KR20080035374A - A pharmaceutically stable suspension of megestrol material - Google Patents

Abstract

A suspension composition comprising megestrol material is provided to improve dispersion of megestrol material during delivery by improving its precipitation rate while its viscosity is low, enhance dosage compliance of a patient, and increase release speed of megestrol material, and temperature stability. A suspension composition comprises 1-15 w/v% of megestrol material such as megestrol acetate as an active ingredient, 0.0001-0.5 w/v% of ploxamer as humectant and 0.01-10 w/v% of a viscosity-regulating agent selected from polyethylene oxide, hydroxypropylmethylcellulose, hydroxypropylcellulose, xanthan gum, guar gum, tragacanth gum, locust bean gum, carrageenan, polyvinylpyrrolidone, polyvinylalcohol, vinylpyrrolidone-vinylacetate copolymer, microcrystalline cellulose-carboxymethylcellulose sodium mixture, micronized crospovidone, carboxymethylcellulose and its derivative, alginic acid and its derivative, silicon emulsion, glycerol and a mixture thereof. Further, the suspension composition additionally comprises a buffer agent, a preservative, a sweetener, an aromatic, a defoamer and a mixture thereof.

Description

Pharmaceutically stable suspension of megestrol substances {A PHARMACEUTICALLY STABLE SUSPENSION OF MEGESTROL MATERIAL}

1 shows the sedimentation rate at room temperature of Comparative Example and Example 6.

2 shows the sedimentation rate at 40 ° C. and 75% relative humidity conditions of Comparative Example and Example 6. FIG.

3 shows the sedimentation rate in a drying oven at 60 ° C. in Comparative Example and Example 6. FIG.

4 shows the change in sedimentation rate after the initial and severe one month of Comparative Example and Example 6.

5 shows the dissolution patterns of Comparative Examples, Examples 1, 2, 5, 6 and Example 9. FIG.

The present invention relates to suspensions of megestrol materials that are physically stable at room temperature, accelerated conditions and harsh conditions and pharmaceutical compositions thereof.

Representative of megestrol materials, megestrol acetate is a 17α-acetoxy-6-methyl-4,6-pregnadiene-3,20-dione of the formula (hereinafter referred to as "megestrol acetate"). Anti-malignancies):

Megestrol acetate is an anti-tumor agent used in palliative therapy of advanced breast cancer and endometrial cancer, and is used for the treatment of significant weight loss in anorexia, cachexia or unknown causes of cancer or AIDS patients. Currently, megestrol acetate is commercially available as a tablet (Leg megestrol tablets, LG Life Sciences) or as a suspension (Megacenic Suspension, Bristol-Myers Squibb). In view of the wide range of megestrol acetate's use in clinical medicine, it is difficult to swallow a tablet or capsule, or if a high dose requires a relatively large amount of tablet It is desirable to have. For this reason, the development of suspensions of megestrol acetate is of great significance and an important point in suspensions is to maintain a stable form without physical and chemical modifications during the shelf life. In evaluating the stability of suspensions, one of the most considerations is the precipitation formation and thus redispersibility of the suspension components. According to the Korean Patent No. 0211192 of Bristol-Myers Squibb Company, it is proposed to measure the sediment height as a general method for measuring the stability of the suspension, and specifically, by measuring the sediment height periodically using a cylinder, The settling rate of the prepared suspension was measured.

In addition, Korean Patent No. 0211192 to Bristol-Myers Squibb Company provides a pharmaceutical composition of megestrol acetate suspension that does not de-desensify during the shelf life of the product. The pharmaceutical composition consists of micronized megestrol acetate, xanthan gum, sodium benzoate, citric acid, sodium citrate, sucrose, flavoring agent and purified water combined with polysorbate 80 and polyethylene glycol 1450. However, the suspension of the patent has a very high viscosity, long time remaining in the oral cavity and tube when taking, resulting in a large amount of waste, which reduces the convenience of taking the patient. This problem is also mentioned in U.S. Patent Publication No. 20050008707. According to the above patent, it is described that the larger the palatalization, the better the redispersibility, but the larger the palatalization, the more uneven pattern can be recognized when visual observation, which may mean that the homogeneity of the active ingredient is low. As a result, a certain amount of active ingredient may not be administered. In addition, the use of polyethylene glycol, which exhibits high viscosity at room temperature, at 20 w / v%, maintains a relatively high sedimentation rate, but consequently exhibits a high viscosity and additionally undergoes a warming process due to difficulties in the manufacturing process due to high viscosity. It has a downside.

U.S. Patent No. 6,028,065 refers to an orally suspended oral suspension of micronized megestrol acetate that is stable in water. In particular, reference is made to suspensions comprising at least one component selected from the group consisting of polyethylene glycol, propylene glycol, glycerol and sorbitol and a surfactant and megestrol acetate, in particular the polysorbate as a surfactant simultaneously with polyethylene glycol It is not used.

United States Patent Application Publication No. 20050008707 to Elan Pharma International discloses a nanoparticle composition comprising megestrol and a surfactant having a particle diameter of 2000 nm or less. Suspensions with a particle size of megestrol acetate of 2000 nm or less are relatively low in viscosity, so there is a small amount in the dose, and high viscosity leads to a long time for injection administration and a disadvantage in that megestrol acetate is likely to remain in the tube. It is said to be possible. It is also mentioned that the smaller the particle size, the faster the drug expression time and the higher the bioavailability. However, in order to reduce the particle size of 50% or more of the megestrol acetate used to 2000 nm or less, there is a disadvantage in that an additional process such as a grinding process, a homogenization process, or a reprecipitation process is required.

U.S. Patent Publication No. 20020028794 to Boehringer Ingelheim notes that megestrol acetate, a hydrophobic solid material, is not easily wetted by water and has a high interfacial tension which is further enhanced by air adsorbed on the particle surface. The use of surfactants to maintain their physical stability has been described. The application describes suspensions comprising megestrol acetate, wetting agents and suspending agents, in particular no polysorbates, polyethylene glycols, glycerol or sorbitol, and propylene glycol in a ratio up to 1.0 w / v% Disclosed is to.

Hughes C. Kundu et al. Disclose in US Patent Publication No. 20030198679 a composition comprising an insoluble active substance and at least one wetting agent and not containing polyethylene glycol, propylene glycol, sorbitol or glycerol as a suspension.

It is an object of the present invention to provide a low viscosity suspension which effectively wets a megestrol material which is a highly hydrophobic active ingredient in water and maintains a uniform dispersion state (ie high sedimentation rate) for a long time despite being low. .

The present invention relates to suspensions containing megestrol material as active ingredient, poloxamer as wetting agent, and viscosity modifier.

Hereinafter, the present invention will be described in detail.

(1) Active Ingredient

Unless stated otherwise herein, megestrol materials used as active ingredients include megestrol; Or stereoisomers, esters or pharmaceutically acceptable salts thereof. Preferred megestrol material is megestrol acetate.

Megestrol materials have a wide range of uses and include advanced breast cancer; Antitumor agents for endometrial cancer; Anorexia in cancer or AIDS patients; Adjuvant therapy for the treatment of breast cancer; cachexy; Or it is used as a treatment for significant weight loss of unknown cause.

The content of the active ingredient used in the suspension of the present invention is 1 to 15 w / v%, preferably 2 to 10 w / v%, more preferably 3 to 9 w / v%. If the amount of the active ingredient is less than 1 w / v%, the single dose is too large, and if the content of the active ingredient is more than 15 w / v%, the viscosity of the final dosage form may be too high, causing discomfort during administration.

(2) wetting agents

Wetting agents used in the suspensions of the present invention, as poloxamers, add hydrophilicity to the interface of the active ingredient so that the active ingredient exhibits a homogeneous distribution in the suspension. Poloxamer is a nonionic surfactant consisting of a copolymer of ethylene oxide and propylene oxide, which forms partial charges on the surface and medium of the active ingredient, preventing or minimizing intergranular agglomeration, preventing caking and resuspending the suspension. Makes it easier.

Poloxamers which can be used in the suspensions of the present invention are not particularly limited, but are preferably poloxamers 124, 184, 185, 188, 237, 338 and 407, more preferably poloxamer 188 or poloxamer 407. .

Preferably, the suspension of the present invention is polyethylene glycol-35 castor oil, polyethylene glycol-40 cured castor oil, caprylocaproyl macrogol glycerides, oleoyl macrogol glycerides, caprylic / capric glycerides, caprylic / Capric triglyceride polyethylene glycol-4 esters and derivatives, glyceryl monooleate, polyethylene glycol-40 stearate, glyceryl citrate / lactate / linoleate / oleate, polyoxyethylene (20) isohexadecyl ether, propylene It may further contain a humectant selected from the group consisting of glycol monolaurate, propylene glycol monocaprylate, sodium lauryl sulfate, dioctylsulfosuccinate and mixtures thereof. More preferably, the suspension agent of the present invention is selected from the group consisting of polyethylene glycol-35 castor oil, polyethylene glycol-40 cured castor oil, caprylic / capric glycerides, polyethylene glycol-40 stearate and mixtures thereof It may further contain a humectant. The content of the humectant used in the suspension of the present invention is 0.0001 to 0.5 w / v%, preferably 0.001 to 0.4 w / v%, more preferably 0.003 to 0.3 w / v%. If the content of the wetting agent is less than 0.0001 w / v%, the wettability of the active ingredient is insufficient. As a result, the active ingredient may float or sink easily. If the amount of the wetting agent exceeds 0.5 w / v%, the wettability of the active ingredient may be excessively settled. Can be faster.

(3) viscosity modifier

Viscosity modifiers slow down the settling rate of the dispersed active ingredient by maintaining the viscosity of the suspension at a constant level, thereby minimizing or delaying precipitation formation so that the active ingredient is distributed homogeneously throughout the suspension. Thus, when a suspension is administered to a patient, the viscosity modifier ensures that a constant dose of active ingredient is taken. The higher the viscosity of the suspension, the slower the rate of precipitation formation, but too high a viscosity can make the patient feel difficult to take. Viscosity modifiers used in the present invention are hydrated in aqueous solution to give viscosity, or float in the aqueous solution without rapidly sinking to retard the settling rate of the active ingredient.

The viscosity modifier used in the suspension of the present invention is not particularly limited as long as it can provide the desired viscosity in the suspension. Preferably, the viscosity modifier is carbomer, polyethylene oxide having a molecular weight of 5,000 to 5,000,000, hydroxypropylmethylcellulose, hydroxypropyl cellulose, xanthan gum, guar gum, tragacanth gum, lucostong gum, carrageenan, polyvinylpi Ralidone, polyvinyl alcohol, vinylpyrrolidone-vinylacetate copolymer, microcrystalline cellulose-carboxymethylcellulose sodium mixture, micronized crospovidone, carboxymethylcellulose and derivatives thereof (e.g., carboxymethylcellulose sodium and carboxymethylcellulose Calcium), alginic acid and its derivatives (e.g. sodium alginate and propylene glycol alginate), silicone emulsions, glycerol and mixtures thereof. More preferably, the viscosity modifier is a carbomer, polyethylene oxide 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 It is selected from the configured group. More preferably, the viscosity modifier is selected from the group consisting of Carbomer 934P, Carbomer 971P, Carbomer 974P and mixtures thereof. Most preferably, the viscosity modifier is Carbomer 971P.

The content of the viscosity modifier used in the suspension of the present invention is 0.01 to 10 w / v%, preferably 0.05 to 5 w / v%, more preferably 0.1 to 4 w / v%. If the content of the viscosity modifier is less than 0.01 w / v%, it is not suitable to maintain the physical stability (e.g. sedimentation rate) of the suspension, so that the active ingredient is suspended or easily precipitates, and if it exceeds 10 w / v%, The viscosity is so high that it is difficult to produce and may cause discomfort in the administration of the patient.

(4) buffers, preservatives, sweeteners, fragrances and antifoams

Preferably, the suspensions of the present invention may further contain buffers, preservatives, sweeteners, fragrances, antifoams or mixtures thereof.

Buffers can be used to provide a liquid formulation that is easy to drink by maintaining the pH of the suspension at a constant level during distribution and providing adequate acidity. The buffer of the present invention can be freely selected from conventional pharmaceutically acceptable buffers. Preferably, the buffer may be citric acid, sodium citrate, tartaric acid and salts thereof, fumaric acid or sodium acetate and the like.

Preservatives can be used to prevent chemical modification of the product during the shelf life. Preservatives used in the present invention may be freely selected from conventional pharmaceutically acceptable preservatives. Preferably, the preservative is benzoic acid, sodium benzoate, methyl paraoxybenzoate, ethyl paraoxybenzoate, paraoxybenzoate (iso) propyl, paraoxybenzoate (iso) butyl, sorbic acid, potassium sorbate, sodium sorbate, dihydroacetic acid, di Sodium hydrochloride, chlorobutanol, benzalkonium chloride, benzenetonium chloride, phenol (p), cresol, chlorocresol and benzyl alcohol, preferably sodium benzoate may be used.

Sweeteners and fragrances can be used to increase medication compliance by reducing the objectionability to medication by making the patient taste better. Sweeteners used in the present invention may be freely selected from conventional pharmaceutically acceptable sweeteners. Preferably, the sweetening agent may be selected from sucrose, fructose, honey, sodium saccharin, cyclate, aspartame, xylitol, erythritol and acesulfame, but sucrose may be preferably used. The fragrance used in the present invention may be freely selected from conventional pharmaceutically acceptable fragrances. Preferably, the fragrance may be lemon lime, lemon essence, strawberry flavor, banana flavor, chocolate flavor and milk flavor, and the like, but is not limited thereto, and a pharmaceutically acceptable conventional one may be used.

Defoamers increase the ease of preparation and taking by inhibiting the production of bubbles that may occur when shaken during preparation and taking. Antifoams used in the present invention can be freely selected from conventional pharmaceutically acceptable antifoams. Preferably, the antifoaming agent may be used such as simethicone, simethicone emulsion, dimethicone, dimethicone emulsion, silicone, silicone emulsion, methyl oleate, glyceryl oleate, sorbitan laurate and sorbitan oleate. Conventional ones can be used.

Buffers, preservatives, sweeteners, fragrances and antifoams can be used conventionally provided in a pharmaceutically acceptable liquid or solid state, the amount of buffers, preservatives, sweeteners, fragrances and antifoams used in the suspension according to the invention It is not particularly limited, and a person skilled in the art can determine the preferred amount of each of them by considering the state of the desired suspension.

Preferably, the suspension according to the invention consists of the following composition.

ingredient Content (w / v%) ingredient Content (w / v%)  Megestrol acetate 4  Sodium citrate 0.09  Poloxamer 188 0.05  Sucrose 5  Carbomer 971P 0.33  Lemon Flavor 0.091  Sodium benzoate 0.1  30w / v% Simethicone Emulsion 0.5  Citric acid 0.13  water Quantity  sum 100

Also preferably, the suspension according to the invention consists of the following composition.

ingredient Content (w / v%) ingredient Content (w / v%)  Megestrol acetate 8  Sodium citrate 0.09  Poloxamer 188 0.05  Sucrose 5  Carbomer 971P 0.33  Lemon Flavor 0.091  Sodium benzoate 0.1  30w / v% Simethicone Emulsion 0.5  Citric acid 0.13  water Quantity  sum 100

Hereinafter, the present invention will be described in more detail based on the following examples. However, these are only for the understanding of the present invention and do not limit the scope of the present invention.

Comparative example

Megace Oral Suspension, Bristol-Myers Squibb, described in Korean Patent No. 0211192 to Bristol-Myers Squibb Company, was used. Table 1 shows the composition of the oral suspension.

ingredient g / 100mL w / v%  Micronized Megestrol Acetate 4.0 4.0  Polyethylene Glycol 1450 20.0 20.0  Polysorbate 80 0.01 0.01  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 # 400639 0.091 0.091  Purified water Quantity

Example 1

A suspension was prepared in the composition shown in Table 2 below.

ingredient g / 100mL  Megestrol acetate 4.0  Cremophor EL 0.04  Concentrated glycerol 0.5  Silicone emulsion 30% 10.0  Poloxamer F127 0.005  Avicel RCD591 0.105  Sodium benzoate 0.2  Citric acid 0.244  Sodium citrate 0.15  Sucrose 5.0  Lemon-lime air freshener 0.091  Purified water Quantity

Manufacturing method:

(1) Preparation of megestrol acetate dispersion: Dissolved by adding Cremopoor EL (polyethyleneglycol-35 castor oil; BASF) and concentrated glycerol in an appropriate amount of purified water, dispersing megestrol acetate, silicone emulsion 30% suspension (Dow Corning) was added, mixed and dispersed by a homogenizer, and separately mixed with poloxamer F127 (poloxamer 407; Sigma) solution dissolved in an appropriate amount of purified water, followed by mixing to prepare a megestrol acetate dispersion.

(2) Preparation of thickening liquid: Avicel RC 591 (microcrystalline cellulose-carboxymethylcellulose sodium mixture; FMC polymer) was added to an appropriate amount of purified water, hydrated, and mixed with a mixer.

(3) Sodium citrate, citric acid, sucrose, sodium benzoate and fragrance were dissolved in purified water.

(4) After the above (1), (2) and (3) were mixed, purified water was added thereto to exactly 100 mL, dispersed with a homogenizer, and sieved through a No. 200 sieve (75 um).

Examples 2-5

Each suspension was prepared with the composition shown in Table 3 below.

division Example 2 Example 3 Example 4 Example 5 ingredient g / 100mL g / 100mL g / 100mL g / 100mL  Megestrol acetate 4.0 4.0 4.0 4.0  Concentrated glycerol 0.5 0.5 0.5 0.5  Silicone emulsion 30% 10.0 10.0 10.0 10.0  Cremophor EL 0.04 0.04 0.04 -  Mirage 52S - - - 0.04  Poloxamer F68 0.005 0.005 0.01 0.005  Emitter 742 0.005 - 0.005 0.005  Hydroxypropylmethylcellulose 60SH 4000 0.105 0.105 0.105 -  Polyethylene oxide molecular weight 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 air freshener 0.091 0.091 0.091 0.091  Purified water Quantity

Manufacturing method:

(1) Megestrol Acetate Dispersion Preparation: Cremophor EL, Myriz 52S (Polyethyleneglycol-40 Stearate; Uniquema), Poloxamer F68 (Poloxamer 188; Sigma), and Emitter 742 in an appropriate amount of purified water Caprylic / Capric glycerides; Sasol GmbH) were added to dissolve and disperse megestrol acetate, 30% suspension of concentrated glycerol and silicone emulsion was added, mixed and dispersed by homogenizer, and mixed to prepare megestrol acetate dispersion. .

(2) Preparation of thickening liquid: Hydroxypropylmethylcellulose 60SH 4000 (Shin-Echu, Japan) or polyethylene oxide molecular weight 5,000,000 (Dow Corning) was added to an appropriate amount of purified water, followed by hydration and mixing with a mixer.

(3) The same process as in (3) and (4) of Example 1 was carried out.

Examples 6-8

Each suspension was prepared with the composition shown in Table 4 below.

division Example 6 Example 7 Example 8 ingredient g / 100mL g / 100mL g / 100mL  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 0.13 0.13 0.13  Sodium citrate 0.09 0.09 0.09  Sucrose 5.0 5.0 5.0  Lemon-lime air freshener 0.091 0.091 0.091  30w / v% Simethicone Emulsion 0.5 0.5 0.5  Purified water Quantity

Manufacturing method:

(1) Preparation of megestrol acetate dispersion: After dissolving poloxamer F68 in an appropriate amount of purified water, megestrol acetate was dispersed and mixed to prepare a megestrol acetate dispersion.

(2) Preparation of thickening liquid: Carbomer EP (Noveon) was added to a suitable amount of purified water, hydrated, and mixed with a mixer.

(3) The same process as in (3) and (4) of Example 1 was carried out.

Examples 9-11

To prepare Examples 9 to 11 with the composition shown in Table 5. The megestrol acetate oral suspension was prepared in the following composition by appropriately adjusting the wetting agent and the viscosity adjusting agent so as to increase the concentration of megestrol acetate and thereby maintain the appropriate physical stability.

division Example 9 Example 10 Example 11 ingredient g / 100mL g / 100mL g / 100mL  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 air freshener 0.091 0.091 0.091  30w / v% Simethicone Emulsion 0.5 0.5 0.5  Purified water Quantity

Manufacturing method:

(1) Preparation of megestrol acetate dispersion: After dissolving poloxamer F68 in an appropriate amount of purified water, megestrol acetate was dispersed and mixed to prepare a megestrol acetate dispersion.

(2) Preparation of thickening liquid: Carbomer was added to an appropriate amount of purified water, hydrated, and mixed with a mixer.

(3) The same process as in (3) and (4) of Example 1 was carried out.

Test Example 1 Sedimentation Rate Measurement

Test Specimens: Suspensions of Comparative Examples and Examples 1-11.

-Test method: It measured using the method described in Korean Patent No. 0211192 of Bristol-Myers Squibb Company. Specifically, about 50 mL of the sample was taken and placed in a volumetric graduated measuring cylinder, and left to stand at room temperature for 1 week. After the precipitation height was measured, the sedimentation rate was calculated based on the following formula.

Table 6 shows the sedimentation rate (%) of the comparative example and each example.

Comparative example Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 Example 10 Example 11 Sedimentation rate (%) 96 81.5 94.4 91 90 83.3 98 93.2 91 98.5 98.3 98.5 Whether or not you write Painting Not written Painting Not written

High sedimentation rate means that the suspension is physically stable. As can be seen from Table 6, the suspension according to the present invention exhibited a high sedimentation rate (81.5% to 98.5%) after being left at room temperature for one week, and thus it was found to be physically stable regardless of whether or not it was written.

Test Example 2 Sedimentation Rate According to Temperature

This test is intended to provide patients with higher quality medicines by comparing the physicochemical stability of suspensions with various temperature conditions that may occur during distribution.

Test Specimen: Suspension of Comparative Example and Example 6.

-Test method: Take about 50 mL of the sample, place it in a volumetric graduated measuring cylinder, seal it, and leave it in (i) room temperature, (ii) 40 ° C and 75% relative humidity or (iii) 60 ° C dry oven, respectively. The sedimentation rate over time was calculated. Tables 7 to 9 and FIGS. 1 to 3 show the test results according to (i) to (iii), respectively.

division 1 week 2 weeks 4 Weeks 8 Weeks 12 Weeks Comparative Example (Megace) 96.0 91.0 72.0 65.0 64.0 Example 6 98.0 96.6 91.2 84.6 80.2

division 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

division 1 day 2 days 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 7 to 9, the comparative megacenic suspending solution (Bristol-Myers Squibbs Inc.) becomes very unstable in physical stability (eg, sedimentation rate) with increasing temperature. This is believed to be due to the properties of polyethyleneglycol 1450 used 20w / v% in the suspension of the comparative example. Polyethyleneglycol 1450 is characterized by a sharp decrease in viscosity as the temperature increases, and the megacetic oral suspension is designed to use this property to prevent de-desaturation of the suspension and to delay precipitation formation. However, it can be seen that the use of polyethylene glycol 1450, an excipient having a relatively large influence of temperature, easily changes the physical properties such as the viscosity of the system with temperature, so that the stability of the system is greatly affected by the temperature. On the other hand, it can be seen that Example 6 maintains a relatively stable physical state at room temperature, 40 ° C. and 75% relative humidity, and 60 ° C. dry oven without defrosting. That is, the present invention minimizes the physical unevenness that may be felt due to the palatation of the megestrol acetate suspension, and maintains a high sedimentation rate for a long time to provide patients with higher quality medicines to improve the quality of medicines. It can increase the reliability and dosage compliance.

Test Example 3: Dissolution Test

Since megestrol acetate is a poorly soluble drug and insoluble in water, this dissolution test is an important test method for predicting the availability of the active ingredient in vivo.

Test Specimens: Suspensions of Comparative Examples, Examples 1, 2, 5, 6 and 9.

-Experimental Method: USW 29, Monograph: Megestrol Acetate Oral Suspension (USP 29), 0.5 w / v% sodium ra with 37 ° C as eluent according to the first method 900 mL of an aqueous solution of uril sulfate was used, and the test was performed at a rotational speed of 25 revolutions per minute using the KEPCO Elution Test Method 2 and the paddle method. Table 10 and FIG. 5 shows the test results.

division 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. 10 minutes 48.4 5.0 97.5 5.2 98.8 2.8 95.9 5.8 98.4 2.3 97.4 5.8 20 minutes 81.2 4.0 98.9 2.1 100.0 1.5 100.5 1.2 99.9 2.3 98.3 3.5 30 minutes 90.6 1.2 99.9 1.1 100.3 2.0 100.3 0.8 100.3 1.6 98.3 2.1

※ S.D. indicates standard deviation.

As can be seen from Table 10, compared with the comparative example, the suspension agent of the present invention had a significantly higher initial dissolution rate of the active ingredient regardless of the amount of the active ingredient. This difference is due to the polyethylene glycol 1450 used in the comparative example and the specific gravity of the comparative example containing polyethylene glycol is about 1.07 g / mL, which is higher than the specific gravity of the example about 1.03 g / mL. That is, the suspension of the Example was evenly distributed throughout the test vessel by the rotation of the paddle immediately after the start of the dissolution test, but the suspension of the Comparative Example sank to the bottom of the test vessel immediately after the start of the dissolution test, showing a lower dissolution rate than the Example. . This is because polyethylene glycol slowly elutes as it is dispersed in the test solution.

Test Example 4: Viscosity Measurement Test

One of the important physical properties of suspensions is viscosity. The viscosity of the suspension is an important factor for maintaining the physical stability of the system. In general, the higher the viscosity, the higher the physical stability of the system, that is, the settling rate. However, if the viscosity is increased for the physical stability of the system, the suspension does not flow well, which may cause inconvenience to the patient. Therefore, maintaining a physically stable and easy to take viscosity is very important in suspensions.

-Test equipment:

  Instrument Name: Brookfield, DV-II + Viscometer

  Device: Spindle Number # 1, 50 revolutions per minute

Test Specimen: Suspension of Comparative Example and Example 6 (250 mL).

The viscosity measurement test results are shown in Table 11 below.

division Viscosity (cps) Comparative Example (Megace) 175 Example 6 56

As can be seen from Table 11, the comparative example was about 3 times higher in viscosity than Example 6. The low viscosity of the suspension according to the invention can provide the patient with ease of taking it when the suspension is taken, and can be easily filled during production to improve productivity.

Test Example 5 Surface Potential Measurement Test of Suspension

The interface of a solid (liquid or gas) in contact with an aqueous solution is charged, except in special cases, attracting counter ions (large ions) from the solution, forming an electrical double layer near the surface. If surfactant ions, such as surfactants, are present in the liquid, they specifically adsorb on the solid surface, greatly changing the surface potential. A factor that determines the stability of the colloidal particles is Zeta Potential. When the zeta potential value is increased, the charge amount is large and the repulsion is stronger, and the stability of the colloidal particles becomes higher. Conversely, as the zeta potential approaches zero, the repulsive force between particles weakens, making it unstable and easy to aggregate. As such, zeta potential is used as an indicator of the properties of colloidal particles, especially physical stability.

This experiment was to compare and verify the physical stability of the suspension by measuring the surface potential (ζ-potential, zeta-potential) of the particles.

-Test equipment: ELS-8000, Electrophoretic Light Scattering, Otsuka, Japan

Medium: purified water

Test Specimen: Suspension of Comparative Example and Example 6.

The electrophoresis test results are shown in Table 12 below.

division Comparative Example (Megace) Example 6 Zeta Potential -1.0 -14.3

As a result of the test, the zeta potential value of the comparative example is close to zero, whereas the zeta potential value of Example 6 is −14.3, which is relatively far from zero. It can be seen that the surface of the megestrol acetate of Example 6 has a partial negative charge relative to that of the suspension of megagel, thereby improving the stability of the suspension due to the interparticle repulsion, and easily redispersing during resuspension after long-term storage. It offers the advantage of doing so. This is the same result as the settling velocity measurement experiment of Test Examples 1 and 2.

Test Example 6: Particle Size Distribution Measurement Test

The particle size distribution of the suspension is a very important factor that characterizes the physical stability of the formulation (eg, sedimentation rate, etc.). In general, the smaller the particles, the higher the sedimentation rate and the higher the physical stability. Particle size distribution measurement test was performed as follows.

Test apparatus: Malvern Instruments Ltd., Mastersizer 2000, Ver. 3.01, Malvern UK

Medium: purified water

Test Specimen: Suspension of Comparative Example and Example 6

Test Method: Using the wet analysis method, appropriate amounts of the suspensions of Comparative Examples and Examples were taken, added to a system filled with purified water, and the initial particle size distribution was measured. After that, the ultrasonic generator was operated for about 30 seconds, and the particle size distribution was measured again. Table 13 below shows the results of the particle size distribution test, showing the median d (0.5).

division Comparative Example (Megace) Example 6 Particle size (um) Early 14.5 7.4 After ultrasound 6.2 5.3

As can be seen from Table 13, the particle size of the megacenic internal suspension as a comparative example is 14.5 um (d (0.5)), the particle size of Example 6 is 7.4 um (d (0.5)), the particle size of the comparative example compared to Example 6 It was about 2 times larger. After the ultrasonic generator was generated for about 30 seconds, the measured values were 6.2 and 5.3, respectively.

Noteworthy is the change in particle size distribution after the initial and ultrasonic generation of Comparative Example and Example 6. In the comparative example, the particle size distribution change before and after the generation of the ultrasonic wave is very large, whereas in the example, it can be seen that the difference before and after the generation of the ultrasonic wave is not large. This is due to the relatively high viscosity resulting from polyethylene glycol and the defrosting of the preparation during storage, which contributed to maintaining the physical stability of the suspension of the comparative example, but due to the low partial charge on the surface of the megestrol acetate particles, aggregation between particles easily occurred. It is believed that the megestrol acetate particles which have been aggregated by generating ultrasonic waves can be interpreted as separated. However, the present invention is believed to have a small change in particle size before and after ultrasonic generation due to the presence of the megestrol acetate particles separately due to the strong interparticle reaction force due to the partial charge of the megestrol acetate particle surface. Although not limited in theory, although relatively low viscosity and palatization are not observed, it is believed that the suspension according to the present invention is physically stable during long-term storage due to strong interparticle repulsion in the suspension.

The present invention provides a stable megestrol acetate oral suspension. The suspension of megestrol material according to the present invention has a relatively high sedimentation rate due to its excellent sedimentation rate, even though it has a lower viscosity than the currently marketed oral suspension for megacereal (Bristol-Myers Squibb Company). Provides a dispersed state of the active ingredient. Thus, it is easy to take when administering the drug of the patient, and it is possible to administer the megestrol substance at a constant dose at each dose. In addition, the suspension of the megestrol substance according to the present invention can exhibit a rapid dissolution rate, can be expected to express a quick effect of the active ingredient when taking. In addition, the stability of the temperature is very excellent, the quality of the change according to the storage and distribution is relatively small, it is possible to contribute to the improvement of quality of life by providing a higher quality medicine to the patient.

Claims (20)

Suspension containing megestrol material as active ingredient, poloxamer as wetting agent and viscosity modifier. The suspension according to claim 1, wherein the active ingredient is megestrol acetate. A suspension according to claim 1, wherein the content of the active ingredient is 1-15 w / v%. 4. A suspension according to claim 3, wherein the content of the active ingredient is 2 to 10 w / v%. The suspension according to claim 1, wherein the wetting agent is poloxamer 124, 184, 185, 188, 237, 338 or 407. The suspension according to claim 1, wherein the wetting agent is poloxamer 188 or poloxamer 407. The polyethylene glycol-35 castor oil, polyethylene glycol-40 cured castor oil, caprylocaproyl macrogol glyceride, oleoyl macrogol glyceride, caprylic / capric glyceride, caprylic / capric triglyceride Polyethylene glycol-4 esters and derivatives, glyceryl monooleate, polyethylene glycol-40 stearate, glyceryl citrate / lactate / linoleate / oleate, polyoxyethylene (20) isohexadecyl ether, propylene glycol monolau A suspension, characterized in that it further contains a humectant selected from the group consisting of latex, propylene glycol monocaprylate, sodium lauryl sulfate, dioctylsulfosuccinate and mixtures thereof. The method of claim 7, wherein the wetting agent is selected from the group consisting of polyethylene glycol-35 castor oil, polyethylene glycol-40 cured castor oil, capric / capric glycerides, polyethylene glycol-40 stearate and mixtures thereof. Suspension. The suspension according to claim 1, wherein the content of the wetting agent is 0.0001 to 0.5 w / v%. The suspension according to claim 1, wherein the content of the wetting agent is 0.001 to 0.4 w / v%. The viscosity modifier of claim 1, wherein the viscosity modifier is carbomer, polyethylene oxide with a molecular weight of 5,000 to 5,000,000, hydroxypropylmethylcellulose, hydroxypropylcellulose, xanthan gum, guar gum, tragacanth gum, lucostong gum, carrageenan, polyvinyl Pyrrolidone, polyvinyl alcohol, vinylpyrrolidone-vinylacetate copolymer, microcrystalline cellulose-carboxymethylcellulose sodium mixture, micronized crospovidone, carboxymethylcellulose and its derivatives, alginic acid and its derivatives, silicone emulsions, glycerol and these Suspensions, characterized in that selected from the group consisting of a mixture of. The method of claim 11 wherein the viscosity modifier is carbomer, polyethylene oxide with a molecular weight of 5,000 to 5,000,000, hydroxypropylmethylcellulose, hydroxypropylcellulose, xanthan gum, microcrystalline cellulose-carboxymethylcellulose sodium mixture, silicone emulsion, glycerol and their Suspensions, characterized in that selected from the group consisting of mixtures. 13. A suspension according to claim 12, wherein the viscosity modifier is selected from the group consisting of Carbomer 934P, Carbomer 971P, Carbomer 974P and mixtures thereof. The suspension according to claim 1, wherein the content of the viscosity modifier is 0.01 to 10 w / v%. The suspension according to claim 1, wherein the content of the viscosity modifier is 0.05 to 5 w / v%. The suspension according to claim 1, further comprising a buffer, a preservative, a sweetener, a fragrance, an antifoam, or a mixture thereof. 1-15 w / v% megestrol acetate as active ingredient; 0.0001 to 0.5 w / v% of poloxamer as wetting agent; And a suspension containing from 0.01 to 10 w / v% carbomer as a viscosity modifier. 2-10 w / v% megestrol acetate as active ingredient; 0.001 to 0.4 w / v% of poloxamer as wetting agent; And a suspension containing from 0.05 to 5 w / v% carbomer as a viscosity modifier. 4 w / v% megestrol acetate; 0.05 w / v% poloxamer 188; 0.33 w / v% carbomer 971P; 0.1 w / v% sodium benzoate; 0.13 w / v% citric acid; 0.09 w / v% sodium citrate; 5.0 w / v% sucrose; 0.091 w / v% fragrance; 0.5 w / v% of 30 w / v% simethicone emulsion; And a suspension containing water as a residue. 8 w / v% megestrol acetate; 0.05 w / v% poloxamer 188; 0.33 w / v% carbomer 971P; 0.1 w / v% sodium benzoate; 0.13 w / v% citric acid; 0.09 w / v% sodium citrate; 5.0 w / v% sucrose; 0.091 w / v% fragrance; 0.5 w / v% of 30 w / v% simethicone emulsion; And a suspension containing water as a residue.

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