JPH0789849A - Sustained release preparation - Google Patents

Abstract

PURPOSE:To obtain a sustained release preparation capable of controlling a bursting time of a film and retaining pharmacodynamic effects for a long time by adding a sufficient amount of a swelling agent and a water-insoluble coating substance to FK739 substance. CONSTITUTION:This preparation contains FK739 substance having a pharmacological activity such as angiotensin II antagonism as a main medicine or its salt, a swelling agent (e.g. hydroxypropylcellulose having low substitution degree) and a water-insoluble coating substance (e.g. ethyl cellulose). This swelling agent is included in an amount enough to burst a film by the swelling agent swollen by water content after the lapse of a prescribed time, normally in an amount of 10-80% based on the preparation. Since elution of FK737 substance is controlled by bursting of the film, the elution rate and elution pattern of the FK737 substance are not influenced on solubility and elution rate of the FK739 substance itself, unlike conventional diffusion control or elution control. The elution rate and pattern of the FK739 substance do not depend on pH change of digestive juice. Further, this preparation is a sustained release preparation capable of completely eluting the FK739 substance from the preparation.

Description

Detailed Description of the Invention

[0001]

This invention relates to angiotensin II.
The present invention relates to a sustained-release preparation using an FK739 substance or a salt thereof having a pharmacological activity such as an antagonistic action, and more specifically, to controlling the rupture time of a membrane coating the preparation to obtain a FK739 substance or a salt thereof. A delay time (hereinafter referred to as lag time) is generated in the elution, and then F
Solubility of K739 substance or its salt itself and pH of digestive juice
The present invention relates to a sustained-release preparation capable of eluting the FK739 substance or a salt thereof without depending on the drug, which is a sustained-release preparation capable of sustaining a long-term drug effect, which prevents the occurrence of side effects and reduces the number of doses taken by patients. It is used in the field of medicine for the purpose of

[0002]

2. Description of the Related Art Matrix tablets prepared by mixing a drug with waxes or a water-insoluble polymer compound for the purpose of sustaining the drug, and microcapsules in which particles containing the drug are coated with a water-insoluble coating material. Alternatively, preparations in which enteric-coated particles that are dissolved by the intestinal fluid and gastric-soluble particles that dissolve in the stomach are mixed at an appropriate ratio have been widely studied, and some of them have been put into practical use.

[0003]

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention In the above-mentioned matrix tablet or microcapsule, the FK739 substance or its salt is continuously dissolved, but the dissolution rate decreases with the passage of time, and as a result, the FK739 substance or its salt is dissolved. Is not completely eluted, and in the case of the FK739 substance or its salt whose solubility depends on pH, the p
There has been a problem that the change in H affects the elution of the FK739 substance or its salt. In addition, the preparation in which enteric particles and gastric particles are mixed has a problem that it is easily affected by the pH of gastric juice, the time of excretion from the stomach, etc., and a sufficient sustaining effect cannot be obtained.

[0004]

The inventors of the present invention have earnestly studied for the purpose of overcoming the above-mentioned problems, and as a result, FK
By adding a water-insoluble coating substance to a preparation produced by adding a sufficient amount of a swelling agent to 739 substance or a salt thereof,
Alternatively, the above-mentioned problems could be solved by applying a water-insoluble coating substance to a preparation produced by adding a water-soluble polymer to the FK739 substance or a salt thereof. The sustained-release preparation using the FK739 substance or a salt thereof as the active ingredient of the present invention is such that, when administered to a living body, the swelling agent in the preparation is swelled by water that permeates through the film made of the water-insoluble coating substance. The FK739 substance or its salt elutes only when the film is broken by its expansive force (that is, a lag time occurs in the elution of the FK739 substance or its salt).

Therefore, since the elution of the FK739 substance or its salt is controlled by the rupture of the membrane, (i) FK7 is completely different from the diffusion control and the elution control as in conventional preparations.
The dissolution rate and pattern of 39 substances or their salts are FK
(Ii) the dissolution rate and pattern of the FK739 substance or its salt do not depend on the change in pH of the digestive juice,
i) It has excellent characteristics such as complete elution from the FK739 substance or its salt or preparation.

[0006] Further, the present inventors have conducted further detailed studies and found that when the dosage form is spherical particles or granules, the amount (concentration) of the water-insoluble coating substance, swelling of each spherical particle or granule Fluctuations in the amount of the agent or the amount of water-soluble polymer cause fluctuations in the lag time among the individual spherical particles or granules.
The dissolution of the K739 substance or its salt occurs according to the 0th-order pattern, or when the dosage form is a tablet, the dissolution of the FK739 substance or its salt occurs promptly after a lag time of a certain time, and swelling in the preparation It was found that the lag time of these formulations can be freely controlled by changing the type and amount of the agent or water-soluble polymer, the type and amount (concentration) of the water-insoluble coating substance, and the size of the formulation. completed.

In the sustained-release preparation of the present invention, when the dosage form is spherical particles or granules, various FK particles can be mixed by appropriately mixing various spherical particles or granules having different lag times.
739 substance or its salt elution pattern, ie, repeat pattern (elution of FK739 substance or its salt occurs repeatedly after a certain time), 0th-order pattern (elution rate of FK739 substance or its salt is constant), reverse primary pattern (FK739 substance Alternatively, the dissolution rate of the salt increases with time) and the sigmoid pattern (F
The elution rate of the K739 substance or a salt thereof is small in the early and late stages of elution and large in the middle period. ) Etc. can be obtained.

When the dosage form is a tablet, the above repeat pattern can be obtained by combining it with a drug product which is rapidly eluted.

Examples of the dosage form of the sustained-release tablet of the present invention include the above-mentioned spherical particles, granules, tablets and the like.

The chemical name of the FK739 substance which is the main drug of the present invention is 2-butyl-3-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] -3.
H-imidazo [4,5-b] pyridine. The FK739 substance which is the main drug of this invention may be a hydrate,
Examples of the salt include alkali metal salts such as sodium salt and potassium salt. Preferable FK739 substance which is the main drug of the present invention is trihydrate of sodium salt of FK739 substance.

Suitable water-soluble polymers used in this preparation are, for example, hydroxypropylmethyl cellulose, polyethylene glycol derivatives (polyethylene glycol 6000, polyethylene glycol 1500).
Etc.) and the like, and preferably hydroxypropylmethyl cellulose and the like.

If desired, the sustained-release preparation of the present invention may further contain a general-purpose additive such as a solubilizer which is usually used in the process of formulation.

Suitable solubilizers include, for example, magnesium hydroxide, calcium carbonate, sodium hydrogen carbonate, arginine, etc., but are not limited to these, and those commonly used in the art can be used. Can be used.

The production method of one embodiment of the sustained-release preparation of the present invention in which the dosage form is spherical particles or granules will be described below.

First, spheres or granules coated or containing the FK739 substance or a salt thereof are produced by a conventional method.

For example, non-pareil granules (spherical granules of sucrose: trademark, manufactured by Freund Sangyo Co., Ltd.) are placed in a centrifugal granulator and rotated, or placed in a fluidized bed granulator and the granules are aerated with air. Blow up and roll.

A suitable solvent (eg water,
The FK739 substance or a salt thereof is coated on the particles while spraying a binder (water-soluble polymer) (for example, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, sodium alginate, etc.) dissolved in ethanol or the like.

As another method, granules containing the FK739 substance or a salt thereof, an excipient (for example, sucrose, lactose, mannitol, microcrystalline cellulose sugar) and additives usually used in this field are prepared by a conventional method. Manufacturing methods are also used.

Then, the spherical particles or granules coated or containing the FK739 substance or salt thereof produced as described above are coated with a swelling agent by the same method as described above. Examples of the swelling agent used here include disintegrating agents [for example, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose calcium, Ac-Di-Sol (ac-di-sol,
Sodium carboxymethyl cellulose: Trademark, manufactured by FM Co., Ltd.), Explotab (Explotab, sodium starch glycolate: trademark, manufactured by Edward Mendel Co., Ltd., starch, agar, etc.), synthetic polymer (for example, polyvinyl acetate, polyacrylic acid, acrylate) Copolymers, polyethylene glycol, etc.), inorganic salts (eg magnesium chloride, calcium sulfate etc.), organic salts (eg sodium carbonate, calcium bicarbonate etc.),
Examples thereof include sugars (for example, d-mannitol, sucrose, glucose and the like), tartaric acid, albumin, urea and the like. Here, the low-substituted hydroxypropyl cellulose is a cellulose substituted with hydroxypropyl having a hydroxypropoxy group weight ratio of 5 to 16%. A foaming agent (for example, a mixture of sodium bicarbonate and tartaric acid) may be used instead of the swelling agent.

In the sustained-release preparation of the present invention, the layers of the FK739 substance or its salt and the swelling agent to be coated are not limited to one layer. That is, if necessary, several layers of the FK739 substance or its salt and the swelling agent may be coated on each other according to the above method in order to obtain the elution pattern of various FK739 substances or their salts.

The amount of the FK739 substance or its salt in the spherical particles or granules thus produced is preferably 0.1 to 50% by weight, but it is not necessarily limited to this and the amount of the FK739 substance or its salt is not limited thereto. It can vary depending on the dose.

The swelling agent needs to be contained in an amount sufficient to cause the membrane to rupture after swelling with water for a predetermined time, and the content of the swelling agent in the preparation is usually 10 to 10. Although it is 80%, this value is appropriately determined depending on the type of swelling agent, the material and amount of the film used, the set time of the lag time, and the like.

A method for producing another embodiment of the sustained-release preparation of the present invention in which the dosage form is spherical particles or granules will be described below. First, a mixture of the FK739 substance or its salt and a swelling agent is coated with the non-barreled grains as the core by the same method as described above.

As another method, a method of producing granules containing the FK739 substance or a salt thereof, a swelling agent, the above-mentioned excipients and additives, etc. by a conventional method is also used.

The preferred amounts of the FK739 substance or its salt and the swelling agent in the spherical particles or granules thus produced are as described above.

The method for producing the sustained-release preparation of the present invention in the form of tablets will be described below. First, the FK739 substance or a salt thereof, a swelling agent, the above-mentioned excipient and a lubricant (eg, magnesium stearate) are mixed, and tablets are produced by a conventional method. The amount of the FK739 substance or its salt and the swelling agent in the tablet is preferably 0.1 to 30% by weight, respectively.
And 10 to 60% by weight, but not necessarily limited to this amount.

Finally, water-insoluble coating substances and additives (eg talc, polyethylene glycol, silicone, diethyl sebacate, dioxide) are formed on the surface of each preparation (spherical particles, granules and tablets) produced by each of the above-mentioned production methods. Titanium or the like) is coated by a conventional method to form a water-insoluble film.

That is, for example, the above-mentioned preparation was placed in a fluidized bed granulator, and while being blown up by air and rolling, a water-insoluble coating substance dissolved in a suitable solvent (ethanol, dichloromethane, etc.) and dissolved or suspended. It is produced by coating additives.

Examples of water-insoluble coating substances include ethyl cellulose, hydroxypropyl cellulose, shellac, polymethylstyrene, polyvinyl acetate, polydiethylaminomethylstyrene, dimethylaminoethylmethacrylate-methylmethacrylate copolymer [eg Eudragit E-30D, Eudragit R
L and Eudragit RS (trademark: manufactured by Rohm Pharma Co., Ltd.), wax, and the like, and ethyl cellulose is most preferable among them.

The amount of the water-insoluble coating substance with respect to the above-mentioned preparation is preferably 1 to 50% by weight, but is not necessarily limited to this amount and can be changed according to the required lag time.

The preferred size of the sustained release preparation of the present invention thus produced has a diameter of 0.5 to 20 mm.

In the case of a membrane-controlled sustained-release preparation, it can be prepared without using the above-mentioned swelling agent. In the case of a membrane-controlled sustained release preparation, the compounding ratio of the FK739 substance and the water-soluble polymer compound is appropriately selected depending on the release time of the main drug.

[0033]

[Effects of the Invention] Typical test results are shown below to show the effects of the present invention. Dissolution test Test formulation A: Formulation obtained in Example 1 below (membrane-controlled formulation 1) Test formulation B: Formulation obtained in Example 2 below (membrane-controlled formulation 2) Test formulation C: Example 3 below Preparation (TES preparation 1) (Amount of ethyl cellulose (concentration) 5.8% by weight) Test preparation D: Preparation obtained in Example 3 (TES preparation 2) (Amount of ethyl cellulose (concentration) 11.7% by weight) %) Test preparation E: Preparation obtained in Example 4 described later (TES preparation 3) (Amount of ethyl cellulose (concentration) 7.0% by weight) Test preparation F: Preparation obtained in Example 4 described later (TES preparation 4) (Amount of ethyl cellulose (concentration) 9.5% by weight) Test preparation G: Preparation obtained in Example 4 (TES preparation 5) (Amount of ethyl cellulose (concentration) 13.9% by weight) Test method: 10th revision Japanese Pharmacy Method Dissolution Test II (Paddle Method) [Second liquid (pH 6.8), 900 ml, 37 ° C, 100
r. p. m] Test results The dissolution test results are shown in Table 1 below.

Absorption test Test method The above-mentioned test preparations B and D are filled in capsules as FK739 so as to be 1 mg / kg per body weight of a beagle dog. This capsule was orally administered to beagle dogs after meals. After a certain time after administration, blood was collected in a heparinized tube. After centrifugation, the blood concentration of FK739 was measured by high performance liquid chromatography. As a comparative control example, an aqueous solution was orally administered to beagle dogs in the same manner as above, and plasma concentration time was evaluated. Test Results Test results are shown in Table 2 below. Table 2

[0035]

EXAMPLES The present invention will be described below with reference to production examples, examples and reference examples. Production Example 1 2-Butyl-3-[[2 '-(1H-tetrazole-5
-Yl) biphenyl-4-yl] methyl] -3H-imidazo [4,5-b] pyridine (28 g) in hot ethanol (300 ml) in sodium hydrogen carbonate (5.7 g).
Of water (140 ml) is added at once. The mixture is stirred at room temperature for 30 minutes and concentrated under reduced pressure. The residue is dissolved in ethanol (400 m). The ethanolic solution is filtered,
Concentrate under reduced pressure. The residue is hot acetonitrile (400 m
Dissolve in l). The precipitate was filtered and washed with acetonitrile to give 2-butyl-3-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] -3.
H-imidazo [4,5-b] pyridine sodium salt (trihydrate) (FK739) is obtained as white crystals.

Example 1 FK739 (18 g) and TC-5R (trademark: manufactured by Shin-Etsu Chemical Co., Ltd., general name: hydroxypropylmethylcellulose)
(1 g) is dissolved in distilled water (100 ml). This solution is coated on spherical sucrose (non-pareil) (80 g) using a fluidized bed granulator (Flow Coater Mini). A solution of ethyl cellulose (20 g) dissolved in ethanol (400 ml) was coated on the obtained FK739-coated particles (50 g) using a fluidized bed granulator (Flow Coater Mini) to obtain sustained release granules.

Example 2 FK739 (18 g), magnesium hydroxide (3.6
g) and TC-5R (1 g) are dissolved in distilled water (100 ml). This solution is coated on spherical sucrose (nonpareil) (80 mg) using a fluidized bed granulator (Flow Coater Mini). The obtained FK739 coated particles (50
Ethyl cellulose (20 g) in ethanol (40 g)
The solution dissolved in 0 ml) was coated using a fluidized bed granulator (Flow Coater Mini) to obtain sustained release granules.

Example 3 TC-5R (100 g) was added to ethanol (1600 ml).
FK739 pulverized into spherical sucrose (non-pareil) (300 g) using a centrifugal granulator (CF-360) while spraying a solution dissolved in dichloromethane (400 ml)
Coat the powder (100 g). The obtained FK7
While spraying the above TC-5R solution on 39 coated particles (300 g), low-substituted hydroxypropyl cellulose (4
50 g) is coated using a centrifugal granulator (CF-360). The particles obtained through this step were coated with a solution of ethyl cellulose (20 g) dissolved in ethanol (300 g) using a fluidized bed granulator (Flow Coater Mini) to obtain two different T contents of ethyl cellulose.
An ES preparation is obtained (TES preparation 1: ethyl cellulose content 5.8%, TES preparation 2: ethyl cellulose content 11.
7%).

Example 4 TC-5R (100 g) was added to ethanol (1600 ml).
FK739 crushed into spherical sucrose (non-pareil) (200 g) using a centrifugal granulator (CF-360) while spraying a solution dissolved in chloromethane and dichloromethane (400 ml).
Powder (1000 g) to magnesium hydroxide (200 g)
Coating the mixture. Low-substituted hydroxypropylcellulose (300 g) while spraying the above TC-5R solution on the obtained FK739 coated particles (300 g).
Is coated using a centrifugal granulator (CF-360). Ethyl cellulose (5
0 g) was dissolved in ethanol (750 g) and coated using a fluidized bed granulator (Flow Coater Mini) to obtain 3 kinds of TES preparations having different ethyl cellulose contents (TES preparation 3: ethyl cellulose content 7. 0
%, TES formulation 4: ethyl cellulose content 9.5%, T
ES formulation 5: ethyl cellulose content 13.9%).

[Brief description of drawings]

FIG. 1 is a cross-sectional view of the membrane-controlled sustained release preparations disclosed in Examples 1 and 2.

2 is a cross-sectional view of the TES sustained release formulations disclosed in Examples 3 and 4. FIG.

[Explanation of symbols]

 1 Drug (FK739) 2 Sucrose particles (nucleus) 3 Swelling agent 4 Membrane

Claims (10)

[Claims] 1. A preparation containing a FK739 substance or a salt thereof, a swelling agent, and a water-insoluble coating substance as a main ingredient, wherein the swelling agent is contained in an amount sufficient to rupture the membrane after a predetermined time has elapsed. Sustained release formulation. 2. The sustained-release preparation according to claim 1, wherein the FK739 substance or its salt and the swelling agent are separated as the main drug. 3. The sustained-release preparation according to claim 1, wherein an FK739 substance or its salt and a swelling agent are mixed as a main ingredient. 4. The sustained-release preparation according to claim 1, wherein the water-insoluble coating substance contains ethyl cellulose. 5. The sustained-release preparation according to claim 1, wherein the swelling agent is a disintegrant. 6. The sustained-release preparation according to claim 5, wherein the disintegrant is low-substituted hydroxypropyl cellulose, sodium starch glycolate or sodium carboxymethyl cellulose. 7. The sustained-release preparation according to claim 1, wherein the dosage form is spherical particles, granules or tablets. 8. The sustained-release preparation according to claim 1, which has various dissolution patterns obtained by mixing preparations having different lag times. 9. A sustained-release preparation comprising an FK739 substance or a salt thereof, a water-soluble polymer and a water-insoluble coating substance as a main ingredient. 10. The sustained-release preparation according to claim 9, wherein the water-insoluble coating substance contains ethyl cellulose.