KR20130025851A - Tablet quickly disintegrating containg megestrol and method for producing the same - Google Patents

Abstract

PURPOSE: A megestrol rapidly disintegrating a tablet and a method for manufacturing the same are provided to ensure quick disintegration and administration convenience and to enhance drug release and absorption. CONSTITUTION: A megestrol rapidly disintegrating a tablet contains megestrol acetate as an active ingredient. The tablet is selected from a group consisting of a rapid disintegrant, a disintegrant, a binder, a flavoring agent, a sweetener, a lubricant, a polymer carrier, and an absorption enhancer. The rapid disintegrant is D-mannitol, sorbitol, fructose, lactose, dextrose, xylitol, white sugar, glucose, maltodextrin, levulose, erythritol, cellulose, fine crystalline cellulose, starch and a derivative thereof, -MELT (Fuji chemical), Ludiflash, spray-dried mannitol(Merck), Starlac(Roquette), and dextrate(Edward Mendell). [Reference numerals] (AA) 0 second; (BB) 10 seconds; (CC) 20 seconds; (DD) 30 seconds; (EE) 40 seconds

Description

Megestrol fast disintegrating tablet and a method for manufacturing the same {TABLET QUICKLY DISINTEGRATING CONTAING MEGESTROL AND METHOD FOR PRODUCING THE SAME}

The present invention relates to megestrol fast disintegrating tablets containing megestrol acetate as an active ingredient and a method for preparing the same.

Megestrol acetate is used as an anticancer agent for cancer appetite, weight loss and cachexia. Megestrol acetate has been developed in various formulations such as tablets and suspensions, such as Megace (Megace, BMS, USA), Megacenic Oral Suspension (Boryeong Pharm., Korea), Epitrol Oral Suspension (LG Life Science, Korea) It is commercially available.

However, patients taking large amounts of drugs, especially those with poor swallowing, have difficulty swallowing the drug. In taking suspensions, there is a hassle in the container (cup or pouch), or it is cumbersome to eat the residue with water, and the formulation in which the megestrol crystals are suspended in the liquid is settled over time. Doing so creates a solid precipitate layer and sometimes does not redistribute the dose. In other words, tablets and capsules, which generally make up the majority of oral preparations, are not easy to take in elderly or children who are difficult to swallow, and in the case of other powders and granules, they can easily remain in the oral cavity after dosing, causing discomfort. And the correct dosage is difficult.

 Therefore, the development of new formulations was needed to improve the compliance, ease of use, and accurate dosage. In order to solve this problem, the research on Sokbung tablets is being actively conducted, and these Sokbung tablets are rapidly disintegrating in the mouth, the drug is expressed quickly, and is a dosage form that can be easily taken when carrying.

Several drugs that dissolve or disintegrate in such oral cavity are known as fast disintegrating tablets.

For example, Japanese Patent Laid-Open No. 62-50445 describes a matrix-type fast disintegrating preparation prepared by preparing an aqueous solution containing gelatin together with a pharmaceutically acceptable active ingredient and lyophilizing it. However, the manufacturing method according to the patent publication is difficult to manufacture by using the manufacturing equipment of the conventional solid preparation, the investment of the equipment according to this, there is a disadvantage that takes much time compared to the general solid preparation in actual production. .

On the other hand, Japanese Patent Laid-Open Publication No. 2-32014 also describes a fast disintegrating tablet in the oral cavity prepared by freeze-drying the sugar, but as in the above technique, it did not solve the problem of equipment for manufacturing and freeze-drying the mold. As a result, mass production is difficult, and due to the nature of the manufacturing method, the hardness of the formulation is low, so that there is a difficulty in normal packaging (PTP) or handling.

U. S. Patent No. 3,885, 026 discloses a method for preparing porous tablets by mixing volatile excipients such as urea, urethane, ammonium carbonate, naphthalene and the like with other tablet components, followed by tableting and heating to volatilize the volatile excipients. However, there is a drawback that the excipients remaining in these tablets can cause fatal harm to the patient.

As such, studies on oral disintegrating agents for oral cavity are actively underway, but the above problems still remain, and in particular, reports on oral disintegrating tablets for oral megestrol, which were provided in suspension and were difficult for the patient to take, have been reported. There is no bar. Therefore, there is a need for studies on megestrol formulations prepared in the form of fast disintegrating tablets of the formulation of megestrol, which is provided only in suspension form.

The present inventors, while studying to improve the bioavailability of megestrol and improve the difficulty of taking, when manufacturing megestrol as a fast disintegrating tablet, can solve the problems of the conventional suspension formulation through rapid dissolution and absorption Revealed and completed the present invention.

It is an object of the present invention to provide megestrol fast disintegrating tablets and methods for their preparation, which are widely used in the form of suspensions to enable rapid absorption of megestrol which has been difficult to take.

In order to achieve the above object, the present invention provides a megestrol fast disintegrating tablet containing megestrol acetate as an active ingredient.

The present invention also provides a method for producing the megestrol fast disintegrating tablet.

The megestrol fast disintegrating tablet according to the present invention is disintegrated more quickly than conventional megestrol in the form of a suspension or suspension, providing convenience of taking, and at the same time increasing the dissolution and absorption of the drug to improve the taste of the drug. The shielding effect can be obtained.

1 is a view showing a result of measuring the time to disintegrate the megestrol oral disintegrating tablet of Example 8.
Figure 2 is a view showing the results of comparing the drug absorption in the beagle of megestrol oral fast disintegrating tablet of Example 2 with the commercially available mega suspension.

The present invention provides megestrol fast disintegrating tablets containing megestrol acetate as an active ingredient.

The tablet may include a pharmaceutically acceptable carrier in addition to the active ingredient megestrol acetate, and the pharmaceutically acceptable carrier may be used without limitation any kind of carrier generally used by manufacturers in the art. .

In addition, the megestrol fast disintegrating tablet may include an agent selected from the group consisting of fast disintegrating agents, disintegrating agents, binders, flavoring agents, sweetening agents, lubricants, polymer carriers, absorption enhancers.

The fast disintegrating agent is di-mannitol, sorbitol, fructose, lactose, dextrose, xyitol, sucrose, glucose, dexstrate, sucrose, fructose, maltose, maltodextrin, leblos, erythritol, cellulose, microcrystalline cellulose, starch And derivatives thereof, -MELT (Fuji chemical), Ludiflash (Basf), spray-dried mannitol (Merck), Starlac (Roquette), Dexrate (Edward Mendell), and Edward Mendell. The fast disintegrating agent may be contained in 10 to 70% by weight relative to the total weight of the tablet.

The disintegrant may be selected from one or two or more from the disintegrants generally used in the manufacture of tablets, preferably, adisole, sodium starch glyconate, collidone, rudy flash, crospovidone, croscarmellose sodium , Calcium carboxymethyl cellulose, pregelatinized starch and ion exchange resin, dicalcium phosphate (Calcium Phosphate, Dibasic) and the like. The disintegrant may be contained in 5 to 40% by weight relative to the total weight of the tablet.

The sweeteners include, but are not limited to, natural sweeteners such as sugar, glucose, honey, and artificial sweeteners such as saccharin, dulcin, cyclamate, aspartame, sorbitol.

The glidants include, but are not limited to, magnesium stearate, zinc stearate, calcium stearate, silicon dioxide, and the like.

The polymer carrier may include a povidone-based polymer, an acrylic acid copolymer-based polymer, a cellulose-based polymer, a polyvinyl alcohol, a polyethylene glycol-based polymer, sucrose fatty acid ester, and the like based on the total weight of the tablet. It may be contained in%.

As the povidone-based polymer, Kollidon 12 PF (Kollidon 12 PF), Kollidon 17 PF (Kollidon 17 PF), Kollidon 25 (Kollidon 25) Kollidon 30, Kollidon 90, and the like.

The acrylic acid copolymer-based polymer may include Eudragit E, Eudragit L, Eudragit S, Eudragit RS, Eudragit RL sold under the trade names Eudragit (Evonik, Germany). Can be.

The cellulose-based polymer may include hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), hydroxypropylmethyl cellulose phthalate (HPMCP), hydroxypropylmethyl cellulose acetate succinate (HPMCAS), and the like. have.

The polyvinyl alcohol-based polymer may include polyvinyl alcohol (PVA) having various molecular weights.

The polyethylene glycol-based polymer may include polyethylene glycol (PEG) having various molecular weights, for example, polymers such as PEG1000, PEG2000, PEG3000, PEG4000, and the like.

As the sucrose fatty acid ester, sucrose palmitate may be preferably used.

The absorption enhancer may be used without limitation in the materials disclosed in the art, but preferably tocopherol polyethylene glycol derivative, sodium lausyl sulfate, sucrose ester, polysorbate 80, macrogol-15 hydroxystearate, vitamin E-tocopherol Polyethylene glycol derivatives and polyoxyl 40 hydrogenated castor oil.

In addition, examples of conventional additives may include thickeners, pH adjusting agents, preservatives, buffers, flavoring agents, coloring agents and the like. The content of such additions preferably comprises 0.01 to 10% by weight, preferably 0.1 to 5% by weight relative to the total weight of the megestrol acetate powder formulation. The thickener includes, but is not limited to, natural cellulose, gelatin, methylcellulose, carbomer, carbopol pregel, and the like. The pH adjusting agent includes, but is not limited to, hydrochloric acid, sodium hydroxide, citric acid, phosphoric acid, lactic acid, tartaric acid, succinic acid, and the like. Preservatives may also include benzoic acid, sodium benzoate, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, sorbic acid, sodium sorbate, potassium sorbate, and the like. Lithium lactate, sodium lactate, potassium lactate, calcium lactate, lithium phosphate, sodium phosphate, potassium phosphate, calcium phosphate, lithium malate, potassium malate, calcium malate, malate, lithium tartarate, sodium tar Tartarate, potassium tartarate, tartarate, lithium succinate, sodium succinate, potassium succinate, calcium succinate, lithium acetate, sodium acetate, calcium acetate, potassium acetate or mixtures thereof. Flavoring agents may include artificial flavors, natural flavorings and herbal essences, and the like, and colorants may include dyes or pigments.

 The megestrol fast disintegrating tablet of the present invention may preferably be used for oral administration.

Also,

1) mixing the megestrol acetate, the fast disintegrating agent, and the binder with an apple of 30 to 40 mesh, followed by mixing;

2) associating the mixture mixed in step 1) with purified water;

3) drying the assembly of step 2) after assembling the 20-40 mesh body;

4) adding a disintegrant, a flavoring agent, a sweetener, and a lubricant to the dry association in step 3) and mixing the mixture; And

It provides a method for producing megestrol rapid disintegrating tablet comprising; 5) tableting the mixture obtained in step 4).

Also,

1) mixing megestrol acetate, a polymer carrier, and a lubricant to dissolve in an organic solvent;

2) spray-drying the dissolved mixed solution of step 1) to prepare a megestrol solid dispersion; And

3) provides a method for producing a megestrol fast disintegrating tablet comprising a; and compressing by mixing the megestrol solid dispersion and disintegrant, sweetener of 2).

The method may be characterized in that the megestrol acetate is mixed with a polymer carrier and a lubricant to dissolve in an organic solvent and spray-dried to obtain a megestrol acetate solid dispersion, followed by direct tableting by mixing a disintegrant and a sweetener. . Excipients for direct hitting, known to disintegrate quickly in addition to the wet method, such as Starlac (Roquette), F-MELT (Fuji chemical), spray-dried mannitol (Merck), dextrate (Edward Mendell), Ludiflash (BASF), and starch sucrose ( Edward Mendell) and the like can also be produced by direct blow dry method. When the oral disintegrant is produced by the dry direct method, it is possible to produce oral disintegrating tablets with better quality in a shorter period than the wet method.

In step 1), the absorption enhancer may be further mixed. The organic solvent includes, but is not limited to, methanol, ethanol, acetone, and the like, and any organic solvent capable of dissolving the components may be used. The amount of the organic solvent is preferably 100 to 150 times the mixture of megestrol acetate, the binder and the lubricant, but may be selected and used in an appropriate amount to dissolve the components.

Spray drying in step 2) is 70 ~ 120 ℃ inside temperature (in temp), 30 ~ 60 ℃ outside temperature (out temp), 70 ~ 120 ℃ nozzle temperature, 120 ~ gas flow rate (gas flow) It is preferably 140 L / min, more preferably, the internal temperature 100 ℃, the external temperature 50 ℃, nozzle temperature 100 ℃, gas flow rate may be 130L / min.

The megestrol solid dispersion may be contained in 30 to 50% by weight based on the total weight of the tablet, but is not limited thereto.

Hereinafter, the present invention will be described in detail with reference to Examples and Experimental Examples. However, the following examples and experimental examples are illustrative of the present invention, and the content of the present invention is not limited by the following examples and experimental examples.

Example  1 to Example  13. Megestrol Fast disintegration  Manufacture of tablets

Example  1 and Example  2

The active ingredient megestrol acetate 12.5% by weight, sugar alcohols (mannitol, sorbitol, erythritol) and pregelatinized starch were apples in a 40 mesh sieve and mixed. The prepared mixture was combined with warmed purified water as a solvent, and the association was assembled into a 30 mesh sieve, and then dried in a 40 ° C. dryer. After dissolving adisol and flavoring agents, sweeteners, and lubricants in the mixture was mixed with a single tablet press to prepare fast disintegrating tablets. Table 1 shows the specific composition of the fast disintegrating tablet comprising a guest roll according to the above production method.

Furtherance Example 1 Example 2 Medicine Megestrol acetate 12.5% 12.5% Fast disintegration Mannitol (EZ) 65% 50% Proctose (Advantose FS 95) 15% Binder Pregelatinized starch 8 % 8 % Disintegrant Acdisol (Ac-Di-Sol) 5% 5% Co-disintegration Collidone CL 6.5% 6.5% Flavoring agent Peppermint 0.1% 0.1% Sweetener Lactose 0.9% Aspartame 0.9% Lubricant Magnesium stearate 2.0% 2.0%

Example  3 to Example  6

Megestrol acetate disintegrating tablets were prepared by making megestrol acetate into a nanopowdered solid dispersion. The composition of the fast dissolving tablets is shown in Table 2.

ingredient Example 3 Example 4 Example 5 Example 6 Medicine Megestrol acetate 9.2% 9.2% 9.2% 9.2% Polymer carrier Collidone 25 46.2% Eudragit RS 46.2% PEG 4000 46.2% HPMCP-55 46.2% Lubricant Magnesium stearate 2.3% 2.3% 2.3% 2.3% Lubricant Silicon dioxide 2.3% 2.3% 2.3% 2.3% Disintegrant Ludiflash 39.9% 39.9% 39.9% 39.9% Sweetener Aspartame 0.1% 0.1% 0.1% 0.1%

The content of megestrol acetate was all 9.2% by weight, and the polymer carrier was Collidone 25 (Example 3), Eudragit RS (Example 4), PEG 4000 (Example 5), HPMCP-55 (Example 6). The glidants magnesium stearate and silicon dioxide were mixed with megestrol acetate and a polymer carrier and dissolved in 100 times methanol. The dissolved mixed solution was spray dried at an internal temperature of 100 ° C., an external temperature of 50 ° C., a nozzle temperature of 100 ° C., and a gas flow of 130 L / min. The megestrol nano powder solid dispersion was obtained through drying. The megestrol solid dispersion, rudy flash, and aspartame were mixed and compressed to tablet 2 g per tablet to prepare megestrol oral disintegrating tablet.

Example  7 to Example  13

Unlike Examples 3 to 6, tocopherol polyethylene glycol derivatives (Examples 7, 8, 11, and 12), sodium lauryl sulfate (Examples 9 and 13), and sucrose ester (Example 10), which are additional absorption enhancers, were used. To prepare megestrol fast disintegrants. Specific compositions of fast disintegrating tablets are shown in Tables 3 and 4.

ingredient Example 7 Example 8 Example 9 Example 10 Medicine Megestrol acetate 9.2% 9.2% 9.2% 9.2% Polymer carrier Collidone 90 36.2% Eudragit S100 30.0% PEG 4000 40.0% HPMCP 40.0% absorption
Enhancer Tocopherol Polyethylene Glycol Derivative 12.3% 18.5% Sodium Lauryl Sulfate 8.5% Sucrose ester 8.5% Lubricant Silicon dioxide 2.3% 2.3% 2.3% 2.3% Disintegrant Ludiflash 39.9% 39.9% 39.9% 39.9% Sweetener Aspartame 0.1% 0.1% 0.1% 0.1%

ingredient Example 11 Example 12 Example 13 Medicine Megestrol acetate 30% 30% 30% Polymer carrier Eudragit L100 15% Eudragit S100 15% Sucrose Palmitate 30% 15% 15% absorption
Enhancer Tocopherol Polyethylene Glycol Derivative 7.3% 13.5% Sodium Lauryl Sulfate 3.5% Sucrose ester Lubricant Silicon dioxide 2.3% 2.3% 2.3% Disintegrant Ludiflash 34.9% 34.9% 34.9% Sweetener Aspartame 0.1% 0.1% 0.1%

More specifically, megestrol acetate, polymer carrier (collidone 90, Eudragit S100, PEG 4000, HPMCP, Eudragit L100, sucrose palmitate), absorption enhancer (tocopherol polyethylene glycol derivative, sodium lauryl sulfate, sucrose Ester), magnesium stearate, and silicon dioxide were mixed and dissolved in 100 times of methanol, and the mixed solution was spray-dried under the same conditions as in Examples 3 to 6 to prepare megestrol nano powder solid dispersion. The obtained megestrol solid dispersion was mixed with Ludflash and sucralose, and compressed to tablet 2 g per tablet to prepare megestrol oral disintegrating tablet.

Experimental Example  One. Megestrol  acetate Sokbung Disintegration Rate  Measure

In order to measure the disintegration rate of the prepared megestrol acetate fast disintegrating tablets, the megestrol acetate fast disintegrating tablet prepared according to Example 8 was immersed in the pharmacopoeial gastric juice, and then the disintegration rate was observed.

The results are shown in Fig.

As shown in Figure 1, the megestrol oral fast disintegrating tablet of the present invention showed a disintegration quickly within 1 minute, through which can be greatly improved the ease of taking when dosing to patients with terminal cancer It was confirmed.

Experimental Example  2. Megestrol  Acetate oral Sokbung  Drug Blood Level Analysis

In order to confirm the improvement of drug absorption of the prepared megestrol acetate oral disintegrating tablets, pharmacokinetic experiments were performed in beagle. Specifically, oral fast disintegrating tablets of Example 2 prepared by tableting a beagle (n = 6) megestrol solid dispersion were administered orally by 100 mg each. After the drug administration, the blood of the beagle was taken 3 ml by time and centrifuged for 10 minutes at 10000rpm. 100 μl of serum was diluted 20-fold with acetonitrile, 100 μl of the supernatant was filtered through a 0.45 μm filter, and 5 μl was analyzed by LC-MS (3200Q TRAP LC / MS / MS). A commercial product (megace suspension, Megace) was used as a comparative group.

The results are shown in FIG.

As shown in Figure 2, the serum concentration of the megestrol acetate oral quick disintegrating tablet of the present invention was shown to be higher than the commercial group (megace suspension) taking group as a control until 9 hours after taking, 3 hours after taking It was confirmed that a very high concentration in serum was present within. Accordingly, it was confirmed that megestrol acetate oral quick disintegrating tablet is a formulation having improved bioavailability because it is rapidly absorbed into the body compared to conventional megestrol drug in suspension form.

Claims (14)

Megestrol fast disintegrating tablet containing megestrol acetate as an active ingredient.
The megestrol sokbung according to claim 1, wherein the tablet comprises an agent selected from the group consisting of a fast disintegrating agent, a disintegrating agent, a binder, a flavoring agent, a sweetening agent, a lubricant, a polymer carrier, and an absorption enhancer. Degradable tablets.
3. The fast disintegrating agent according to claim 2, wherein the fast disintegrating agent is di-mannitol, sorbitol, fructose, lactose, dextrose, xyitol, sucrose, glucose, dextrate, sucrose, fructose, maltose, maltodextrin, leblos, erythritol, cellulose , Consisting of microcrystalline cellulose, starch and derivatives thereof, -MELT (Fuji chemical), Ludiflash (BASF), spray-dried mannitol (Merck), Starlac (Roquette), dextrate (Edward Mendell), and Edward Mendell Megestrol fast disintegrating tablet, characterized in that at least one selected from the group.
The megestrol fast disintegrating tablet according to claim 3, wherein the fast disintegrating agent is contained in 10 to 70% by weight based on the total weight of the tablet.
3. The disintegrant according to claim 2, wherein the disintegrant is adisole, sodium starch glyconate, collidone, rudy flash, crospovidone, croscarmellose sodium, carboxymethylcellulose calcium, pregelatinized starch and ion exchange resin, diphosphoric acid Megestrol fast disintegrating tablet, characterized in that at least one selected from the group consisting of calcium (Calcium Phosphate, Dibasic).
The megestrol fast disintegrating tablet according to claim 5, wherein the disintegrant is contained in an amount of 5 to 40% by weight based on the total weight of the tablet.
The method of claim 2, wherein the polymer carrier is a povidone-based polymer Kollidon 12 PF (Kollidon 12 PF), Kollidon 17 PF (Kollidon 17 PF), Kollidon 25 (Kollidon 25), Kollidon 30 (Kollidon 30) , Kollidon 90; Eudragit E, Eudragit L, Eudragit S, Eudragit RS, Eudragit RL of the acrylic acid copolymer series; Sucrose palmitate, a sucrose fatty acid ester; Cellulose hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), hydroxypropylmethyl cellulose phthalate (HPMCP), hydroxypropylmethyl cellulose acetate succinate (HPMCAS); Polyvinyl alcohol; And polyethylene glycol; megestrol fast disintegrating tablet, characterized in that at least one selected from the group consisting of.
The megestrol fast disintegrating tablet according to claim 7, wherein the polymer carrier is contained in an amount of 10 to 50% by weight based on the total weight of the tablet.
3. The absorption enhancer of claim 2, wherein the absorption enhancer is a tocopherol polyethylene glycol derivative, sodium lausyl sulfate, sucrose ester, polysorbate 80, macrogol-15 hydroxystearate, vitamin E-tocopherol polyethylene glycol derivative and polyoxyl 40 hydrogenation. Megestrol fast disintegrating tablet, characterized in that at least one selected from the group consisting of castor oil.
The megestrol fast disintegrating tablet according to any one of claims 1 to 9, wherein the megestrol fast disintegrating tablet is for oral administration.
1) mixing the megestrol acetate, the fast disintegrating agent, and the binder with an apple of 30 to 40 mesh, followed by mixing;
2) associating the mixture mixed in step 1) with purified water;
3) drying the assembly of step 2) after assembling the 20-40 mesh body;
4) adding a disintegrant, a flavoring agent, a sweetener, and a lubricant to the dry association in step 3) and mixing the mixture; And
5) preparing a megestrol fast disintegrating tablet comprising the step of: tableting the mixture obtained in step 4).
1) mixing megestrol acetate, a polymer carrier, and a lubricant to dissolve in an organic solvent;
2) spray-drying the dissolved mixed solution of step 1) to prepare a megestrol solid dispersion; And
3) a method for preparing megestrol fast disintegrating tablets comprising the step of mixing and compressing the megestrol solid dispersion of 2), a disintegrant, and a sweetener.
The method for preparing megestrol fast disintegrating tablet according to claim 12, wherein the absorption enhancer is further mixed in step 1).
The method of claim 12, wherein the spray drying step 2) is the internal temperature (In temp) 70 ~ 120 ℃, Out temperature (30 ~ 60 ℃), nozzle temperature (head temp) 70 ~ 120 ℃, gas flow rate A process for producing megestrol fast disintegrating tablets, which is carried out under the conditions of 120 to 140 ° C.

Images