A PRARMACEUTICALLY STABLE SUSPENSION OF MEGESTROL NL\TERL\L
TECHNICAL FIELD
The present invention relates to a suspension of megestrol material which is physically Stahle under room temperature, accelerated conditions and severe conditions. and a pharmaceuticai composition thereof.
BACKGROUND ART
H
Megestrol acetate is a generic name of 17a-acetoxy-6-methyl-4,6- pregnadiene-3,20-dione of the following Formula 1 ("megestrol acetate," helow) which is an anti-malignant tumor
agent:
[Formula 1 ]
o
H
f CK
Megestrol acetate is an anti-tumor agent used for relief therapy in advanced breast cancer and endometrial cancer, and is used for the purpose of treating inappetence, cachexia or
noliceable weight loss of unknov\Ti ongin in cancer or AIDS patienis. Megesirci aceiare is currently on sale in the market in forms of tablet (LG Megestrol Tab.: LG Life Science, Co. Ltd.) or suspension (Megace Suspension: Bristol-Myers Squibb). In view of wide use of megestrol acetate in clinical medicine, a pharmaceutical dosage form of liquid phase is preferable when a patient has a trouble in swallowing tablet or capsule. or is required to intake a relatively large amount of tablets due to a high dosage. For such reasons, the development of a suspension of megestrol acetate has an important meaning. In suspension, it is important to maintain a stable form without physical/chemical deterioration during the period of circulation. One of the factors to be considered mostly in evaluating the stability of a suspension is Sedimentation of components in the suspension and redispersibility thereof. Korean Patent No. 0211192 by Bristol-Myers Squibb Company suggests a measurement of Sedimentation height as a general method for evaluating the stability of a suspension. In this patent, a Sedimentation ratio of flocculated suspension is determined by measuring the height of Sedimentation periodically with using cylinder.
Also, the Korean Patent No. 0211192 by Bristol-Myers Squibb Company provides a pharmaceutical composition of megestrol acetate suspension which is not deflocculated
during the preservation period of the product. This pharmaceuncal composiuDn consisis of micronized megestrol acetate in combination with polysorbate 80 and polyethyleneglycol 1450, xanthan gum, sodium benzoate, citric acid, sodium citrate, sucrose, flavoring agent, and water. However, the suspension in this patent is very viscous, and thus the time to remain in mouth and tube when orally administered is long. As a result, the drug's loss amount becomes large, causing inconvenience to patients in oral administration.
These problems are also mentioned in US Patent Publication No. 20050008707 A. This patent describes that the more flocculated, the better redispersibility. However, if the flocculation increases, heterogeneity may be observed by the naked eye, which may mean that the homogeneity of active component is low. As a result, a desired amount of active component may not be administered. Also, the use of polyethyleneglycol showing high viscosity at room temperature in an amount of 20 w/v% maintains a relatively high Sedimentation ratio, but results in high viscosity, thereby requiring additional heating procedure to solve difficulty in production process due to the high viscosity.
US Patent No. 6,028,065 mentions a flocculated oral suspension of micronized megestrol acetate which is stable in water. In panicular. the patent meri:iorä5 a suspension comprising at least one component selected from the group consisting of polyethyleneglycol, propylene glycol, glycerol and sorbitol; Surfactant; and megestrol acetate, particularly indicating that polysorbate as a Surfactant is not used with polyethyleneglycol simultaneously.
US Patent Publication No. 20050008707 A by Elan Pharma International suggests a nanoparticle composition comprising megestrol having a particle size of 2000 nm or less, and Surfactant. This patent mentions that the suspension of megestrol acetate having a particle size of 2000 nm or less has a relatively low viscosity, and so the remaining amount in oral cavity after administration is small, and also can solve the problems that it takes a long time in injection administration, and megestrol acetate easily remains in tube, due to the high viscosity. Also, the patent mentions that since the particle size is small, the time to show drug effectiveness can be shortened, and the bioavailability can increase. However, to make the particle size of more than 50% of megestrol acetate used at least to 2000 nm or less, additional procedures such as pulverizing, homogenizing or re- precipitating are required.
US Patent Publication No. 20020028794 A by Boehringer Ingelheini menücns that megestrol acetate which is a hydrophobic solid material is not wetted easily b) water, and has high surface tension reinforced by air adsorbed on the particle surface, and also describes a use of Surfactant to maintain physical stability of a suspension. This application describes a suspension comprising megestrol acetate, Wetting agent. and suspending agent, and particularly Claims that the suspension comprises propylene glycol in 1.0 w/v% or less, but does not comprise polysorbate, polyethyleneglycol, glycerol or sorbitol.
US Patent Publication No. 20030198679 A by Subhas C Kundu, et al discloses a composition comprising insoluble active material and at ieast one Wetting agent, but not comprising polyethyleneglycol, propylene glycol, glycerol or sorbitol, as suspending agent.
DISCLOSURE OF THE INVENTION
The object of the present invention is to provide a low viscous suspension wherein megestrol material, which is a very hydrophobic active ingredient, is wetted effectively in water and maintains long-term homogeneous dispersion State (i.e. high Sedimentation ratio) in spite of the low viscosirv.
The present invention relates to a suspension comprising a megestrol material as active ingredient, a poloxamer as Wetting agent, and a viscosity Controlling agent.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a graph representing Sedimentation ratios at room temperature in Comparative Example and Example 6.
Figure 2 is a graph representing Sedimentation ratios under 40°C and 75%RH condition in Comparative Example and Example 6.
Figure 3 is a graph representing Sedimentation ratios in 60°C drying oven in Comparative Example and Example 6.
Figure 4 is a couple of photographs representing changes in Sedimentation ratio between initial State and a State after one month under severe condition, in Comparative Example
and hxample 6.
Figure 5 is a graph representing dissolution patterns in Examples 1, 2, 5, 6 and 9.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is explained in detail below.
(1) Active ingredient
Unless described otherwise herein, megestrol materiai used as active ingredient means megestrol; or stereoisomers, esters or pharmaceutically acceptable salts thereof. Preferred megestrol materiai is megestrol acetate.
Megestrol materiai has a wide use, and is used as anti-tumor agent to advanced breast cancer and endometrial cancer; auxiliary therapy in a treatment of breast cancen and medicament for treating inappetence, cachexia ,or noticeable weight loss of unknown origin in cancer or AIDS patients.
The amount of the acti\ e ingredient in the present suspension is ! to 15 . \ preferabiy 2 to 10 w/v%, and more preferably 3 to 9 w/v9c. If the amount of the active ingredient is less than 1 w/v%, the amount for one dose becomes too large. If the amount is greater than 15 w/v%, the viscosity of final dosage form is too high, whereby the administration may be inconvenient.
(2) Wetting agent
The Wetting agent used in the present suspension is poloxamer making the active ingredient exhibit homogeneous distribution in the suspension by providing hydrophilicity to the surface of the active ingredient. Poloxamer is a non-ionic Surfactant comprising copolymer of ethylene oxide and propylene oxide, prevents the caking phenomenon, and makes the redispersion of the suspension easy by forming partial Charge at the surface of the active ingredient and medium enough to prevent or minimize coagulation of particles.
The poloxamer preferably used for the present suspension includes, bat is not limited to, poloxamers 124, 184, 185, 188, 237, 338 and 407, and more preferably, poloxamer 188 or poloxamer 407.
Freferably. me presenl suspension may funher comprise a wening agem seiecLco from me group consisting of polyethyleneglycol-35 castor oiL polyethyleneglycol-40 hydrogenated castor oil, caprylocaproyl macrogol glyceride, oleoyl macrogol glyceride, caprylic/capric glyceride, caprylic/capric triglyceride polyethyleneglycol-4 ester and derivatives thereof, glyceryl monooleate, polyethyleneglycol-40 stearate, glyceryl citrate/lactate/linoleate/oleate, polyoxyethylene (20) isohexadecyl ether, propylene glycol monolaurate, propylene glycol monocaprylate, sodium lauryl sulfate, dioctylsulfosuccinate, and mixtures thereof. More preferably, the present suspension may further comprise a Wetting agent selected from the group consisting of polyethyleneglycol-35 castor oil, polyethyleneglycol-40 hydrogenated castor oil, caprylic/capric glyceride, polyethyleneglycol-40 stearate, and mixtures thereof. The amount of the Wetting agent in the present suspension is 0.0001 to 0.5 w/v%, preferably 0.001 to 0.4 w/v%, and more preferably 0.003 to 0.3 w/v%. If the amount of the Wetting agent is less than 0.0001 w/v%, the Wetting of the active ingredient is not sufficient, and so the active ingredient may float or settle down easily. If the amount is greater than 0.5 w/v%, the Wetting of the active ingredient is excessive, and so the Sedimentation velocity may increase.
(3) Viscosity Controlling agent
Tne \ isco5it\" Controlling agent decreases üie sedimeniarion \elociL> oi üie iisDers^d acn^e ingredients by maintaining the viscosity of the suspension at a constant ievel. and so minimizes or delays the formation of precipitates to distribute the active ingredients homogeneously in the whole suspension during the period of circulation. Thus, when the suspension is administered to patients, the viscosity Controlling agent guarantees an intake of a pre-determined amount of active ingredient. The Sedimentation velocity decreases as the suspension's viscosity increases, but too high viscosity may make intake difficult to patients. The viscosity Controlling agent used in the present invention is hydrated in aqueous Solution to exhibit viscosity, or floats in aqueous Solution without sinking rapidly, thereby delaying the Sedimentation.
The viscosity Controlling agent used in the present suspension is not limited specially as long as it can provide a desired viscosity to the suspension. Preferably, the viscosity Controlling agent is selected from the group consisting of carbomer, polyethyleneoxide with a molecular weight of 5,000 to 5,000,000, hydroxypropylmethylcellulose. hydroxypropylcellulose, xanthan gum, gua gum, tragacanth gum, locust bean gum, carrageenan, polyvinylpyrrolidone, polyvinylalcohol, vinylpyrrolidone-vinylacetate copolymer, microcrystalline cellulose-carboxymethylcellulose sodium mixture, micronized
crospo\idone. carboxymethylceliüiose and derivaiives üiereof ifor exampis. sodiurr; carboxymethylcellulose and calcium carboxymethylceliüiose), alginic acid and deriNatixes thereof (for example, sodium alginate and propyleneglycol alginate), silicone emulsion, glycerol, and mixtures thereof. More preferably, the viscosity Controlling agent is selected from the group consisting of carbomer, polyethyleneoxide with a molecular weight of 5.000 to 5,000,000, hydroxypropylmethylcellulose, hydroxypropylcellulose, xanthan gum, microcrystalline cellulose-carboxymethylcellulose sodium mixture, silicone emulsion, glycerol, and mixtures thereof. Still more preferably, the viscosity Controlling agent is selected from the group consisting of carbomer 934P, carbomer 97IP, carbomer 974P, and mixtures thereof. Most preferably, the viscosity Controlling agent is carbomer 971P.
The amount of the viscosity Controlling agent in the present suspension is O.Ol to 10 w/v'/c, preferably 0.05 to 5 w/v%, more preferably 0.1 to 4 w/v%. If the amount of the viscosity Controlling agent is less than O.Ol w/v%, the physical stability of the suspension (i.e. Sedimentation ratio) may not be maintained properly, and so the active ingredient may float or precipitate easily. If the amount is greater than 10 w/v%, the viscosity is too high, and so the production may become difficult, and the intake to patients may be difficult.
(4) Buffers, preservatives, sweeteners, flavors and antifoaming agents
Preferably, the present suspension may further comprise buffen preservative, sweetener, flavor, antifoaming agent, or mixtures thereof.
The buffer can be used to provide a suspension which is easy to drink. by maintaining the suspension's pH at a constant level during the period of circulation, and providing appropriate acidity to the suspension. The buffer in the present invention can be selected freely from pharmaceutically acceptable conventional buffers. Preferably, citric acid sodium citrate, tartaric acid and salts thereof, fumaric acid, or sodium acetate can be used as the buffer.
The preservative can be used to prevent the chemical deterioration of products during the period of circulation. The preservative in the present invention can be selected freely from pharmaceutically acceptable conventional preservatives. Preferably, the preservative can be selected from benzoic acid, sodium benzoate, methyl paraoxybenzoate, ethyl paraoxybenzoate, (iso)propyl paraoxybenzoate, (iso)butyl paraoxybenzoate, sorbic acid, potassium sorbate, sodium sorbate, dehydroacetic acid, sodium dehydroacetate, chlorobutanol, benzalkonium Chloride, benzenthonium Chloride, phenol (p type), cresol.
chiorocresoL and benzyl alcohol. More preferabl}, scdium benzoate can
The sweetener and flavor can be used to improve the administration compliance by providing a good taste to patients in administration to reduce aversion to the administration. The sweetener in the present invention can be selected freely from pharmaceutically acceptable conventional sweeteners. Preferably, the sweetener can be selected from sucrose, fructose, honey, sodium Saccharin, cyclamate, aspartame, xylitol, erythritoL acesulfame or the like. More preferably, sucrose can be used. The flavor in the present invention can be selected freely from pharmaceutically acceptable conventional flavors. Preferably, lemon lime flavor, lemon essence, strawberry flavor, banana flavor, chocolate flavor, milk flavor or the like can be used, but are not limited thereto.
The antifoaming agent increases convenience in production and administration of the suspension by suppressing the generation of bubbles when the suspension is shaken in formulation and administration. The antifoaming agent in the present invention can be selected freely from pharmaceutically acceptable conventional antifoaming agents. Preferably, simethicone, simethicone emulsion, methyl oleate, glyceryl oleate, sorbitan laurate, sorbitan oleate or the like can be used, but are not limited thereto.
Pharmaceutically acceptable conventional kinds provided in liquid or soiid staie can be used as the buffer, preservative, sweetener, flavor and antifoaming agent. The amounts of the buffer, preservative, sweetener, flavor and antifoaming agent used in the present suspension are not limited specially. A skilled artisan can choose a preferable amount of use for each of them, depending on a desired State of the suspension.
Preferably, the suspension according to the present invention comprises the components as shown in the following Table 1. [Table 1]
Preferable composition of the present suspension
Component Amount (w/v%) Component Amount (w/v%)
Megestrol acetate 4 Sodium citrate 0.09
Poloxamer 188 0.05 Sucrose 5
carbomer 97IP 0.33 Lemon flavor 0.091
Sodium benzoate 0.1 30w/v% simethicone emulsion 0.5
Citric acid 0.13 Water Appropriate amount
Total 100

Also preferably, the suspension according to the present invention comprises the components as shown in the following Table 2.
[labie 21
Another preferable composition of the present suspension
Component Amount (w/v%) Component Amount (w/v%)
Megestrol acetate 8 Sodium citrate 0.09
Poloxamer 188 0.05 Sucrose 5
carbomer 97IP 0.33 Lemon flavor 0.091
Sodium benzoate 0.1 30w/v% simethicone emulsion 0.5
Citric acid 0.13 Water Appropriate amount
Total 100

The present invention will be more specifically explained by the following examples. However, it should be understood that the following examples are intended to illustrate the present invention, and cannot be used to limit the scope of the present invention in any manner.
Comparative Example
Megace Oral Suspension (Bristol-Myers Squibb) described in Korean Patent No. 02i II92, which is sold in the market, was used. The composition of the oral suspension is shown in the following Table 3. [Table 3]
Composition of Megace Oral Suspension
Component g,nortmL v^/v^
Micronized megestrol acetate 4.0 4.0 1
Polyethyleneglycol 1450 20.0 20.0 1
Polysorbate 80 O.Ol O.Ol
Xanthan gum, TF 0.2 0.2
Sodium benzoate 0.2 0.2
Citric acid 0.244 0.244
Sodium citrate 0.15 0.15
Sucrose 5.0 5.0
Lemon lime flavor #400639 0.091 0.091
Purified water Appropriate amount

Exatnple 1
A suspension was prepared according to the composition shown in the following Table 4. [Table 4]
Composition of the suspension in Example 1
Component g/lOOmL
Megestrol acetate 4.0
Cremophor EL 0.04
Concentrated glycerol 0.5
Silicone emulsion 30% 10.0
PoloxamerF127 0.005
Avicel RC591 0.105
Sodium benzoate 0.2
Citric acid 0.244
Sodium citrate 0.15
Sucrose 5.0
Lemon lime flavor 0.091
Purified water Appropriate amount

Preparaiion procedure:
(1) Preparation of megestrol acetate dispersion: To an appropriate amount of purified \\ ater Cremophor EL (Polyethyleneglycol-35 castor oil; BASF) and concentrated glycerol were added and dissolved, and then megestrol acetate was dispersed therein. Silicone emulsion of 30% (Dow Corning) was added thereto and mixed. The mixture was dispersed by homogenizer, and a Solution of poloxamer Fl27 (Poloxamer 407; Sigma), which was separately prepared by dissolving the poloxamer in an appropriate amount of purified water, was added thereto and mixed to prepare megestrol acetate dispersion.
(2) Preparation of thickener Solution: To an appropriate amount of purified water, Avicel RC591 (microcrystalline cellulose-carboxymethyl cellulose sodium mixture; FMC polymer) was added and hydrated, and then mixed by mixer.
(3) Sodium citrate, citric acid, sucrose, sodium benzoate and flavor were dissolved in purified water.
(4) The mixtures of the above (1), (2) and (3) were mixed together, and purified water was added thereto to make the total volume of lOOmL. The resultant mixture was dispersed by homogenizer and passed through a sieve of No. 200 (aperture; 75//ra).
Examples 2 to 5
i>uspensions were prepared respectiveiy, accorcing to the compositions shcat^ in üie
follovving Table 5.
[Table 5]
Compositions of the suspensions in Examples 2 to 5
Example No. 2 3 4 5
Component g/lOOmL g/lOOmL g/lOOmL g/lOOmL
Megestrol acetate 4.0 4.0 4.0 4.0
Concentrated glycerol 0.5 0.5 0.5 0.5
Silicone emulsion 30% lO.O 10.0 10.0 10.0
Cremophor EL 0.04 0.04 0.04 -
Myrj 52S - - - 0.04
Poloxamer F68 0.005 0.005 O.Ol 0.005
Imwitor 742 0.005 - 0.005 0.005
Hydroxypropylmethylcellulose 60SH 4000 0.105 0.105 0.105 -
Polyethyleneoxide (Mw: 5,000,000) - - - 0.105
Sodium benzoate 0.1 0.1 0.1 0.1
Citric acid 0.13 0.13 0.13 0.13
Sodium citrate 0.09 0.09 0.09 0.09
Sucrose 5.0 5.0 5.0 5.0
Lemon lime flavor 0.091 0.091 0.091 0.091
Purified water Appropriate amount

Preparation procedura:
(1) Preparation of megestrol acetate dispersion: To an appropriate amount of purified water, Cremophor EL, Myrj 52S (Polyethyleneglycol-40 Stearate; Uniqema), Poloxamer F68 iPoloxamer 188; Sigmaj and Imwitor 742 icapniic/capric giyceride: Sasel Gn^bH. ■^.ere added and dissolved, and then megestrol acetate was dispersed therein. Concentrated glycerol and silicone emulsion 30% were added thereto and mixed. The mixture was dispersed by homogenizer, and mixed to prepare megestrol acetate dispersion.
(2) Preparation of thickener Solution: To an appropriate amount of purified water, Hydroxypropylmethylcellulose 60SH 4000 (Shinetsu, Japan) or Polyethyleneoxide with the molecular weight of 5,000,000 (Dow Corning) was added and hydrated, and then mixed by mixer.
(3) The same procedures as the steps (3) and (4) in Example 1 were conducted.
Examples 6 to 8
Suspensions were prepared respectively, according to the compositions shown in the
following Table 6.
[Table 6]
Compositions of the suspensions in Examples 6 to 8
Example No. 6 7 8
Component g/lOOmL g/lOOmL g/lOOmL
Megestrol acetate 4.0 4.0 4.0
Poloxamer F68 0.05 0.15 0.25
Carbomer 0.33 0.33 0.33
Sodium benzoate 0.1 0.1 0.1

Citric acid V. ! 0.! 3
i Sodium citrate 0.09 0.09 0.Ct9
Sucrose 5.0 5.0 5.0 !
Lemon lime flavor 0.091 0.091 0.091
30w/v% simethicone emulsion 0.5 0.5 0.5
Purified water Appropriate amount

Preparation procedure:
(1) Preparation of megestrol acetate dispersion: To an appropriate amount of purified water, Poloxamer F68 was added and dissolved, and then megestrol acetate was dispersed therein and mixed to prepare megestrol acetate dispersion.
(2) Preparation of thickener Solution: To an appropriate amount of purified water, Carbomer EP (Noveon) was added and hydrated, and then mixed by mixer.
(3) The same procedures as the steps (3) and (4) in Example 1 were conducted.
Examples 9 to 11
Suspensions for Examples 9 to 11 were prepared respectively, according to the compositions shown in the following Table 7. The concentration of megestrol acetate was increased, and in order to maintain suitable physical stability, the Wetting agent and the viscosity Controlling agent were adjusted properly, to prepare oral suspensions of the compositions shown in the following Table 7.
ilabie 7]
Compositions of the suspensions in Examples 9 to 11
Example No. 9 10 11
Component g/lOOmL g/lOOmL g/lOOmL
Megestrol acetate 8.0 8.0 8.0
Poloxamer F68 0.05 0.06 0.04
Carbomer 0.363 0.363 0.363
Sodium benzoate 0.1 0.1 0.1
Citric acid 0.13 0.13 0.13
Sodium citrate 0.09 0.09 0.09
Sucrose 5.0 5.0 5.0
Lemon lime flavor 0.091 0.091 0.091
30w/v% simethicone emulsion 0.5 0.5 0.5
Purified water Appropriate amount

Preparation procedure:
(1) Preparation of megestrol acetate dispersion: To an appropriate amount of purified waten Poloxamer F68 was added and dissolved, and then megestrol acetate was dispersed therein and mixed to prepare megestrol acetate dispersion.
(2) Preparation of thickener Solution: To an appropriate amount of purified water, carbomer was added and hydrated, and then mixed by mixer.
(3) The same procedures as the steps (3) and (4) in Example 1 were conducted.
Test Example 1; Measurement of Sedimentation velocity
- Tested sampies: The suspensions prepared in Compararive Exampie and Exe
- Test method: The measurements were conducted according to a method described in Korean Patent No. 0211192 by Bristol-Myers Squibb Company. Concretely. about 50mL of sample was placed in a cylinder marked with degrees in volume unit, and sealed tightly. After keeping the sample in a cylinder at room temperature for one week, the Sedimentation heisht was measured, and the Sedimentation ratio was calculated by the following equation.
Sedimentation ratio (%)
= [Sedimentation height after a certain period / Total suspension height at initial State] x 100
The calculated Sedimentation ratios are shown in the following Table [Table 8]
Calculated Sedimentation ratios
Comparative Exampie No.
Exampie 1 2 3 4 5 6 7 8 9 10 11
Sedimentation ratio (%) 96 81.5 94.4 91 90 83.3 98 93.2 91 98.5 98.3 98.5
Flocculation Flocculated Not Flocculated Flocculated Not Flocculated

High sedimentarioR ratio means that ihe suspension is ph%sicalh' stable. Ai can bc see- from Table 8. the suspensions according to tiie present invention exhibited high Sedimentation ratios after being kept at room temperature for one week, which shows that they were physically stable regardless of whether they were flocculated or not.
Test Example 2: Sedimentation velocity according to temperature
The present test has a meaning of providing a patient with a medicament of good quality by comparing physical/chemical stabilities of suspension according to various temperature conditions which might occur in the circulation of the medicament.
- Tested samples: The suspensions prepared in Comparative Example and Example 6.
- Test method: About 50mL of sample was placed in a cylinder marked with degrees in volume unit and sealed tightly. After keeping the sample ander the conditions of, (i) room temperature, (ii) 40°C and 75%RH, and (iii) 60°C drying oven, each, the Sedimentation ratios were calculated. The test results under the conditions (i) to (iii) are shown in the following Tables 9 to 11 and Figures 1 to 3, respectively.
[Table 9]
Calculated Sedimentation ratios under the condition (i)
1 week 2 weeks 4 weeks 8 weeks 12 weeks
Comparative Example (Megace) 96.0 91.0 72.0 65.0 64.0

Examole 6
98.Ö 96.6 91.2 84.6
[Table 10]
Calculated Sedimentation ratios under the condition (ii)
1 week 2 weeks 3 weeks 4 weeks 6 weeks 8 weeks 10 weeks
Comparative
Example
(Megace) 93.0 77.0 72.0 66.8 63.0 60.8 59.6
Example 6 98.0 96.0 94.0 89.8 87.0 83.0 81.0

[Table 11]
Calculated Sedimentation ratios under the condition (iii)
1 day 2days 3
days 5 days 1 week 2 weeks 3 weeks 5 weeks
Comparative
Example
(Megace) 94.2 87.4 81.6 71.8 68.0 62.1 60.2 57.3
Example 6 99.0 98.4 97.5 95.7 94.1 88.2 84.3 79.4

As can be seen from Tables 9 to 11, the Comparative Example of Megace oral suspension (Bristol-Myers Squibb) became physically (for example, Sedimentation velocity) very unstable according to the elevation of temperature. This is estimated to be caused from the characteristics of polyethyleneglycol 1450 used in 20 w/v% for the suspension of the Comparative Example. The viscosity of polyethyleneglycol 1450 decreases rapidly as the temperature elevates, and Megace oral suspension was designed to prevent the
deflCKCujation of the suspension, and delay the precipimte formation by using such characteristics. However, because of using polyethyleneglycol 1450 as excipient on which temperature has a relatively large influence, Megace oral suspension has a disadvantage that the stability of the system is affected greatly by the temperature. In comparison, the suspension of Example 6 maintained a relatively stable physical State under the conditions of room temperature, 40°C and 75%RH, and 60°C drying oven even though it was not flocculated. That is, according to the present invention, the observable physical heterogeneity in appearance caused from the flocculation of megestrol acetate suspension can be minimized, and the high Sedimentation ratio can be maintained for a relatively long period, and so it is possible to provide patients with medicaments of good quality, and improve the confidence to the medicament quality and the compliance in administration.
Test Example 3: Dissolution test
The dissolution test is important to predict the availability of active ingredient in a in vivo since megestrol acetate is hardly soluble in water.
- Tested samples: The suspensions prepared in Comparative Example and Examples 1, 2, 5, 6 and 9
- Test method: According to the l" method among the dissolution test methods in the US
Pharmacopoeia 29. Monograph: Megestroi Acerate Oral Suspension. 9(X;mL ■:: 0.5 u sodium laurylsulfate aqueous Solution at 37 °C was used as test medium, and the test was conducted at a rotation speed of 25 rpm by using the paddle method according to the dissolution test method in the Korean Pharmacopoeia. The test results are shown in the following Table 12 and Figure 5. [Table 12]
Dissolution test results
Comparative Example (Megace) Example 1 Example 2 Example 5 Example 6 Example 9
Time Average S.D. Average S.D. Average S.D. Average S.D. Average S.D. Average S.D.
10min. 48.4 5.0 97.5 5.2 98.8 2.8 95.9 5.8 98.4 2.3 97.4 5.8
20min. 81.2 4.0 98.9 2.1 100.0 1.5 100.5 1.2 99.9 2.3 98.3 3.5
30min. 90.6 1.2 99.9 I.l 100.3 2.0 100.3 0.8 100.3 1.6 98.3 2.1
^ S.D.: Standard Deviation

As can be seen from Table 12, in comparison with Comparative Example, the suspension of the present invention exhibited remarkably high initial dissolution ratios regardless of the amount of active ingredient. Such difference is from the polyethyleneglycol 1450 used in Comparative Example. The suspension of Comparative Example containing the polyethyleneglycol had the specific gravity of about 1.07g/mL which is gi'eater than that of
abolii i.05g/mL in ihe Examples. That is. shoniv after siarting the dissoiuuc-n irsu ine suspensions of the Examples exhibited an equal disiribution throughout the eniire lest Container by the rotation of paddle. In comparison, even shortly after starting the dissolution test, the suspension of Comparative Example exhibited settling down in the test Container, thereby showing a low dissolution ratio, which was because the polyethyleneglycol was dissolved slowly upon being dispersed in the test Solution.
Test Example 4; Viscositv measurement
Viscosity is one of important physical properties of suspension. Viscosity of suspension is an important factor for maintaining the physical stability of the suspension system. Generally, as the viscosity becomes higher, the physical stability of the system, i.e.. the Sedimentation ratio, becomes higher. However, the increase of the viscosity for the sake of physical stability of the system results in lowering flowability of the suspension, which may cause inconvenience in administration to patients. Therefore, it is very important to maintain the viscosity of suspension to an appropriate level enough to provide the physical stability and the easiness of administration. - Apparatus for measurement:
Name: Brookfield, DV-II+ Viscometer
Condirion: Spindie No. #K 50 rpm - Tested samples: The suspensions prepared in Comparative Example and Example 6 (250mL)
The viscosity measurement results are shown in the following Table 13. [Table 13]
Viscosity measurement results
Viscosity (cps)
Comparative Example (Megace) 175
Example 6 56

As can be seen from Table 13, in comparison with Example 6, the suspension of Comparative Example had higher viscosity by three times. The low viscosity of the present suspension can provide conveniencc in administration to patients, and make the filling of product in production process easy, thereby improving the productivity.
Test Example 5: Measurement of surface Potential of suspension
Except for special cases, the surface of solid (liquid or gas) in contact with aqueous Solution takes Charge, and withdraws counter-charged ions (counter ions) in the Solution, to form electrical double layer near the surface. If surface-activating ions, for example, Surfactants, exist in the liquid phase, they are adsorbed specificaih onto the solid surface, anc ;nange the surface potential gi'eatly. Zeta potential may be a factor for determining stabiiity of colloidal particles. If the zeta potential increases, the electrically charged amount increases, and the repulsion becomes strong, thereby improving the stabiiity of colloidal particles. If the zeta potential goes to 0, the repulsion between the particles becomes weak. thereby destabilizing the particles and causing coagulation. As explained above, the zeta potential is used as an index to represent the property of colloidal particles, especially physical stabiiity thereof.
The present test was to compare and verify the physical stabiiity of suspension by measuring the surface potential (^-potential, Zeta-potential) of particles.
- Apparatus for measurement: ELS-8000, Electrophoretic Light Scattering, Otsuka, Japan
- Medium: Purified water
- Tested samples: The suspensions prepared in Comparative Example and Example 6
The measurement results by electrophoresis are shown in the following Table 14. [Table 14]
Surface potential measurement results
Comparative ExampSe Example ^
(Megace)
1 Zeta Potential -1.0 i
-14.3 !

As can be seen from the measurement results, the zeta potential of Comparative Example was dose to 0, whereas that of Example 6 was -14.3 which was relatively far from 0. This shows that the stability of the suspension of Example 6 was improved by repulsion between particles that was caused from the relative partial negative Charge on the surface of megestrol acetate in Example 6, in comparison with the Megace oral suspension. Thus, the present suspension has an advantage of providing easiness in re-dispersing when it is re- suspended after a long-term storage, which is consistent with the results of the Sedimentation velocity measurements of Test Examples 1 and 2.
Test Example 6: Measurement of particle size distribution
The particle size distribution in suspension is a very important factor characterizing the physical stability (for example, Sedimentation ratio, etc.) of the formulation. Generally, as the particle size becomes smaller, the Sedimentation ratio increases, and the physical Stability is improved.
The measurement of particle size distribution was conducted according to the following: - Apparatus for measurement: Malvern Instruments Ltd., Mastersizer 2000, Ver. 3.01,
Mäh ern UK
- Medium: Purified water
- Tested samples: The suspensions prepared in Comparative Example and Example 6
- Test procedura: By using the wet analysis method, each of certain amounts of the suspensions of Comparative Example and Example 6 was added to a system filled with purified water and the initial particle size distribution was measured. Then, the sample was sonicated for about 30 seconds by using ultrasonic wave generator, and the particle size distribution was measured again. The particle size distribution measurement results are shown in the following Table 15 representing the medium values d (0.5).
[Table 15]
Particle size distribution measurement results
Comparative Example (Megace) Example 6
Particle size
im) Initial State 14.5 lA
After the sonication 6.2 5.3

As can be seen from Table 15, the Megace oral suspension of Comparative Example exhibited the particle size of 14.5 ßm [d (0.5)] whereas the suspension of Example 6 exhibited the particle size of 7.4 pm [d (0.5)], which shows that the particle size of Comparative Example was larger than that of Example 6 by about two times. After the ultrasonication for about 30 seconds, the measured particle sizes of Comparative Example
and txample 6 were 6.2 and 5.3, respectively. wiihoui a big difrerence mereberweei..
The changes in particle size distiibutions between the initial State and after the ultrasonication in Comparative Example and Example 6 should be noted. In the Comparative Example, the change in particle size distribution before and after the ultrasonication was very big, whereas that of Example 6 was small. Such large change in particle size distribution of the Comparative Example is estimated to come from the easy coagulation of particles due to low partial Charge on the surface of megestrol acetate particles, even though the relatively high viscosity from polyethyleneglycol and the flocculation of the suspension during the storage contributed to maintain the physical stability of the Comparative Example's suspension. And, it can be interpreted that the coagulated megestrol acetate particles were separated by the ultrasonication. However, in the present invention, the megestrol acetate particles existed separately from each other by the strong repulsion due to the partial Charge on the surface of megestrol acetate particles, thereby exhibiting small change in particle size before and after the ultrasonication. In spite of the relatively low viscosity and no flocculation, the long-term physical stability of the present suspension comes from the strong repulsion between the particles in the suspension.
INDUSTRIAL APPLICABILm
The present invention provides a stable oral suspension of megestrol acetate. The suspension of megestrol material according to the present invention has remarkably excellent Sedimentation ratio, and so provides relatively excellent dispersion State of active ingredient during the period of circulation, in spite of relatively low viscosity compared with Megace oral suspension (Bristol-Myers Squibb Company) which is cuiTently on sale. Therefore, patients can take the medicament easily, and the amount of megestrol material in each administration can be maintained constantly. Also, the suspension of megestrol material according to the present invention shows rapid dissolution velocity, and so when it is administered, the rapid exhibition of effect of the active ingredient can be expected. Further, the suspension of the present invention has excellent stability depending on temperature, and so the change in quality according to the storage and circulation conditions is relatively small, thereby providing higher quality of medicaments to patients and contributing to improve the quality of life.

CLAIMS
1. A suspension comprising a megestrol material as active ingredient. a polo.xamer as Wetting agent, and a viscosity Controlling agent.
2. The suspension according to claim 1, wherein the active ingredient is megestrol acetate.
3. The suspension according to claim 1, wherein the amount of the active ingredient is 1 to 15 w/v%.
4. The suspension according to claim 3, wherein the amount of the active ingredient is 2 to 10 w/v%.
5. The suspension according to claim 1, wherein the Wetting agent is poloxamer 124, 184. 185, 188, 237, 338 or 407.
6. The suspension according to claim 1, wherein the Wetting agent is poloxamer 188 or poloxamer 407.
7. The suspension according to Claim 1, further comprising a uemng agent seiecied from the group consisting of polyethyleneglycol-35 castor oil, polyethylenegi\col-40 hydrogenated castor oil, caprylocaproyl macrogol glyceride, oleoyl macrogol glyceride, caprylic/capric glyceride, caprylic/capric triglyceride polyethyleneglycol-4 ester and derivatives thereof, glyceryl monooleate, pQlyethyIeneglycol-40 stearate, glyceryl citrate/lactate/linoleate/oleate, polyoxyethylene (20) isohexadecyl ether, propylene glycol monolaurate, propylene glycol monocaprylate, sodium lauryl Sulfate, dioctylsulfosuccinate, and mixtures thereof.
8. The suspension according to claim 7, wherein the Wetting agent is selected from the group consisting of polyethyleneglycol-35 castor oil, polyethyleneglycol-40 hydrogenated castor oil, caprylic/capric glyceride, polyethyleneglycol-40 stearate, and mixtures thereof
9. The susjjension according to claim 1, wherein the amount of the Wetting agent is 0.0001 to 0.5 w/v%.
10. The suspension according to claim 1, wherein the amount of the Wetting agent is 0.001 to 0.4 w/v%.
11. The suspension according to claim 1, wherein ihe viscosity Controlling agenl is selected from the group consisting of carbomer, polyethyleneoxide with molecular weight of 5,000 to 5,000,000, hydroxypropylmethyicellulose, hydroxypropylcellulose, xanthan gum, gua gum, tragacanth gum, locust bean gum, carrageenan, polyvinylpyrrolidone. polyvinylalcohol, vinylpyrrolidone-vinylacetate copolymer, microcrystalline cellulose- carboxymethylcellulose sodium mixture, micronized crospovidone, carboxymethylcellulose and derivatives thereof, alginic acid and derivatives thereof, silicone emulsion, glycerol, and mixtures thereof.
12. The suspension according to claim 11, wherein the viscosity Controlling agent is selected from the group consisting of carbomer, polyethyleneoxide with molecular weight of 5,000 to 5,000,000, hydroxypropylmethyicellulose, hydroxypropylcellulose, xanthan gum, microcrystalline cellulose-carboxymethylcellulose sodium mixture, silicone emulsion. glycerol, and mixtures thereof.
13. The suspension according to claim 12, wherein the viscosity Controlling agent is selected from the group consisting of carbomer 934P, carbomer 97IP, carbomer 974P and
mixiures chereof.
14. The suspension according to claim 1, wherein the amount of the viscosity Controlling agent is O.Ol to 10 w/v%.
15. The suspension according to claim 1, wherein the amount of the viscosity Controlling agent is 0.05 to 5 w/v%.
16. The suspension according to claim 1, further comprising buffer, preservative, sweetener, flavor, antifoaming agent, or mixtures thereof.
17. A suspension comprising 1 to 15 w/v% of megestrol acetate as active ingiedient, 0.0001 to 0.5 w/v% of poloxamer as Wetting agent, and O.Ol to 10 w/v% of carbomer as viscosity Controlling agent.
18. A suspension comprising 2 to 10 w/v% of megestrol acetate as active ingredient, 0.001 to 0.4 w/v% of poloxamer as Wetting agent, and 0.05 to 5 w/v% of carbomer as viscosity Controlling agent.
19. A suspension comprising 4 w/v% of megestrol acetate; 0.05 \v/v% of poloxamer 188; 0.33 w/v% of carbomer 97IP; 0.1 w/v% of sodium benzoate; 0.13 w/v% of citric acid; 0.09 w/v% of sodium citrate; 5.0 w/v% of sucrose; 0.091 w/v% of flavor; 0.5 w/v% of simethicone emulsion (30 w/v%); and water as remainder.
20. A suspension comprising 8 w/v% of megestrol acetate; 0.05 w/v% of poloxamer 188; 0.33 w/v% of carbomer 97IP; 0.1 w/v% of sodium benzoate; 0.13 w/v% of citric acid; 0.09 w/v% of sodium citrate; 5.0 w/v% of sucrose; 0.091 w/v% of flavor; 0.5 w/v% of simethicone emulsion (30 w/v%); and water as remainder.