JP7004448B2 - Lymaprost-containing lyophilized composition and Limaprost-containing pharmaceutical composition - Google Patents

Description

The present invention relates to stabilizing pharmaceutical compositions. In particular, the present invention relates to a lyophilized composition containing limaprost, which is a drug for prostaglandins.

Limaprost is a prostaglandin E1 derivative that increases peripheral blood flow and suppresses platelet aggregation, thus improving ischemic symptoms such as ulcer, pain and cold sensation associated with obstructive thrombovascular inflammation. It is also used to improve subjective symptoms such as lower limb pain and numbness associated with acquired lumbar spinal stenosis and walking ability.

The composition containing limaprost has hygroscopicity and absorbs water so that the active ingredient (lymaprost) is very easily decomposed. Normally, it is packed in an aluminum bag together with a desiccant such as silica gel or zeolite on top of PTP packaging, and is in a sealed packaging form to avoid the influence of humidity from the outside.

So far, an example using β-cyclodextrin has been reported as an attempt to improve the stability of a drug (Patent Document 1).

Patent No. 4890657

An object of the present invention is to provide a lymaprost-containing freeze-dried composition, which is more stable than the existing lymaprost alphadex tablets.

In one embodiment of the invention is provided a lymaprost-containing lyophilized composition comprising limaprost alphadex, β-cyclodextrin and dextrin. The lyophilized composition (lyophilized portion) is composed of limaprost alphadex, β-cyclodextrin and dextrin.

The present inventors have found that, surprisingly, a lymaprost-containing freeze-dried composition containing dextrin and β-cyclodextrin is stable in a diligent study to solve the above problems.

In one embodiment of the present invention, dextrin may be 50% by weight to 95% by weight based on the lyophilized portion.

It was confirmed that the dextrin was stable when it was 50% by weight to 95% by weight based on the freeze-dried portion.

In one embodiment of the present invention, there is provided a limaprost-containing pharmaceutical composition comprising the above-mentioned lymaprost-containing lyophilized composition and a divalent metal salt additive.

As a result of various studies, the present inventors have found that the increase of related substances can be suppressed by adding magnesium stearate to a lymaprost-containing lyophilized composition containing dextrin and β-cyclodextrin. Furthermore, the present inventors have found that the increase of related substances can be suppressed by adding magnesium stearate / calcium stearate. Here, it was suggested that the divalent metal ion may contribute to the stability in comparison with the fact that the substance to be added is stearic acid / stearyl fumarate cannot suppress the increase of related substances.

In one embodiment of the invention, the divalent metal salt additive is carmellose calcium, magnesium silicate, zinc stearate, magnesium stearate, calcium stearate, magnesium carbonate, precipitated calcium carbonate, calcium sulfate or magnesium sulfate hydration. It may be a divalent metal salt additive selected from at least one of the substances.

In one embodiment of the present invention, a pharmaceutical preparation in which the pharmaceutical composition is packaged in PTP is provided. Further, a pharmaceutical preparation in which the pharmaceutical composition is packaged in a glass or plastic container is provided.

It is possible to provide a lymaprost-containing lyophilized composition and a lymaprost-containing lyophilized composition, which are more stable than the existing lymaprost alphadex tablets.

（１） The pharmaceutical composition of the present invention contains limaprost alphadex, β-cyclodextrin and dextrin. The lyophilized composition (lyophilized portion) of the present invention is composed of limaprost alphadex, β-cyclodextrin and dextrin. Limaprost alphadex is represented by the following compound (1).

(1)

The chemical name of Limaprost alphadex is (E) -7-[(1R, 2R, 3R) -3-hydroxy-2-[(3S, 5S)-(E) -3-hydroxy-5-methyl-1-nonenyl). ] -5-oxocyclopentyl] -2-heptenoic acid α-cyclodextrin clathrate compound (CAS Registry Number: 100459-01-6). This compound is known and can be produced by a known method, for example, the method described in JP-A-55-100360.

In the composition of the present invention, limaprost alphadex, β-cyclodextrin and dextrin are dissolved in a solvent (for example, water, an organic solvent (for example, ethanol, acetone, etc.), etc.) and freeze-dried according to a conventional method (step (1). )), It can be manufactured by adding an additive as needed.

（２） When limaprost in the composition of the present invention is decomposed, the decomposition product is mainly abbreviated as 17S, 20-dimethyl-trans-Δ2 ^- PGA ₁ (hereinafter abbreviated as 11-deoxy compound) shown in the following compound (2). ) Is known to be generated.

(2)

In addition, it is known that 17S, 20-dimethyl-trans-Δ ^2-8 -iso-PGE ₁ (hereinafter, abbreviated as 8-iso form) and the like are also produced. The production rate of the 11-deoxy compound can be shown, for example, as a ratio (area ratio) of the amount of the 11-deoxy compound in the composition to the total amount of the limaprost, the 11-deoxy compound, and the 8-iso compound. This area ratio refers to the peak area ratio of the chromatogram of high performance liquid chromatography (HPLC).

The 11-deoxy form can be calculated by quantifying limaprost and the decomposition products of limaprost (8-iso form, 11-deoxy form) and setting the sum of the limaprost and the decomposition product as 100. For example, this quantification can be calculated from the peak area of the HPLC chromatogram.

The amounts of limaprost and 11-deoxy and 8-iso forms can be measured using known analytical methods (eg, high performance liquid chromatograph, gas chromatograph, thin layer chromatograph).

Specifically, it is carried out according to the following HPLC test conditions. By using this method, it is possible to measure the amount of limaprost and degradation products and calculate the ratio of limaprost and degradation products. Further, by using this method, the amount of 11-deoxy compound can be measured.
HPLC test conditions :
Detector: Ultraviolet absorptiometer (measurement wavelength: 220 nm);
Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 25 cm is filled with 5 μm of tricontylsilylated silica gel for liquid chromatography;
Column temperature: Constant temperature around 25 ° C;
Mobile phase: 0.02 mol / L potassium dihydrogen phosphate test solution / acetonitrile mixed solution (31:19);
Flow rate: Adjust so that the retention time of Limaprost is about 20 minutes.

The pharmaceutical composition of the present invention is useful for treating peripheral circulatory disorders such as thromboangiitis obliterans or lumbar spinal canal stenosis. The pharmaceutical composition of the present invention is preferably a solid preparation (for example, tablets, granules, capsules, etc.). More preferably, it is a tablet (for example, nucleated tablet, coating tablet, coating granule, three-layer tablet, etc.).

The pharmaceutical composition of the present invention contains limaprost alphadex, β-cyclodextrin and dextrin. The amount of dextrin is preferably 50% by weight to 95% by weight based on the freeze-dried portion (details will be described later). The dextrin is preferably 500% by weight to 2500% by weight based on Limaprost alphadex.

The pharmaceutical composition of the present specification may further contain an additive (formation base) in addition to dextrin, β-cyclodextrin and limaprost alfadex. The additive may be any one generally used in the production of solid preparations, for example, excipients, binders, lubricants, disintegrants, flavoring agents, odorants, surfactants, etc. A fragrance, a colorant, an antioxidant, a concealing agent, an antistatic agent, a fluidizing agent, a wetting agent and the like can be appropriately blended and used in one type or two or more types.

Excipients include, for example, glucose, fructose, maltose, lactose, isomerized lactose, reduced lactose, sucrose, D-mannitol, erythritol, maltitol, xylitol, palatinose, trehalose, sorbitol, corn starch, horse belly starch, etc. Examples thereof include wheat starch, rice starch, crystalline cellulose, talc, anhydrous silicic acid, anhydrous calcium phosphate, precipitated calcium carbonate, calcium silicate and the like.

Examples of the binder include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone, polyvinylpyrrolidone, methyl cellulose, polyvinyl alcohol, carboxymethyl cellulose, partially pregelatinized starch, pregelatinized starch, sodium alginate, pullulan, gum arabic powder, gelatin, dextrin and the like. These may be used alone or in combination of two or more as appropriate. The binder is preferably hydroxypropylmethylcellulose or hydroxypropylcellulose.

The pharmaceutical composition of the present invention may contain a lubricant. Lubricants include lithium stearate, magnesium stearate, calcium stearate, barium stearate, zinc stearate, calcium laurate, barium laurate, zinc laurate, calcium ricinolate, barium ricinolate, zinc ricinolate, octylic acid. Examples include zinc, carmellose calcium, magnesium oxide, magnesium carbonate, and precipitated calcium carbonate. The lubricant may be a metal soap, and the metal soap includes lithium stearate, magnesium stearate, calcium stearate, barium stearate, zinc stearate, calcium laurate, barium laurate, zinc laurate, calcium ricinolate. , Barium ricinolate, zinc ricinolate, zinc octylate, and preferably selected from at least one of magnesium stearate or calcium stearate.

Examples of the disintegrant include low-degree-of-substitution hydroxypropyl cellulose, carmellose, carmellose calcium, carboxymethyl starch sodium, chrome carmellose sodium, crospovidone, hydroxypropyl starch, corn starch and the like.

Examples of the flavoring agent include sucrose, D-sorbitol, xylitol, citric acid, ascorbic acid, tartaric acid, malic acid, aspartame, acesulfame potassium, somatine, sodium saccharin, dipotassium glycyrrhizinate, monosodium glutamate, and 5'-inosic acid. Examples thereof include sodium, 5'-sodium guanylate, and the like.

Examples of the odorant include trehalose, malic acid, maltose, potassium gluconate, anise essential oil, vanilla essential oil, cardamom essential oil and the like. Examples of the surfactant include polysorbate (polysorbate 80 and the like), polyoxyethylene / polyoxypropylene copolymer, sodium lauryl sulfate and the like. Examples of the fragrance include lemon oil, orange oil, menthol, peppermint oil and the like. Examples of the colorant include titanium oxide, edible yellow No. 5, edible blue No. 2, iron sesquioxide, yellow iron sesquioxide and the like. Examples of the antioxidant include sodium ascorbate, L-cysteine, sodium sulfite, vitamin E and the like.

Examples of the concealing agent include titanium oxide and the like. Examples of the antistatic agent include talc and titanium oxide. Examples of the fluidizing agent include light anhydrous silicic acid, talc, and hydrous silicon dioxide. Examples of the wetting agent include polysorbate 80, sodium lauryl sulfate, sucrose fatty acid ester, macrogol, hydroxypropyl cellulose (HPC) and the like.

The pharmaceutical product of the present invention can be produced by a known method, and can be granulated by using, for example, a rolling granulator, a stirring granulator, a flow granulator, a centrifugal rolling granulator, a dry granulator, or the like. Granulation can be produced by the above.

As the solid preparation of the present invention, for example, the granules obtained by the above method can be used as they are as granules. The solid preparation of the present invention also includes capsules containing the above granules. Capsules can be produced by known methods, for example, the granules, and if necessary, those to which an additive is added are hard capsules (for example, gelatin capsules, hydroxypropylmethylcellulose (HPMC) capsules, purulan capsules, polyvinyl alcohol). (PVA) capsules and the like) can be filled by using a capsule filling machine. The pharmaceutical product of the present invention also includes tablets containing the above granules. Tablets can be produced by a known method, for example, by mixing the above granules and additives and tableting them with a rotary tableting machine or the like. It is also possible to prepare a mixed powder containing a drug or the like without performing granulation and tablet it with a rotary tableting machine or the like.

The pharmaceutical composition of the present invention can be made into a pharmaceutical preparation by packaging as necessary. In addition to ordinary PTP packaging, the pharmaceutical composition of the present invention may be stored in highly moisture-proof packaging such as highly moisture-proof PTP, double-sided aluminum PTP, and SP packaging, which is relatively impermeable to moisture. can. After each of the above-mentioned packaging forms, it is also possible to further perform pillow packaging and store the product. A desiccant can also be included in the pillow packaging. The desiccant is not particularly limited, and examples thereof include silica gel, calcium chloride, calcium oxide (quick lime), magnesium chloride, silica aluminum gel, and zeolite, but from the viewpoint of safety, ease of use, hygiene, and the like. In particular, silica gel (in a bag or sheet type) is preferable, and sheet type silica gel is preferable from the viewpoint of ease of use and hygiene.

[Production method]
The lyophilized portion can be prepared by dissolving limaprost alphadex, dextrin, and β-cyclodextrin in water and lyophilizing.

The freeze-drying conditions are not particularly limited. For example, the contents are frozen by cooling at a shelf temperature of -50 ° C, and then dried at a shelf temperature of 10 ° C until the product temperature and the shelf temperature become the same (primary drying). ), After that, the shelf temperature is set to 10 ° C., and the product is dried for 24 hours or more (secondary drying).

The freeze-dried composition can be pulverized and sieved, excipients, lubricants and the like can be added according to each formulation, and the mixture can be tableted according to a conventional method to obtain a pharmaceutical composition.

The type of excipient and the method of addition can be selected according to various dosage forms of the pharmaceutical composition. For example, a pharmaceutical composition for tablets can be produced by mixing the freeze-dried composition prepared as described above with an excipient, and tableting and drying.

The pharmaceutical product of the present invention may be packaged in a pillow package or a double-sided aluminum PTP package. Packaging is preferably carried out, for example, under dry conditions while maintaining a low water activity value of the pharmaceutical composition of the present invention. Further, the pharmaceutical preparation of the present invention may be produced by packaging the pharmaceutical composition of the present invention in a glass or plastic container.

Examples are shown below, and the present invention will be described in more detail, but the present invention is not limited to these examples.

[Stability test of freeze-dried product alone 1]
First, a stability test was conducted only in the freeze-dried part.

(Example 1)
As a lyophilized portion, per tablet, dissolve 0.17 mg of limaprost alfadex, 1.00 mg of dextrin, and 0.17 mg of β-cyclodextrin at a ratio of 36.0 mg of purified water and freeze-dry. Prepared by As freeze-drying conditions, the contents are frozen by cooling at a shelf temperature of -50 ° C, then dried at a shelf temperature of 10 ° C until the product temperature and the shelf temperature become the same (primary drying), and then the shelf. The temperature was set to 10 ° C., and the product was dried for 24 hours or more (secondary drying). The solid content was 1.34 mg per tablet.

(Comparative Example 1)
A lyophilized composition was obtained in the same manner as in Example 1 except that 1.00 mg of dextran 40 was added instead of 1.00 mg of dextrin.

(Comparative Example 2)
A lyophilized composition was obtained in the same manner as in Example 1 except that 1.00 mg of dextran 70 was added instead of 1.00 mg of dextrin.

The above Examples 1, Comparative Example 1 and Comparative Example 2 were stored at 40 degrees Celsius / 75% relative humidity for 6 days without packaging such as blister packs. The rate of formation of the decomposition product (11-deoxy form) of Limaprost at the start and after 6 days was analyzed by high performance liquid chromatography (HPLC).

The decomposition product formation rate was calculated with the sum of Limaprost and the decomposition product as 100. The analysis results are shown in Table 1 below.

From Example 1, Comparative Example 1 and Comparative Example 2, it was confirmed that the use of dextrin is more stable than the use of dextran 40 and dextran 70.

[Stability test 2 for freeze-dried products alone]
Subsequently, the stability test of the freeze-dried product alone was carried out for β-cyclodextrin.

( Comparative Example 9 )
As a lyophilized portion, lyophilize by dissolving 0.17 mg of limaprost alfadex, 3.50 mg of dextrin, and 0.08 mg of β-cyclodextrin at a ratio of 36.0 mg of purified water per tablet. Prepared by letting. As freeze-drying conditions, the contents are cooled to a shelf temperature of -50 ° C, and then dried at a shelf temperature of 10 ° C until the product temperature and the shelf temperature become the same (primary drying). , The shelf temperature was set to 10 ° C., and the product was dried for 24 hours or more (secondary drying). The solid content was 3.75 mg per tablet. The ratio of dextrin to the lyophilized portion was 93.3%, and the ratio of β-cyclodextrin to the lyophilized portion was 2.13%.

( Comparative Example 10 )
A lyophilized composition was obtained in the same manner as in Comparative Example 9 , except that 0.17 mg of β-cyclodextrin was added.

( Comparative Example 11 )
A lyophilized composition was obtained in the same manner as in Comparative Example 9 except that 0.30 mg of β-cyclodextrin was added.

( Comparative Example 12 )
A lyophilized composition was obtained in the same manner as in Comparative Example 9 except that 0.50 mg of β-cyclodextrin was added.

(Comparative Example 3)
A lyophilized composition was obtained in the same manner as in Comparative Example 9 except that β-cyclodextrin was not added.

The above Comparative Examples 9 to 12 and Comparative Example 3 were stored at 40 degrees Celsius / 75% relative humidity for 6 days without packaging such as blister packs. The rate of formation of the decomposition product (11-deoxy form) of Limaprost at the start and after 6 days was analyzed by high performance liquid chromatography (HPLC).

The decomposition product formation rate was calculated with the sum of Limaprost and the decomposition product as 100. The analysis results are shown in Table 2 below.

It can be seen that the higher the amount of β-cyclodextrin, the more stable it is.

[Stability test of freeze-dried product alone 3]
Subsequently, the stability test of the freeze-dried product alone was carried out for dextrin.

( Comparative Example 12 )
As a lyophilized portion, lyophilize by dissolving 0.17 mg of limaprost alfadex, 3.50 mg of dextrin, and 0.50 mg of β-cyclodextrin at a ratio of 36.0 mg of purified water per tablet. Prepared by letting. As freeze-drying conditions, the contents are frozen by cooling at a shelf temperature of -50 ° C, then dried at a shelf temperature of 10 ° C until the product temperature and the shelf temperature become the same (primary drying), and then the shelf. The temperature was set to 10 ° C., and the product was dried for 24 hours or more (secondary drying). The solid content was 4.17 mg per tablet. The ratio of dextrin to the lyophilized portion was 83.9%, and the ratio of β-cyclodextrin to the lyophilized portion was 12.0%.

(Example 6)
A lyophilized composition was obtained in the same manner as in Comparative Example 12 , except that 2.00 mg of dextrin was added.

(Example 7)
A lyophilized composition was obtained in the same manner as in Comparative Example 12 , except that 1.00 mg of dextrin was added.

(Comparative Example 4)
A lyophilized composition was obtained in the same manner as in Comparative Example 12 , except that dextrin was not added.

The above Comparative Examples 12, Examples 6 to 7 and Comparative Example 4 were stored at 40 degrees Celsius / 75% relative humidity for 6 days without packaging such as blister packs. The rate of formation of the decomposition product (11-deoxy form) of Limaprost at the start and after 6 days was analyzed by high performance liquid chromatography (HPLC).

The decomposition product formation rate was calculated with the sum of Limaprost and the decomposition product as 100. The analysis results are shown in Table 3 below.

From the above, it was found that the amount of dextrin added was stable in the order of 1.00 mg (most stable), 2.00 mg, 3.50 mg, and no addition.

[Effects of adding divalent metal salt additives]
Subsequently, the stability test of the Limaprost-containing pharmaceutical composition was carried out.

The freeze-dried composition can be pulverized and sieved, excipients, lubricants and the like can be added according to each formulation, and the mixture can be tableted according to a conventional method to obtain a pharmaceutical composition.

( Reference example 1 )
The lyophilized composition of Comparative Example 12 contains 20.00 mg of carmellose, 24.00 mg of β-cyclodextrin, 41.50 mg of lactose hydrate, 10.00 mg of dextrin, 0.20 mg of light anhydrous silicic acid, and stearate per tablet. Tablets were obtained by mixing to a ratio of 1.00 mg of magnesium and tableting.

( Reference example 2 )
Tablets were obtained in the same manner as in Reference Example 1 except that 2.00 mg of magnesium stearate was added instead of 1.00 mg.

(Comparative Example 5)
Tablets were obtained in the same manner as in Reference Example 1 except that 1.50 mg of stearic acid was added instead of magnesium stearate.

The above Reference Examples 1 and 2 and Comparative Example 5 were stored at 30 degrees Celsius / 75% relative humidity for 3 months without packaging such as blister packs. The rate of formation of the decomposition product (11-deoxy form) of Limaprost at the start and after 3 months was analyzed by high performance liquid chromatography (HPLC).

The decomposition product formation rate was calculated with the sum of Limaprost and the decomposition product as 100. The analysis results are shown in Table 4 below.

Comparing Comparative Example 5 to which stearic acid was added with Reference Example 1 to which 1.00 mg of magnesium stearate was added and Reference Example 2 to which 2.00 mg of magnesium stearate was added, magnesium stearate containing a divalent metal salt was added to the rear end. It was found that the addition can suppress the increase of related substances.

Subsequently, for the purpose of cleaning the lubricant, the formulation shown in Table 5, specifically, any of stearic acid, stearyl sodium fumarate, magnesium stearate, and calcium stearate is added to the posterior end. I considered the prescription.

( Reference example 3 )
In the freeze-dried composition of Comparative Example 12 , carmellose 20.00 mg, β-cyclodextrin 24.00 mg, lactose hydrate 10.00 mg, dextrin 41.50 mg, light anhydrous silicic acid 0.20 mg, and stearate per tablet. Tablets were obtained by mixing to a ratio of 0.50 mg of magnesium and tableting.

( Reference example 4 )
Tablets were obtained in the same manner as in Reference Example 3 except that 1.00 mg of magnesium stearate was added instead of 0.50 mg.

( Reference example 5 )
Tablets were obtained in the same manner as in Reference Example 3 except that 1.50 mg of magnesium stearate was added instead of 0.50 mg.

( Reference example 6 )
Tablets were obtained in the same manner as in Reference Example 3 except that 1.50 mg of calcium stearate was added instead of 0.50 mg of magnesium stearate.

(Comparative Example 7)
Tablets were obtained in the same manner as in Reference Example 3 except that 1.50 mg of stearic acid was added instead of 0.50 mg of magnesium stearate.

(Comparative Example 8)
Tablets were obtained in the same manner as in Reference Example 3 except that 1.50 mg of stearyl fumarate was added instead of 0.50 mg of magnesium stearate.

The above Reference Examples 3 to 6 and Comparative Examples 7 to 8 were stored at 30 degrees Celsius / 75% relative humidity for 3 months without packaging such as blister packs. The rate of formation of the decomposition product (11-deoxy form) of Limaprost at the start and after 3 months was analyzed by high performance liquid chromatography (HPLC).

The decomposition product formation rate was calculated with the sum of Limaprost and the decomposition product as 100. The analysis results are shown in Table 5 below.

First, in Comparative Examples 7 to 8 and Reference Examples 3 to 6 , it was the formulation to which magnesium stearate or calcium stearate was added to the posterior end that made it possible to suppress related substances. Therefore, it can be seen that the increase of related substances in the limaprost-containing pharmaceutical composition can be suppressed by adding magnesium stearate or calcium stearate rather than adding stearic acid or stearyl fumarate to the posterior end.

And, although it overlaps with the above, it can be seen that stearic acid and stearyl fumarate cannot suppress the increase of related substances in the limaprost-containing pharmaceutical composition.

Unlike stearic acid and stearyl sodium fumarate, magnesium stearate and calcium stearate both contain divalent metal ions, so that the divalent metal ions suppress the increase of related substances in the limaprost-containing pharmaceutical composition, that is, It is presumed that it contributes to the stability of the pharmaceutical composition containing limaprost. Therefore, it can be said that the limaprost-containing pharmaceutical composition containing the above-mentioned lymaprost-containing freeze-dried composition and a divalent metal salt additive is a highly stable limaprost-containing pharmaceutical composition. The divalent metal salt additive is an additive (for example, a lubricant) that constitutes a divalent metal salt, and is carmellose calcium, magnesium silicate, zinc stearate, magnesium stearate, calcium stearate, and carbonic acid. Examples thereof include magnesium, precipitated calcium carbonate, calcium sulfate or magnesium sulfate hydrate.

Based on each of the above formulations and the results thereof, the present invention can provide a lymaprost alphadex-containing preparation and a lymaprost-containing lyophilized composition having superior stability to the existing lymaprost alphadex tablets.

Claims (3)

A lymaprost-containing lyophilized composition comprising limaprost alphadex, β-cyclodextrin and dextrin .
A lymaprost-containing lyophilized composition in which the dextrin is 60% by weight to 75% by weight based on the lymaprost-containing lyophilized composition . A lymaprost-containing pharmaceutical composition comprising the lymaprost-containing lyophilized composition according to claim 1 and a divalent metal salt additive. The divalent metal salt additive is selected from at least one of carmellose calcium, magnesium silicate, zinc stearate, magnesium stearate, calcium stearate, magnesium carbonate, precipitated calcium carbonate, calcium sulfate or magnesium sulfate hydrate. The lymaprost-containing pharmaceutical composition according to claim 2 .