KR100841082B1 - Flocculated suspension of megestrol acetate - Google Patents

Abstract

An emulsified suspension of megestrol acetate with improved phase stability is provided. The emulsified suspending agents of megestrol acetate are finely divided megestrol acetate at a concentration of 1.5 to 15% by weight / volume (% w / v), polyoxyethylen castor oil at a concentration of 0.01 to 0.1% by weight / volume and 0.4 to Xanthan gum at 1.0% weight / volume concentration.

Megestrol acetate, polyoxyethylene hardened castor oil, cremopher, xanthan gum

Description

Flocculated suspension of megestrol acetate

The present invention relates to pharmaceutical compositions containing megestrol acetate. More specifically, the present invention provides a finely divided megestrol acetate at a concentration of 1.5 to 15% by weight / volume (% w / v), polyoxyethylene castor oil at a concentration of 0.01 to 0.1% by weight / volume and 0.4 to 1.0. It relates to an orally suspended oral suspension comprising xanthan gum in% weight / volume concentration.

Megestrol acetate is a 17-alpha-acyloxy-6-methylpregna-4,6-diene- circulated under the tradename Megace by Bristol-Myers Squibb as an anti-tumor, antineoplastics. 3, common name for 20-dion. It is used to treat anorexia, cachexia or significant weight loss in cancer or AIDS patients.

Megestrol acetate is also possible in many pharmaceutical formulations, such as tablet capsules, but liquid pharmaceutical administration when patients cannot swallow tablets or capsules or need to consume relatively large amounts of megestrol acetate due to high doses. Is preferred. Megestrol may be hydrophobic in oral suspension in its pharmaceutical formulation.

The present invention relates to an orally suspended oral suspension of such megestrol acetate. Oral suspending agents are required to maintain phase stability without de-desaturation during the shelf life.

The technical problem to be achieved by the present invention is to provide an orally suspended suspension of megestrol acetate having a novel pharmaceutical composition that maintains stability during the shelf life, that is, good dispersibility and redispersibility.

Technical problems of the present invention are not limited to the technical problems mentioned above, and other technical problems not mentioned will be clearly understood by those skilled in the art from the following description.

The present invention relates to pharmaceutical compositions containing megestrol acetate. More specifically, the present invention relates to micronized megestrol acetate at a concentration of 1.5 to 15% w / v (% w / v), polyoxyethylene castor oil at a concentration of 0.01 to 0.1% w / v and 0.4 to 1.0% w / v It relates to a written oral suspension containing a volume concentration of xanthan gum.

However, the present invention is not limited to the embodiments disclosed below, but will be implemented in various forms, and only the present embodiments are intended to complete the disclosure of the present invention, and the general knowledge in the art to which the present invention pertains. It is provided to fully convey the scope of the invention to those skilled in the art, and the invention is defined only by the scope of the claims.

Thus, well-known structures and well-known techniques in some embodiments are not described in detail in order to avoid obscuring the present invention. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

Flocculated suspension is a suspending agent in which loose particulate matter is formed in a network. Suspension is a formulation made by suspending a drug evenly in a liquid, and a suspension made by a suitable method by adding a suspending agent or other suitable additives, purified water or oil to a solid medicine and making it homogeneous. Floccules, defined as stable tablets, generally contain varying amounts of entrapped liquid medium or vehicle in the network structure and tend to clump together in weak aggregates. The entrained suspending agent does not become caked at standstill and is easily dispersed by stirring. Control of surfactants, wetting agents, protective colloidal suspending agents is generally required to prevent de-desorption or flocculation and ultimately provide a stable bed that can withstand caking. Preservative buffer sweeteners and flavoring agents are also used.

Megestrol acetate is a 17-alpha-acyloxy-6-methylpregna-4,6-diene-3, 20-dione, marketed under the tradename Megace by Bristol-Myers Squibb as an anti-tumor agent. Common name for. The concentration of megestrol acetate is, for example, in an oral pharmaceutical composition containing undifferentiated megestrol acetate which is 15 to 150 mg / ml, preferably 20 to 120 mg / ml, most preferably 40 mg / ml. It is about.

Since the size of the dispersed particles in the suspending agent is governed by the particle size of the raw powder, the raw powder, i.e., megestrol acetate, is ground in advance to obtain micronized megestrol acetate. The enzymatic suspension of megestrol acetate according to one embodiment of the present invention needs to have a particle weight of 90% or less of micronized megestrol acetate and a mass average diameter of 3.0 to 10 microns.

Polyethylene castor oil is used as an emulsifying agent, solubilizing agent, wetting agent to lower the interfacial tension of hydrophobic solid megestrol acetate and disperse it in water. Megestrol acetate is a hydrophobic solid that is not easily wetted by water and has a relatively high interfacial tension imparted by trapped air adsorbed on the surface of the particles. The micronized megestrol acetate particles according to one embodiment of the present invention are dispersed in water with a surfactant or wetting agent, such as polyethylene glycol oil, to reduce the interfacial tension between particulates, trapped gas and water. The amount of surfactant is particularly important in providing a stable textbook. Surfactant refers to a substance that is strongly adsorbed on the surface of water or the interface between water and solid, water and oil, and consequently decreases the interfacial tension in a relatively small amount.

Polyoxyethylene castor oil may be a material having a mixture of hydrophilic and hydrophobic components as a nonionic surfactant. For example, polyoxyethylene hardened castor oil may be polyoxyethylene castor oil 5 (Acconon CA-5; PEG-5 castor oil, Polyoxyl 5 castor oil, polyoxyethylene 5 castor oil), polyoxyethylene castor oil 9 (Polyoxyl 9 castor oil) oil, Acconon CA-9: Castor oil POE-9, PEG-9 castor oil; polyethylene 9 castor oil; Protachem CA-9), Polyoxyl 15 castor oil, Acconon CA-15: Castor oil POE -15, PEG-15 castor oil; polyethylene 15 castor oil; Protachem CA-15), polyoxyl 35 castor oil, Cremophor EL; Etocas 35; glycerol polyethyleneglycol ricinoleate; polyethoxylated castor oil; polyoxyethylene 35 castor oil ), Polyoxyl 40 castor oil, Croduret 40, PEG-40 castor oil, polyethylene 40 castor oil, Protachem CA-40, Polyoxyl 40 hydrogenated castor oil Castor oil POE-40 ; Croduret 40; Nonionic GR-40; PEG-40 castor oil, Cremophor RH 40, Eumulgin HRE 40, glycerol polyethyleneglycol oxystearate, hydrogenated castor oil, Lipocol HCO-40, Lipocol LAV HCO 40, POE-40, PEG 40 hydrogenated castor oil, Nikkol HCO 40, Nonionic GRH-40, polyoxyethylene 40 castor oil, Protachem CAH-40), polyoxyethylene Polyoxyl 60 hydrogenated castor oil, Cremophor RH60, hydrogenated castor oil POE-60, PEG-60 hydrogenated castor oil; polyethoxylated hydrogenated castor oil; Lipocol HCO-60, Nikkol HCO 60, polyoxyethylene 60 hydrogenated castor oil; Protachem CAH-60) and the like.

As described in Table 9 below, good phase stability is maintained as a surfactant used in the polyoxyethylene-cured castor oil megestrol suspending agent. For example, polyoxy ethylene hardened castor oil 5, polyoxy ethylene hardened castor oil 9, polyoxy ethylene hardened castor oil 15, polyoxy ethylene hardened castor oil 35, polyoxy ethylene hardened castor oil 40, polyoxy ethylene hardened castor oil 60 shows higher phase stability than the conventional surfactant, for example, than the combination of polysorbate 80 and polyethylene glycol.

Polyoxyethylene-cured castor oil 60 exists as a solid at room temperature and has a slight odor and taste.

In the case of polyoxyethylene castor oil 35, hydrophobic components account for about 83% of the total mixture. The main component is glycerol polyethylene glycol ricinoleate. Other hydrophobic components include some unaltered castor oil and fatty acid esters of polyethylene glycol. About 17% of the hydrophilic component is composed of polyethylene glycol and ethoxylates. Polyoxyethylene castor oil 35 is a pale yellow viscous liquid, and becomes clear and transparent at 26 ° C or higher. It has a peculiar smell and becomes a clear liquid when heated above 26 ℃. Polyoxyethylene-cured castor oil 35 shows superior phase stability among polyoxyethylene-cured castor oil, in particular, after polyoxyethylene-cured mipa-free oil 40.

Polyoxyl 40 hydrogenated castor oil (Cremophor RH40) is composed of about 75% of the hydrophobic component, the main components of the fatty acid of glycerol polyethylene glycol and glycerol polyethylene glycol It consists of a fatty acid ester. The hydrophilic moiety consists of polyethylene glycol and glycerol ethoxylate. Since polyoxyethylene hardened castor oil 40 has a very mild smell and taste in oral formulations, it may be used preferentially over polyoxyethylene castor oil 35 or polyoxyethylene castor oil 60 and may be used to dissolve drugs such as megestrol acetate. Of course.

In a preferred embodiment of the present invention, it is preferable to use polyoxyethylene-cured castor oil 40 as a surfactant among the derivatives of polyoxyethylene castor oil, but the present invention is not limited thereto, and various derivatives of polyoxyethylene castor oil may be used.

When polyoxyethylene hardened castor oil 40 is used as a surfactant, the concentration of 0.05 to 0.1% may be preferably used. This is because it shows the best phase stability at the concentration of 0.05 ~ 0.1%. If polyoxyethylene hardened castor oil is not used, the stirring process takes a long time to wet the megestrol acetate. On the other hand, excessive use of surfactants can lead to elution of megestrol acetate, which can lead to an unpleasant taste. In addition, the suspended suspension is not caked at standstill and must be easily redispersed by stirring. Polyoxyethylene-cured castor oil 40 can be redispersed quickly.

Xanthan gum is a high molecular weight polysaccharide with thixotropic properties with instant viscous recovery. Xanthan gum is used in the suspending agent to ensure that the megestrol acetate microparticles remain uniformly suspended for a long time during drug administration. Maintaining a uniformly suspended state means easy dispersion and redispersion and good phase stability. The better the stability of the phase, the more constant the administration of the drug during the retention period. In one embodiment of the present invention, xanthan gum is preferably used as a 0.5 to 1.0% weight / volume suspending agent. This is because precipitation is likely to occur at concentrations of 0.5% by weight / volume or less, and stirring is not easy due to high viscosity at 1.0% by weight / volume or more.

The present invention also employs conventional preservatives, buffers, sweeteners and flavoring agents.

Sodium citrate can be exemplified as a buffer, but is not limited thereto. For example 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 mixtures thereof It includes.

Preferably, the buffer used in the pharmaceutical formulation is one or more citrate buffers. For example, lithium citrate monohydrate, sodium citrate monohydrate, potassium citrate monohydrate, calcium citrate monohydrate, lithium citrate dihydrate, sodium citrate dihydrate, potassium citrate dihydrate, calcium citrate dihydrate Water, lithium citrate trihydrate, sodium citrate trihydrate, potassium citrate trihydrate, calcium citrate trihydrate, lithium citrate tetrahydrate, sodium citrate tetrahydrate, potassium citrate tetrahydrate, calcium citrate tetrahydrate, Lithium citrate pentahydrate, sodium citrate pentahydrate, potassium citrate pentahydrate, calcium citrate pentahydrate, lithium citrate hexahydrate, sodium citrate hexahydrate, potassium citrate hexahydrate, calcium citrate hexahydrate, lithium sheet Hydrate heptahydrate, sodium citrate heptahydrate, Cerium citrate comprises heptahydrate, calcium citrate heptahydrate.

pH adjusting agents may be further included in the suspension according to one embodiment of the invention. The pH adjusting agent may be, for example, hydrochloric acid, sodium hydroxide, citric acid, phosphoric acid, lactic acid, tartaric acid, succinic acid or mixtures thereof.

As a sweetener, it contains dextrose, saccharin, sodium saccharin, syrup, lactose, mannitol, glucose, high fructose, white sugar, sorbitol, stevioside, honey, aspartame, oligosaccharide, etc. , Paraoxybenzoic acid propyl, paraoxybenzoic acid methyl, paraoxybenzoic acid butyl, paraoxybenzoic acid ethyl, sorbic acid, sodium sorbate, potassium sorbate, and the like.

As the flavoring agent, one or more kinds of artificial flavors, natural flavors, and herbal essences may be used, and preferably, 0.01% orange essence may be used.

Purified water can be used as a solvent. Filter, fill and pack in equivalent dose to one megestrol acetate dose.

The composition of the enchanted suspending agent according to one embodiment of the present invention comprises 4% megestrol acetate, 0.5% xanthan gum, 0.1% polyethylene-cured castor free 40 based on% weight / volume, 0.1% sodium benzoate, 0.3% citric acid, 0.06% sodium citrate, 20% sucrose, 0.01% orange essence and the remaining purified water.

< Example  1>

Orange flavored oral suspension containing 40 mg of megestrol acetate per ml of megestrol acetate oral suspension has the composition shown in Table 1 below (prepared 100 ml).

TABLE 1

ingredient mg Of ml % w / v Micronized megestrol acetate 40mg 4 Xanthan Gum 5mg 0.5 Polyoxyethylene Cured Castor Oil 40 1mg 0.1 Sodium benzoate 1mg 0.1 Citric acid 3mg 0.3 Citrate sodium 0.6mg 0.06 White sugar 200 mg 20 Orange Essence 1mg 0.1 Purified water q.s 1ml

The preparation of megestrol suspension using the above components is carried out as follows. 50 ml of purified water is heated to dissolve 0.1 g of sodium benzoate, and then cooled, and 0.5 g of xanthan gum and 20 g of white sugar are added and stirred to uniformly hydrate the xanthan gum. Separately, 0.1 g of polyoxyethylene-cured castor oil 40 and 4 g of micronized megestrol acetate are added to 20 ml of purified water, and the mixture is dispersed by mixing with a homogenizer. The xanthan gum solution was passed through a screen, the two solutions were combined, and 0.3 g of citric acid, 0.06 g of citrate salt and 0.1 g of orange essence were added, stirred, marked and filtered to prepare an oral suspension containing 40 mg / ml of megestrol acetate. To prepare.

< Example  2>

A megestrol acetate oral suspension containing xanthan gum 0.6% w / v was prepared in the same manner as in Example 1.

TABLE 2

ingredient mg Of ml % w / v Micronized megestrol acetate 40mg 4 Xanthan Gum 6mg 0.6 Polyoxyethylene Cured Castor Oil 40 1mg 0.1 Sodium benzoate 1mg 0.1 Citric acid 3mg 0.3 Citrate sodium 0.6mg 0.06 White sugar 200 mg 20 Orange Essence 1mg 0.1 Purified water q.s 1ml

< Example  3>

A megestrol acetate oral suspension containing xanthan gum 0.75% w / v was prepared in the same manner as in Example 1.

TABLE 3

ingredient mg Of ml % w / v Micronized megestrol acetate 40mg 4 Xanthan Gum 7.5mg 0.75 Polyoxyethylene Cured Castor Oil 40 1mg 0.1 Sodium benzoate 1mg 0.1 Citric acid 3mg 0.3 Citrate sodium 0.6mg 0.06 White sugar 200 mg 20 Orange Essence 1mg 0.1 Purified water q.s 1ml

< Example  4>

A megestrol acetate oral suspension containing 0.2% w / v of polyoxyethylene hardened castor oil 40 was prepared in the same manner as in Example 1.

TABLE 4

ingredient mg Of ml % w / v Micronized megestrol acetate 40mg 4 Xanthan Gum 6mg 0.6 Polyoxyethylene Cured Castor Oil 40 2mg 0.2 Sodium benzoate 1mg 0.1 Citric acid 3mg 0.3 Citrate sodium 0.6mg 0.06 White sugar 200 mg 20 Orange Essence 1mg 0.1 Purified water q.s 1ml

<Comparative Example 1> Using PEG as polysorbate makes the megestrol acetate suspension (Patent Publication 10-0211192 Experimental Example 1).

 TABLE 5 (100ml Preparation)

ingredient mg Of ml % w / v Micronized Megestrol Acetate 40mg 4 Xanthan Gum 2mg 0.2 Polyethylene glycol 1450 200 mg 20 Polysorbate 80 0.1mg 0.01 Sodium benzoate 2mg 0.2 Citric acid 2.44mg 0.244 Citrate sodium 0.15mg 0.015 White sugar 50 mg 5 Lemon lime flavor 0.91 mg 0.0091 Purified water q.s 1ml

The preparation of megestrol suspension using the above components is carried out as follows.

About 90% PEG is dissolved (heated) and the same weight of water and polysorbate 80 are combined to make a solution. The solution is cooled to room temperature, micronized megestrol acetate is added and dispersed using a homogenizer. Xanthan gum is dispersed separately in about 10% of the molten PEG, and the gum slurry is then added to water to hydrate uniformly. Citric acid, sodium citrate, white sugar, sodium benzoate and flavoring agents are then added to the gum dispersion, stirred, labeled and filtered to produce an oral suspension containing 40 mg / ml megestrol acetate.

<Comparative Example 2> using PEG as Tokyu glyphosate sodium (docusate sodium) to produce the megestrol acetate suspension (US 6,656,505 B2 Experimental Example 1).

TABLE 6 (100ml Preparation)

ingredient mg Of ml % w / v Micronized Megestrol Acetate 40mg 4 Xanthan Gum 2mg 0.2 Polyethylene glycol 1450 200 mg 20 Docusate sodium 0.2mg 0.02 Sodium benzoate 1.88mg 0.188 Citric acid 2.44mg 0.244  Citrate sodium 0.15mg 0.015 Brown sugar syrup 76mg 7.6 Lemon lime flavor 0.45 mg 0.045 Purified water q.s 1ml

The preparation of megestrol suspension using the above components is carried out as follows. About 90% PEG is dissolved (heated) and the same weight of water and docusate sodium are combined to make a solution. The solution is cooled to room temperature, micronized megestrol acetate is added and dispersed using a homomixer. Xanthan gum is dispersed separately in about 10% of the molten PEG, and the gum slurry is then added to water to hydrate uniformly. Citrate, sodium citrate, sucrose syrup, sodium benzoate and flavoring agents are then added to the gum dispersion, stirred, labeled and filtered to produce an oral suspension containing 40 mg / ml of megestrol acetate.

< Comparative Example 3> Docusate Sodium is prepared in the same process as in Comparative Example 1 was prepared by changing the polyoxyethylene (40) stearate to 0.5% (US 6,656,505 B2 Experimental Example 4).

<Comparative Example 4> embodiment mandeuldoe by the same process as in Example 1 is prepared except for xanthan gum.

<Comparative Example 5> The embodiment example 1 and the same manufacturing process as xanthan gum mandeuldoe 0.2% w / v.

< Comparative Example 6> Prepared in the same manner as in Example 1, except that polyoxyethylene cured castor oil 40 was prepared.

In Comparative Example 6, separation of the layers does not occur well, but creaming occurs and dispersion is not performed properly.

< Comparative Example 7> It is prepared by the same process as Experimental Example 1, but was replaced with HPMC 2906 1% w / v instead of xanthan gum.

< Comparative Example 8> Prepared by the same process as Experimental Example 1, but prepared by replacing with HPMC 2906 1.5% w / v instead of xanthan gum.

If the concentration of HPMC exceeds 1.5% w / v, the viscosity becomes too high, making it difficult to handle in the manufacturing process, and the solubility is poor, so that other additives do not melt well to form a suspension.

Mandeuldoe to <Comparative Example 9> Example 1 and the same process is prepared except the sodium benzoate.

Mandeuldoe to <Comparative Example 10> Example 1 and the same process except for the citric acid is prepared.

To <Comparative Example 11> Example 1, the same process mandeuldoe prepared except the sodium citrate.

< Comparative Example 12> Prepared in the same manner as in Example 1, but without white sugar.

<Comparative Example 13> mandeuldoe by the same process as in Example 1 is prepared except the orange essence.

More detailed information about the present invention will be described through the following specific experimental examples, and details not described herein will be omitted because it can be inferred technically by those skilled in the art. Examples are for explaining the present invention, but the present invention is not limited to this experimental example.

<Experimental Example 1> Example and comparative example Stability Test

One of the most important considerations in evaluating the acceptability of suspending agents is the stability of the suspending agent. In general, the greater the palatability, the better the redispersibility. To measure this, the precipitate height was generally measured. This method can also be used to determine the physical stability of megestrol acetate suspending agents. The precipitate height was measured periodically without disturbing the system. Volumetric graduated cylinders were used to measure the rate of precipitation of the entrained suspension.

The precipitate height was measured by periodically measuring the examples and the comparative examples and shown in Table 7 as% of the initial total suspension height.

TABLE 7

Time (week) 0 4 15 30 Example 1 100 99 99 99 Example 2 100 99 99 99 Example 3 100 99 99 99 Example 4 100 99 98 96 Comparative Example 1 100 85 60 40 Comparative Example 2 100 87 63 40 Comparative Example 3 100 85 62 41 Comparative Example 4 100 56 39 30 Comparative Example 5 100 83 75 55 Comparative Example 6 100 99 99 99 Comparative Example 7 100 82 64 42 Comparative Example 9 100 99 99 99 Comparative Example 10 100 99 99 99 Comparative Example 11 100 99 98 97 Comparative Example 12 100 99 99 99 Comparative Example 13 100 99 99 99

Table 7 shows that in the preparation of megestrol suspension, polyoxyethylene-cured castor oil containing 40 and xanthan gum has no phase separation and good dispersion without cake phenomenon under 0.5% w / v. When polyoxyethylene-cured castor oil 40 was contained, the viscosity was low, and it was found that redispersibility was good even when phase separation occurred. Sweeteners, preservatives, fragrances, and buffers were found to be independent of phase stability, and when compared with the comparative examples, the examples of the present invention showed fairly good phase stability.

< Experimental Example  2> Xanthan sword  Optimal concentration

In order to find the optimal concentration of xanthan gum was prepared in the same manner as in Example 1, but a suspension was prepared with only the following three components. Megestrol acetate 40 mg / ml, polyoxyethylene hardened castor oil 40 0.1% w / v was fixed and the concentration of xanthan gum was adjusted as shown in Table 8 to examine the phase stability over time.

TABLE 8

Xanthan Gum  Concentration percent w / v Time (week) 0 4 15 30 52 2 100 100 100 99 99 One 100 100 99 99 99 0.75 100 100 99 99 99 0.5 100 10 99 99 99 0.4 100 95 89 86 83 0.3 100 92 78 67 67 0.2 100 82 73 53 51 0.1 100 68 65 43 40 0 100 54 37 28 25

It was found that the phase stability was very ideal when the concentration of xanthan gum was 0.5% or more. If the concentration is used in excess of 1%, the viscosity is high, difficult to handle and the solubility is reduced, the concentration was 0.5 ~ 1.0% was the most preferable concentration.

< Experimental Example  3> by type of surfactant Phase separation  Degree

Megestrol acetate 40 mg / ml, xanthan gum was prepared by fixing 0.1% w / v and using the surfactant type and concentration% w / v shown in Table 9 and examined the phase stability over time. Each precipitate height is expressed as% of initial total suspension height.

TABLE 9

 Surfactant concentration,% w / v Time (week) 0 2 4 8 15 Polysorbate 80, 0.01% + Polyethylene Glycol 1450, 20%  100  97  83  72  51 Polysorbate 80, 0.01% 100 82 45 34 29 Polysorbate 20, 0.01% 100 75 40 29 25 Docusate sodium, 0.02 100 85 49 36 31 Docusate sodium, 0.02 100 85 49 36 31 Polyoxyethylene (40) stearate, 0.5% 100 78 51 32 28 Lecithin, 0.2 100 73 38 26 21 Sodium lauryl sulfate, 0.05% 100 81 47 36 24 Docusate sodium, 0.02 100 85 49 36 31 Polyoxyethylene Cured Castor Oil 5 0.1% 100 98 81 70 55 Polyoxyethylene Cured Castor Oil 9 0.1% 100 97 83 67 56 Polyoxyethylene Cured Castor Oil 15 0.1% 100 97 84 69 57 Polyoxyethylene Cured Castor Oil 35 0.1% 100 98 86 72 62 Polyoxyethylene Cured Castor Oil 40 0.1% 100 98 89 76 65 Polyoxyethylene Cured Castor Oil 60 0.1% 100 98 85 71 57

According to the phase stability of each type of surfactant shown in Table 9, it was found that the polyoxyethylene-cured castor oil type showed good phase stability. Polyoxyethylene Cured Castor Oil 5, Polyoxyethylene Cured Castor Oil 9, Polyoxyethylene Cured Castor Oil 15, Polyoxyethylene Cured Castor Oil 35, Polyoxyethylene Cured Castor Oil 40, Polyoxyethylene Cured Castor Oil 60 It was found that surfactants of polysorbate 80 and polyethylene glycol combination oil 40, followed by polyoxyethylene-cured castor oil 35, showed good phase stability among polyoxyethylene-cured castor oil.

 < Experimental Example  4> Polyoxyethylene Cured Castor Oil  40 optimized concentrations

In order to find the optimal concentration of polyoxyethylene hardened castor oil 40, it was prepared in the same manner as in Example 1, but a suspension was prepared using only the following three components. Megestrol acetate 40 mg / ml, xanthan gum was fixed 0.1% w / v, and the concentration of polyoxyethylene hardened castor oil 40 was adjusted as shown in Table 10 to observe the phase stability over time. Sediment height is expressed as% of initial total suspending height.

TABLE 10

Polyoxyethylene Cured Castor Oil  40 Concentration percent w / v Time (week) 0 One 2 3 5 0 100 93 84 72 60 0.05 100 92 85 75 62 0.1 100 90 83 73 59 0.2 100 83 63 52 35 0.3 100 74 51 30 13 0.5 100 65 43 22 8

In the case of using polyoxyethylene-cured castor oil 40 as a surfactant or humectant, defrosting was achieved at any concentration. Polyoxyethylene hardened castor oil 40 was found to be excellent in stability at a concentration of 0.05 ~ 0.1% through the experimental example. If polyoxyethylene-cured castor oil was not used, the stirring process to wet the megestrol acetate took a long time. On the other hand, excessive use of surfactants could result in the dissolution of megestrol acetate, resulting in an unpleasant taste. Finally, the use of polyoxyethylene-cured castor oil at a concentration of 0.05-0.1% was most preferred.

< Experimental Example 5 > Polyoxyethylene Cured Castor Oil  40 redistribution time

The suspended suspending agent does not cake at rest and should be easily redispersed by stirring. The degree of redispersion is shown in [Table 11] by measuring the time for redispersion of 4 weeks old samples using a vortex mixer.

 TABLE 11

Time in seconds Example 1 1 sec Example 2 1 sec Comparative Example 1 5 sec Comparative Example 2 4 sec Comparative Example 3 6 sec Comparative Example 4 9 sec Comparative Example 5 5 sec

Example 1 and Example 2 containing polyoxyethylene-cured castor oil 40 as a surfactant and containing more than 0.5% of xanthan gum have a redispersion time within a short time compared to other comparative examples because the phase separation hardly occurs. As a result, it was found that the redispersant was excellent as a suspending agent.

The megestrol acetate suspending agent according to the embodiment of the present invention prevents precipitation production and has excellent phase stability with good dispersibility and redispersibility.

Claims (7)

Micronized megestrol acetate at a concentration of 1.5-15% weight / volume (% w / v); Polyoxyethylene castor oil at a concentration of 0.05 to 0.1% weight / volume; And Xanthan gum at a concentration of 0.5 to 1.0% weight / volume, The sum of said polyoxyethylene castor oil and said xanthan gum is 0.55 to 1.1% by weight / volume concentration. delete delete According to claim 1, An oral suspension for oral suspension wherein the concentration of the micronized megestrol acetate is 40 mg / ml. The method according to claim 1 or 4, The polyoxy ethylene castor oil is polyoxy ethylene castor oil 5 (Polyoxyl 5 castor oil), polyoxy ethylene castor oil 9 (Polyoxyl 9 castor oil), polyoxy ethylene castor oil 15 (Polyoxyl 15 castor oil), polyoxy ethylene castor oil Polyoxyl 35 castor oil, Polyoxyl 40 castor oil, Polyoxyl 40 hydrogenated castor oil 40, or Polyoxylylene hydrogenated castor oil 60 Oral suspending agent. According to claim 1, An enlightened oral suspension further comprising a preservative, a buffer, a sweetener and a flavoring agent. The method of claim 6, The megestrol acetate is 4% weight / volume, the xanthan gum is 0.5% weight / volume, the polyoxyethylene castor oil is 0.1% weight / volume of polystyrene-cured castor oil 40, and the preservative is 0.1% weight / Volume of sodium benzoate, the buffer is 0.06% weight / volume of citrate sodium and 0.3% weight / volume of citric acid, the sweetener is 20% weight / volume of sucrose, and the flavoring agent is 0.01% weight / volume Is the orange essence of An enchanted oral suspension further comprising a residual amount of purified water.