JP2006089386A - Suspension medicine composition containing steroid or steroid derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a steroid-containing medicine composition that has high safety, exceedingly excellent absorption of an active ingredient from an applied site and improved stability to light and permeates a medicine to the bottom of eyeball especially in the case of an eye drop. <P>SOLUTION: An aqueous suspension preparation comprises steroid or a steroid derivative as an active ingredient, has 0.005μm-5μm center of its particle diameter distribution and ≤10μm median diameter of the particle diameter distribution. The aqueous suspension preparation is applied, for example, to an eye drop, a nasal drop, an oral agent, a lotion agent, an ointment, or the like. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a stable and suspendable pharmaceutical composition containing a steroid or a steroid derivative as an active ingredient and having a high pharmacological effect.

Since steroids have a strong anti-inflammatory effect and have advantages such as rapid action compared to other non-steroidal drugs, oral preparations such as capsules, tablets, dry syrups, and fine granules, and eye drops Etc. are used in the medical field.
In general, when an orally or dermally administered drug is sparingly soluble, absorption is low and bioavailability decreases. In this respect, steroids are no exception, and steroids and steroid derivatives in the preparations that are actually marketed are drugs that are extremely insoluble in water, and therefore have low absorption from the digestive tract, skin, and eyes. For this reason, in order to maintain the effective blood drug concentration, a large amount of drug is administered, which imposes a burden on the patient and often causes side effects. Therefore, development and research of preparations with improved absorption from the digestive tract, skin and eyes are desired.

  Steroids are poorly water-soluble drugs, and when formulated into oral, topical, eye drops, nose drops, injections, etc., they are formulated as aqueous suspensions in which the drug is suspended. . However, when this aqueous suspension is left for a long time, there is a problem that the dispersed steroid particles are secondarily aggregated and settled, and thus various proposals have been made conventionally.

  For example, when a suspending aid, a polyhydric alcohol, or a saccharide is used in combination with a suspending agent, an eye drop characterized by a slow sedimentation rate of the drug and excellent redispersibility ( JP-A-5-951), a suspension-type eye drop containing a cellulosic polymer and a nonionic surfactant to improve the redispersibility of the active ingredient (JP-A-11-279052), and D as a suspending agent Ophthalmic solution comprising a suspending agent selected from the group consisting of mannitol, D-sorbitol, xylitol, propylene glycol, citrate, and mixtures thereof (JP-A-10-36253), poorly soluble When a water-soluble polymer within the concentration range where the decrease in surface tension stops from the concentration at which the surface tension of the drug begins to decrease is added to the aqueous drug solution, re-dispersion is easy and aggregation of dispersed particles or cake Aqueous suspensions which do not cause grayed (JP 2003-55262) and the like.

The present invention has been made in view of the above-mentioned problems, and the purpose thereof is high in safety, extremely excellent in the absorption of an active ingredient from an application site, has good stability, and particularly for eye drops. It is intended to provide a steroid-containing pharmaceutical composition that can penetrate a drug to the bottom of the eyeball.
JP-A-5-951 JP-A-11-279052 Japanese Patent Laid-Open No. 10-36253 JP 2003-55262 A

It is also known that the sedimentation rate can be slowed by reducing the particle size of the drug, but doing so will also reduce the redispersibility (Junichi Miyazaki and Masahiko Takano, “Eye drops, how to make them” Application ", pp. 111-113, published by Nanzandou, 1962). Thus, the inventors have intensively studied by means of reducing the particle size, and found that there is a certain relationship between the particle size of steroid and the redispersibility.
That is, the center of the particle size distribution of the steroid is in the range of 0.005 μm to 5 μm (preferably 0.005 μm to 2 μm), and the 90% median diameter of the particle size distribution is 10 μm or less. It has been found that it becomes a suspension with good redispersibility that does not cause aggregation and caking. Further, in the region of the particle diameter, the inventors have found that the stability to light is further increased and the absorption from the gastrointestinal tract and the skin, particularly the eyeball, is increased, and the present invention has been basically completed.

  According to the present invention, the safety is high, the absorbability of active ingredients from the digestive tract and skin (including the eyes) is extremely excellent, and the stability is good. A steroid-containing pharmaceutical composition capable of penetrating a drug can be provided. In the present invention, “skin” means “single or multi-layered tissue covering the surface of metazoans” (Ojirin (second edition), Sanseido (1995-11-3)), retina, cornea It is a concept that also includes the cells that make up the isoeye.

Next, the best mode for carrying out the present invention will be described in detail, but the technical scope of the present invention is not limited by the following embodiments or examples, and without changing the gist thereof, Various modifications can be made. Further, the technical scope of the present invention extends to an equivalent range.
The center of the particle size distribution of the steroid or steroid derivative used in the present invention is preferably 0.005 to 5 μm, and the 90% median diameter of the particle size distribution is preferably 10 μm or less. However, the center of the particle size distribution is 0.005 μm to 5 μm, 0.005 μm to 2 μm, 0.005 μm to 0.5 μm, 0.01 μm to 5 μm, 0.01 μm to 2 μm, 0.01 μm to 0.5 μm, It is preferable that the particle size distribution is 0.05 μm to 5 μm, 0.05 μm to 2 μm, 0.05 μm to 0.5 μm, or 0.05 μm to 0.1 μm, and the 90% median diameter of the particle size distribution is 10 μm or less, 8 μm or less, 6 μm Below, it is preferable that it is 4 micrometers or less and 2 micrometers or less. The numerical range relating to the center of the particle size distribution and the 90% median size of the particle size distribution can be set in any combination according to the purpose.
Examples of steroids include, but are not limited to, fluorometholone, dexamethasone, hydrocortisone acetate, prednisolone acetate, beclomethasone propionate, and fluticasone propionate. One or two or more selected from the group consisting of the steroids exemplified above may also be used.

  The particle size distribution of a powder generally indicates a distribution having a certain spread approximated to a normal distribution when the logarithm of the particle diameter is taken on the horizontal axis and the frequency% is taken on the vertical axis. For this reason, even if the center of the particle size distribution is 0.005 μm to 5 μm, the distribution is wide, so that particles of 5 μm or more are included. In the present invention, the 90% median diameter of the steroid particle size distribution is 10 μm or less (in other words, the proportion of particles having a particle size larger than 10 μm is less than 10% with respect to the spread of the particle size distribution. ) Is important. By setting it as such conditions, the steroid fine particle carries out Brownian motion and the sedimentation by secondary aggregation is suppressed. Furthermore, since the contact area to the digestive tract, skin, and mucous membrane can be increased and the cell space can be passed, absorption is enhanced. Furthermore, in the present invention, in addition to improving the stability of steroids to light, it is possible to increase intraocular mobility after instillation.

The increase in absorption and the improvement in light stability are correlated with the size of the particles. When the center of the particle size distribution is 5 μm or more, or when the 90% median diameter exceeds 10 μm, the absorption from the digestive tract and the skin becomes low and the light becomes unstable.
The aqueous suspension in the present invention has an effect of suppressing secondary aggregation only by the energy with which the fine particles undergo Brownian motion because the particle diameter is too small, and further, a surfactant and / or a water-soluble polymer is added, By making the absolute value of the zeta potential of the steroid particles in the range of 20 mV to 150 mV, the redispersibility can be improved. The type of surfactant, the type of water-soluble polymer, and the amount of drug used to adjust the zeta potential vary depending on the pH, but are preferably in the range of 0.05% to 3%.

  Surfactants include quaternary amine surfactants such as benzethonium chloride and benzalkonium chloride, polyoxyethylene higher alcohol ethers, polyoxyethylene sorbitan fatty acid esters, glycerin fatty acid esters, polyoxyethylene hydrogenated castor oil , Polyoxyethylene fatty acid ester, polyoxyethylene nonyl phenyl ether, polyoxyethylene octyl phenyl ether, sorbitan fatty acid ester, propylene glycol fatty acid ester, fatty acid polyethylene glycol, polyglycerin fatty acid ester, sucrose fatty acid ester, etc. And the like.

Examples of the water-soluble polymer include methyl cellulose, ethyl cellulose, propyl methyl cellulose, propyl cellulose, carboxymethyl cellulose, polyvinyl alcohol, and polyvinyl pyrrolidone.
The steroid content in the present invention is not particularly limited. Usually, the concentration is the same as the content of the actually used preparation of 0.01% to 1%, but a higher concentration steroid suspension is prepared and diluted to the use concentration to prepare the preparation. Is also possible.
In addition, excipients, bases, stabilizers, preservatives, pH adjusters, ointment bases, etc. that are widely used in pharmacology are added, oral preparations, eye drops, nasal drops, ointments, lotions It can be used as an agent. For example, the following components can be mentioned.
Examples of excipients include lactose, sucrose, sucrose, starch, and crystalline cellulose.

Examples of isotonic agents include sodium chloride, potassium chloride, calcium chloride, mannitol and the like.
Base ingredients include glycerin, butylene glycol, dipropylene glycol, propylene glycol, ethanol, isopropanol, sorbitol, mannitol, xylitol, glucose, epsilon aminocaproic acid, glycine, glutamate, sodium hyaluronate, glycerin stearate, polyethylene glycols, Alcohols such as carboxyvinyl polymer, polyvinylpyrrolidone, polyvinyl alcohol, cetyl alcohol, isostearyl alcohol, stearyl alcohol, hexyl decanol, octyldodecanol, silicone oils such as methylpolysiloxane, methylphenylpolysiloxane, dodecamethylpolysiloxane, avocado Oil, almond oil, olive oil, cacao butter, beef tallow, sesame oil, wheat germ Oil, safflower oil, turtle oil, cocoon oil, persic oil, castor oil, grape oil, macadamia nut oil, mink oil, yellow egg oil, safflower oil, fats and oils such as owl, coconut oil, rosehip oil, orange luffy oil, jojoba Liquid waxes such as oil, liquid hydrocarbons such as liquid paraffin, liquid petrolatum, squalane, squalene, higher fatty acids such as lauric acid, myristic acid, oleic acid, ethyl linoleate, isopropyl myristate, hexyl laurate, myristic acid Examples thereof include fatty acid esters such as octyl dodecyl, decyl oleate, octyl dodecyl oleate, and hexyl decyl dimethyloctanoate.

Examples of the stabilizer include sodium edetate, sodium sulfite, sodium hydrogen sulfite, sodium thiosulfate, dibutylhydroxytoluene, tocopherol and the like.
Examples of the refreshing agent include menthol, mint oil, camphor, and eucalyptus oil.
Examples of the preservative include paraoxybenzoic acid ester, chlorobutanol, phenylethyl alcohol, base benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, alkylpolyaminoethylglycines, sorbic acid and the like.

Examples of pH adjusters include hydrochloric acid, sulfuric acid, acetic acid, lactic acid, citric acid, tartaric acid, malic acid, lactic acid, phosphoric acid, boric acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, monoethanolamine, diethanolamine, diethylamine, Ammonia and salts thereof can be mentioned.
Ointment base: Vaseline, paraffin, plastic base, silicone, lard, wax, single ointment, single lead plaster, hydrophilic ointment, hydrophilic petrolatum, purified lanolin, aquahole, euselin, neoserin, water-absorbing ointment, hydrous lanolin, hydrophilic plastin base , Macrogols, sol base, gel hydrocarbon, and the like.

In the present invention, the above-mentioned aqueous suspension is dehydrated, and the above-described excipients, bases, stabilizers, preservatives, pH adjusters, ointment bases and the like that are widely used in pharmacology are added, and oral Or an external preparation. If these preparations are dispersed and suspended in water (dry syrups, powders, etc.) or taken simultaneously with water (tablets, capsules, etc.), steroids are suspended in water in the stomach and intestines. It becomes a state. In addition, the preparation of the present invention can be applied to the skin after being suspended in use.
Next, representative examples of the method for producing the preparation of the present invention will be described below, but the technical scope of the present invention is not limited by these examples.

  A steroid having a particle size distribution center of 30 μm to 100 μm can be purchased. By applying this to various pulverizers / dispersers, a steroid having a predetermined particle size can be obtained. Examples of pulverizers include ball mills, vibrating ball mills, centrifugal ball mills, rod mills, micron mills, jet mills, centrifugal fluidized ball mills, hammer mills, pin mills, atomizers, various homogenizers, mixers, ultrasonic waves, high-pressure homogenizers, and ultra-thin film type high-speed rotation. A pulverizer can be exemplified, and one or more of these pulverization and dispersion methods can be used to refine the steroid. Among these, an ultra-thin film type high-speed rotary pulverizer can be preferably used.

As a method for producing this product, when necessary for steroids, water (water whose pH is adjusted with a pH adjuster as necessary) and / or a surfactant and / or a water-soluble polymer are added, The absolute value of the zeta potential of the steroid is set in the range of 20 mV to 150 mV, and then pulverized and dispersed using an ultra-thin film type high-speed rotary pulverizer to obtain a refined product having a desired particle size distribution.
Furthermore, after dehydrating using an evaporator, vacuum dryer or freeze dryer, adding lactose and kneading, it is made into granules or powder. It can also be tableted into tablets.

Next, the present invention will be specifically described with reference to examples.
Steroids purchased commercially. Each component was weighed in accordance with the amount of components in Table 1 below, and preliminarily pulverized and dispersed with a homogenizer (Clearmix 2.2S, manufactured by M Technique Co., Ltd.) at 9000 rpm for 30 minutes. Furthermore, in Examples 1-3, it refined | miniaturized with the ultra-thin film type high speed rotary crusher (SS-5-100 type | mold, the product made from M Technique Co., Ltd.), and was pulverized and dispersed. On the other hand, in Comparative Example 1, neither the homogenizer process nor the high-speed rotary pulverizer process was performed. In Comparative Examples 2 to 4, only the homogenizer process was performed, and the process by the high-speed rotary pulverizer was not performed.

実施例１〜３、又は比較例１〜４に従って得られた各試験液につき、中心粒子径（粒子径分布の中心）、及び９０％メジアン径を測定した。中心粒子径、及び９０％メジアン径は、粒度分布測定装置（ＳＡＬＤ−７０００、島津製作所製）のフローセルを使用して求めた。

About each test liquid obtained according to Examples 1-3 or Comparative Examples 1-4, the center particle diameter (center of particle diameter distribution) and 90% median diameter were measured. The central particle diameter and 90% median diameter were determined using a flow cell of a particle size distribution measuring device (SALD-7000, manufactured by Shimadzu Corporation).

In Examples 1 to 3, the center particle diameter was 0.05 μm to 4.5 μm, and the 90% median diameter was 1.5 μm to 9 μm. On the other hand, in Comparative Example 1 in which neither the homogenizer treatment nor the high-speed rotary pulverizer treatment was performed, the center particle diameter was 50 μm and the 90% median diameter was 120 μm. Further, in Comparative Examples 2 to 4 in which only the homogenizer treatment was performed, the center particle diameter was 5 μm to 6 μm, and the 90% median diameter was 11 μm to 20 μm, which was larger than the range of the present invention.
The following tests related to absorbency were performed on the samples of Examples 1 to 3 and Comparative Examples 1 to 4.

<Skin permeability test>
Human artificial cultured skin (Test Skin Hi, manufactured by Toyobo Co., Ltd.) was fixed to a vertical Franz cell (effective area 0.035 cm ² , reservoir volume 15 mL) so that the dermis layer was on the donor side. The reservoir solution was a 20% polyethylene glycol solution. To the donor side, 1.0 mL of each solution of Examples 1 to 3 and Comparative Examples 1 to 4 was added. The time when the solution was added to the donor side was regarded as zero time, and the reservoir solution was sampled over time. The steroid concentration in the sampling solution was measured by HPLC, and the steroid transferred from the dermis side to the donor side was evaluated.

The results are shown in FIG. As shown in the figure, Comparative Examples 1 to 4 had low steroid skin permeability, and the maximum value (Comparative Example 3) did not exceed 200 μg / mL even after 4 hours. Further, Comparative Example 1 had the lowest skin permeability. In Comparative Example 1, since neither homogenizer treatment nor high-speed rotary pulverizer treatment was performed, the particle diameter was large even compared with Comparative Examples 2 to 4, and thus it was considered that the skin permeability was inferior.
On the other hand, in Examples 1 to 3, the steroid concentration gradually increased from the start of the test, and increased remarkably after 2.5 hours. After 4 hours, all the cases showed a high value of 500 μg / mL or more. showed that.
When Example 1, Comparative Example 1, and Comparative Example 2 were compared, it was found that the skin permeability of the steroid was improved as the particle size was smaller. The same thing was also clarified from the comparison between Example 2 and Comparative Example 3 and the comparison between Example 3 and Comparative Example 4.

<Comparison of absorbability by oral administration>
5 mL (50 mg as a steroid) of each test solution of Example 1, Comparative Example 1, and Comparative Example 2 was administered to Japanese white male rabbits using an intragastric sonde. About 1 mL of blood was collected from the ear vein over time until the start of administration at 0 hours, and the unchanged steroid concentration in plasma was measured by HPLC.
The results are shown in Table 3 and FIG.

比較例１及び比較例２では、Ｃｍａｘ（血漿中ステロイド濃度の最大値）は、約４０μｇ／ｍＬであり、Ｔｍａｘ（最大濃度に達したときの時間）は、３時間〜４時間であった。また、ＡＵＣ（曲線下面積）は、１３４μｇ／ｍＬ・ｈｒ〜１６８μｇ／ｍＬ・ｈｒであった。

In Comparative Example 1 and Comparative Example 2, Cmax (the maximum value of plasma steroid concentration) was about 40 μg / mL, and Tmax (time when the maximum concentration was reached) was 3 to 4 hours. The AUC (area under the curve) was 134 μg / mL · hr to 168 μg / mL · hr.

On the other hand, in Example 1, Cmax was about 90 μg / mL, Tmax was 1.5 hours, and AUC was 281 μg / mL · hr.
From these results, compared with Comparative Example 1 and Comparative Example 2, Example 1 shows that Cmax and AUC are about twice as high, so that the absorption rate from the gastrointestinal tract is improved. . Moreover, in Example 1, it was shown that Tmax was shortened to the short time and the absorption rate became high.

<Light stability test>
10 mL of each of the test solutions of Examples 1 to 3 and Comparative Examples 1 to 4 were placed in a glass transparent vial and irradiated with light from a 2000 Lux · hr light source using a light irradiation tester. The test solution in each vial was sampled over time, the steroid concentration was measured by HPLC, and the residual ratio (%) of steroid was evaluated.
The results are shown in FIG. As is apparent from the figure, in Comparative Example 1, steroid degradation was rapidly observed after the start of the test, and the residual rate was lower than 40% on the 25th day. In Comparative Examples 2 to 4, steroid decomposition was observed after the start of the test, and the residual rate on the 25th day (1.2 × 10 ⁶ Lux · Hr) was about 60% in Comparative Example 2 and Comparative Example 4. In Comparative Example 3, it was about 65%. From these results, in Comparative Examples 1 to 4, steroids were significantly degradable with respect to light.

On the other hand, in Examples 1 to 3, the stability of steroids was extremely high, and the remaining rate on the 25th day from the start of the test was a high value of 95% or more.
When Example 1, Comparative Example 1, and Comparative Example 2 were compared, it was found that the smaller the particle size, the greater the stability to light. The same thing was also clarified from the comparison between Example 2 and Comparative Example 3 and the comparison between Example 3 and Comparative Example 4. Thus, it has been shown that the steroid suspension has high light stability when the central particle diameter is 5 μm or less and the 90% median diameter is 10 μm or less.

<Intraocular transfer test>
Japanese white male rabbits were instilled once with 0.5 mL of the test solution of Example 1 or Comparative Example 1 (5 mg as steroid), and the eyeballs were removed after 4 hours. The removed eyeball was cut for each tissue of the cornea, conjunctiva, lens, sclera, and retina. After each tissue was accurately weighed, the concentration of steroid present in each tissue was measured using HPLC.

The results are shown in FIG. Compared to Comparative Example 1, it was found that in Example 1, the steroid concentration was high in all tissues of the cornea, conjunctiva, lens, sclera, and retina. In particular, in the sclera and retina located in the fundus, the steroid concentration ratio (Example 1 / Comparative Example 1) was high. In Example 1, it was considered that the fine steroid suspension entered the gap between the orbit and the eyeball, and the drug was transferred to the retina through the sclera.
From these results, it was found that the product of this example was a steroid preparation having high intraocular transferability.

  From the above test results, the product of the present invention is highly safe, has excellent absorption of the active ingredient from the digestive tract and skin (including the eyes), has good light stability, especially for eye drops. It was revealed that the pharmaceutical composition is a steroid-containing pharmaceutical composition that can penetrate the drug to the bottom of the eyeball.

It is a graph which shows a result when performing a skin permeation test using the steroid formulation of Examples 1-3 and Comparative Examples 1-4. 2 is a graph showing changes in fluorometholone plasma concentration over time when the steroid preparations of Example 1, Comparative Example 1 and Comparative Example 2 were orally administered to rabbits. It is a graph which shows the daily steroid residual rate change when the steroid formulation of Examples 1-3 and Comparative Examples 1-4 is applied to a light irradiation tester. It is a graph which shows a result when an intraocular transferability test is done using the steroid preparation of Example 1 and Comparative Example 1.

Claims (9)

An aqueous suspension comprising a steroid or a steroid derivative as an active ingredient, the center of the particle size distribution being 0.005 μm to 5 μm, and the 90% median diameter of the particle size distribution being 10 μm or less. The aqueous suspension according to claim 1, wherein the center of the particle size distribution is from 0.005 µm to 2 µm. The steroid is one or more selected from the group consisting of fluorometholone, dexamethasone, hydrocortisone acetate, prednisolone acetate, beclomethasone propionate, and fluticasone propionate, according to claim 1 or 2. An aqueous suspension. The aqueous suspension according to any one of claims 1 to 3, which is an eye drop. The aqueous suspension according to any one of claims 1 to 3, which is a nasal drop. The aqueous suspension according to any one of claims 1 to 3, which is an oral preparation. It is a lotion agent, The aqueous suspension agent in any one of Claims 1-3. The aqueous suspension according to any one of claims 1 to 3, which is an ointment. A pharmaceutical composition comprising the dehydrated aqueous suspension according to any one of claims 1 to 3 and a pharmaceutically acceptable ingredient.

Images