KR100900915B1 - Suspension formulation containing megestrol acetate and preparation method thereof - Google Patents

Abstract

The present invention relates to suspension formulations containing megestrol acetate and methods for their preparation. In particular, by using a method for preparing a suspension formulation containing stable documented megestrol acetate, it is possible to prepare and use conventional instruments and devices such as mixers generally used in the manufacture of pharmaceuticals, and to use gellan gum as a thickener. As a result, the elution pattern was improved compared to the commercially available agent without improving the suspension stability and causing problems such as phase separation or precipitation even with time. Therefore, the preparation according to the present invention is a safer, simpler and more economical suspension formulation than the prior art, and can be usefully used as a stable and documented pharmaceutical composition.

Megestrol acetate, suspension formulation, macrogol 15 hydroxystearate, gellan gum

Description

Suspension formulation containing megestrol acetate and preparation method

1 shows the suspension stability of the suspension formulation of Example 1 of the invention,

2 shows the suspension stability of the suspension formulation of Example 2 of the invention,

3 shows the suspension stability of the suspension formulation of Example 3 of the invention,

4 shows the suspension stability of the suspension formulation of Example 4 of the present invention,

5 shows a suspension stability comparison between the suspension formulation of the present invention and a commercial formulation,

6 shows the suspension stability of suspension formulations prepared outside the scope of the present invention.

The present invention relates to suspension formulations containing megestrol acetate and methods for their preparation.

Liquid formulations such as solutions, suspensions, and syrups are important ways of delivering the drug to the subject. Such formulations are known to provide ease of administration to some patients who have difficulty swallowing solid formulations and to improve the taste or texture of the administered drug to increase their acceptance in a particular group of patients. The advantage of liquid formulations is also that they can continuously vary the metering of the dosage and provide infinite dosage flexibility.

In particular, suspensions are more advantageous liquid formulations, in which some active substances which are chemically unstable in solution become stable upon suspension. In addition, some actives have an unpleasant taste in solution, but taste better when suspended undissolved particles. Suspensions are a particular type of dispersant that has an inner (suspended) layer of particulate material that is essentially insoluble in the outer layer consisting of the medium or vehicle in suspension, but which is uniformly dispersed throughout the outer layer.

The entrapped suspension has a loose collection of particulate matter in which the discrete particles are networked together. Floccules, defined as stable tablets, generally contain a liquid medium or vehicle entrapped in a network and tend to clump together in weak aggregates. The entrained suspension is not caked at standstill but is easily dispersed by stirring. Demulsified suspension formulations generally require the control of surfactants, wetting agents and protective colloid / suspensioning agents to provide a stable defrost that can withstand cakeing possible by withstanding de-desaturation or flocculation. Megestrol acetate, the active ingredient of the present invention, is preferably used as a suspension formulation with a substance that is not easily wetted by water.

Megestrol acetate is 17-alpha-acyloxy-6-methylpregna-4,6-diene-3,20-dione, which is an active substance used as an antitumor agent, and Bristol-Myers Squibb Corporation Is distributed under the trade name Megace. The megestrol acetate is disclosed in Labrie US Pat. No. 4,656,885 for a combination therapy for the treatment of female breast cancer characterized by administration of progesterone with anti-androgens. In particular, it is disclosed that anti-androgens are formulated in tablets or capsules for oral administration with conventional pharmaceutical excipients (eg, spray dried lactose and magnesium stearate). In addition, U.S. Patent No. 4,760,053 reports on the treatment of sex steroid related tumors by a combination therapy involving the use of megestrol acetate. However, there is no description of the form or composition of the pharmaceutical formulation for treatment.

In addition, U.S. Patent No. 4,775,661 to Labrie reports on a combination therapy for treating female breast cancer in which megestrol acetate is disclosed as a suitable steroidal anti-androgen. Furthermore, it is disclosed that megestrol acetate as an active substance can be mixed with a binder such as polyethylene glycol and contain unsensitized substances in tablet or dragee nuclei.

JNVon Roenn et al. (Annals. Of Internal Medicine, 109, 840-841, 1988) describe the use of megestrol acetate for the treatment of malignancies associated with human immunodeficiency virus (HIV) infection. It is. However, the form or composition of the formulation is not reported.

Korean Patent No. 10-0211192 discloses a process for the preparation of oral pharmaceutical compositions that form stable sustained species suspending agents containing undifferentiated megestrol acetate in combination with polysorbate and polyethylene glycol. . However, the conventional suspension formulations, such as the conventional ones, have a problem in that the release rate of megestrol acetate is lowered due to the aggregation phenomenon during the dissolution test process, and especially when stored for a long time, phase separation occurs, in particular, centrifugation (3000). Rotation per minute, 1 minute) there was a problem such as distinct phase separation occurs.

Thus, the present inventors, while studying to prepare a suspension formulation containing a stable written megestrol acetate, by solving a conventional problem as described above and finding a way to obtain a suspension formulation in a simpler way, Succeeded in preparing a suspension formulation containing stable phased megestrol acetate without phase separation to complete the present invention.

It is an object of the present invention to provide a process for the preparation of a suspension formulation containing megestrol acetate.

Another object of the present invention is to provide a suspension formulation containing megestrol acetate.

In order to achieve the above object, the present invention comprises the steps of dissolving micronized megestrol acetate and macrogol 15 hydroxystearate in water to obtain a suspended solution (step 1); Mixing a thickening gellan gum with a buffer, a sweetener and a preservative and dissolving in water to obtain a solution (step 2); And mixing the two solutions obtained in the above steps 1 and 2, and adding a flavoring agent to obtain a suspension formulation (step 3), thereby providing a method for preparing a suspension formulation containing megestrol acetate.

Hereinafter, the present invention will be described in detail.

In the preparation method of the suspension formulation according to the present invention, step 1 is a step of dissolving the micronized megestrol acetate and macrogol 15 hydroxystearate represented by the following formula (1) in water to obtain a suspended solution.

Megestrol acetate of Formula 1 is 17-alpha-acyloxy-6-methylpregna-4,6-diene-3,20-dione, which is a drug used as an antitumor agent. Megestrol acetate is disclosed in Labrie US Pat. No. 4,656,885 for a combination therapy for the treatment of female breast cancer characterized by administration of progesterone with anti-androgens. In particular, it is disclosed that anti-androgens are formulated in tablets or capsules for oral administration with conventional pharmaceutical excipients (eg, spray dried lactose and magnesium stearate). In addition, U.S. Patent No. 4,760,053 reports on the treatment of sex steroid related tumors by a combination therapy involving the use of megestrol acetate. However, the form or composition of the pharmaceutical agent used in the treatment is not described.

The macrogol 15 hydroxystearate (trade name; Solutol HS15, BASF) is a nonionic surfactant, in the present invention serves both as a suspending agent and antifoaming agent. In general, an antifoaming agent is used to remove bubbles generated in the manufacturing process using a thickener or suspending agent, but in the present invention, it can be prepared without using a separate antifoaming agent such as polysorbate or polyethylene glycol. Therefore, there is an advantage that does not require a bubble removing process using a vacuum. Yet the present invention may also show the advantage of no phase separation over time, which is indicated by the problem of suspension formulations.

The amount of macrogol 15 hydroxystearate of step 1 is preferably 0.1 to 1.0% (w / v) concentration, when the amount of macrogol 15 hydroxystearate is less than 0.1% (w / v), suspension There is a problem of phase separation or sedimentation due to poor stability, and when exceeding 1.0% (w / v), there is a problem that the astringent taste due to the excessive surfactant. In addition, the amount of megestrol acetate in step 1 is preferably used to a suitable amount for treatment.

In the method of preparing a suspension formulation according to the present invention, step 2 is a step of mixing a gellan gum, a thickener, a buffer, a sweetener and a preservative, and dissolving it in water to obtain a solution.

The thickener is preferably gellan gum (Gellan gum LT100, CPKelco) to improve the viscosity and taste instead of xanthan gum generally used as a pharmaceutical additive. In general, when xanthan gum is used to prepare a suspension formulation, the viscosity may be increased and suspended, but there is a problem of generating bubbles. Xanthan gum is a causative agent of foaming, which makes it difficult to control the final mark during the preparation process. It is therefore essential to use a separate antifoam to remove the foam generated. In addition, when xanthan gum is used, xanthan gum is agglomerated during the elution process to hinder the dissolution rate of the suspension, and thus has a disadvantage of inhibiting the body absorption rate during oral administration. However, the gellan gum used in the present invention is a food additive generally used to increase the adhesiveness and viscosity of foods, to improve the stability of suspension, and to improve the physical properties and feel of foods. Therefore, since the present invention uses gellan gum to improve suspension stability, not only phase separation or precipitation of the prepared suspension formulation is suppressed, but also no bubbles are generated, and thus no separate antifoaming agent is required.

The amount of gellan gum in step 2 is preferably in a concentration of 0.04 to 0.07% (w / v). When the amount of gellan gum is less than 0.04% (w / v), problems of suspension stability inhibition, phase separation and precipitation occur And, if it exceeds 0.07% (w / v), there is a problem that the jelly is formed by increasing the excessive viscosity.

The buffer is a chemical added to adjust the pH index, it may be used one or more selected from the group consisting of lactic acid, citric acid and acetic acid or their sodium salt, it is preferred to use citric acid and sodium citrate. However, the buffer of the present invention is not limited thereto.

The sweetener is a substance used to improve the taste when the taste is bad in the pharmaceutical preparation for oral administration, lactose, white sugar, sorbitol, fructose, glucose and the like can be used, it is preferable to use white sugar. However, the sweetener of the present invention is not limited thereto.

The preservatives are substances added for long-term preservation of the pharmaceutical preparation, and must satisfy the condition that they should not be harmful, do not change the therapeutic effect, and should not interfere with tests that evaluate the quality of the pharmaceutical preparation. As the preservative, sodium benzoate, potassium silicate, sodium propionate, calcium propionate, methyl paraoxybenzoate and the like can be used, and sodium benzoate is preferably used. However, the preservative of the present invention is not limited thereto.

In the method for preparing a suspension formulation according to the present invention, step 3 is a step of mixing the two solutions obtained in steps 1 and 2 and adding a flavoring agent to obtain a suspension formulation. The megestrol acetate solution obtained in step 1 and the solution obtained by mixing the gellan gum obtained in step 2 with a buffer, a sweetener and a preservative are mixed with each other, and then, by adding and adding a flavoring agent, a stable paper-ized suspension of the present invention. Formulations can be obtained.

The flavoring agent is a substance that offsets the discomfort by adding flavor to the pharmaceutical formulation, fruit flavor, orange flavor, lemon flavor, lime flavor and the like can be used.

The present invention also provides a suspension formulation containing megestrol acetate prepared by the above method.

Suspension formulations prepared by the process of the invention are aqueous suspensions comprising water as a solvent and are suspension formulations containing stable documented megestrol acetate. The suspension refers to a liquid formulation in which solid particulates are dispersed in a liquid. At this time, the suspension formulation of the present invention is prepared by gellan gum at a concentration of 0.04 to 0.07% (w / v), macrogol 15 hydroxystearate at a concentration of 0.1 to 1.0% (w / v) and micronized megesth Roll acetate.

Suspension formulations containing megestrol acetate according to the invention have the following advantages over the prior art.

First, it is safer, simpler and more economical than conventional technologies.

Secondly, conventional apparatus and apparatuses, such as mixers, are generally used for the manufacture of pharmaceuticals.

Third, gellan gum used as a thickener improves the suspension stability and does not cause problems such as phase separation or precipitation even with time.

Fourth, it shows an excellent elution pattern compared with the commercially available mega suspension.

In addition, the suspension formulation of the present invention shows little or no residual feeling in the mouth compared to commercially available formulations upon oral administration, and has a high viscosity, so that the residue remains in a small portion or a single-dose package for precise dose administration. Unlike commercially available formulations, the low viscosity allows for minimal losses in weighing subdivisions and allows for accurate dose administration.

As shown in the external photograph of FIG. 1 , the stable documented suspension formulation of the present invention can be seen that the suspension stability is superior to the commercial formulation without phase separation or precipitation. In addition, as a result of the dissolution test in 0.5% sodium lauryl sulfate solution, the viscosity of the suspension formulation is increased in proportion to the amount of gellan gum used, and the dissolution rate is different in Examples 1 to 4 in dissolution test method 1 for all 85 It appeared as% or more, and confirmed that it was excellent compared with the commercial formulation.

The suspension formulation prepared according to the preparation method of the present invention is excellent in comparison with the commercially available mega suspension, by using gellan gum as a thickener, improving suspension stability and causing no problems such as phase separation or precipitation over time. An elution pattern is shown. Therefore, the preparation according to the present invention is a safer, simpler and more economical suspension formulation than the prior art, and can be usefully used as a stable and documented pharmaceutical composition.

The formulation may contain a diluent (e.g. sucrose, mannitol, sorbitol, cellulose or glycine) in addition to the suspension of the present invention as needed and may be a disintegrant or boiling mixture such as starch, agar, alginic acid or its sodium salt or It may further contain an absorbent, a colorant, a preservative and a sweetener.

Hereinafter, the present invention will be described in detail by way of examples. However, the following examples are merely to illustrate the invention, the present invention is not limited by the following examples.

Examples 1 to 4 Preparation of Suspension Preparation Containing Megestrol Acetate According to the Present Invention

A suspension formulation containing megestrol acetate was prepared using the ingredients and components (weight ratios) shown in Table 1 below. Macrogol 15 hydroxystearate was added to water and dissolved in water, followed by homogeneous suspension by addition of micronized megestrol acetate. Further, gellan gum was dispersed in water warmed to 90 ° C., and then dissolved by adding citric acid, sodium citrate, sodium benzoate and white sugar. The two solutions thus prepared were homogeneously mixed at 60 ° C., cooled to 40 ° C., and then flavored and mixed to obtain a suspension formulation. The viscosity of the suspension formulation obtained after preparation is shown together in Table 1 . In addition, the external photographs of Examples 1 to 4 are shown in FIGS . 1 to 4 , and the external photographs comparing the suspension stability of Example 1 and the commercially available megestrol suspension (Daewon Pharmaceutical) are shown in FIG. 5 . Indicated.

Raw material Example 1 Example 2 Example 3 Example 4 Macrogol 15 hydroxystearate 0.50 0.50 0.50 0.10 Megestrol acetate 4.00 4.00 4.00 4.0 water 15.70 15.70 15.70 16.10 Citric acid 0.17 0.17 0.17 0.17 Sodium citrate 0.01 0.01 0.01 0.01 Sodium benzoate 0.20 0.20 0.20 0.20 water 74.28 74.27 74.25 74.28 Gellan gum (LT100) 0.04 0.05 0.07 0.04 White sugar 5.00 5.00 5.00 5.00 Lemon Lime Flavor 0.10 0.10 0.10 0.10 Sum 100.0 100.0 100.0 100.0 Viscosity (cp) 37.1 86.4 827.6 32.8

Examples 1 to suspension formulations of 4 showed the all similar elution pattern of the viscosity depending on the amount of gellan point difference but, Figures 1 to 4, the exemplary suspension formulations of Examples 1-4 of the present invention There was no phase separation or precipitation. As shown in Figure 5 , while the commercial formulation (right) is observed distinct phase separation, the suspension formulation (left) of Example 1 of the present invention can be confirmed that the suspension stability is superior to the commercial formulation without phase separation.

Comparative Examples 1 to 3 Preparation of Suspension Formulations Containing Megestrol Acetate Outside the Range of the Invention

The suspension formulation containing megestrol acetate was obtained by the same method as Examples 1-3 using the component and component ratio (weight ratio) of following Table 2 . The viscosity of the suspension formulation obtained after preparation is shown together in Table 2 .

Raw material Comparative Example 1 Comparative Example 2 Comparative Example 3 Macrogol 15 hydroxystearate 2.00 1.00 1.00 Megestrol acetate 4.00 4.00 4.00 water 15.20 15.20 15.20 Citric acid 0.17 0.17 0.17 Sodium citrate 0.01 0.01 0.01 Sodium benzoate 0.20 0.20 0.20 water 74.28 74.24 74.29 Gellan gum (LT100) 0.04 0.08 0.03 White sugar 5.00 5.00 5.00 Lemon Lime Flavor 0.10 0.10 0.10 Sum 100.0 100.0 100.0 Purity (cp) - 1012.9 22.1

In the case of the formulation of Comparative Example 1, which used more surfactant than the scope of the present invention, astringent taste occurred, and the formulation of Comparative Example 2, in which a lot of gellan gum was used, had a high viscosity to form jelly. In addition, the formulation of Comparative Example 3 in which less gellan gum was used than the scope of the present invention, as shown in Figure 6 , the suspension stability was inhibited phase separation and precipitation was observed.

Experimental Example 1 Dissolution Test in 0.5% Sodium Lauryl Sulfate Solution

A dissolution test was performed for 30 minutes using a 0.5% sodium lauryl sulfate solution (900 ml) at 25 revolutions per minute (rpm) using the US Pharmacopeia 2 method (paddle method). It was tested according to the US Pharmacopoeia Megestrol Suspension Dissolution Assay Tests 1, 2 and 3. Commercially available formulations used here are megacene suspensions (Boryeong Pharmaceuticals) and megestrol suspensions (Daewon Pharmaceuticals). The dissolution test results are shown in Tables 3 to 5 together with the viscosity of the suspension formulation.

Test 1. Take 160 mg megestrol and add it to the eluate. Viscosity (cp) After 10 minutes After 20 minutes After 30 minutes Boryeong Pharmaceutical 219.7 34 53 68 Daewon Pharmaceutical 496.8 22 44 50 Example 1 37.1 92 94 96 Example 2 86.4 89 93 97 Example 3 827.6 87 92 95 Example 4 32.8 93 94 97

Test 2. Test by adding 10 ml of megestrol suspension simultaneously with paddle operation Viscosity (cp) After 10 minutes After 20 minutes After 30 minutes Boryeong Pharmaceutical 219.7 45 68 82 Daewon Pharmaceutical 496.8 36 57 78 Example 1 37.1 94 96 96 Example 2 86.4 92 96 97 Example 3 827.6 91 94 95 Example 4 32.8 94 94 97

Test 3. Test with 10 ml of megestrol suspension for 10-15 seconds simultaneously with paddle operation Viscosity (cp) After 10 minutes After 20 minutes After 30 minutes Boryeong Pharmaceutical 219.7 71 87 91 Daewon Pharmaceutical 496.8 68 84 88 Example 1 37.1 95 96 97 Example 2 86.4 94 94 96 Example 3 827.6 93 94 97 Example 4 32.8 96 95 97

In the prepared suspension formulations of Examples 1 to 4 of the present invention, the viscosity of the gellan gum was increased in proportion, but the viscosity of the suspension formulation of the present invention was generally lower than that of commercially available formulations. In the case of Example 3, the viscosity was higher than that of the commercially available formulations. However, in Example 3, which had the highest viscosity and was expected to be disadvantageous to the dissolution test, although the viscosity was higher than that of a commercially available formulation, the dissolution rate was superior to 85% even in Test 1. In addition, all of Examples 1 to 4 showed excellent dissolution rates of 90% or more in Tests 2 and 3, indicating that the suspension formulation of the present invention was superior to the commercially available formulations.

As described above, according to the present invention, using a method for preparing a suspension formulation containing stable documented megestrol acetate, a conventional apparatus and apparatus such as a mixer generally used in the manufacture of pharmaceuticals can be used and manufactured. By using gellan gum as a thickening agent, the suspension stability was improved, and the elution pattern was superior to that of commercially available agents without causing problems such as phase separation or precipitation even with time. Therefore, the preparation according to the present invention is a safer, simpler and more economical suspension formulation than the prior art, and can be usefully used as a stable and documented pharmaceutical composition.

Claims (4)

Dissolving macrogol 15 hydroxystearate, adjusted to a final content of 0.1-1.0% (w / v), in water with micronized megestrol acetate to obtain a suspended solution (step 1); Dissolving gellan gum, a thickener adjusted to a final content of 0.04-0.07% (w / v), in water together with a buffer, sweetener and preservative to obtain a solution (step 2); And Mixing the two solutions obtained in step 1 and step 2 and additionally adding a flavoring agent to obtain a suspension formulation (step 3). delete delete Sustained megestrol acetate containing suspension formulation prepared by the method of claim 1.

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