WO2013019024A1 - Preparation for oral administration with improved bioavailability of megestrol acetate, and method for improving bioavailability of megestrol acetate preparation for oral administration - Google Patents

Abstract

The present invention relates to a preparation for oral administration with improved bioavailability of megestrol acetate, and a method for improving the bioavailability of a megestrol acetate preparation for oral administration. The preparation for oral administration containing megestrol acetate of the present invention shows excellent dissolution rate and bioavailability, and thus equal or superior effects can be obtained compared with a conventional megestrol acetate suspension, even with a much smaller dose. In addition, if prepared into a tablet, it is possible to simultaneously overcome the problem of physical stability of a suspension and to maximize the convenience of drug administration to a patient.

Description

 【Specification】

 [Name of invention]

 Method for improving bioavailability of oral administration with improved bioavailability of acetic acid megestate and preparation of oral acetate acetate for oral administration

[Technical field]

 The present invention relates to a preparation for oral administration with improved bioavailability of acetic acid megest and a method for improving bioavailability of acetic acid megest for oral administration.

[Background technology]

17 α-Acetyloxy-6-methylpregna-4,6-diene—megestrol acetate, also known as 3,20-dione, is a synthetic compound with progesterone effects similar to those of progesterone. Progestin. Acetate megestrol is used in abortion, endometriosis and menstrual irregularities, and in a variety of uses, including hormone replacement therapy in the treatment of breast cancer, contraception and postmenopausal women. In particular, megestrol acetate acetate is frequently prescribed as an appetite enhancer for patients in a wasting state such as HIV wasting, cancer wasting, or loss of appetite. ^\

Megestrol acetate is sold under the trade name Megace ^® by paah Pharma shoe tikeol (Par Pharmaceuticals, Inc.) and Myers seuppeob (Bristol Myers Squibb Co.) to Bristow. Typical commercial formulations are relatively large doses, for example, pharmaceutical acetate oral suspension contains 40 mg of micronized acetic acid megest sugar, and its pharmaceutical insert Acetate megest is recommended as the initial adult dose of oral suspension at 800 mg / day (20 / day).

Megestrol acetate can be used in various pharmaceutical formulations, such as tablets and capsules, but liquid suspensions are used when patients cannot swallow tablets or capsules or when high doses (more than 800 rag) are required. Accordingly, many researchers have studied the technology of formulating megestrol acetate as a suspending agent. Patent documents related to this include Korean Patent Publication No. 10-841082 (Sustained Acetic Acid Suspension) and Korean Patent Application Publication No. 10-900915 (Suspension containing acetic acid megest) Formulations and preparation methods thereof) and Korean Patent Application Laid-Open No. 10-2011—42874 (suspensions including acetic acid megest).

 However, in the case of the above-mentioned suspension containing acetic acid megest has a disadvantage of low bioavailability. In addition, suspensions of acetic acid megestes have high viscosity and have relatively long residence times in the mouth and tubing, and these viscous materials can be used in patient populations, particularly patients with consumption problems and in which tubes are inserted. There is a disadvantage that is not well accepted. In order to overcome this drawback, studies have been made to reduce the particles of acetic acid megestate. For example, Korean Patent Application Laid-Open No. 10-2008-24213 discloses milling, homogenization, precipitation, Nanoparticulate megestrol formulations prepared using a frozen or template emulsion method are described. However, when formulating megestrol acetate megestrol by the above method, a long time homogenization process is required, and the drug is decomposed due to the high temperature generated during the homogenization process. Throughout this specification, numerous citations and patent documents are referenced and their citations are indicated. The disclosures of cited documents and patents are incorporated herein by reference in their entirety, so that the level of the technical field to which the present invention belongs and the contents of the present invention are more clearly explained.

[Content of invention]

 [Problem to solve]

The present inventors endeavored to develop a formulation of acetic acid megest for oral administration with good drug absorption. As a result, acetic acid megestrol, a polymer carrier, and a lubricant were mixed, dissolved in an organic solvent, and dried to prepare acetic acid megest, and the prepared acetic acid megest was dissolved in a conventional formulation. It was confirmed that the megest is superior to the suspending agent, and the present invention was completed. Accordingly, it is an object of the present invention to provide a formulation for oral administration in which the bioavailability of acetic acid megestate containing powder or granules is improved.

 Another object of the present invention is to provide a method for improving the bioavailability of acetic acid megestrol formulation for oral administration. Other objects and advantages of the present invention will become apparent from the following detailed description, claims and drawings. [Measures of problem]

 According to one aspect of the present invention, the present invention comprises a mixture of acetic acid megestrol, a polymer carrier and a lubricant in an organic solvent and dried to dry the powdered or granulated acetic acid megest into powder or granules. , Provides an oral formulation with improved bioavailability of megestrol acetate. The present inventors endeavored to develop a formulation of acetic acid megest for oral administration with good drug absorption. As a result, acetic acid megest was mixed with a polymer carrier and a lubricant, dissolved in an organic solvent and dried to prepare acetic acid megest powder formulation, and the dissolution rate and bioavailability of the prepared acetic acid megestrol powder formulation were It confirmed that it was superior to megestrol suspension, and completed this invention.

 According to a preferred embodiment of the present invention, the acetate acetate powder or granule of the present invention can improve the bioavailability of acetic acid megest when the oral administration of the finally prepared acetate acetate of the present invention To the extent possible, a mixture of acetic acid megest, a polymer carrier and a lubricant in an appropriate weight ratio can be prepared by dissolving in an organic solvent and drying.

 Preferably, the acetic acid megestrol powder or granule is powdered by dissolving a mixture containing an acetic acid megestrol, a polymer carrier and a lubricant in a weight ratio of 1: 1—10: 0.05—1 in an organic solvent and drying it. Or granulated.

 The acetic acid megest, the preferred weight ratio of the polymer carrier and the lubricant

1: 1-10: 0.05-1, more preferably 1: 1-9: 0.05-1, even more preferably 1: 1-8: 0.05-15 more preferably 1: 1-7: 0.05-1, even more preferably 1: 1-6: 0.05-1, even more preferably 1: 1-5 : 0.05-1; Even more preferably 1: 1-10: 0.08-0.8, even more preferably 1: 1-9: 0.08-0.8, even more preferably 1: 1-8: 0.08-0.8, even more preferably 1: 1-7: 0.08-0.8, even more preferably 1: 1-6: 0.08-0.8, even more preferably 1: 1-5: 0.08-0.8; Even more preferably 1: 1-10: 0.09-0.6, even more preferably 1: 1-9: 0.09-0.6, even more preferably 1: 1-8: 0.09-0.6, even more preferably 1: 1-7: 0.09-0.6, even more preferably 1: 1-6: 0.09-0.6, even more preferably 1: 1-5: 0.09-0.6; Even more preferably 1: 1-10: 0.1-0.5, even more preferably 1: 1-9: 0.1-0.5, even more preferably 1: 1-8: 0.1-0.5, even more preferably 1: 1—7: 0.1-0.5, even more preferably 1: 1-6: 0.1-0.5, even more preferably 1: 1-5: 0.1-0.5.

 In the present invention, the acetic acid megestrol powder or granules may be powdered or granulated by spray drying, freeze drying, fluidized bed drying, evaporation drying or coprecipitation.

 Preferably, the method for powdering or granulating is spray drying, coprecipitation or fluid bed drying, more preferably spray drying.

In the present invention, the spray drying conditions are internal temperature (in temp) 80-120 ^° C, outside temperature (out temp) 40-60 ^° C, head temp 70-110 ^° C, gas flow rate (gas flow) 120 It is preferably -135 L / min, but can be adjusted to suit the characteristics and manufacturing conditions of each manufacturer of the spray dryer.

 Acetate megestrol powder of the present invention refers to a fine powder containing acetic acid megest, a polymer carrier and a lubricant, and typically has a particle size of 10 or less. In addition, the acetic acid megest granules of the present invention refers to particles having a size of 1-10 kPa by powders of the acetic acid megest.

 The polymer carrier of the present invention includes a povidone-based polymer, an acrylic acid copolymer-based polymer, a cellulose-based polymer and a polyvinyl alcohol-based polymer.

Examples of the povidone-based polymer include collidone 12 PF and collidone 17, which are commercially available under the trade name Collidone (BASF Germany). PFCKollidon 17 PF), Kollidon 25, Kollidon 30 and Collidone 90F.

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

 The cellulose-based polymers include hydroxypropyl cellulose (HPC), hydroxypropyl methyl salose (HPMC), hydroxypropyl methyl cellulose phthalate (HPMCP) and hydroxypropyl methyl salose acetate. Succinate (HPMCAS), including but not limited to.

 The polyvinyl alcohol-based polymer includes polyvinyl alcohol (PVA) of various molecular weights.

 Glidants of the present invention include, but are not limited to, magnesium stearate, zinc stearate, kale stearate, silicon dioxide and talc.

 The organic solvent of the present invention includes methane, ethane and acetone, but is not limited thereto. Any organic solvent capable of dissolving all of the above components may be used. The amount of the organic solvent is preferably 100-150 times with respect to the mixture of acetic acid megest, polymer carrier and lubricant, but may be used by selecting an appropriate amount to dissolve the components.

According to one preferred embodiment of the invention, the acetate megestrol powder or granules of the invention exhibit improved pharmacokinetic profile properties. Specifically, oral administration of acetic acid megest powder or granules, preferably acetic acid megest powder to the beagle in an amount of 100 mg, 700-1600, preferably 730-1550, more preferably 750-1520 C _max (ng / m) value and / or AUC _Iast (ng * h /) value of 5000-8500, preferably 5100-8300, more preferably _5200-8200 . As demonstrated in the experimental example below, the pharmacokinetic profile of the acetic acid megest powder of the present invention shows about 1.3 times -2.3 times better bioavailability compared to the commercially available megacenic suspension.

The acetic acid megest according to the present invention has a spherical morphology of powder or granules with a particle size of less than 10 1, preferably less than 4, and an average of The particle diameter is 100-1000 nm, preferably 400-600 ran.

 Formulations for oral administration of the present invention include a pharmaceutically acceptable carrier, which is commonly used in the preparation of lactose, dextrose, sucrose, sorbbi, manny, starch, acacia rubber calcium phosphate, water Syrups and mineral oils, and the like, but is not limited thereto. In addition to the above components, oral preparations of the present invention may be added to thickeners, pH adjusters, preservatives, laxatives, lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, coloring agents, suspending agents, dispersants, known absorption accelerators or preservatives. It can be included as.

 The thickener includes, but is not limited to, natural cellulose, gelatin, methyl cellulose, carbomer, and carbopol freegel.

 The pH adjusting agent includes, but is not limited to, hydrochloric acid, sodium hydroxide, citric acid, phosphoric acid, lactic acid, tartaric acid and succinic acid.

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

 The laxative agent is citrate laxate, lithium lactate, sodium lactate, potassium lactate, chamomile lactate, lithium phosphate, sodium phosphate, potassium phosphate, chamophosphate, lithium malate, potassium malate chame malate, malate , Lithium tartarate, sodium tartrate, potassium tartrate, tartrate, lithium succinate, sodium succinate, potassium succinate, calcium succinate, lithium acetate, sodium acetate, calcium acetate, potassium acetate and their Including, but not limited to, the complex.

 The sweetener is a natural sweetener such as sugar glucose, honey and saccharin, ducin

artificial sweeteners such as, but not limited to, dulcin, cyclamate, aspartame, and sorbitol.

 The flavoring agent includes, but is not limited to, artificial flavors, natural flavors, and herbal essences.

The colorants include, but are not limited to, dyes and pigments. The dispersant includes an organic dispersant of sorbitan and a paraffin dispersant, It is not limited to this.

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

 Acetate acetic acid formulations of the present invention have been developed for oral administration, and can be used for a variety of purposes, including abortion, endometriosis, dysmenorrhea, treatment of breast cancer, or appetite stimulants for patients in a wasting state. .

 The content of the additive may preferably include 0.01-10% by weight, preferably 0.1-5% by weight of acetic acid megest based on the total weight of the powder formulation.

 According to one preferred embodiment of the present invention, the oral preparation of the present invention may further include vitamin C. Oral administration formulation of the present invention containing vitamin C, by maximizing the convenience of the patient by improving the uncomfortable taste that occurs when taking megestrol acetate, can be taken simultaneously with acetic acid megest and vitamin C There are advantages to it. In addition, by preparing the formulation for oral administration of the present invention using vitamin C can improve the stability and shelf life of the product.

 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.

Suitable dosages of the formulations for oral administration of the present invention vary depending on factors such as formulation method, mode of administration, age, weight, sex, morbidity, food, time of administration, route of administration, rate of excretion and response to the patient. In general, the skilled practitioner can readily determine and prescribe a dosage effective for the desired treatment or prophylaxis. In the case of conventional acetate _megestrol suspending agent was a high dose of 800 mg or more daily _ᅤ formulation of the oral administration of the present invention is improved bioavailability, enjoy a daily dose of about 400-500 mg dosage.

Formulations for oral administration of the present invention may be formulated using pharmaceutically acceptable carriers and / or excipients in unit dosage form according to methods readily available to those skilled in the art. Can be prepared or incorporated into a multi-dose container. have.

 Preparations for oral administration of the present invention may be formulated in the form of tablets, granules, powders, capsules and syrups by conventional methods. According to another aspect, there is provided a method for improving bioavailability of an acetate megestrol formulation for oral administration comprising the following steps:

 (a) dissolving a mixture of acetic acid megest, a polymer carrier and a lubricant, in an organic solvent and drying to prepare a powder or granule of acetic acid megest; And

 (b) formulating the powder or granules into a formulation for oral administration. Since the method of improving the bioavailability of the oral administration of acetate acetate for oral administration of the present invention is related to the method for preparing the formulation for oral administration with improved bioavailability of the above-mentioned megestrol acetate megestrol of the present invention, the common contents between the two The description is omitted to avoid excessive complexity of the specification.

 In step (a) of the present invention, the organic solvent may be used without limitation various organic solvents, including acetic acid megest, methane capable of dissolving a mixture including a polymer carrier and a lubricant. The amount of the organic solvent is preferably 100-150 times the amount of megestrol acetate, a polymer carrier, and a mixture of a lubricant, but may be used by selecting an appropriate amount to dissolve the components.

 Formulation of the step (b) may be a general manufacturing method such as wet granulation method, dry granulation method, extrusion molding or direct-driven method. If the density of the adsorbent used for the preparation of the oral preparation is high, it may be formulated using a direct blow method instead of the dry granulation method.

 When preparing acetic acid megestrol formulation for oral administration according to the method of the present invention, the bioavailability of acetic acid megest is significantly improved.

【Effects of the Invention】

The features and advantages of the present invention are summarized as follows: (a) The present invention provides an oral preparation having an improved bioavailability of acetic acid megest and a method for improving the bioavailability of an acetic acid megest for oral administration.

 (b) The preparation for oral administration containing acetic acid acetate of the present invention shows excellent dissolution rate and bioavailability, so that the conventional acetic acid megest can be obtained with an equivalent effect even at a much lower dosage than a suspension, and prepared as a tablet. In one case, the physical stability problems of the suspension can be overcome while at the same time maximizing patient convenience.

 (c) The preparation for oral administration containing acetic acid megest of the present invention can be prepared in a short time by a simple process by mixing acetic acid megest, polymer carrier and lubricant in a specific weight ratio, dissolving in an organic solvent and drying. to be.

[Brief Description of Drawings]

 Figure 1 is a photograph of the particle form of the megestrol acetate acetate formulation of the present invention at 1000 times magnification with a scanning electron microscope.

 Figure 2 is a graph showing the dissolution rate analysis results of the acetate formulation of the present invention powder formulation.

^'Figure 3 is the analysis of the blood levels by administration of megestrol acetate powder of the present invention to beagle graph.

[Specific contents to carry out invention]

 Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention in more detail, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention. . Example

Example 1 Preparation of Powder Formulation of Acetate Acetate Using Spray Drying

Acetate megestrol ： PVP 25 (povidone K 25) ： magnesium stearate ： silicon dioxide 1: 5: 0.05-0.25 ： 0.05-0.25 It was mixed by weight ratio. The mixture was dissolved in 100-150 times of methane and spray-dried with a nano spray dryer (β-90 / buchi) to prepare acetic acid megest powder formulation. Spray drying conditions are as follows: in temp 80-120 ^° C, out temp 40-60 ^° C, head temp 70-110 ^° C, gas flow 120 -135 L / min. Example 2 Preparation of Powder Formulation of Acetate Acetate Using Spray Drying ②

 Acetate acetate was mixed with PVP 25 (povidone K 25): magnesium stearate and silicon dioxide at a weight ratio of 1: 3: 0.05-0.25: 0.05-0.25. The mixture was dissolved in 100-150 times of methane 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: Preparation of powder formulation of acetic acid megest using spray drying

 Acetate 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 the amount of methane and spray dried with a spray dryer to prepare acetic acid megest powder formulation. At this time, the spray drying conditions were the same as in Example 1. Example 4 Preparation of Powder Formulation of Acetate Acetate Using Spray Drying

 Acetate acetate was mixed in a weight ratio of: PVP 25 (povidone K 25): tocope in a weight ratio of TPGS: magnesium stearate: silicon dioxide 1: 3: 0.5: 0.05-0.25: 0.05-0.25. The mixture was dissolved in 100-150 times of methane 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 1: Observation of acetic acid megest in particle form of powder formulation

Example 1-4 A powder formulation megestrol acetate, and methoxy geyiseu suspension (Megace ^®) coating the particles of gold ions were observed at: 1000-fold magnification with a scanning electron microscope (SirionTM / SUPER DRY Π) manufactured. The observation result is shown in FIG.

As shown in FIG. 1, commercially available Megace® suspension (Megace ^® ) particles have an irregular shape, but the powdered formulation of acetic acid megest obtained through spray drying of the present invention has a spherical shape. At this time, the size of the megestrol acetate acetate formulation was less than 2 urn, the average particle diameter was 500 nm. Experimental Example 2: Dissolution rate analysis of the powder formulation of acetic acid megest

 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, the acetic acid megest prepared in Example 1-4 was taken 20 rag each powder formulation was added to 900 ^ phosphate complete solution (pH 7.4) test solution to observe the elution for 24 hours. At this time, the temperature of the test solution was maintained at 37 ° C, the rotational speed of the paddle was 50rpm. 1 iirf of the test solution was taken for each hour, filtered through a 0.45 filter, and used for 100-rank analysis. Analysis was performed by LCXwaters 2695D). Analytical conditions are mobile phase acetonitrile / water = 60/40 (v / v), UV = 288 nm, flow rate = 1 m ^ / min. The results are shown in FIG.

2, the case of a powder preparation of acetic acid methoxy guest of the invention has been shown and maintain the dissolution rate of 10 to 15%, in the case of methoxy geyiseu suspension (Megace ^®) are commercially available is shown a low dissolution rate of less than 5¾. Experimental Example 3: Analysis of bioavailability of acetic acid megest powder formulation

In order to check the blood concentration of the acetate megestrol powder formulation of the present invention, pharmacokinetic experiments were performed on beagles. Specifically, acetic acid megestrol powder formulations prepared in Examples 1 and 2 were administered orally for each 100 rag per beagle. After drug administration, the blood of the beagle was taken 3 ιιώ by time and centrifuged for 10 minutes at 100 rpm. 100 fiH of serum was taken and 20-times dilution with acetonitrile. 100 ^ of the supernatant was taken and filtered through a 0.45 filter and 5 ^ 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. Table 1

 Pharmacokinetic Parameters of Powdered Methactate of the Invention (n = 6)

표 1 및 도 3에 나타난 바와 같이, 본 발명의 초산 메게스트롤 분말 제제 (실시예 1 및 2의 제제)의 생체이용률은 시판제품인 메게이스 현탁액에 비해 각각 약 1.3배 및 약 2.3배 정도 높게 나타났다. 이상으로 본 발명의 특정한 부분을 상세히 기술하였는바， 당업계의 통상의 지식을 가진 자에게 있어서 이러한 구체적인 기술은 단지 바람직한 구현 예일 뿐이며， 이에 본 발명의 범위가 제한되는 것이 아닌 점은 명백하다. 따라서 본 발명의 실질적인 범위는 첨부된 청구항과 그의 등가물에 의하여 정의된다고 할 것이다.

As shown in Table 1 and Figure 3, the bioavailability of the acetate megestrol powder formulation of the present invention (the formulation of Examples 1 and 2) was about 1.3 times and about 2.3 times higher than the commercially available mega suspension, respectively. . The specific parts of the present invention have been described in detail above, and it is apparent to those skilled in the art that these specific technologies are merely preferred embodiments, and thus the scope of the present invention is not limited thereto. Therefore, the substantial scope of the present invention will be defined by the appended claims and equivalents thereof.

Claims

[Patent Claims] [Claim 1]  Oral with improved bioavailability of acetic acid megests, including powdered or granulated megestrol acetate megestrol powders or granules, by dissolving and drying a mixture comprising acetic acid megestrol, a polymeric carrier and a lubricant Formulations for administration. [Claim 2]  The method of claim 1, wherein the acetate megestrol powder or granules are prepared by dissolving a mixture containing acetic acid megest, a polymer carrier and a lubricant in a weight ratio of 1: 1-10: 0.05-1 in an organic solvent, and drying the mixture. Formulation for oral administration, characterized in that the powdered or granulated. [Claim 3]  The preparation for oral administration according to claim 1, wherein the powdering or granulation is by spray drying. [Claim 4]  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. Formulation. [Claim 5] The method according to claim 4, wherein the povidone-based polymer is selected from the group consisting of collidone 12 PFCKollidon 12 PF, Kollidon 17 PF, Kollidon 25, Kollidon 30 and Collidone 90F The formulation for oral administration, characterized in that one or more. [Claim 6]  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. [Claim 7]  The method of claim 4, wherein the cellulose-based polymer is composed of hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose phthalate and hydroxypropylmethyl salulose acetate succinate Oral formulations, characterized in that at least one selected from the group. [Claim 8]  The formulation for oral administration according to claim 1, wherein the lubricant is at least one selected from the group consisting of magnesium stearate, zinc stearate, calcium stearate, silicon dioxide and talc. . [Claim 9]  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. [Claim 10] The method of claim 1, wherein the spray drying conditions are the internal temperature (in temp) 80-120 ^° C, the external temperature (out temp) 40-60 ^° C, head temp 70-110 ^° C and gas flow rate (gas flow) Formulation for oral administration, characterized in that 120-135L / min phosphorus. [Claim 111]  The preparation for oral administration according to claim 1, wherein the preparation for oral administration further comprises a thickener, a pH adjusting agent, a preservative, a laxative, a sweetening agent, a flavoring agent, a coloring agent, a dispersing agent, or an absorption accelerator. [Claim 12]  2. The formulation for oral administration according to claim 1, wherein the formulation of the formulation for oral administration is selected from the group consisting of tablets, powders, granules, capsules and syrups. [Claim 13]  The oral preparation of claim 1, wherein the oral preparation further comprises vitamin C. [Claim 14]  The formulation for oral administration according to claim 1, wherein the acetic acid megest powder or granules exhibits the following pharmacokinetic profile characteristics upon oral administration to a beagle in an amount of 100 mg: (i) C _max (ng / mO: 700-1600; or (ii) AUCias _t (ng * h /): 5000-8500. [Claim 15]  Method for improving the bioavailability of the formulation of acetic acid megest for oral administration comprising the following steps:  (a) dissolving a mixture of acetic acid megest in a polymer carrier and a lubricant, in an organic solvent and drying to prepare a megestrol acetate powder or granules; And  (b) formulating the powder or granules into a formulation for oral administration.