JPS6339814A - Slowly releasing tranilast preparation and long-acting tranilast preparation containing same - Google Patents

Abstract

PURPOSE:To provide a long-acting drug preparation for oral administration, composed of a slowly releasing component containing toranylast treated with an enteric substance as an active component and a quickly releasing tranilast component, capable of maintaining high drug concentration in blood for a long period and expected to exhibit sufficient clinical effect. CONSTITUTION:A slowly releasing tranilast preparation is prepared by coating (A) tranilast [N-(3,4-dimethoxycinnamoyl)anthranylic acid] known as a remedy for allergic diseases with (B) an enteric substance (a substance soluble at a critical pH of >=5.0, preferably >=5.5) such as cellulose acetate phthalate, methacrylic acid/methyl methacrylate copolymer, etc., by spraying, centrifugal flow coating, etc. The slowly releasing component is compounded with a quickly releasing component containing tranilast free from treatment with the enteric substance at a ratio to give a tranilast content ratio in both components of 2:8-8:2 by weight to obtain the objective long-acting preparation.

Description

Detailed Description of the Invention [Field of Industrial Application] The present invention relates to a slow-soluble spreading agent for tranilast, which is a therapeutic agent for allergic diseases, and a long-lasting oral drug for tranilast containing the same as one of its components. Regarding formulations.

[Conventional technology]

Tranilast, whose chemical name is N-(3,4-dimethoxycinnamoyl)anthodinilate, is a therapeutic agent for allergic diseases. Its mechanism of action is different from that of conventional symptomatic treatment agents, as it inhibits the release of chemical mediators, making it a drug that is close to treating the cause of the disease. It is used in the form of tablets or capsules and has received high praise. Unlike conventional sodium cromoglycate (trade name: Intal), tranilast fine granules or tranilast capsules can be administered as an oral preparation because they are absorbed from the gastrointestinal tract, and are useful for I to moderate allergic diseases. , it is possible to continue taking medication for a long period of time while continuing daily life without being hospitalized.

In addition, as one of the conventional technologies for long-acting preparations, there are two types of preparations: fast-dissolving preparations that rapidly disintegrate in the stomach and are absorbed there, and enteric-coated preparations in which an appropriate amount of an enteric coating is applied to the fast-dissolving preparation. , so-called multiple-u mixed in a specific ratio
nlts dosage? Long-acting preparations for A, such as antibiotics and analgesics, have been developed and put into practical use. However, - numerically speaking, this multiple of drugs -
When making a long-lasting preparation by the units dosage method, it is impossible to even design the desired preparation unless the underlying factors are clarified. Various factors include the specificity of the absorption site in the gastrointestinal tract of the drug side;

Factors that affect drug solubility (e.g., influence of pH in digestive juices, presence or absence of crystallization water, type of salt, drug particle size, form of M agent, etc.), drug biological half-life, and coating with enteric substances When making a drug slow-acting, there are physical and chemical factors of the glaze, such as the lack of migration of the drug into the coating film, and these are characteristics of each drug. Among these, the site of drug absorption in the gastrointestinal tract is particularly important.

Regarding the tranilast related to the present invention, it has been found that it essentially does not dissolve in the 11th (l (1, 2)) defined by the Japanese Pharmacopoeia. Research on the absorption site (Nakazawa et al., Basic and Clinical 13 (11, 25-33, 1979) has revealed that there is almost no patina absorption and that it is well absorbed only from the duodenum.These straw bundles Therefore, it has been assumed that tranilast fine particles also exhibit Sono-like absorption behavior.

Therefore, the above-mentioned slow-dissolving component coated with enteric-coated substances is considered to have little meaning in the case of tranillas, and even more so when combining a fast-dissolving component that quickly disintegrates in blue with an enteric-coated slow-dissolving component. multiple-units-dos
It has been assumed that age-type preparations are meaningless since they are not absorbed through the bloodstream.

[Problem that the invention seeks to solve]

When tranilast fine granules or tranilast capsules are administered to humans after meals, their blood concentration reaches the maximum blood concentration (Cmax) approximately 2 to 4 I# after administration, and is then rapidly excreted from the body after a short Kfi. The half-life of the blood concentration is approximately 5 hours, and it is thought that the effect virtually disappears within this time period. On the other hand, among the diseases targeted by this drug, in allergic diseases such as bronchial asthma, the so-called morning dipping phenomenon, in which attacks occur frequently in the early morning, is viewed as a problem.

Even if this drug is administered before bedtime, its duration is insufficient considering the half-life of the drug concentration in the blood.

In other words, even if this drug is used prophylactically, in order to prevent morning dipping, at least all blood
It is required that ll- remain open for 10 hours at a high level.

Furthermore, from another perspective, in the case of formulations that require medication to be taken three times a day, such as the current tranilast fine granules or tranilast capsules, people often forget to take the medication, especially during the daytime, and it is difficult to take the medication as directed by the doctor. Statistical studies show that F! is not complied with. A: It is certainly true that a drug formulation that requires fewer doses is desired from the perspective of improving compliance.

From the above viewpoint, the present inventors have arrived at the present invention as a result of intensive research in order to develop a formulation that can maintain blood concentration at a high level for a long period of time and can be expected to have sufficient clinical effects. did.

[Means for solving problems]

The present invention provides a slow-dissolving formulation of tranilast whose active ingredient is tranilast treated with an enteric-coated substance, a slow-f6 formulation of tranilast whose active ingredient is tranilast treated with an Fj1-soluble substance, and a slow-dissolving formulation of tranilast whose active ingredient is tranilast treated with an Fj1-soluble substance; This is a long-acting preparation of tranilast, which contains tranilast as an active ingredient and a quickly dissolving component of tranilast.

The enteric substance in the present invention has a critical pH value of 5.0 or more,
Preferably, it is a substance that dissolves at a temperature of 5.5 or higher, specifically cellulose acetate 7 talate, cellulose succinate phthalate, etc. Examples include methyl hydroxycellulose phthalate, hydroxypropyl methylcellulose phthalate, and methacrylic acid/methyl methacrylate copolymer 60, which may be used in conjunction with a suitable plasticizer 2 dispersion separating agent. In particular, methacrylic acid/methyl methacrylate copolymer 60, which has a low transferability to the film of tranilast, is a particularly preferred material. The critical pH value mentioned here is defined as follows. In accordance with the method prescribed in the Japanese Pharmacopoeia General Test Methods and Disintegration Test Methods, a certain amount of each preparation was placed directly into 6 glass tubes or into an auxiliary tube, and then placed into 6 glass tubes. The disintegration test is carried out by keeping the liquid temperature at 37°C and changing the pH of the disintegration liquid. Measure the time (disintegration time) in which all the preparations disintegrate and disappear from the glass tube or auxiliary tube by vertical movement. By plotting the relationship between disintegration time and pH on a graph, the pH value at which disintegration occurs can be determined.

This pH value is defined as the critical pH value.

When such an enteric substance is coated on the fast-dissolving component of tranilast described below by a known method such as a conventional spray method or a centrifugal fluid coating method, the slow-dissolving preparation or component of tranilast of the present invention can be obtained. .

The long-acting preparation of tranilast in the present invention is composed of a fast-dissolving component and a slow-dissolving component, and is highly concentrated in the blood! ! , means a long-lasting formulation.

The fast-dissolving ingredient in the present invention refers to a normal ingredient or preparation that has not been subjected to special sustaining treatment or enteric treatment,
Powders and fine granules according to conventional methods.

It may be formulated into granules, pills, 9 tablets, etc.

Types of excipients and disintegrants are regular powders and S granules.

Those used in manufacturing preparations such as tablets may be used, and additives such as sugars, starches, celluloses, etc. may be used.

Examples of sugars include white sugar, lactose, grape MI, sorbitol, etc.; examples of starches include corn, starch, wheat codestarch, potato starch, and hydroxyglobil starch; and examples of celluloses include crystalline cellulose, carboxymethyl cellulose, and sodium carboxymethyl cellulose. , carboxymethylcellulose calcium, hydroxypropylmethylcellulose and the like.

However, considering disintegration, rapid dissolution, and stability over time, white sugar and corn starch are preferred.

1 selected from carboxymethyl cellulose calcium
Preferably, 81 or higher is used. Furthermore, it is possible to formulate a formulation by adding an appropriate binder, dissolution promoter, etc. according to a conventional method, but please be careful as the dissolution characteristics will vary greatly depending on the Tffi of the binder, the amount used, the method of use, etc. is necessary. Examples of the binder that can be used include methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, noripur starch, gelatin, and oleic starch.

In the sustained-release preparation of the present invention, the slowly soluble components are not limited to those of class -a, but it is also possible to use two or more components having different critical elution pHs. The blending ratio of the slow-soluble component and the fast-soluble component is the IT ratio of 11 tranilast contained in the former to 2 tranilast contained in the latter.
The ratio is preferably in the range of 28 to 8:2, more preferably 7:3 to 3.

As a long-acting formulation. Mixed powder, mixed (composite)
Fine granules, mixed (composite) granules, etc. are preferred, and these may further be made into capsules.

Alternatively, for example, it may be a single preparation composed of slow-dissolving granules coated with fast-dissolving powder. It was thought that there was almost no absorption and that it was absorbed mainly in the duodenum.

The duodenum is an intestinal tract with a length of approximately 25 mm, and orally administered food, drugs, etc. are dissolved in an extremely short period of time, and enteric-coated substances are rapidly dissolved from this area to the small intestine, and the drugs inside are released into the blood. It will be absorbed into.

When considering these matters, cephalexin (
antibiotics) multiple-units dosag
Formulations manufactured using enteric-coated substances, which are often used in e-type long-acting formulations, have lower bioavailability (blood concentration, Calculate the integral value of the area under the time curve, area and
er curve (indicated by the abbreviation AUC), and the time lag in concentration in the blood (meaning slow solubility, ie slow effect) was thought to be unpredictable.

However, the present inventors produced granules of a slowly dissolving component coated with an enteric coating material and a fast dissolving component that is easily disintegrated by gastric juice, so that the dosage of both as tranilast would be exactly the same. When administered to humans on an empty stomach,
When we measured its blood concentration, we surprisingly found that the AUC of the slow-dissolving granules of the present invention was equivalent to that of the fast-dissolving granules, and that the time to reach the maximum blood concentration (T m
ax) found that the fast-dissolving granules also had a 3-hour delay.

As mentioned in the prior art section, it has been reported that several drugs have been made into long-lasting formulations using the same technology, but in the case of pH-dependent slow-dissolving formulations, compared to fast-dissolving ingredients, It has been found that, in some cases, a significant decrease in bioavailability is often observed, and even if this decrease is avoided, the Cmax is considerably decreased15.

Regarding the fit of uncoupling (delayed effect), the inventors' experiments showed that
Despite being administered on an empty stomach, which has the quickest transit time in the gastrointestinal tract, the fact that it was possible to achieve a significant reduction in drug delivery (delayed effect) as described above is beyond our expectations. It has become possible to obtain excellent long-lasting preparations when the slow-soluble components are blended in an appropriate ratio.

Hereinafter, the present invention will be explained in detail with reference to Examples and Examples.

Reference example 1 A fast-dissolving preparation with the following composition was prepared by the following method.

A mixture of 24.9 parts (by weight, the same applies hereinafter) of a ball nucleating agent consisting of 100 parts white sugar and corn starch, 5 parts of tranilast and 3 & 4 parts of corn starch, 90 (pvp -90) While spraying Inglobil alcohol (IPA) solution, centrifugal fluid coating method (rotor rotation speed 2 180 rpm, slit air flow rate: 150t/-~40017m, product temperature: 10
℃, granulated with spray liquid 1115-20d/m), 50
Thoroughly dried in a hot air dryer at °C. The granules were again put into the centrifugal fluid coating granulator [(70 Indian Industries) button, and granulated while spraying an aqueous solution of pulverized white sugar 3α3mt-5% hydroxyglobil cellulose (RPC-L) (rotor rotation speed 180 rpm). , slit air flow rate: 15017 m, product temperature: 10°C, spray liquid amount: 5 txl/m) L, and dried again at 50°C.

After drying, the granules were classified, and spherical particles that passed through a 12-mesh screen and did not pass through a 24-mesh screen were used as a fast-dissolving preparation.

Reference example 2 A fast-dissolving preparation with the following composition was prepared by the method described below.

(F'"211 3411 spherical core consisting of 5 parts white sugar and corn starch
36.1 parts of a mixture consisting of 5 parts of tranilast and 1 part of corn corn and 58 parts of 1 part of corn was added to 90 parts of I
While spraying the PA solution, they were laminated and granulated using a centrifugal fluid coating granulator in the same manner as in Reference Example 1, and thoroughly dried in a hot air dryer at 50°C. After drying, the granules were classified and passed through a 12-mesh screen.
The prototype particles that did not pass through the Sosch screen were made into a fast-dissolving formulation.

Example 1 A coating solution containing an enteric substance and having the following composition was prepared as v3.

47 parts of IPA 100 parts of the fast-dissolving formulation obtained in Reference Example 2 were placed in a centrifugal fluid coating granulator, and while the granules were uniformly rolled by hot air and centrifugal force, the above coating liquid was sprayed at a constant rate. Spray, coat (rotor: 120 rpm)
.

Slit air i: 400 t/wa, slit air temperature near 0°C, spray liquid amount: l 5 d/
m.

Product temperature: 40 to 60°C). Coating liquid 2
After spraying 70 parts, the resulting preparation was thoroughly dried in warm air to remove the solvent.

Furthermore, the granules were classified, and particles that passed through a 12-mesh screen and did not pass through a 24-mesh screen were used as slow-dissolving preparations.

The obtained granules were placed in 6 auxiliary cylinders of a disintegration tester at 0.00% each.
Twelve samples were collected.

Separately, four types of phosphate buffers with pH values of &5, 6.0, 6.5, and 7.0 were prepared and the disintegration time of the granules was measured using a conventional method. As a result, the time it took for all the granules to disintegrate and fall from the auxiliary cylinder was approximately 5 minutes for pH 6, 5, 7, and 0, and approximately 20 minutes for pl (ao);
In the case of 5.5, it did not disintegrate even after 60 minutes or more.

Example 2 A coating liquid containing an enteric material was prepared by replacing Eudragit L-100 with Eudragit S-100 among the ingredients shown in Example IK.

100 parts of the fast-dissolving preparation obtained in Reference Example 1 were placed in a centrifugal R and dynamic co-coating granulator, and 330 parts of the present coating liquid was sprayed into the granulator. Similarly, the solvent was removed by thoroughly drying with Km air. The obtained granules were classified, and particles that passed through a 12-mesh screen and did not pass through a 24-mesh screen were used as slow-dissolving preparations.

When the disintegration time was measured using the same method as in Example 1 and the critical pH value was determined, it was found to be approximately 7.

Example 3 The drug dissolution behavior of the slow-dissolving granules obtained in Example 1.2 was measured according to the dissolution test method specified in the Japanese Pharmacopoeia. All elution solutions were based on phosphate buffer. In both granules, tranilast began to be rapidly eluted several minutes after the start of the test, and almost 100% of tranilast was eluted in about 10 minutes.

Both granules were separately packaged into approximately 12 portions each by heat-sealing the polyethylene laminate/aluminum film metatarsal. These packaged products were placed in a constant temperature and humidity chamber at 40℃ and 75℃RH% for 6 minutes.
After storing for several months and performing a waiting test, a similar dissolution test was performed.

The time ('rs>) for half of the contained tranilast to elute (-J) was read from the elution curve and summarized in Table 1.

Table 1 The dissolution behavior of all granules was sufficiently fast and long-term A.
It does not change in any way even under standby conditions.

It was found that tranilast existed stably in the granules, and there was no migration of the contents or deterioration of the coating due to chemical reactions.

Example 4 Using the fast-dissolving formulation obtained in Reference Example 2 and the slow-dissolving formulation obtained in Example 1, a fast-dissolving formulation and a slow-fi formulation equivalent to 150 Misaki were prepared as tranilast. The drug was orally administered to four volunteers (each on an empty stomach) on an empty stomach, and the blood temperature of 0°C was measured over time. The results are shown in Figure 1.

Based on actual measurements, T maχ, Cma, x of each formulation
.

A U Co” work (AUC from 0 hours to infinite time)
The half-life was determined and shown in Table 2.

Tmax and Cmaxfi of fast-dissolving formulation, each processing time, 3α
1 μf? /d, 4 hours each for slow-dissolving formulations,
29.2μ? /ml, T for fast-dissolving and slow-dissolving formulations
The max difference was 3 hours. However, the slow-dissolving preparation of the present invention exhibits its drug efficacy with a delay of about 3 hours. On the other hand, the elimination half-life α phase is 19 hours for the former and 4.0 hours for the latter.
The disappearance half-life 1υjβ phase showed extremely similar values of a4 hours and 6.5 hours, respectively. Also, both A U Co-0
5 were almost the same. That is, it can be seen that the bioavailability of tranilast does not change at all even if it is made to be slowly soluble.

From the results shown in Table 2, it can be seen that the formulation containing the rapidly dissolving component of tranilast is an excellent long-lasting formulation.

〔Effect of the invention〕

Based on the 7 almacokinetic parameters (Table 2) of the fast-dissolving formulation and the slow-dissolving formulation determined from the measured values of serum concentration in Example 4, the serum concentration of the mixed explosive was calculated.
A fast-dissolving preparation containing an amount equivalent to 100 Ilv of tranilast that exhibits the same serum concentration and pharmacokinetics as the regular preparation when this mixed preparation containing an amount equivalent to 150q tranilast is administered once in the morning and once in the evening (12 hours apart) 3 times a day (
The blood dynamics of both drugs were compared, and the results are shown in Figure 2. The following was inferred from Figure 2.

(1) The serum concentration of the long-acting preparation of the present invention when administered annually was clearly more sustained than that of the conventional preparation when administered annually.

(2) 10 μP/-(
In the former case, the duration of the serum concentration is 1'lJl, which corresponds to the amount that suppresses approximately 70% of the released histamine when adding white blood cell blood collected from atopic tracheal asthma patients to house dust. The latter was equal to or higher than rEj.

It is thought that the long-acting preparation of the present invention maintains a serum concentration suggesting clinical efficacy for a long period of time, and is less likely to cause a decrease in compliance. Considering the above--the usefulness of layers is expected.

[Brief explanation of the drawing]

The first element shows the time course of the serum concentration of tranilast when a fast-dissolving formulation and a slow-dissolving formulation are administered to humans. FIG. 2 is a diagram showing the time course (simulation) of the serum concentration of a long-acting formulation and a regular formulation of tranilast. Figure 1

Claims (5)

[Claims] (1) A slow-dissolving preparation of tranilast whose active ingredient is tranilast treated with an enteric substance. (2) A long-acting preparation of tranilast consisting of a slow-dissolving component of tranilast whose active ingredient is tranilast treated with an enteric substance and a fast-dissolving component of tranilast whose active ingredient is tranilast not treated with an enteric substance. (3) The long-acting preparation of tranilast according to claim 2, wherein the content ratio of tranilast in the slow-dissolving component to tranilast in the fast-dissolving component is 2:8 to 8:2 (weight ratio). (4) The long-acting preparation of tranilast according to claim 2 or 3, wherein the long-acting preparation is a composite granule of slow-dissolving granules and fast-dissolving granules. (5) The long-acting preparation of tranilast according to claim 2 or 3, which is constructed by coating a slow-dissolving component with a fast-dissolving component.