When using the direct hit method, as known in the pharmaceutical art, direct hitting excipients such as anhydrous lactose, spray dried lactose, microcrystalline cellulose and calcium dihydrogen phosphate may be used together. The wet granulation method uses water or ethanol to coalesce the mixed powder, granulates it, and compresses the granules obtained by drying again.

In step iii), the contained wax penetrates into the matrix voids by heating for a time above the melting point of the wax-like lipid excipient using the agent obtained in step ii), i.e., at a temperature and time at which the excipient does not melt on the surface of the agent. . For example, heating is performed at a temperature of 3 ° C. or higher, preferably 3 to 10 ° C., higher than the melting point of the wax-like lipid excipient for 1 to 7 hours. In the case of mixing two waxes, excipients with a high melting point are based. For example, the melting point of Freshroll ATO 5 ^® is 53-57 ° C, and the melting point of Compritol 888 ATO ^® (glyceryl behenate) is 70 ° C. It is preferable to make it about 1 hour at ° C. If the temperature is too high or the heat treatment time is too long, the wax-like lipid excipient melts and flows on the surface of the formulation, so it is desirable to maintain a suitable temperature and time to preserve the appearance of the formulation.

In step iii), the tablet obtained in step iv) is gradually cooled to room temperature, for example.

In the present invention, other conventional release modifiers, for example, polyvinylacetate, polyethylene oxide, hydroxypropylalkylcellulose, hydroxyalkylcellulose, sodium alginate, xanthan gum, locust bean gum, amoniomethacrylate copolymer, meta At least one selected from the group consisting of anionic copolymers of methacrylic acid methyl or methacrylic acid, acetyl succinate hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate and carboxyvinyl polymer (Carbopol ^® ) Can be used together. In addition, the formulation of the present invention may be prepared in dragees, film-coated tablets and the like using a coating agent commonly available in the pharmaceutical field.

Hereinafter, the present invention will be described in more detail with reference to Examples, which are intended to aid the understanding of the present invention but are not intended to limit the scope of the present invention in any way.

Example 1 Preparation of Sustained-Release Tablets ⑴

5 g of Labrafil ^® M 1944 CS were coated with good mixing with 150 g of tramadol hydrochloride. After homogeneous mixing, the mixture was adsorbed with 5 g of colloidal silicon dioxide. The adsorbate was mixed with 48 g of Freshol ATO 5 ^® and 70 g of Lubritab ^® , and then appled with a No. 60 sieve. Talc and magnesium stearate were added to the mixture to prepare a sustained release tablet of tramadol hydrochloride having a weight of 290 mg per tablet using a long axis 13 mm single axis 7 mm punch. This tablet was dispersed in a single layer on a wide plate and heat-treated in an oven at 70 ° C for 2 hours. After heat treatment it was cooled to room temperature to obtain a homogeneous tablet in which the matrix structure was rearranged. The amount of each component per unit tablet is shown in Table 1 below.

Composition of tablets Example 1  Mg / tablet Weight percent per tablet Hydrochloric acid 150 51.7 Freshroll ATO 5 ^® 48 16.6 Lubritab ^® 70 24.14 Labrador ^® M 1944 CS 5 1.72 Colloidal silicon dioxide 5 1.72 Talc 7 2.4 Magnesium Stearate 5 1.72 Sum 290 100

Example 2 Preparation of Sustained-Release Tablets ⑵

LabrafilTM ^® M 1944 CS 7 g and then uniformly mixed in ethanol, 3 g, was covered with mixing tramadol hydrochloride and 150 g. After drying at 50 ° C. for 1 hour, ethanol was removed and adsorbed with 7 g of colloidal silicon dioxide. The adsorbate was mixed with 48 g of freshol ATO 5 ^® and 70 g of Lubritab ^® and then apologies in a No. 60 sieve. Magnesium stearate was added to this mixture, and a sustained-release tablet of tramadol hydrochloride having a weight of 290 mg per tablet was prepared using a long axis 13 mm single axis 7 mm punch. This tablet was dispersed in a single layer on a wide plate and heat-treated in an oven at 68 ° C for 5 hours. After heat treatment it was cooled to room temperature to obtain a homogeneous tablet in which the matrix structure was rearranged. The amount of each component per unit tablet is shown in Table 2 below.

Composition of tablets Example 2  Mg / tablet Weight percent per tablet Hydrochloric acid 150 51.7 Freshroll ATO 5 ^® 48 16.6 Lubritab ^® 70 24.1 Labrador ^® M 1944 CS 7 2.4 Colloidal silicon dioxide 7 2.4 Magnesium Stearate 8 2.8 Sum 290 100

Example 3: Preparation of Sustained-Release Tablets ⑶

LabrafilTM ^® M 1944 CS 9 g After uniformly mixed in ethanol, 4 g, were coated with mixing tramadol hydrochloride and 150 g. After homogeneous mixing, the mixture was adsorbed with 9 g of colloidal silicon dioxide. The adsorbate was mixed with 45 g of Freshol ATO 5 ^® and 65 g of Lubritab ^® and then apologies in a No. 60 sieve. Talc and magnesium stearate were added to the mixture to prepare a sustained release tablet of tramadol hydrochloride having a weight of 290 mg per tablet using a 11 mm short axis 9 mm elliptical punch. This tablet was dispersed in a single layer on a wide plate and heat-treated in an oven at 68 ° C for 5 hours. After heat treatment it was cooled to room temperature to obtain a homogeneous tablet in which the matrix structure was rearranged. The amount of each component per unit tablet is shown in Table 3 below.

Composition of tablets Example 3  mg / tablet Weight percent per tablet Hydrochloric acid 150 51.7 Freshroll ATO 5 ^® 45 15.5 Lubritab ^® 65 22.4 Labrador ^® M 1944 CS 9 3.1 Colloidal silicon dioxide 9 3.1 Talc 8 2.8 Magnesium Stearate 4 1.4 Sum 290 100

Example 4 Preparation of Sustained-Release Tablets ⑷

LabrafilTM ^® M 1944 CS 10 g and then uniformly mixed in ethanol, 5 g, was covered with mixing tramadol hydrochloride and 150 g. After homogeneous mixing, the mixture was adsorbed with 7 g of colloidal silicon dioxide. The adsorbate was mixed with 48 g of freshol ATO 5 ^® and 70 g of Lubritab ^® and then apologies in a No. 60 sieve. Magnesium stearate was added to this mixture, and a sustained-release tablet of tramadol hydrochloride having a weight of 290 mg per tablet was prepared using an 11 mm single axis 9 mm elliptical punch. This tablet was dispersed in a single layer on a wide plate and heat-treated in an oven at 68 ° C for 5 hours. After heat treatment it was cooled to room temperature to obtain a homogeneous tablet in which the matrix structure was rearranged. The amount of each component per unit tablet is shown in Table 4 below.

Composition of tablets Example 4  mg / tablet Weight percent per tablet Hydrochloric acid 150 51.7 Freshroll ATO 5 ^® 48 16.6 Lubritab ^® 70 24.1 Labrafil® M 1944 CS 10 3.5 Colloidal silicon dioxide 7 2.4 Magnesium Stearate 5 1.7 Sum 290 100

Example  5: Sustained release  Preparation of tablets ⑸

LabrafilTM ^® M 1944 CS 9 g After uniformly mixed in ethanol, 4 g, were coated with mixing tramadol hydrochloride and 150 g. After homogeneous mixing, the mixture was adsorbed with 9 g of colloidal silicon dioxide. The adsorbate was mixed with 45 g of Freshol ATO 5 ^® and 65 g of Lubritab ^® , granulated with 80% ethanol, appled with a No. 20 sieve, and re-established with No. 20 sieve. Talc and magnesium stearate were added to the mixture to prepare a sustained release tablet of tramadol hydrochloride having a weight of 290 mg per tablet using a 11 mm short axis 9 mm elliptical punch. This tablet was dispersed in a single layer on a wide plate and heat-treated in an oven at 68 ° C for 5 hours. After heat treatment it was cooled to room temperature to obtain a homogeneous tablet in which the matrix structure was rearranged. The amount of each component per unit tablet is shown in Table 5 below.

Composition of tablets Example 5  mg / tablet Weight percent per tablet Hydrochloric acid 150 51.7 Freshroll ATO 5 ^® 45 15.5 Lubritab ^® 65 22.4 Labrador ^® M 1944 CS 9 3.1 Colloidal silicon dioxide 9 3.1 Talc 8 2.8 Magnesium Stearate 4 1.4 Sum 290 100

Example 6: Preparation of Sustained-Release Tablets ⑹

LabrafilTM ^® M 1944 CS 12 g and then uniformly mixed in ethanol, 6 g, was covered with mixing tramadol hydrochloride and 150 g. After homogeneous mixing, the mixture was adsorbed with 6 g of colloidal silicon dioxide. The adsorbate was mixed with 45 g of Freshol ATO 5 ^® and 65 g of Lubritab ^® , granulated with 80% ethanol, appled with a No. 20 sieve, and re-established with No. 20 sieve. Talc and magnesium stearate were added to the mixture to prepare a sustained release tablet of tramadol hydrochloride having a weight of 290 mg per tablet using a 11 mm short axis 9 mm elliptical punch. This tablet was dispersed in a single layer on a wide plate and heat-treated in an oven at 68 ° C for 5 hours. After heat treatment it was cooled to room temperature to obtain a homogeneous tablet in which the matrix structure was rearranged. The amount of each component per unit tablet is shown in Table 6 below.

Composition of tablets Example 6  mg / tablet Weight percent per tablet Hydrochloric acid 150 51.7 Freshroll ATO 5 ^® 45 15.5 Lubritab ^® 65 22.4 Labrador ^® M 1944 CS 12 4.1 Colloidal silicon dioxide 6 2.1 Talc 8 2.8 Magnesium Stearate 4 1.4 Sum 290 100

Experimental Example  1: dissolution test

The dissolution aspect of the drug from the tramadol hydrochloride sustained release tablet prepared according to Examples 1 to 6 was measured using the second method (paddle method) of the USP dissolution test method. As a test solution, 900 mL of a phosphate buffer solution of pH 6.5 was used, and the rotation speed of the paddle was 100 rpm. After the eluate was taken and filtered according to a predetermined time, the content of tramadol hydrochloride in the filtrate was measured by high performance liquid chromatography (HPLC). In Comparative Example 1, the dissolution patterns were compared using a tablet prepared as in Example 1 but not coated with a hydrophobic carrier, adsorbed with an adsorbent, and not subjected to heat treatment. The results are shown in Table 7 below and FIG. 1.

Dissolution Rate by Hour (%) Hours (hr) Comparative Example 1 Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 0.5 40.55 - - - - - - One 64.53 17.7 18.3 18.1 15.7 18.4 18.1 2 93.04 25.0 25.8 25.5 21.4 26.3 24.6 3 - 30.4 31.8 31.1 26.3 32.7 29.5 4 - 35.4 36.9 35.7 30.2 38.3 33.6 6 - 43.9 45.7 44.2 37.8 48.1 41.0 8 - 51.7 53.2 51.1 45.0 57.0 47.2 12 - 64 64.9 61.9 54.0 66.1 56.4 16 - 74.9 75.2 71.4 63.0 75.8 65.5 20 - 83.6 82.4 79.9 71.2 81.2 71.2 24 - 89.1 87.7 85.2 77.8 86.9 78.3

Example 7 Preparation of Sustained-Release Tablets

LabrafilTM ^® M 1944 CS 12 g and then uniformly mixed in ethanol, 6 g, was covered with mixing tramadol hydrochloride and 150 g. After homogeneous mixing, the mixture was adsorbed with 7 g of colloidal silicon dioxide. The adsorbate was mixed with 45 g of Freshol ATO 5 ^® and 65 g of Lubritab ^® , granulated with 80% ethanol, appled with a No. 20 sieve, and re-established with No. 20 sieve. Talc and magnesium stearate were added to the mixture to prepare a sustained release tablet of tramadol hydrochloride having a weight of 290 mg per tablet using a 11 mm short axis 9 mm elliptical punch. This tablet was dispersed in a single layer on a wide plate and heat-treated in an oven at 68 ° C for 5 hours. After heat treatment it was cooled to room temperature to obtain a homogeneous tablet in which the matrix structure was rearranged. The amount of each component per unit tablet is shown in Table 8 below.

Composition of tablets Example 7  Mg / tablet Weight percent per tablet Hydrochloric acid 150 51.72 Freshroll ATO 5 ^® 45 15.52 Lubritab ^® 65 22.4 Labrador ^® M 1944 CS 12 4.14 Colloidal silicon dioxide 7 2.41 Talc 7 2.41 Magnesium Stearate 4 1.4 Sum 290 100

Experimental Example 2: Dissolution Test

Experimental Example except that pH 4.0 and pH 6.5 buffers were used for the tablets prepared in Example 7 and commercially available Zytram ^® XL sustained-release tablets (150 mg / tablet, Mundipharma), respectively. Dissolution test was carried out according to the same method as in 1. The results are shown in Table 9 and FIG.

Example 8 Preparation of Sustained-Release Tablets ⑻

LabrafilTM ^® M 1944 CS 12 g and then uniformly mixed in ethanol, 4 g, were coated with mixing tramadol hydrochloride and 200 g. After homogeneous mixing, the mixture was adsorbed with 12 g of colloidal silicon dioxide. The adsorbate was mixed with 64 g of Freshol ATO 5 ^® and 93 g of Lubritab ^® , granulated with 80% ethanol, appled with a No. 20 sieve, and re-established with No. 20 sieve. Talc and magnesium stearate were added to the mixture to prepare a sustained-release tablet of tramadol hydrochloride having a weight of 387 mg per tablet and a hardness of 4 to 6 kp using an 11 mm short axis 9 mm elliptical punch. This tablet was dispersed in a single layer on a wide plate and heat-treated in an oven at 68 ° C for 5 hours. After heat treatment it was cooled to room temperature to obtain a homogeneous tablet in which the matrix structure was rearranged. The amount of each component per unit tablet is shown in Table 10 below.

Composition of tablets Example 8 Mg / tablet Weight percent per tablet Hydrochloric acid 200 51.7 Freshroll ATO 5 ^® 64 16.5 Lubritab ^® 93 24.0 Labrador ^® M 1944 CS 12 3.1 Colloidal silicon dioxide 12 3.1 Magnesium Stearate 6 1.6 Sum 387 100

Experimental Example 3: Dissolution Test

In Experimental Example 1 except that 900 ml of water was used for tablets prepared in Example 8 and commercially available Zitram ^® XL sustained-release tablets (200 mg / tablet, MundiPharma) and the rotational speed of the paddles was set at 50 rpm. Dissolution test was carried out according to the same method. The results are shown in Table 11.

Dissolution Rate by Hour (%) Hours (hr) Zitram ^® XL Sustained Release Example 8 0.25 9.4 9.2 0.5 14.5 12.7 One 21.9 17.9 1.5 27.3 21.8 2 31.6 25.0 3 38.1 30.4 5 48.2 39.9 6 52.1 43.8 8 58.6 51.2 10 64.0 57.7 12 68.2 63.2 24 86.7 86.9

Experimental Example 4: SEM Photographing

Changes in the internal structure of the tablet after heat treatment were investigated by SEM photography. In other words, the tablets of Comparative Example 1 and the tablets of Example 1 were cut in the middle by hand, and their cross sections were coated with platinum, and then subjected to an electric field scanning electron microscope (FESEM, manufactured by JEOL, model name JSM7000F) under an acceleration voltage of 15 kv. Observation was made at fold magnification. The photographs respectively taken are shown in FIGS. 2A and 2B. As shown in FIGS. 2A and 2B, when the monolayer surface of the tablet is not heat-treated, many voids remain, but the cross-section of the heat-treated tablet is filled with wax excipients to fill the voids in the tablet, and the matrix structure inside the tablet is rearranged. It could be confirmed.

Sustained release solid preparations according to the present invention, by releasing the drug uniformly over a long time, not only can reduce the side effects of the drug and maintain the effective blood concentration for a long time, but also requires expensive equipment with little type and amount of excipients It can be manufactured in an economical and convenient way.

Claims (12)

Iii) the drug is coated with a liquid or semi-solid hydrophobic carrier selected from the group consisting of vegetable oils, mineral oils, synthetic oils, amphoteric surfactants having an HLB value of less than 6, phospholipid lecithin and mixtures thereof, followed by colloidal dioxide Adsorbing with an adsorbent selected from the group consisting of silicon, talc and mixtures thereof; Ii) glyceryl selected from the group consisting of glyceryl palmitostearate, glyceryl behenate, glyceryl stearate, cetyl palmitate, stearyl palmitate, stearyl stearate and mixtures thereof Mixing with fatty acid esters or fatty acid ester excipients to prepare a matrix solid formulation; Iii) heating the formulation of step ii) at a temperature above the melting point of the excipient such that the excipient melts to fill voids formed within the matrix; Iii) cooling the solid formulation of step iii): Prepared by a method comprising a step, A sustained-release solid preparation comprising a drug in a water-insoluble matrix of the excipient, wherein the drug is coated with a hydrophobic carrier and adsorbed with an adsorbent, and voids in the matrix are filled with the excipient. delete The drug of claim 1, wherein the drug is an analgesic agent, an antiallergic agent, an antihypertensive agent, an antibiotic, a bronchodilator / anti-asthma agent, an antiarrhythmic agent, a cell growth inhibitor and a metastasis inhibitor, an antimigraine agent, a gastrointestinal drug, an oral diabetes treatment, an urinary incontinence drug , Sustained release solid preparations selected from the group consisting of pharmaceutically acceptable salts and esters thereof, and combinations thereof. The sustained release solid preparation of claim 3, wherein the drug is tramadol or a pharmaceutically acceptable salt thereof. delete The sustained-release solid preparation according to claim 1, which contains 10 to 80 parts by weight of the excipient with respect to 100 parts by weight of the drug. delete The sustained-release solid preparation according to claim 1, wherein the amount of the liquid or semi-solid hydrophobic carrier is 1 to 10 parts by weight based on 100 parts by weight of the drug, and the amount of the adsorbent is 50 to 150 parts by weight based on 100 parts by weight of the liquid or semi-solid hydrophobic carrier. . The sustained release solid preparation of claim 1, further comprising a wax selected from the group consisting of carnauba wax, beeswax, pewter, paraffin, microcrystalline wax, hardened oil, and mixtures thereof. 2. Alkylcellulose, polyvinylacetate, polyethylene oxide, hydroxypropylalkylcellulose, hydroxyalkylcellulose, sodium alginate, xanthan gum, locust bean gum, ammoniomethacrylate copolymer, methacrylic acid and methacrylic acid Sustained release solids further comprising a release modifier selected from the group consisting of anionic copolymers of acid methyl or ethyl esters, acetylsuccinate hydroxypropylmethylcellulose, phthalic acid hydroxypropylmethylcellulose, carboxyvinyl polymers and mixtures thereof Formulation. Iii) the drug is coated with a liquid or semi-solid hydrophobic carrier selected from the group consisting of vegetable oils, mineral oils, synthetic oils, amphoteric surfactants having an HLB value of less than 6, phospholipid lecithin and mixtures thereof, followed by colloidal dioxide Adsorbing with an adsorbent selected from the group consisting of silicon, talc and mixtures thereof; Ii) glyceryl selected from the group consisting of glyceryl palmitostearate, glyceryl behenate, glyceryl stearate, cetyl palmitate, stearyl palmitate, stearyl stearate and mixtures thereof Mixing with fatty acid esters or fatty acid ester excipients to prepare a matrix solid formulation; Iii) heating the formulation of step ii) at a temperature above the melting point of the excipient such that the excipient melts to fill the voids formed inside the matrix; Iii) cooling the solid formulation of step iii): Method for producing a sustained release solid formulation, comprising the step. The method for producing a sustained release solid preparation according to claim 11, wherein the step (iii) heats the solution at a temperature of 3 to 10 ° C. higher than the melting point of the excipient for 1 to 7 hours.

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