KR101967199B1 - Stability improved pharmaceutical composition comprising limaprost by using fluid-bed granulator - Google Patents

Abstract

The present invention relates to the formulation of Limafrost. The present invention is characterized by including lima frost alfadex, beta -cyclodextrin, and pregelatinized starch.

Description

TECHNICAL FIELD [0001] The present invention relates to a pharmaceutical composition comprising Limafrost, which improves stability using a fluidized-bed granulator.

The present invention relates to the formulation of Limafrost.

Lima frost is a prostaglandin E1 derivative that is useful as a preventive or therapeutic agent for peripheral circulatory disorders. Lima Frost has been shown to improve blood flow obstruction and improve lower back pain, lower limb or gait ability by increasing nerve tissue blood flow. Commercially available medicines contain 5 μg of lima frost per unit formulation. In order to improve subjective symptoms and gait ability by means of lumbar lumbar spinal stenosis, oral administration of 15 ug (3 tablets) per day is usually administered on an adult basis in three divided doses, and ischemic symptoms such as ulceration, pain, (6 tablets) daily for three times in an adult. The main ingredient in commercial drugs is Limafrost Alphadex. Lima Frost Alphadex is highly absorbed in the digestive tract after oral administration and high in radioactivity in liver, kidney and bladder after 6 hours of oral administration of 15 ug / kg once, And 72 hours later, it was analyzed to be almost completely lost in all tissues.

Lima Frost is hygroscopic and absorbs moisture and is susceptible to degradation. In addition, the content of lima frost per unit sugar in the market is only 5 ug. This corresponds to 166.67 ug in terms of Limaflost Alphadex. Therefore, in the formulation of lima frost, it is important to block the hygroscopicity and ensure uniformity of the drug per unit preparation. Hereinafter, a method of isolating hygroscopicity of lima frost or ensuring uniformity in the prior art will be examined.

Korean Patent Registration No. 10-0833211 proposes granules which are freeze-dried by mixing glucans. In this document, freeze-dried granules are generally used as injections. However, it has been recognized that the use of freeze-dried granules in oral preparations is not general and is not economically practical. However, freeze-drying is performed using glucan, , And it was able to secure stability. In this example, purified tablets are prepared by dissolving lima frost alfadex and dextran in purified water and mixing the freeze-dried powder with dextrin or the like.

Korean Patent Registration No. 10-1504862 proposes mixing of? -Cyclodextrin. In this literature, cyclodextrin has been used for solubilization of compounds, shielding or stabilization of dirt, etc., and achieving the above object by encapsulating the main ingredient, but it can contribute to improvement of stability even by simple mixing, not collapse . In the examples of this document, a lyophilized product is obtained by combining lima frost alfadex with dextran in purified water, followed by tableting of beta-cyclodextrin by post-mixing of the lima frost alfadex / dextran lyophilized product.

Korean Patent Registration No. 10-1242039 proposes granules obtained by adopting PVP as binder in anhydrous ethanol. This document explains that lima frost alfadex is not dissolved in the step of obtaining granules, and that when suspended in a granulated state as a PVP binder, the dissolution of inclusion can be effectively blocked and the stability of the foam can be improved. In the examples of this document, the tablets obtained by suspending lima frost alfadex and PVP in anhydrous ethanol, and then blending them into microcrystalline cellulose and lactose hydrate are mixed with the lubricant and mixed with the lubricant.

Korean Patent Registration No. 10-1432244 proposes a dry granule containing microcellulose or cellactose as a carrier in lima frost alfadex. The literature describes that when mixed with a particular carrier and dry granulated, the water stability was improved and the content uniformity was maintained. Korean Patent Laid-Open Publication No. 10-2014-0021081 proposes a molten compact with a polymer having a lower melting point than that of the main component. The literature suggests that melt compression can improve the uniformity of the content of the main component. An embodiment of the document discloses hot melt extrudates of lima frost and poloxamer.

Korean Patent Registration No. 10-0833211 Korean Patent Publication No. 10-1504862 Korean Registered Patent No. 10-1242039 Korean Patent Registration No. 10-1432244 Korean Patent Publication No. 10-2014-0021081

Korean Patent Publication Nos. 10-0833211 and 10-1504862 lyophilize lima frost alfadex into purified water. However, even if the lyophilization process proceeds at a low temperature, lima frost is susceptible to moisture, and thus may be decomposed in the process. In addition, free water incorporated in the lyophilized product is not fixed in the distribution process, .

Korean Patent Registration No. 10-1242039 does not adopt purified water but suspends lima frost alfadex in anhydrous ethanol. Since the solvent is not purified water, it is less likely to be decomposed by moisture during the process or to incorporate free water into the granule. However, since anhydrous ethanol is a potentially explosive solvent, it is not suitable for mass production processes.

Korean Patent Publication No. 10-1432244 discloses a carrier having low inherent moisture and good fluidity. However, even if the dry granular fluidity is excellent, coagulable excipients can not be employed, so that a process failure such as sticking may occur There is a possibility that the homogeneity of the main component is not satisfactory.

Korean Patent Laid-Open Publication No. 10-2014-0021081 suggests a molten compact, but the melting process is relatively costly and can not be regarded as an efficient process since it is not possible to unambiguously exclude the possibility of adversely affecting the main component .

The present inventor has sought to overcome the limitations of the prior art described above. That is, it is possible to improve the stability of lima frost even if purified water is used without employing a solvent having a risk of explosion such as anhydrous ethanol, to reduce the incidence of process failures, to ensure homogeneity of main components, And to overcome the optimal formulation that can be obtained without involving a specific step.

The present invention has solved the above-mentioned problems through the following means.

1. A pharmaceutical composition comprising lima frost alpha-dex and beta -cyclodextrin and obtained as a fluidized bed granulator by using an alcohol / water mixed solvent, wherein the pregelatinized starch is a granular material obtained as the fluidized bed granule Or after mixing with the powder obtained as the fluidized bed granules.

2. The pharmaceutical composition according to 1 above, wherein the pharmaceutical composition comprises lima frost alfadex, beta -cyclodextrin and pregelatinized starch, and granules obtained as a fluidized bed granulator using an ethanol / water mixed solvent.

3. The pharmaceutical composition according to the above 1, which comprises a mixture of lima frost alpha-dex and? -Cyclodextrin, followed by post-mixing of the granules obtained as a fluidized bed granulator using an ethanol / water mixed solvent and pregelatinized starch Gt;

4. The pharmaceutical composition according to the above 1, which comprises a mixture of lima frost alfadex and? -Cyclodextrin, followed by post-mixing of the pregelatinized starch into a pellet obtained as a fluidized bed granulator using an ethanol / water mixed solvent Gt;

5. The pharmaceutical composition according to the above 4, wherein the pellet is coated with a polymer base (HPMC or the like).

6. The pharmaceutical composition according to any one of 1 to 5, wherein the concentration of ethanol in the ethanol / water mixed solvent is 30-80%.

7. The pharmaceutical composition according to any one of 1 to 6 above, wherein the total content of pregelatinized starch in the powder or in the powder is from 5 to 50% of the total weight.

The present invention is excellent in uniformity of main component and excellent in stability. In addition, the incidence of process failures is low and it is possible to formulate without involving a specific process such as melting. In addition, the stability of the main component can be improved without employing a solvent having the risk of explosion such as anhydrous ethanol.

Fig. 1 shows the result of a flexible material test as in Experimental Example 1. Fig.

Limafrost is a compound that has a chemical name of (E) -7 - [(1R, 2R, 3R) -3-hydroxy- Nodenyl] -5-oxocyclopentyl] -2-heptanoic acid. The formula is as follows.

[Chemical Formula 1]

The present invention can employ the known main ingredient of Limafrost as a raw material medicine. For example, the present invention can utilize lima frost alfadex. Lima Frost Alphadex is a compound in which Limafrost is embedded in alpha -cyclodextrin and its chemical name is (E) -7 - [(1R, 2R, 3R) -3-hydroxy- (E) -3-hydroxy-5-methyl-1-nodenyl] -5-oxocyclopentyl] -2-heptanoic acid alpha cyclodextrin. The formula is as follows.

(2)

For reference, Lima Frost Alphadex is introduced as a raw material drug. However, the effect of the formulation of the present invention is not limited to the range of the present invention, Garima Frost Alphadex, because it can appear equally against any Limafrost main component other than Limafrost Alphadex.

The present invention is characterized in that the process comprises a powder obtained as a fluidized bed granulator. As described above, in the prior art, processes such as freeze-drying, dry granulation or melt compression have been adopted for obtaining granules. However, freeze-drying has adopted purified water, which can not be said to inhibit degradation of lima frost by purified water even if it is dried at a low temperature with low reactivity, and has excellent stability due to the free water embedded in the product inevitably It exposes the disadvantage that it can not. In addition, since dry granules can be obtained by using a sticky excipient, granules can be basically obtained. Therefore, even if the fluidity is selected by selecting a good excipient, there is a possibility that the process disorder may occur basically and the excipients agglomerate to obstruct the homogeneity of the main ingredient There is room to do. Further, melt compression can not be assured that there is no possibility of causing degradation of lima frost as a special process, which causes improvement in the process cost. The inventors of the present invention paid attention to the fluidized bed granules by avoiding the above conventional recognition.

Although the exact cause is unknown, the present invention is not limited to the case where Limafrost alpha-dex and? -Cyclodextrin are mixed with a solution of ethanol / purified water in an alcohol / purified water mixed solvent which is not anhydrous ethanol. The present inventors have found through experiments that it is possible to secure not only the uniformity but also the stability of lima frost when the optional excipient is dispersed and spray dried in the fluidized bed granulator, thereby completing the present invention. In particular, the inclusion of free gelatinized starch showed excellent stability. The ratio of alcohol / purified water mixture is preferably 30-80%. If anhydrous alcohol is employed, there is a risk of explosion, and the present invention is effective in securing water stability even if anhydrous alcohol is not adopted. When the concentration of alcohol does not satisfy the lower limit and the upper limit, It can be a problem. That is, if the concentration of the alcohol exceeds 80%, the risk of explosion increases. If the concentration of alcohol is less than 30%, the inclusion of purified water may occur in the granules and the stability may be lowered. The alcohol may be any known solvent. For example, an alcohol having 1 to 4 carbon atoms can be adopted, and ethanol can be used.

The present invention is characterized in that the starting material β-cyclodextrin and pregelatinized starch are essentially combined. Β-Cyclodextrin and pregelatinized starch can be formulated in a granule or in a post-mix. For example, in one embodiment of the present invention, a pregelatinized starch is post-mixed in a fluidized bed granule comprising lima frost alfadex and beta -cyclodextrin to obtain an oral solid preparation. Or in another embodiment according to the present invention, a solid preparation for oral use is obtained as a fluidized bed granule comprising lima frost alfadex, beta -cyclodextrin and pregelatinized starch. The solid preparations for oral use thus obtained are more stable than the conventional preparations.

? -cyclodextrin is a component which appeared in Korean Patent Publication No. 10-1504862. However, Korean Patent Registration No. 10-1504862 and the present invention are fundamentally different from each other in terms of principle for solving the problems. Korean Patent Publication No. 10-1504862 discloses a method for mass-mixing β-cyclodextrin as an excipient in the course of post-mixing as described above. Specifically, Korean Patent Registration No. 10-1504862 discloses a method for producing β-cyclodextrin Of the total weight of the tablet is mixed with 30-99% or more of the total weight of the tablet and 50-95% of the total weight of the tablets is more preferably introduced, thereby inducing an excessive amount of? -Cyclodextrin. In contrast, the present invention is formulated in such a small amount that the total amount of the? -Cyclodextrin to be incorporated into the fluidized bed granules or the post-mix is less than 30% of the total weight of the preparation. When β-cyclodextrin is blended into the fluidized bed granules, 0.5 to 10 parts by weight of the main component is added when the weight of the main component is 1.

The pregelatinized starch is also referred to as pregelatinized starch, and may be formulated in an amount of 5-50% by weight based on the total weight of the preparation. The stability is lowered when the lower limit is not satisfied, and when the upper limit is exceeded, problems may arise in processes such as granulation and the humidity is increased.

The obtaining of the fluidized bed granules according to the present invention and the implementation of the final formulation comprising the granules can be carried out according to any known formulation technique. If necessary, additives such as other binders, lubricants, excipients, disintegrants, etc., which are mixed in the powder or granules may be used by those skilled in the art. For example, as disclosed in the prior art, Lactose extract, Lahan and extract, corn starch, potato starch, lactose, lactose, maltose, mannitol, sorbitol, xylitol, erythritol, sodium saccharin, aspartame, acesulfame potassium, sucralose, licorice extract, [0040] Any of the pharmaceutically addable substances known in the HANDBOOK OF PHARMACEUTICAL EXCIPIENTS, etc., without any particular limitation, unless specifically emphasized in the present invention, such as wheat starch, sodium hydrogen carbonate, sodium chloride, microcrystalline cellulose, methylcellulose, ethylcellulose and hypromellose Can be selected.

The present invention is preferable in preparing solid preparations for oral administration. For example, the present invention is a composition suitable for implementation with tablets, capsules and the like.

For example, in one embodiment according to the present invention, lima frost alpha -dex and beta -cyclodextrin are mixed with a binder made of ethanol / purified water and PVP, and then, using a suitable excipient such as pregelatinized starch and lactose hydrate, Followed by spray drying to obtain a powder, followed by post-mixing with an optional additive such as a lubricant to form a solid preparation for oral administration. On the other hand, the? -Cyclodextrin and the pregelatinized starch may be contained in the granule as described above, may be included in the post-mix, or may be included in both the powder and the post-mix.

Alternatively, in one embodiment of the present invention, limaprost alpha -dex and beta -cyclodextrin are mixed with a binding agent such as PVP and a binding solution prepared from ethanol / purified water, spray-coated on any core for a known pellet, A post-gelatinized starch and an anti-aging additive may be mixed to form a solid preparation for oral administration. Particularly, when such a pellet is implemented, it may be more preferable for the secondary coating to be performed on the drug layer of lima frost alpha dex with a polymer base in view of stability. In this case, there is no particular limitation on the polymer base, but ethanol can be used as a coating solvent, and ingredients that do not interfere with drug elution can be employed. For example, hydroxypropyl methylcellulose and the like can be used. The content of the polymer base material for the secondary coating is suitably selectable.

The present invention is further illustrated by the following examples. It should be noted that the embodiments are not intended to limit the scope of the present invention.

[Experimental Example 1] Comparison of degree of stabilization of lima frost according to pregelatinization starch ratio

Lima frost alfadex and beta -cyclodextrin were dissolved in water, and povidone was dissolved in ethanol. The two solutions were mixed, and then spray-dried in a fluidized bed granulator using a pregelatinized starch and an excipient to obtain granules. Here, the amount of pregelatinized starch was used in an amount of 5 to 80% based on the total weight. A solid preparation for oral administration was prepared by mixing any additives, and this was packaged in an Alu-bag and left in a chamber at 60 ° C and 80% RH for 5 days. The supernatant was measured by UPLC. The major suppository of lima frost was found to be 11-deoxy, and 11-deoxy was measured as a stabilizing index of lima frost. (Improved Stability of OPALMON Tablets under Humid Conditions IV: Effect of Polysaccharides and Disintegrants on Stability and Dissolution Property of OPALMON Tablets - Chem. Pharm. Bull. 56 (1) 7-11 (2008)). Hereinafter, 11-deoxy is referred to as a flexible substance.

The prescription and suppository results were as shown in Tables 1 and 2.

Analysis condition

Column: Kinetex EVO C18 (150 mm x 4.6 mm, 5 um) or equivalent column

Mobile phase: a mixed solution of 0.02 M potassium dihydrogenphosphate solution: acetonitrile: isopropanol (12: 3.5: 2, v / v / v)

Detection wavelength: UV, 215 nm

Injection amount: 100 uL

Flow rate: 0.3 mL / min

Example 6 Example 7 Comparative Example 1 Comparative Example 2 Example 8 Example 9 Example 10 weight(%) weight(%) weight(%) weight(%) weight(%) weight(%) weight(%) I'm Lima Frost Alphadex 0.1667 0.1667 0.1667 0.1667 0.1667 0.1389 0.1111 ? -cyclodextrin 0.1667 0.1667 0.1667 0.1667 0.1667 0.1389 0.1111 Povidone 12.0 12.0 12.0 12.0 12.0 10.0 8.0 Low-substituted hydroxypropylcellulose 16.5 6.5 16.5 16.7 13.3 Lactose baggage 30.0 30.0 26.5 6.5 50.0 25.0 20.0 Pregelatinized starch 50.0 60.0 80.0 20.0 30.2 23.3 Microcrystalline cellulose after Pregelatinized starch 40.0 ? -cyclodextrin 16.7 13.3 Microcrystalline cellulose 20.6 Hardened vegetable oil 1.2 1.2 1.2 1.2 1.2 1.2 1.2 total 100.0 100.0 100.0 100.0 100.0 100.0 100.0 11-Deoxy (%) 1.42% 0.98% - - 2.12% 1.00% 1.00%

The stability of Limafrost increased as the ratio of total starch increased, and the amount of 11-deoxyindene was reduced when the preparation was left in harsh conditions for 5 days. However, when the total amount of starch was over 60%, it was difficult to formulate granules in the fluidized bed granulator. Therefore, it is most preferable that the amount of pregelatinized starch is 5 to 50% by weight based on the total weight.

[Experimental Example 2] Comparison of total starch change

The pretreated starch was changed to another excipient, and the preparation was implemented as in Experimental Example 1, and the result of the suppository was obtained as shown in Table 3 and FIG.

Example 11 Comparative Example 3 Comparative Example 4 Comparative Example 5 weight(%) weight(%) weight(%) weight(%) I'm Lima Frost Alphadex 0.1667 0.1667 0.1667 0.1667 ? -cyclodextrin 0.1667 0.1667 0.1667 0.1667 Povidone 12.0 12.0 12.0 12.0 Low-substituted hydroxypropylcellulose 21.47 21.47 21.47 21.47 Lactose baggage 30.0 30.0 30.0 30.0 after Pregelatinized starch 35.0 Corn starch 35.0 dextrin 35.0 Dextrose 35.0 Hardened vegetable oil 1.2 1.2 1.2 1.2 total 100.0 100.0 100.0 100.0 11-Deoxy (%) 1.10% 9.93% 21.44% 25.15%

It was difficult to secure the stability of Limafrost when the whole starch was changed to another excipient. When the formulation was left in harsh conditions for 5 days, the amount of 11-Deoxyfatty increased by at least 25%.

[Experimental Example 3] Comparison of changing ethanol ratio

Ethanol ratio was changed to obtain a formulation, and then the same procedure as in Experimental Example 1 was carried out to obtain the result of the flexible material as shown in Table 4. [

Example 12 Example 13 Example 14 Example 15 Comparative Example 6 weight(%) weight(%) weight(%) weight(%) weight(%) I'm Lima Frost Alphadex 0.1667 0.1667 0.1667 0.1667 0.1667 ? -cyclodextrin 0.1667 0.1667 0.1667 0.1667 0.1667 Povidone 12.0 12.0 12.0 12.0 12.0 Low-substituted hydroxypropylcellulose 21.47 21.47 21.47 21.47 21.47 Lactose baggage 30.0 30.0 30.0 30.0 30.0 Pregelatinized starch 35.0 35.0 35.0 35.0 35.0 after Hardened vegetable oil 1.2 1.2 1.2 1.2 1.2 total 100.0 100.0 100.0 100.0 100.0 EtOH ratio (%) 80% 70% 50% 30% 10% 11-Deoxy (%) 1.12% 1.15% 1.96% 3.32% 4.90%

As the content of water in the binding solution increased, the incidence of 11-Deoxy, a flexible substance, increased. The stability of water-sensitive lima frost is considered to be influenced by the amount of water used in the granule manufacturing process. Compared with existing commercial formulations, the range of about 30% to 80% ethanol concentration in the fluidized bed granulator is preferable for the stable formulation .

[Experimental Example 4] Comparative experiment using pellet

38% by weight of nonpolar rail beads (NPS) having a size of 180-300 μm was put into a fluidized bed coater, and 0.16667% of Limafost Alphadex, 0.16667% of β-cyclodextrin and 12% of povidone were dissolved in 70% ethanol at a concentration of 5% One solution was sprayed to prepare drug-coated pellets. The pellets coated with lima frost were coated with 15% by weight of opaque coating agent and 80% ethanol, as shown in Table 5, to prepare pellets.

Comparative Example 7 Example 16 Example 17 Example 18 weight(%) weight(%) weight(%) weight(%) core NPS 38.0 38.0 38.0 38.0 1 ^st Layer Lima Frost Alphadex 0.1667 0.1667 0.1667 0.1667 ? -cyclodextrin 0.1667 0.1667 0.1667 0.1667 Povidone 12.0 12.0 12.0 12.0 2 ^nd Layer Opa Dry 15.0 15.0 15.0 0 After mixing Pregelatinized starch 18.5 33.5 18.5 Low-substituted hydroxypropylcellulose 10.0 15.0 Microcrystalline cellulose 23.5 15.0 15.0 Hardened vegetable oil 1.20 1.20 1.20 1.20 total 100.0 100.0 100.0 100.0 11-Deoxy (%) 5.10% 2.21% 0.95% 2.83%

Claims (7)

A pharmaceutical composition comprising lima frost alpha-dex and beta -cyclodextrin and obtained as a fluidized bed granulator using an alcohol / water mixed solvent, wherein the pregelatinized starch is mixed in the powder obtained by the fluidized bed granule Or after mixing with the powder obtained as the fluidized bed granules. The pharmaceutical composition according to claim 1, which comprises granules obtained as a fluidized bed granulator using an ethanol / water mixed solvent containing lima frost alfadex,? -Cyclodextrin and pregelatinized starch. The pharmaceutical composition according to claim 1, which comprises a mixture of lima frost alfadex and? -Cyclodextrin, followed by post-mixing of the granules obtained as a fluidized bed granulator using an ethanol / water mixed solvent and pregelatinized starch Composition. The pharmaceutical composition according to claim 1, which comprises a mixture of lima frost alfadex and? -Cyclodextrin, followed by post-mixing of the pregelatinized starch into a pellet obtained as a fluidized bed granulator using an ethanol / water mixed solvent Composition. The pharmaceutical composition according to claim 4, wherein the pellet is coated with a polymer base. 6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the concentration of ethanol in the ethanol / water mixed solvent is 30-80%. delete

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