KR20130014715A - Oral formulation comprising megestrol acetate powder with enhanced bioavailability, and method for preparing the same - Google Patents

Abstract

The present invention relates to a preparation for oral administration and a method for preparing the same, comprising a megestrol acetate acetate with improved bioavailability. Acetate megestrol powder formulation according to the present invention is dissolved in an organic solvent by mixing megestrol acetate, a binder and a lubricant in a specific weight ratio, and spray-drying, superior dissolution rate and bioavailability than conventional megestrol suspensions It is economical because the manufacturing process is simple and can be manufactured in a short time by a simplified method.

Description

Oral dosage form including megestrol acetate powder with enhanced bioavailability, and method for preparing the same}

The present invention relates to a preparation for oral administration and a method for preparing the same, comprising a megestrol acetate acetate with improved bioavailability.

Megestrol acetate (megestrol acetate) are 17-alpha-acyloxy-6-methyl-4,6-diene-3,20-dione as a program regeuna, Bristol-Myers squeezing beusa methoxy geyiseu ^(? Megace) by a commercially available It is becoming. Acetate megestrol is used in the treatment of anorexia, cachexia, or significant weight loss in cancer or AIDS patients.

Megestrol acetate can be used in various pharmaceutical formulations such as tablets and capsules, but it has been developed and used as a liquid suspension when patients cannot swallow tablets or capsules or require high doses (800 mg or more).

Therefore, a lot of research is being conducted on the technology for formulating megestrol acetate as a suspending agent, and as a patent document related to this, Korean Patent Publication No. 10-841082 discloses a written suspension of acetic acid megestrol as a suspension agent, Korea Patent Publication No. 10-900915 describes a suspension formulation containing megestrol acetate and a method for preparing the same, and Korean Patent Publication No. 10-2011-42874 discloses a suspending agent containing acetate megestrol.

However, the suspension containing the above-described acetate agar-agar has a disadvantage of low bioavailability.

In order to overcome this drawback, studies have been made to reduce the particles of acetic megestrol continuously. For example, Korean Patent Publication No. 10-2008-24213 discloses milling, homogenization, precipitation, Nanoparticulate megestrol formulations prepared using freezing, template emulsion methods, or combinations thereof are described. However, when formulating megestrol acetate in the above method has a number of problems, such as a long time homogenization process is required and the drug is decomposed due to the high temperature generated in the homogenization process.

On the other hand, in recent years, a lot of research to reduce the particle size of the drug by using a spray drying technology to increase the solubility or bioavailability of the drug. However, there is no research to reduce the particle size of megestrol acetate using spray drying.

Therefore, there is an urgent need for the development of an acetate megestrol formulation which increases the bioavailability after decreasing the particle size of the megestrol acetate using spray drying.

The inventors of the present invention, while studying the acetate megestrol formulation which increased the bioavailability by reducing the particle size of the acetate megestrol, and mixed with a specific weight ratio of the megestrol acetate, the polymer carrier and the lubricant, dissolved in an organic solvent Spray dried to prepare a megestrol acetate acetate formulation, it was confirmed that the dissolution rate and bioavailability of the prepared acetate megestrol powder formulation is superior to the conventional megestrol acetate suspension, and completed the present invention.

Therefore, the present invention is to provide a formulation for oral administration and a method for preparing the same comprising a megestrol acetate megestrol powder with improved bioavailability.

The present invention is oral administration comprising megestrol acetate megestrol powder, characterized in that the mixture of megestrol acetate, a polymer carrier and a lubricant in a weight ratio of 1: 1 to 10: 0.05 to 0.25, dissolved in an organic solvent and spray-dried It provides a formulation.

In addition,

1) preparing a mixed solution by mixing megestrol acetate, a polymer carrier and a lubricant at a weight ratio of 1: 1 to 10: 0.05 to 0.25, and dissolving it in an organic solvent; and

2) providing a preparation method for oral preparations comprising acetic acid megestrol powder, comprising the step of spray-drying the mixed solution to produce acetic acid megestrol powder.

Hereinafter, the present invention will be described in detail.

Oral administration formulation comprising megestrol acetate megestrol powder of the present invention, a megestrol acetate, a polymer carrier and a lubricant are mixed in a weight ratio of 1: 1 to 10: 0.05 to 0.25, dissolved in an organic solvent and spray-dried It is characterized by.

The polymer carrier may include a povidone-based polymer, an acrylic acid copolymer-based polymer, a cellulose-based polymer, a polyvinyl alcohol-based polymer, and the like.

As the povidone-based polymer, Kollidon 12 PF (Kollidon 12 PF), Kollidon 17 PF (Kollidon 17 PF), Kollidon 25 (Kollidon 25) 30, collidone 90F, and the like, but is not limited thereto.

The acrylic acid copolymer-based polymer includes Eudragit E, Eudragit L, Eudragit S, Eudragit RS, Eudragit RL sold under the trade names Eudragit (Evonik, Germany). It is not limited to this.

The cellulose-based polymer includes hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), hydroxypropylmethyl cellulose phthalate (HPMCP), hydroxypropylmethyl cellulose acetate succinate (HPMCAS), etc. It is not limited to this.

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

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

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 amount of the mixture of megestrol acetate, a polymer carrier and a lubricant, but may be used by selecting an appropriate amount to dissolve the components.

The spray drying conditions are 80 ~ 120 ℃ inside temperature (in temp), 40 ~ 60 ℃ outside temperature (out temp), 70 ~ 110 ℃ head temp, gas flow rate (gas flow) 120 ~ 135L / min Is preferably.

The formulation for oral administration of the present invention may further include conventional additives such as thickeners, pH adjusting agents, preservatives, buffers, sweeteners, flavoring agents, colorants, dispersants or absorption accelerators. The content of the additive may include 0.01 to 10% by weight, preferably 0.1 to 5% by weight based on the total weight of the megestrol acetate 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.

The preservatives include, but are not limited to, benzoic acid, sodium benzoate, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, sorbic acid, sodium sorbate, potassium sorbate, and the like.

The buffer includes citrate buffer, lithium lactate, sodium lactate, potassium lactate, calcium lactate, lithium phosphate, sodium phosphate, potassium phosphate, calcium phosphate, lithium malate, potassium malate, calcium malate, malate , Lithium tartrate, sodium tartrate, potassium tartrate, tartrate, lithium succinate, sodium succinate, potassium succinate, calcium succinate, lithium acetate, sodium acetate, calcium acetate, potassium acetate or their Including but not limited to mixtures.

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 flavoring agents include, but are not limited to, artificial flavors, natural flavors, and herbal essences.

The colorant includes, but is not limited to, a dye or a pigment.

The dispersant includes, but is not limited to, an organic dispersant and a paraffin dispersant of sorbitan.

The absorption accelerators include, but are not limited to, polysorbate 80, macrogol-15 hydroxystearate, vitamin E-TPGS, polyoxyl 40 hydrogenated castor oil, sodium lauryl sulphate, and the like.

The particle form of the megestrol acetate acetate formulation according to the present invention is spherical, the particle size is less than 10 μm, preferably less than 2 μm, and the average particle diameter is 100 to 1000 nm, preferably 500 nm.

Acetate megestrol powder formulation according to the present invention is dissolved in an organic solvent by mixing megestrol acetate, a binder and a lubricant in a specific weight ratio, and spray-drying, superior dissolution rate and bioavailability than conventional megestrol suspensions It is economical because the manufacturing process is simple and can be manufactured in a short time by a simplified method.

Preparations for oral administration according to the present invention can be formulated in the form of tablets, powders, granules, capsules, syrups and the like by conventional methods.

The dosage of the formulation for oral administration according to the present invention varies depending on the weight, age, sex, health condition, diet, administration time, administration method, excretion rate and severity of the disease. In the case of conventional acetate megestrol suspension, the daily dose was higher than 800 mg, but in the case of the acetic acid megestrol powder formulation of the present invention, the daily dose was increased to about 400 to 500 mg to reduce the dose, once a day. It is preferable to administer dividedly to several times.

Acetate megestrol powder formulation according to the present invention is superior in dissolution rate and bioavailability than conventional megestrol acetate suspension, and the manufacturing process is simple and can be prepared in a short time by a simplified method is economical.

1 is a view of the particle form of the megestrol acetate acetate formulation of the present invention at a 1000x magnification with a scanning electron microscope.
Figure 2 is a view showing the dissolution rate analysis results of the acetate megestrol powder formulation of the present invention.
3 is a diagram analyzing the blood concentration by administering the acetic acid megestrol powder of the present invention to the beagle.

Hereinafter, preferred embodiments of the present invention will be described in order to facilitate understanding of the present invention. However, the following examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited by the examples.

Example  One  : Spray drying  Acetic acid Megestrol  Preparation of Powder Formulations

Megestrol acetate: PVP 25 (povidone K 25): magnesium stearate: silicon dioxide (silicon dioxide) was mixed in a weight ratio of 1: 5: 0.05-0.25: 0.05-0.25. The mixture was dissolved in 100-150 times methanol and spray-dried with a nano spray dryer B-90 / buchi to prepare a megestrol acetate formulation. The spray drying conditions are as follows: the internal temperature (in temp) is 80 ~ 120 ℃, the outside temperature (out temp) is 40 ~ 60 ℃, head temp is 70 ~ 110 ℃, gas flow rate (gas flow) 120-135 L / min.

Example  2  : Spray drying  Acetic acid Megestrol  Preparation of Powder Formulations

Megestrol acetate: PVP 25 (povidone K 25): magnesium stearate: silicon dioxide were mixed in a weight ratio of 1: 3: 0.05 to 0.25: 0.05 to 0.25. The mixture was dissolved in 100-150 times methanol and spray dried with a spray dryer to prepare a megestrol acetate formulation. At this time, the spray drying conditions were the same as in Example 1.

Example  3  : Spray drying  Acetic acid Megestrol  Preparation of Powder Formulations

Megestrol acetate: Eudragit L100: Magnesium stearate: Silicon dioxide was mixed at a weight ratio of 1: 3: 0.05-0.25: 0.05-0.25. The mixture was dissolved in 100-150 times methanol and spray dried with a spray dryer to prepare a megestrol acetate formulation. At this time, the spray drying conditions were the same as in Example 1.

Example  4  : Spray drying  Acetic acid Megestrol  Preparation of Powder Formulations

Megestrol acetate: PVP 25 (povidone K 25): tocopherol TPGS: magnesium stearate: silicon dioxide were mixed at a weight ratio of 1: 3: 0.5: 0.05 to 0.25: 0.05 to 0.25. The mixture was dissolved in 100-150 times methanol and spray dried with a spray dryer to prepare a megestrol acetate formulation. At this time, the spray drying conditions were the same as in Example 1.

Experimental Example  One  Acetic acid Megestrol  Observation of Particle Forms in Powder Formulations

Acetate megestrol powder formulations prepared in Examples 1 to 4, and Megaseth suspension (Megace ^? ) Particles were coated with gold ions, and then observed at 1000-fold magnification with a scanning electron microscope (SirionTM / SUPER DRY II). .

The results are shown in Fig.

As shown in Figure 1, commercially available mega suspension (Megace ^? ) Particles form an irregular shape, it was confirmed that the acetate megestrol powder formulation obtained through the spray drying of the present invention to form a sphere. At this time, the size of the megestrol acetate formulation was less than 2 µm, and the average particle diameter was 500 nm.

Experimental Example  2  Acetic acid Megestrol  Dissolution Rate Analysis of Powdered Formulations

In order to confirm the dissolution rate of the acetate megestrol powder formulation of the present invention, the dissolution test was performed by the paddle method. Specifically, 20 mg of the acetate megestrol powder formulation prepared in Examples 1 to 4 was taken, respectively, and placed in 900 ml of phosphate buffer (pH 7.4) test solution, and elution was observed for 24 hours. At this time, the temperature of the test solution was maintained at 37 ℃, the rotation speed of the paddle was 50rpm. After taking 1 ml of the test solution over time, the resultant was filtered through a 0.45 μm filter, and 100 μl was used for the analysis. Analysis was performed by LC (waters 2695D). Analytical conditions are mobile phase acetonitrile / water = 60/40 (v / v), UV = 288 nm, flow rate = 1 ml / min.

The results are shown in Fig.

As shown in Figure 2, in the case of the acetate megestrol powder formulation of the present invention maintained a dissolution rate of about 10-15%, in the case of a commercially available mega suspension (Megace ^? ) Showed a lower dissolution rate of less than 5%.

Experimental Example  3  Acetic acid Megestrol  Blood Level Analysis of Powdered Formulations

In order to confirm the blood concentration of the acetate megestrol powder formulation of the present invention, pharmacokinetic experiments were performed in beagle. Specifically, 100 mg of the acetate megestrol powder formulations prepared in Examples 1 and 2 were orally administered per beagle (n = 6). After the administration of the drug, the blood of the beagle was taken 3 ml every hour and centrifuged for 10 minutes at 10000rpm. 100 μl of serum was taken and diluted 20-fold with acetonitrile. 100 μl of the supernatant was collected and filtered through a 0.45 μm filter, and 5 μl was analyzed by LC-MS (3200Q TRAP LC / MS / MS). As a comparison group, a commercial product (megace suspension, Megace ^? ) ^Was used.

The results are shown in Table 1 and FIG.

Pharmacokinetic Parameters (n = 6) of Acetate Megestrol Powder Formulations of the Present Invention Example 1 Example 2 Tome geyiseu suspension ^(Megace?) C _max (ng / ml) 751.12 1512.70 746.1 T _max (h) 6.50 3.92 12.92 AUC _last (ng * h / ml) 53375 8168.3 3412.4

As shown in Table 1 and Figure 3, the bioavailability of acetic acid megestrol powder formulations (Examples 1 and 2) of the present invention was about 1.3 times and about 2.3 times higher than the commercial product (megace suspension), respectively. .

Claims (12)

Megestrol acetate, a polymer carrier and a lubricant are mixed in a weight ratio of 1: 1 to 10: 0.05 to 0.25, dissolved in an organic solvent and spray-dried, the formulation for oral administration comprising a megestrol acetate powder . The method of claim 1, wherein the polymer carrier is at least one selected from the group consisting of a povidone-based polymer, an acrylic acid copolymer-based polymer, a cellulose-based polymer, and a polyvinyl alcohol-based polymer. . According to claim 2, wherein the povidone-based polymer is a group consisting of Kollidon 12 PF, Kollidon 17 PF, Kollidon 25, Kollidon 25, and Collidone 90F It is at least one selected from, characterized in that the formulation for oral administration. The polymer of the acrylic acid copolymer series is at least one member selected from the group consisting of Eudragit E, Eudragit L, Eudragit S, Eudragit RS and Eudragit RL. , Preparations for oral administration. According to claim 2, wherein the cellulose-based polymer is hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), hydroxypropylmethyl cellulose phthalate (HPMCP), and hydroxypropylmethyl cellulose acetate succinate (HPMCAS Oral dosage form, characterized in that at least one member selected from the group consisting of. According to claim 1, wherein the lubricant is magnesium stearate, zinc stearate (zinc stearate), calcium stearate and silicon dioxide (silicon dioxide), characterized in that at least one selected from the group consisting of, oral formulations. The preparation for oral administration according to claim 1, wherein the organic solvent is at least one selected from the group consisting of methanol, ethanol and acetone. According to claim 1, The spray drying conditions are the internal temperature (in temp) of 80 ~ 120 ℃, the outside temperature (out temp) of 40 ~ 60 ℃, the head temp is 70 ~ 110 ℃, gas flow rate (gas flow) Is 120 ~ 135L / min phosphorus, characterized in that the formulation for oral administration. The oral preparation of claim 1, wherein the oral preparation further comprises a thickener, a pH adjusting agent, a preservative, a buffer, a sweetening agent, a flavoring agent, a coloring agent, a dispersing agent, or an absorption accelerator. 10. The method of claim 9, wherein the absorption promoter is one selected from the group consisting of polysorbate 80, macrogol-15 hydroxystearate, vitamin E-TPGS, polyoxyl 40 hydrogenated castor oil, and sodium lauryl sulfate It is the above, The formulation for oral administration. The oral preparation of claim 1, wherein the oral preparation is one or more formulations selected from the group consisting of tablets, powders, granules, capsules, and syrups. 1) preparing a mixed solution by mixing megestrol acetate, a polymer carrier and a lubricant at a weight ratio of 1: 1 to 10: 0.05 to 0.25, and dissolving it in an organic solvent; and
2) A method of preparing an oral preparation comprising the megestrol acetate acetate composition according to claim 1, comprising spray drying the mixed solution to produce megestrol acetate megestrol powder.

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