KR20120121944A - Pharmaceutical composition of limaprost with improved stability and method for preparing thereof - Google Patents

Abstract

PURPOSE: An oral formulation containing dry granules of limaprost or limaprost alfadex is provided to ensure stability during processes and after packing and to improve productivity. CONSTITUTION: A dry granule contains limaprost or limaprost alpha-cyclodextrin encapsulated compound; or microshellac and shellactose. The dry granule additionally contains pharmaceutically acceptable additives. A pharmaceutical composition with improved stability contains the dry granule and pharmaceutically acceptable additive. A formulation for oral administration with improved stability contains the composition. The formulation is a tablet, powder, granule, or capsule. A method for manufacturing the formulation for oral administration comprises: a step of mixing limaprost or limaprost alfadex with microshellac or shellactose; a step of pressing the mixture and drying and granulating; and a step of mixing the dry granules with pharmaceutically acceptable additives. [Reference numerals] (AA) Moisture absorption test(25°C/75%RH); (BB) Moisture absorption; (CC) Elapse time; (DD) Embodiment 1; (EE) Comparative embodiment 4; (FF) Commercial formulation

Description

Pharmaceutical composition with improved stability and method for preparing the same

A stable oral formulation comprising the dry granules of limaprost or limaprod alphadex of the present invention. More specifically, the present invention relates to dry granules comprising limaprost or limaprost alphadex and microcellac or cellulose as carriers, pharmaceutical compositions comprising said dry granules, oral dosage formulations having improved stability comprising said compositions. And it relates to a manufacturing method thereof.

Limaprost or its alpha-cyclodextrin inclusion compound, Limaprost alfadex, is a prostaglandin E1 derivative that is useful as a prophylactic or therapeutic agent for peripheral circulation disorders, particularly chronic obstructive thrombosis (burger disease) or It is a medicine useful for improving the symptoms of lumbar spinal stenosis. It is also a drug having pharmacological characteristics and antithrombotic activity on platelets.

By the way, the drug is relatively unstable and difficult to manufacture because it causes dehydration under conditions above room temperature or in the presence of a small amount of acid, base, or water, similar to a general prostaglandin compound.

Since limaprost alphadex tablets have hygroscopic properties and thus absorb moisture and are liable to decompose limaprost as an active ingredient, commercially available preparations (e.g., Opalmon tablets of Dong-A Pharmaceutical) are used in aluminum packaging (Alu-) to avoid the effects of humidity. Alu packaging). However, a pharmaceutical composition containing an active ingredient that is unstable with respect to humidity may not maintain stability even when stored in a package having low moisture permeability or sealed packaging. This is because the moisture contained in the pharmaceutical composition additive or the water mixed in the process of preparing the pharmaceutical composition is not released out of the package, and thus the active ingredient may be decomposed by the intrinsic water or the active water.

Therefore, there have been many studies on methods for stably formulating without losing the pharmacological activity of these drugs, for example, methods using stabilizers, methods of lyophilization, methods using complex compounds, and solid dispersions. And the like.

As a technique for stably formulating limaprost alphadex, Japanese Patent Laid-Open Nos. 7-157431 and 7-109254 provide a stable injectable preparation by lyophilizing limaprost alphadex and polysaccharides, To apply to the formulation for the preparation takes too long and high moisture resistance due to porosity, even if sealed packaging there is a problem that can be decomposed Lima Lima alphadex by the intrinsic moisture. In addition, Korean Patent Laid-Open Publication No. 2008-0099562 provides a solid dispersion in which limaprost or limaprost alphadex is mixed with hydroxy propyl methyl cellulose (HPMC) or collidone, but such a solid dispersion has high hygroscopicity and stability. This results in lowering, and due to the possibility of organic solvents that may remain after drying, there is a particular problem that quality control is required.

Therefore, in order to stably formulate limaprost or limaprod alphadex, it is essential to improve its stability against moisture.

On the other hand, limaprost alphadex tablets are 100mg per tablet, 0.16667mg of limaprost alphadex in one tablet (5µg as limaprost), and the content of the main ingredient is very low at 0.17%, making it difficult to secure content uniformity. Formulation. Content uniformity is a guarantee that the amount of the active ingredient is prepared within the range that can be effective for each tablet, the content uniformity must be secured in order to market this formulation. When manufactured by a wet method in which the main component is dissolved in water or an organic solvent as in the prior art, it may be easier to secure content uniformity. However, the cost of expensive equipment, economical efficiency due to long manufacturing time, and safety for organic solvents In particular, problems such as stability to moisture occur.

Therefore, there is a need for a limaprost or limaprost alphadex composition and a method of manufacturing that can satisfy both economical and stability, as well as content uniformity.

Accordingly, the researchers of the present invention have endeavored to develop a limaprost or limaprost alphadex formulation that meets both economicality, improved stability to moisture, and content uniformity, and thus mixed limaprost or limaprost alphadex with a specific carrier. The present invention was completed by confirming that the preparation of the formulation by dry granulation can improve the stability to moisture and maintain excellent content uniformity.

One object of the present invention is to provide dry granules comprising limaprost or limaprost alphadex, and microcelac or cellulose as carriers.

Another object of the present invention is to provide a pharmaceutical composition with improved stability comprising the dry granules and a pharmaceutically acceptable additive.

Another object of the present invention is to provide a solid preparation for oral administration with improved stability comprising the composition.

Another object of the present invention is to provide a method for preparing the oral dosage formulation.

As one aspect for achieving the above object, the present invention is limaprost or limaprost alphadex; And it relates to a dry granule comprising one or more selected from the group consisting of microcellac and cellulose.

As used herein, the term "Limaprost" has the chemical name (E) -7-[(1R, 2R, 3R) -3-hydroxy-2-[(3S, 5S)-(E)- 3-hydroxy-5-methyl-1-nonenyl] -5-oxocyclopentyl] -2-heptanoic acid, wherein the compound refers to a compound having the formula:

Also used herein is limaprost, limaprost or a pharmaceutically acceptable salt thereof or a inclusion compound thereof. Pharmaceutically acceptable salts of limaprost include non-toxic salts such as sodium or potassium salts.

As used herein, the term "Limaprost alfadex" refers to a compound containing limaprost with alpha-cyclodextrin, the generic name of limaprost alpha-cyclodextrin inclusion compound, and the chemical name (E)- 7-[(1R, 2R, 3R) -3-hydroxy-2-[(3S, 5S)-(E) -3-hydroxy-5-methyl-1-nonenyl] -5-oxocyclopentyl] 2-heptanoic acid alphacyclodextrin is a clathrate compound, and refers to a compound having the formula:

Limaprost or limaprost alphadex is a prostaglandin El derivative, useful as a prophylactic or therapeutic agent for peripheral circulatory disorders, and particularly useful for ameliorating the symptoms of obstructive thrombosis (burger disease) or lumbar spinal stenosis, a chronic disease. Among the limaprosts, limaprost alphadex is more preferred for oral administration.

Limaprost can be manufactured by a well-known method, for example, the method of Unexamined-Japanese-Patent No. 55-100360. In addition, the salt and clathrate compound of limaprost can be obtained by the method well-known from limaprost, for example, since the chemical | medical agent containing limaprost alphadex is marketed, it can refer to this.

As used herein, the term "dry granules" means granules formed substantially without the use of externally applied granulation solvents such as water or ethanol.

Since limaprost alphadex contains very small amounts of about 0.17% of the active ingredient limaprost alphadex, the separation of the mixture does not occur in the process of mixing and tableting limaprost alphadex, resulting in increased tablet content. Uniform production is a very difficult task. To solve this problem, we can consider the wet method and the dry method. First, the wet method is a method of dissolving limaprost alphadex with water or an organic solvent together with a carrier, and freeze-drying or spray-drying, most of the conventional techniques. However, the wet method is disadvantageous in terms of stability to moisture.

Therefore, the inventors of the present invention used a dry granulation method substantially free of water or an organic solvent to prepare a formulation that is easy to manufacture and excellent in stability to moisture. The dry granulation method is economical because the manufacturing process is simple and the manufacturing time is short, and the moisture resistance is low without using water, thereby preventing the intrinsic moisture during the manufacturing process, thereby improving stability to moisture.

However, even with the dry granulation method, there remains a problem of ensuring the content uniformity of the active ingredient. The present inventors have selected such a carrier by selecting a specific carrier that allows a small amount of limaprost alphadex to be uniformly mixed through the dispersion. Solved. The carrier chosen by the present inventors has good fluidity, a lot of pores and a large surface area, very low humidity, very low inherent moisture or free water, so that limaprost alphadex can adhere and mix well on the surface of the carrier. It is a carrier having excellent compressibility. In order to select such a specific carrier, the inventors measured the loss of dryness, angle of repose and compression of the candidate additives usable as carriers of the pharmaceutical composition, respectively. The angle of repose is the maximum angle of inclination that can maintain its inclination when the granulated material is naturally stacked on a plane, and the smaller the angle, the better the fluidity. In addition, the compressibility is a percentage (%) obtained by dividing the difference between the bulk density and the tap density by the apparent density, which is one of the characteristics contributing to the fluidity. The inventors have found that the separation loss is reduced while the carrier, i.e., a homogeneously mixed mixture, which satisfies all of the conditions having good fluidity with a loss of drying of 1% or less, low intrinsic moisture, 40 ° or less in repose angle, and 35% or less in compressibility. Excellent carriers were selected that could produce tablets of uniform content while not occurring.

Preferably, the carrier in the present invention comprises at least one carrier selected from microcellac and cellulose.

As used herein, the term “microcell lock” refers to a spray dried mixture of lactose and microcrystalline cellulose, including, for example, a spray dried mixture containing about 75% by weight lactose and about 25% by weight microcrystalline cellulose. Microcellac may use, but is not limited to, Microcelac® 100 sold by Meggle. As used herein, the term “cellulose” refers to a spray dried mixture of lactose and powdered cellulose, including, for example, a spray dried mixture containing about 75% by weight lactose and about 25% by weight powdered cellulose. Cellulose may be used by, but is not limited to, Cellulose® 80 sold by Meggle.

In the dry granules of the present invention, limaprost alphadex and microcelac or cellulose are in a weight ratio of 1: 1 to 1: 600, preferably 1: 5 to 1: 400, more preferably 1:50 to 1: 200. May be included.

In a specific experimental example of the present invention, in order to confirm the effect on the fluidity and mixing binding strength of the preparation containing the microcelac or cell lactose as a carrier, the preparation using the microcelac or cell lactose as a carrier, and lactose (Tablettose® as a carrier) 80) or bulk formulations with microcrystalline cellulose (Vivapur® 112), bulk density, tap density and compressibility index were measured, respectively. As a result, when limaprost alphadex with poor fluidity was mixed with microcellac or cellulose, it was confirmed that the fluidity was excellent due to the low compressibility. This is because limaprof alpha has many voids on the surface of the microcellac or cellulose. It can be evaluated that the mixing binding force and fluidity with the dex were excellent (see Table 4 of the experimental example).

The dry granules of the present invention may further comprise a pharmaceutically acceptable additive in addition to the microcellac or cellulose. The additive may improve the preparation, compressibility and physical properties of the granules, and may include, for example, one or more of fillers or diluents, binders, disintegrants, lubricants, and other conventional additives known in the art, such as It may include a commonly used desiccant, sweetener or humectant.

Fillers or diluents can be added to increase the volume of the granules and the volume of the resulting formulation and to improve dry binding properties, and the binder can be used to impart cohesion to the granules and tablets to make the formulation more physically stable, Release may be added to facilitate disintegration or disruption of the tablet after administration of the tablet.

Lubricants include magnesium stearate, stearic acid, hydrogenated castor, in small amounts, such as from about 0.01 to 2% by weight, to prevent the dry granulation, such as Limaprost alphadex powder, from adhering to the rollers during roller compaction and to facilitate the compaction operation. Free, talc, silicon dioxide or mixtures thereof can be added. About 1 wt% of stearic acid was also used in the specific preparation of the present invention.

The dry granules of the present invention containing microcellac or cellulose as carriers had the best mixing degree due to the smallest variation in the content of each position in the mixing test after granulation (see Table 5 of the Experimental Example), and even after being prepared as tablets. Content uniformity was better than that of the comparative and commercial formulations (FIG. 1). In addition, the humidity level is lower than that of the comparative and commercially available formulations (FIG. 2), and as a result, the problem in which the stability may be reduced by the intrinsic moisture in the case of being stored in an accelerated condition and stored in an aluminum package may be solved. It was confirmed (see Table 7 of the experimental example). Therefore, the dry granules of the present invention can be usefully used to prepare limaprost or limaprost alphadex-containing pharmaceutical compositions and oral formulations with improved stability.

Thus, as another aspect, the present invention relates to a pharmaceutical composition with improved stability comprising the dry granules and pharmaceutically acceptable additives and to a formulation for oral administration with improved stability comprising the composition.

In the compositions and formulations, at least 90%, or at least 95%, or substantially all of the limaprost or limaprost alphadex is present in the dry granules.

The oral preparation is preferably a tablet, powder, granules or capsules, but is not limited thereto. The shape of the tablet is not particularly limited, and it may be an uncoated tablet having a shape such as a circle, an ellipse, a rectangle, and a coated tablet of the above-mentioned shape.

The pharmaceutical compositions and oral formulations of the present invention may comprise, in addition to dry granules, generally pharmaceutically usable additives. In order to distinguish this from intragranular additives contained in the dry granules, it may be expressed as an extragranular additive. For example, stabilizers, surfactants, lubricants, lubricants, solubilizers, buffers, sweeteners, bases, adsorbents, copulating agents, binders, suspending agents, curing agents, antioxidants, varnishes, flavoring agents, flavoring agents, pigments, coating agents , Wetting agents, fillers, defoamers, fresheners, chewing agents, antistatic agents, colorants, dragees, isotonic agents, emollients, emulsifiers, tackifiers, thickeners, foaming agents, pH adjusting agents, excipients, dispersants, disintegrants, waterproofing agents, preservatives, Preservatives, dissolution aids, glidants, and the like can be added as necessary.

Specific examples of formulation additives include purified white sugar, glucose, trehalose, lactose, maltose, mannitol, sorbitol, xylitol, erythritol, saccharin sodium, aspartame, acesulfame potassium, sucralose, licorice extract, and stevia extract. , Extract, corn starch, sleep starch, wheat starch, sodium bicarbonate, sodium chloride, crystalline cellulose, methyl cellulose, ethyl cellulose, hypromellose, hydroxypropyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, carboxymethyl Cellulose calcium, hypromellose phthalate ester, cellulose acetate phthalate, dextrin, alpha starch, gum arabic, tragacanth, gelatin, sodium alginate, polyvinyl pyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, magnesium stearate, Talc, hydrogenated vegetable oil, macrogol, polyoxy Tylene hardened castor oil 60, hydrous silicon dioxide, silicone oil, agar, shellac, glycerin, aromatic essential oils, water-soluble food colorings, iron sulfate, yellow ginseng iron dioxide, iron trioxide, brown iron oxide, black iron oxide, titanium dioxide, lake pigment, Citrus flavors and coffee flavors such as benzoic acid, sodium benzoate, paraoxy benzoic acid, polysorbate 80, glycerin fatty acid esters, pewter, medium chain fatty acid triglycerides, ascorbic acid, tocopherol, sodium thiosulfate, sodium edetate, orange or lemon, Chocolate flavors, yogurt flavors, milk flavors, plant essential oils such as lemon oil, peppermint oil, spare mint oil, spice oil, and the like, may be cited, but are not particularly limited as long as they are pharmaceutically usable.

In another aspect, the present invention relates to a method of preparing the oral dosage formulation.

More specifically, the present invention relates to

(a) mixing limaprost or limaprost alphadex with at least one member selected from the group consisting of microcellac and cellulose,

(b) compressing the mixture to dry granulate, and

(c) a method of preparing a formulation for oral administration with improved stability, comprising mixing the dry granules obtained in step (b) with a pharmaceutically acceptable additive.

Hereinafter, the manufacturing method will be described in more detail step by step.

Step (a) is a step of mixing limaprost or limaprost alphadex with at least one member selected from the group consisting of microcellac and cellulose.

Step (a) may be mixed with pharmaceutically acceptable intragranular additives, and the intragranular additives may preferably comprise a lubricant. Lubricants may be added in small amounts to provide lubrication during the dry granulation step, such as to prevent the Limaprost alphadex powder from sticking in the roller compactor and to facilitate the compaction operation. About 1 wt% of stearic acid was also used in the specific preparation of the present invention. In addition, the additives in the granules may include one or more fillers or diluents, binders, disintegrants, and the like, and may include other commonly used desiccants, sweeteners or humectants.

Step (b) is a step of dry granulating by compressing the mixture of step (a).

Dry granulation in the present invention may be by roller compacting or slugging, preferably by roller compaction. Roller squeezing refers to a method of producing granules through a method of compressing the powder at a constant pressure while passing the powder between the two rollers. The roller-compressed mixture may be milled or sieved to obtain granules of suitable size. Formulation is the crushing or sieving of the granules to a suitable particle size, which may be a fitz-mill, co-mill, oscillator, etc., and the pulverized particles may be Particle size granules can be obtained.

Step (c) is a step of mixing the dry granules obtained in step (b) with a pharmaceutically acceptable additive.

The dry granules obtained in step (b) are pharmaceutically acceptable extragranular additives, for example stabilizers, surfactants, lubricants, lubricants, solubilizers, buffers, sweeteners, bases, adsorbents, coppers, binders, Suspending agents, curing agents, antioxidants, brightening agents, flavoring agents, flavoring agents, pigments, coating agents, wetting agents, fillers, antifoaming agents, freshening agents, chewing agents, antistatic agents, coloring agents, dragees, isotonic agents, emollients, emulsifiers, tackifiers, Thickeners, blowing agents, pH adjusting agents, excipients, dispersants, disintegrants, waterproofing agents, preservatives, preservatives, dissolution aids, glidants and the like may be added and mixed as necessary. In addition, when formulated into tablets, after mixing the additives may be compressed into tablets using a tableting machine (for example, Rotary tableting machine, ERWEKA) commonly used in the pharmaceutical field.

The oral preparations containing limaprost or limaprost alphadex prepared as described above can be used to treat obstructive thrombovascularitis or lumbar spinal stenosis because they maintain the original activity of the active ingredient, and improve the stability and content uniformity of water. It can be usefully prepared and used as an oral preparation.

The preparation according to the present invention is not only secured stability during the process and after packaging to improve the stability to moisture, it is possible to long-term storage, and the production process is simple to improve the productivity and economic efficiency, applied as an oral preparation Because it provides convenience and ease, and maintains good content uniformity and activity, Limaprost can be usefully used for the treatment of the desired disease.

Figure 1 shows the individual content uniformity degree for each of the formulation of Example 1 and Comparative Example 1, and 10 tablets of the commercial formulation.
Figure 2 shows the humidity change of the formulation of Example 1 and Comparative Example 4, and the commercial formulation over time.

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

Example  And Comparative example .

Table 1 shows the content (% by weight) of the components contained in the composition preparation and comparative preparation according to the present invention.

Example 1 Example 2 Comparative Example 1 Comparative Example 2 Comparative Example 3 Limafrost Alphadex 5% 5% 5% 5% 5% Microcellac® 100 ¹⁾ 94% - - - 94% Celactose®80 ²⁾ - 94% - - - Tablettose®80 ³⁾ - - 94% 73% - Vivapur®112 ⁴⁾ - - - 21% - Stearic acid One% One% One% One% One% Sum 100% 100% 100% 100% 100% Dry granules ○ ○ ○ ○ X

1) Spray dried 75% by weight of lactose and 25% by weight of microcrystalline cellulose (Meggle, Germany)

2) spray drying 75% by weight of lactose and 25% by weight of powdered cellulose (Meggle, Germany)

3) alpha-lactose monohydrate (Meggle, Germany)

4) Microcrystalline cellulose (JRS Pharma, Germany)

< Example  1>

10 g of Limaprost alphadex and 30 g of Microcelac®100 were mixed, and then mixed with 158 g of Microcelac®100 and 2 g of stearic acid, dry granulated with a roller compactor, sieved through a 30 mesh sieve, and the mixtures were mixed for 20 minutes in a V-Mixer. .

< Example  2>

After mixing 10 g of limaprost alphadex and 30 g of cellulose®80, 158 g of cellulose®80, 2 g of stearic acid and dry granules with a roller compactor were granulated in a 30-mesh sieve, and the formulations were mixed in a V-Mixer for 20 minutes.

< Comparative example  1>

10 g of Limaprost Alphadex and 30 g of Tablettose®80 were mixed, and then mixed with 158 g of Tablettose®80 and 2 g of stearic acid, dry granulated with a roller compactor, sieved in a 30mesh sieve, and the formulations were mixed for 20 minutes in a V-Mixer.

< Comparative example  2>

10 g of Limaprost alphadex and 42 g of Vivapur®12 were mixed, then mixed with 146 g of Tablettose®80 and 2 g of stearic acid, dry granulated with a roller compactor, sieved with a 30mesh sieve, and the formulations were mixed for 20 minutes in a V-Mixer.

< Comparative example  3>

After mixing 10 g of Limaprost alphadex and 30 g of Microcelac®100, 158 g of Microcelac®100 and 2 g of stearic acid were mixed in a V-Mixer for 20 minutes.

< Comparative example  4>

The weight ratio of limaprost alphadex and hydroxypropyl cellulose was 1.667: 100, and dissolved in 80% ethanol to prepare a solid dispersion by spray drying. 20.33 g of this solid dispersion, 75.67 g of anhydrous lactose, 90 g of microcrystalline cellulose, 10 g of crospovidone, 1 g of anhydrous silicon dioxide, and 3 g of stearic acid were dried and granulated with a roller compactor, sieved to a 30mesh sieve, and the sieved material was then formed in a V-Mixer. Mix for 20 minutes.

Experimental Example  One. Lima Frost  Of containing formulation Carrier  selection

In order to select a carrier having low intrinsic moisture and good fluidity as a carrier to be used in preparing a pharmaceutical preparation including limaprost alphadex, loss of dryness, angle of repose and compressibility of candidate additives that can be used as a carrier of the pharmaceutical composition. ) Were respectively measured.

Loss on drying was measured at 80 ° C./30 minutes with an infrared moisture meter (MX-50), and the angle of repose was measured with an angle meter (ITOH). The degree of compression represents the percentage (%) obtained by dividing the difference between the bulk density and the tap density by Campbell.

The results are shown in Table 2 below. In general, however, additives with high drying loss were excluded.

additive Loss on Drying (%) Repose angle (°) Compression degree (%) Remarks Tablettose®80 0.2 32 29.8 Meggle SuperTab®AN21 ^{1 )} 0.2 39 29.4 DMV Corporation Vivapur®112 1.2 38 41.8 FMC Corporation Microcellac® 100 0.5 31 22.0 Meggle Celactose® 80 0.7 34 31.6 Meggle Starlac® ²⁾ 2.4 29 19.3 Meggle Prosolv® ³⁾ 4.5 33 18.9 JRS Corporation Mannitol 0.2 46 32.2 Roquette Ludipress® ^{4 )} 2.9 37 16.6 Basf Corp

1) Lactose-free (DMV-Fonterra, Germany)

2) spray drying of 85% by weight of lactose monohydrate and 15% by weight of corn starch (Meggle, Germany)

3) silicated microcrystalline cellulose (JRS Pharma, Germany)

Alpha-lactose monohydrate + povidone + crospovidone (BASF, Germany)

As shown in Table 2, microcellac and cellulose were selected as carriers to be used in the present invention, which satisfies all of the conditions of good fluidity with a loss of drying of less than 1%, an angle of repose of 40 ° or less and a degree of compression of 35% or less. .

Experimental Example  2. Comparison of physical properties

In order to confirm the physical properties of the formulation comprising limaprost alphadex as an active ingredient and microcellac or cellulose as a carrier, a mixture was prepared in the following weight percent, and then bulk density and tap density. density and compressibility index were measured, respectively. In order to measure more precisely, the physical properties were measured at the stage before the dry granulation of each mixture, and the results are shown in Table 4.

F-1 F-2 F-3 F-4 Limafrost Alphadex 5% 5% 5% 5% Microcellac® 100 94% - - - Celactose® 80 - 94% - - Tablettose®80 - - 94% 73% Vivapur®112 - - - 21% Stearic acid One% One% One% One%

Bulk Density (g / L) Tap Density (g / L) Compression degree (%) Limafrost Alphadex 442 655 48.2 F-1 516 617 19.6 F-2 415 522 25.8 F-3 521 695 33.4 F-4 513 674 31.4

As shown in Table 4, it was found that when F-1 and F-2 using microcelac or cellulose were mixed, the fluidity was remarkably excellent when the limaprost alphadex having poor fluidity was mixed. In particular, the lower compressibility values of F-1 and F-2 mixed with Limaprost alphadex than the single compressibility of each additive shown in Table 2 indicate that pores in the form of particles of microcellac and cellulose There are many, and the voids can be evaluated as the result of the filling of limaprost alphadex to improve the mixing and fluidity.

Experimental Example  3. Mixing test

After the mixing of Examples 1 and 2 and Comparative Examples 1 to 3 was completed, samples were taken at each of the left, middle, and right positions of the V-mixer to measure the degree of mixing. The test results shown in Table 5 below were obtained by the following high performance liquid chromatography method.

<Method>

Detector: UV absorbance photometer (215 nm)

Column lum: Gemini C18 (150mm × 4.6mm, 5um)

Mobile phase: 0.02M mixture of potassium dihydrogen phosphate solution, acetonitrile and isopropanol (50:25:10)

Flow rate: 1mL / min

Example 1 Example 2 Comparative Example 1 Comparative Example 2 Comparative Example 3 Left 98.3% 98.6% 95.5% 104.9% 95.2% medium 101.3% 101.2% 97.1% 96.9% 94.5% Right 98.9% 98.1% 103.8% 97.3% 100.7% Average 99.5% 99.3% 98.8% 99.7% 96.8% Relative standard deviation 1.30% 1.37% 3.64% 3.69% 2.86%

As shown in Table 5, in Examples 1 to 2, the content variation of each position in the mixer was low, indicating that the mixing degree was relatively excellent.

Experimental Example  4. Content uniformity test

The mixture prepared in Examples 1 to 2 and Comparative Examples 1 to 3 was compressed into tablets of 100 mg per tablet, and then 10 tablets were taken to determine individual content uniformity. In addition, commercially available formulations (compositions of Korean Patent No. 0833211) were also measured and compared in the same manner. Specifically, it was tested by the following high performance liquid chromatography method, the results are shown in Table 6 and Figure 1 (content: 90 ~ 110%).

<Method>

Detector: UV absorbance photometer (215 nm)

Column: Zorbax Eclipse C18 (250mm × 4.6mm, 5um)

Mobile phase: 0.02 M potassium dihydrogen phosphate solution, acetonitrile and isopropanol mixture (9: 5: 2)

Flow rate: 1mL / min

Example 1 Example 2 Comparative Example 1 Comparative Example 2 Comparative Example 3 Commercially available Average content 101.1% 101.0% 100.2% 97.3% 99.2% 103.5% Relative standard deviation 3.21% 3.48% 9.22% 8.87% 7.37% 3.70% Content 106.3% 105.5% 114.1% 111.2% 110.4% 109.0% Minimum content 96.4% 96.1% 84.9% 87.4% 87.9% 96.4%

As shown in Table 6 and Figure 1, the tablets according to Examples 1 and 2 had a much smaller content deviation of the individual tablets than the comparative example, and showed better content uniformity than the lyophilized commercial preparations. Therefore, it was found that the content uniformity was excellent when dry granules were prepared using microcellac or cellulose as a carrier.

Experimental Example  5. Humidity test

After preparing 100 mg tablets per tablet of the mixture prepared in Examples 1 and 2, and Comparative Example 4, with a commercially available formulation (composition of Korea Patent No. 0833211) at 25 ℃, relative humidity 75% over time Humidity (%) was tested by measuring mass change.

As a result, as shown in FIG. 2, the humidity of Example 1 containing microcelac was remarkably low. On the other hand, the spray-drying Comparative Example 4 and the freeze-dried commercial formulation were relatively high in humidity, and the humidity proceeded rapidly. Therefore, according to the present invention it can be seen that the moisture is easily condensed according to the humidity of the workplace during the manufacturing process to solve the problem that the stability may be reduced by the intrinsic moisture even after packaging.

Experimental Example  6. Stability Test

Example 1, Comparative Example 4 and commercially available formulations (composition of the Republic of Korea Patent No. 0833211) in an unpacked tablet state under accelerated conditions (40 ℃ / 75% relative humidity) and kept open, and separately wrapped in aluminum (Alu-Alu packaging) Stability test over time was stored in accelerated conditions (40 ℃ / 75% relative humidity) in the) state. The results are shown in Table 7 below. The numerical values shown in Table 7 show the contents over time when the initial content of limaprost alphadex is 100%.

Early Opening Alu-Alu Packaging 3 days 7 days 4 weeks 8 weeks 12 Weeks 16 weeks Example 1 100% 93.4% 84.9% 99.3% 97.6% 97.0% 96.3% Comparative Example 4 100% 85.0% 61.2% 96.5% 90.1% 86.6% 82.9% Commercially available 100% 89.1% 75.7% 98.9% 97.3% 96.1% 95.8%

As can be seen in Table 7, according to the properties of the lymproast alphadex formulations which are very unstable to moisture, the formulations kept open under accelerated conditions showed a sharp drop in content, but in Example 1, the humidity was relatively high. The rate of lowering the content was much lower. In addition, it was found that the stability of Example 1 is more excellent in the aluminum (Alu-Alu) packaged state so as not to be moisture permeable.

Claims (10)

Limaprost or limaprost alpha-cyclodextrin inclusion compounds; And at least one selected from the group consisting of microcellac and cellulose.
The dry granule of claim 1, further comprising a pharmaceutically acceptable additive.
The method of claim 1, wherein the limaprost or limaprost alpha-cyclodextrin inclusion compound; And at least one selected from the group consisting of microcellac and cellulose in a weight ratio of 1: 1 to 1: 600.
4. A pharmaceutical composition with improved stability comprising the dry granules of any one of claims 1 to 3 and a pharmaceutically acceptable additive.
Oral administration with improved stability comprising the composition of claim 4.
The formulation of claim 5 in the form of a tablet, powder, granule or capsule.
The agent according to claim 5, for the treatment of obstructive thrombosis or lumbar spinal stenosis.
(a) mixing limaprost or limaprost alphadex with at least one member selected from the group consisting of microcellac and cellulose,
(b) compressing the mixture to dry granulate, and
(c) mixing the dry granules obtained in step (a) with a pharmaceutically acceptable additive to prepare a formulation for oral administration with improved stability according to claim 5.
The method of claim 8, wherein step (a) further mixes a pharmaceutically acceptable additive.
The method of claim 8, wherein step (b) is by roller compaction.

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