JP2003146878A - Readily soluble solid preparation containing nilvadipine, and method for producing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a readily soluble solid preparation containing nilvadipine as an active ingredient, and having improved solubility and bioavailability. SOLUTION: This readily soluble solid preparation having the improved solubility and good bioavailability is produced by formulating a hydroxypropyl cellulose and a polyvinylpyrrolidone in specific proportions with the nilvadipine. This preparation is the one which is not laminar and which has no barrier layer for regulating the release of the nilvadipine, and contains 0.5-10 pts.wt. hydroxypropyl cellulose and 0.5-10 pts.wt. polyvinylpyrrolidone based on 1 pt.wt. nilvadipine.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an easily soluble solid preparation containing nilvadipine as an active ingredient and a method for producing the same.

[0002]

BACKGROUND ART Nilvadipine is a 1,4-dihydropyridine calcium antagonist, which has a vasodilatory effect on coronary arteries, vertebral arteries and other peripheral blood vessels, and is used as a therapeutic drug for angina, arrhythmia, hypertension and the like. Has been.

However, since nilvadipine has a very low solubility in water, for example, when it is orally administered as it is,
It has a drawback that it is not well absorbed in blood and its bioavailability is low.

[0004] Therefore, after dissolving nilvadipine in an organic solvent solution of hydroxypropylmethylcellulose, which is a water-soluble polymer compound, the organic solvent is removed to give a solid solution, which is a preparation having improved solubility and migration into blood. It has been reported (Japanese Patent Publication No. 4-1245). Usually, kneading using a solution dissolved with a polymer as a binder is conceivable. However, when hydroxypropylmethylcellulose used as a solid solution forming additive is dissolved in an organic solvent together with nilvadipine, this solution becomes viscous, and its handleability is poor for use as a binder solution in a fluidized bed method and a kneading method. Moreover, there is a drawback that the solvent cost and the manufacturing cost increase when the solution is diluted.

The solubility of nilvadipine in a molten state is dispersed in a water-soluble polymer and then cooled to produce a solid dispersion (JP-A-5-139974).
A method for producing a solid dispersion having improved bioavailability has been reported. In addition, a method for producing a solid dispersion of a poorly soluble drug having improved bioavailability by kneading the poorly soluble drug and a water-soluble polymer base while heating at a temperature at which they do not melt (Japanese Patent Laid-Open Publication No. HEI 5 (1999)). -26
No. 2642) has been reported. However, since these inventions are characterized by heating to a high temperature of 150 ° C. or higher, they require special equipment and are disadvantageous in that they pose a risk to production.

Thus, it is difficult to improve the solubility of nilvadipine, which is extremely insoluble in water, and to prepare an easily soluble solid preparation having excellent bioavailability. Was desired to be developed.

[0007]

In view of such circumstances, the present invention intends to provide a solid formulation of nilvadipine, which contains nilvadipine as an active ingredient and has improved solubility and bioavailability, and a method for producing the same. To do.

[0008]

Means for Solving the Problems The inventors of the present invention have diligently studied a solid soluble preparation of nilvadipine, and by adding hydroxypropylcellulose and polyvinylpyrrolidone to nilvadipine, the solubility is improved,
It has been found that it is possible to produce a solid formulation of nilvadipine that has good bioavailability.

When nilvadipine was blended with only hydroxypropyl cellulose, the solubility was improved in the initial stage of preparation of the preparation, but the solubility tended to decrease with time. Further, when only polyvinylpyrrolidone was blended with nilvadipine, the solubility could not be sufficiently improved although there was no change with time.

It has been found, however, that when nilvadipine is blended with both hydroxypropylcellulose and polyvinylpyrrolidone, their drawbacks are complemented with satisfactory results. In addition, polyethylene glycol and a surfactant that can be used for oral preparations, polysorbate 8
By adding 0 or sodium lauryl sulfate,
It has also been found that the hydrophilicity of the solid preparation is increased and the solubility is further improved.

That is, the easily soluble solid formulation of nilvadipine of the present invention is a non-layered formulation containing nilvadipine, hydroxypropyl cellulose and polyvinylpyrrolidone, which is not provided with a barrier layer for controlling the release of nilvadipine. 0.5 to 10 parts by weight of hydroxypropyl cellulose per 1 part by weight (for example, 1
.About.5 parts by weight) and polyvinylpyrrolidone in an amount of 0.5 to 10 parts by weight (for example, 1 to 5 parts by weight).
Polyethylene glycol or a surfactant may be further added to this formulation. Further, in another embodiment, the easily soluble solid formulation of nilvadipine of the present invention is a formulation containing nilvadipine, hydroxypropylcellulose, polyvinylpyrrolidone, polyethylene glycol or a surfactant, and is prepared by using 1 part by weight of nilvadipine. It is contained in a ratio of 1 to 5 parts by weight of propylcellulose and 1 to 5 parts by weight of polyvinylpyrrolidone. The surfactant may be polysorbate 80 or sodium lauryl sulfate. The amount of polyethylene glycol may be 0.1 to 1.0 part by weight of polyethylene glycol relative to 1 part by weight of nilvadipine, and the amount of the surfactant used is 1 part by weight of nilvadipine. The activator may be present in a proportion of 0.01 to 0.1 part by weight. Further, the preparation may be coated with a coating agent (hydroxypropyl cellulose, polyvinylpyrrolidone, a coating agent containing polyethylene glycol, etc.).

[0012] The present invention also discloses a method for producing a solid preparation containing nilvadipine, hydroxypropyl cellulose and polyvinylpyrrolidone (a readily soluble solid preparation of nilvadipine) by granulating by a fluidized bed method or a kneading method.
In this method, as a binder solution in the fluidized bed method or the kneading method, 0.5 to 10 parts by weight of hydroxypropyl cellulose and 0.5 to 10 parts by weight of polyvinylpyrrolidone were dissolved in an organic solvent with respect to 1 part by weight of nilvadipine. The solution may be used as a binder solution for granulation, and nilvadipine, hydroxypropylcellulose and polyvinylpyrrolidone are dissolved in an organic solvent, and a solution to which polyethylene glycol or a surfactant is further added is used as a binder solution. You may granulate it. For example, a fluidized bed method in which a solution of nilvadipine, hydroxypropyl cellulose, and polyvinylpyrrolidone dissolved in an organic solvent is sprayed on an inert additive to dry it, or the solution is kneaded with an inert additive, and granulated. The above-mentioned preparation may be produced by a kneading method of drying, dissolving nilvadipine, hydroxypropylcellulose and polyvinylpyrrolidone in an organic solvent, and further spraying a solution containing polyethylene glycol or a surfactant on an inert additive. Granulation may be carried out by a fluidized bed method in which the solution is dried, or by a kneading method in which the solution is kneaded with an inert additive, granulated and dried.

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION In the process for producing the preparation of the present invention, a solution of nilvadipine, hydroxypropylcellulose and polyvinylpyrrolidone dissolved in an organic solvent, or polyethylene glycol or polysorbate 80 or sodium lauryl sulfate was added thereto. Since the solution is directly used as the binder solution of the fluidized bed method or the kneading method, a device for heating to a high temperature is not required, and ordinary manufacturing equipment can be used. The final preparation can be manufactured more easily and at a stretch.

The nilvadipine easily soluble solid preparation of the present invention comprises:
It can be manufactured by either a fluidized bed method or a kneading method.

The fluidized bed method is, for example, a solution in which nilvadipine, hydroxypropyl cellulose and polyvinylpyrrolidone are dissolved in an organic solvent, or a solution obtained by further adding polyethylene glycol or polysorbate 80 or sodium lauryl sulfate is added in an inert manner which is usually used for pharmaceuticals. It can be produced by spraying an agent or the like and drying.

The kneading method is, for example, a solution in which nilvadipine, hydroxypropyl cellulose and polyvinylpyrrolidone are dissolved in an organic solvent, or a solution obtained by further adding polyethylene glycol or polysorbate 80 or sodium lauryl sulfate is added in an inert manner which is usually used for pharmaceuticals. It can be produced by kneading with an agent, granulating and drying.

The solution in which nilvadipine, hydroxypropylcellulose and polyvinylpyrrolidone are dissolved in the fluidized bed method or the kneading method, or the solution in which polyethylene glycol or polysorbate 80 or sodium lauryl sulfate is further added has a low viscosity. The feature is that it can be directly used as a binding solution by the kneading method and the manufacturing method can be simplified.

The organic solvent used in the present invention is not particularly limited, but examples thereof include those which usually dissolve nilvadipine and further hydroxypropyl cellulose and polyvinylpyrrolidone, such as methanol and ethanol.

The hydroxypropyl cellulose used in the preparation of the present invention is 0.5 parts by weight based on 1 part by weight of nilvadipine.
˜10.0 parts by weight is used, and especially 1.0 to 5.0 parts by weight is preferred.

The hydroxypropyl cellulose used in the present invention has a grade of 1 to 10 mm ² / S (2%, 20 ° C.), and particularly preferably a grade of 1 to 5 mm ² / S (2%, 20 ° C.). .

The polyvinylpyrrolidone used in the preparation of the present invention is used in an amount of 0.5 to 10 parts by weight, preferably 1.0 to 5.0 parts by weight, based on 1 part by weight of nilvadipine.

The polyvinylpyrrolidone used in the present invention is 1-10 mm ² / S (2%, 20 ° C.),
Particularly, a grade of 1 to 5 mm ² / S (2%, 20 ° C.) is preferable.

The polyethylene glycol or polysorbate 80 or sodium lauryl sulphate used in the formulations of the present invention may be added to a binding solution of nilvadipine, hydroxypropyl cellulose and polyvinylpyrrolidone dissolved in an organic solvent.

The polyethylene glycol used in the present invention is used in an amount of 0.1 to 1.0 part by weight, preferably 0.1 to 0.5 part by weight, based on 1 part by weight of nilvadipine.

The surfactants used in the present invention, polysorbate 80 and sodium lauryl sulfate are nilvadipine 1
0.01 to 0.1 part by weight is used, and 0.01 to 0.05 part by weight is particularly preferable.

The nilvadipine easily soluble solid preparation obtained as described above can be made into various dosage forms such as tablets, granules and fine particles, if necessary. In addition, additives such as an excipient, a disintegrant, a lubricant, a coloring agent, and a flavoring agent may be added as necessary for various preparations.

Examples of the excipient include crystalline cellulose, lactose, D-mannitol, purified sucrose, calcium hydrogen phosphate, calcium citrate and the like.

Examples of the disintegrant include low-substituted hydroxypropyl cellulose, starch, carboxymethyl starch, carboxymethyl cellulose calcium and the like.

Examples of the lubricant include magnesium stearate, calcium stearate, stearic acid, talc, hardened oil and the like.

Further, the preparation of the present invention may be coated with a coating agent such as a film-coated tablet in order to improve the stability, aesthetics, taste and flavor of the main drug and ease of administration. Further, the coating agent at this time may contain hydroxypropyl cellulose, polyvinylpyrrolidone, or polyethylene glycol.

[0031]

EXAMPLES The contents of the present invention will be described in more detail with reference to the following reference examples and examples. The easily soluble solid preparation of the present invention is not limited to the description of each example.

Dissolution test Test method Dissolution test method described in the Japanese Pharmacopoeia (paddle method, 50 rp)
m, water 900 ml, 37 ° C.). The sample was equivalent to 2 mg of nilvadipine, and the elution amount was measured 30 minutes after the start of the elution test by the HPLC method. The results are shown in Table 1.

[0033]

[Table 1] HPC: Hydroxypropyl cellulose PVP: Polyvinylpyrrolidone PEG: Polyethylene glycol

From the above results, it is clear that the solid formulation of nilvadipine according to the present invention, which is easily soluble, has a high elution property, and therefore has a high absorptivity of nilvadipine and a high bioavailability. "Reference examples and examples"

[0035]   Reference example 1 (kneading method; HPC only) Composition per tablet Nilvadipine 2.0 mg Hydroxypropyl cellulose 10.0mg Lactose 27.7 mg Crystalline cellulose 40.0mg Low-substituted hydroxypropyl cellulose 10.0mg Magnesium stearate 0.3 mg Ethanol (70.0 ml) ────────────────────────────────                                           90.0 mg

Lactose, crystalline cellulose and low-substituted hydroxypropyl cellulose are mixed for 10 minutes in a Shinagawa mixer or a high speed mixer. Separately, hydroxypropyl cellulose is dissolved in ethanol with a propeller stirrer, and then nilvadipine is further added to prepare a completely dissolved solution. This solution is added to the above mixture, kneaded, dried at 50 ° C. by a shelf dryer, and then sized by a power mill. Magnesium stearate was added in a V-type mixer and mixed for 7 minutes.
The tablets are compressed so that each tablet contains 2 mg of nilvadipine. The obtained tablets were film-coated by a conventional method to give film-coated tablets.

[0037]   Reference example 2 (kneading method; PVP only) Composition per tablet Nilvadipine 2.0 mg Polyvinylpyrrolidone 10.0 mg Lactose 27.7 mg Crystalline cellulose 40.0mg Low-substituted hydroxypropyl cellulose 10.0mg Magnesium stearate 0.3 mg Ethanol (70.0 ml) ────────────────────────────────                                           90.0 mg

Lactose, crystalline cellulose and low-substituted hydroxypropyl cellulose are mixed for 10 minutes with a Shinagawa mixer or a high speed mixer. Separately, polyvinylpyrrolidone is dissolved in ethanol with a propeller stirrer, and then nilvadipine is further added to prepare a completely dissolved solution. This solution is added to the above mixture, kneaded, dried at 50 ° C. by a shelf dryer, and then sized by a power mill. Magnesium stearate is added in a V-type mixer and mixed for 7 minutes, and the mixture is tableted by a rotary tableting machine so that each tablet contains 2 mg of nilvadipine. The obtained tablets were film-coated by a conventional method to give film-coated tablets.

[0039]   Reference example 3 (fluidized bed method; HPC) Composition per tablet Nilvadipine 2.0 mg Hydroxypropyl cellulose 10.0mg Lactose 72.7 mg Low-substituted hydroxypropyl cellulose 5.0 mg Magnesium stearate 0.3 mg Ethanol (70.0 ml) ────────────────────────────────                                           90.0 mg

After hydroxypropyl cellulose is dissolved in ethanol with a propeller stirrer, nilvadipine is further added to prepare a completely dissolved solution. Using this solution as a binding solution, lactose is granulated by a fluidized bed granulator or a tumbling fluidized bed granulator (intake air temperature 60 ° C.), then dried at 60 ° C. and sized by a power mill. Magnesium stearate is added in a V-type mixer and mixed for 7 minutes, and the mixture is tableted by a rotary tableting machine so that each tablet contains 2 mg of nilvadipine. The obtained tablets were film-coated by a conventional method to give film-coated tablets.

[0041]   Reference Example 4 (fluidized bed method; PVP) Composition per tablet Nilvadipine 2.0 mg Polyvinylpyrrolidone 10.0 mg Lactose 72.7 mg Crystalline cellulose 40.0mg Low-substituted hydroxypropyl cellulose 5.0 mg Magnesium stearate 0.3 mg Ethanol (70.0 ml) ────────────────────────────────                                           90.0 mg

After polyvinylpyrrolidone is dissolved in ethanol with a propeller stirrer, nilvadipine is further added to prepare a completely dissolved solution. Using this solution as a binding solution, lactose is granulated by a fluidized bed granulator or a tumbling fluidized bed granulator (intake air temperature 60 ° C.), then dried at 60 ° C. and sized by a power mill. Magnesium stearate is added in a V-type mixer and mixed for 7 minutes, and the mixture is tableted by a rotary tableting machine so that each tablet contains 2 mg of nilvadipine. The obtained tablets were film-coated by a conventional method to give film-coated tablets.

[0043]   Example 1 (kneading method; HPC, PVP) Composition per tablet Nilvadipine 2.0 mg Hydroxypropyl cellulose 6.0 mg Polyvinylpyrrolidone 4.0 mg Lactose 27.7 mg Crystalline cellulose 40.0mg Low-substituted hydroxypropyl cellulose 10.0mg Magnesium stearate 0.3 mg Ethanol (70.0 ml) ────────────────────────────────                                           90.0 mg

Lactose, crystalline cellulose and low-substituted hydroxypropyl cellulose are mixed for 10 minutes with a Shinagawa mixer or a high speed mixer. Separately, hydroxypropylcellulose and polyvinylpyrrolidone are dissolved in ethanol with a propeller stirrer, and then nilvadipine is further added to prepare a completely dissolved solution. This solution was added to the above mixture and kneaded, and then heated in a tray dryer at 50 ° C.
After drying in, it is sized with a power mill. Add magnesium stearate in a V-type mixer and mix for 7 minutes,
2 nilvadipine per tablet on a rotary tablet machine
Compress to contain mg. The obtained tablets were film-coated by a conventional method to give film-coated tablets.

[0045]   Example 2 (fluidized bed method; PVP + HPC) Composition per tablet Nilvadipine 2.0 mg Hydroxypropyl cellulose 5.0mg Polyvinylpyrrolidone 5.0 mg Lactose 67.7mg Low-substituted hydroxypropyl cellulose 10.0mg Magnesium stearate 0.3 mg Ethanol (70.0 ml) ────────────────────────────────                                           90.0 mg

Hydroxypropyl cellulose and polyvinylpyrrolidone are dissolved in ethanol with a propeller stirrer, and then nilvadipine is further added to prepare a completely dissolved solution. Using this solution as a binding solution, lactose is granulated by a fluidized bed granulator or a tumbling fluidized bed granulator (intake air temperature 60 ° C.), then dried at 60 ° C. and sized by a power mill. Magnesium stearate is added in a V-type mixer and mixed for 7 minutes, and the mixture is tableted by a rotary tableting machine so that each tablet contains 2 mg of nilvadipine. The obtained tablets were film-coated by a conventional method to give film-coated tablets.

[0047]   Example 3 (fluidized bed method; PVP + HPC + PEG) Composition per tablet Nilvadipine 2.0 mg Hydroxypropyl cellulose 4.0 mg Polyvinylpyrrolidone 6.0 mg Polyethylene glycol 0.5 mg Lactose 67.2mg Low-substituted hydroxypropyl cellulose 10.0mg Magnesium stearate 0.3 mg Ethanol (70.0 ml) ────────────────────────────────                                           90.0 mg

Hydroxypropyl cellulose, polyvinylpyrrolidone and polyethylene glycol are dissolved in ethanol with a propeller stirrer, and then nilvadipine is further added to prepare a completely dissolved solution. Using this solution as a binding solution, lactose is granulated by a fluidized bed granulator or a tumbling fluidized bed granulator (intake air temperature 60 ° C.), then dried at 60 ° C. and sized by a power mill. Magnesium stearate is added in a V-type mixer and mixed for 7 minutes, and the mixture is tableted by a rotary tableting machine so that each tablet contains 2 mg of nilvadipine. The obtained tablets were film-coated by a conventional method to give film-coated tablets.

[0049]   Example 4 (fluidized bed method; PVP + HPC + polysorbate 80) Composition per tablet Nilvadipine 2.0 mg Hydroxypropyl cellulose 5.0mg Polyvinylpyrrolidone 5.0 mg Polysorbate 80 0.05 mg Lactose 67.65mg Low-substituted hydroxypropyl cellulose 10.0mg Magnesium stearate 0.3 mg Ethanol (70.0 ml) ────────────────────────────────                                           90.0 mg

After hydroxypropyl cellulose, polyvinylpyrrolidone and polysorbate 80 are dissolved in ethanol with a propeller stirrer, nilvadipine is further added to prepare a completely dissolved solution. Using this solution as a binding solution, lactose is granulated by a fluidized bed granulator or a tumbling fluidized bed granulator (intake air temperature 60 ° C.), then dried at 60 ° C. and sized by a power mill. Magnesium stearate is added in a V-type mixer and mixed for 7 minutes, and the mixture is tableted by a rotary tableting machine so that each tablet contains 2 mg of nilvadipine. The obtained tablets were film-coated by a conventional method to give film-coated tablets.

The stable aqueous solution preparation of the present invention containing nilvadipine or a pharmacologically acceptable salt thereof as an active ingredient is not limited to the above-mentioned examples, but deviates from the gist of the present invention. It goes without saying that various changes can be made within the range not covered.

[0052]

As described above, according to the easily soluble solid preparation of the present invention containing nilvadipine as an active ingredient, the solubility and bioavailability are improved,
Moreover, the excellent effect that a solid formulation of nilvadipine easily soluble can be obtained with a simpler formulation can be obtained.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 47/38 A61K 47/38 A61P 9/06 A61P 9/06 9/08 9/08 9/10 9 / 10 103 103 9/12 9/12 43/00 111 43/00 111 F term (reference) 4C076 AA36 AA44 CC11 CC13 DD08F EE16 EE23 EE32 FF05 FF22 GG12 GG13 GG14 GG17 4C086 AA01 AA02 BC26 MA03 MA05 MA07 MA34 MA35 MA36 NA52 NA02 NA02 ZA39 ZA40 ZA42

Claims (12)

[Claims] 1. A non-layered preparation containing nilvadipine, hydroxypropylcellulose and polyvinylpyrrolidone, which is not provided with a barrier layer for controlling the release of nilvadipine, wherein hydroxypropylcellulose 0. A readily soluble solid preparation of nilvadipine, characterized by containing 5 to 10 parts by weight and 0.5 to 10 parts by weight of polyvinylpyrrolidone. 2. The preparation according to claim 1, which comprises 1 to 5 parts by weight of hydroxypropylcellulose and 1 to 5 parts by weight of polyvinylpyrrolidone with respect to 1 part by weight of nilvadipine. 3. The preparation according to claim 1, further comprising polyethylene glycol or a surfactant. 4. A preparation containing nilvadipine, hydroxypropylcellulose, polyvinylpyrrolidone and polyethylene glycol or a surfactant, wherein 1 to 5 parts by weight of hydroxypropylcellulose and 1 to 5 parts of polyvinylpyrrolidone are used per 1 part by weight of nilvadipine. A readily soluble solid preparation of nilvadipine, characterized in that it is contained in a ratio of parts by weight. 5. The preparation according to claim 3, wherein the surfactant is polysorbate 80 or sodium lauryl sulfate. 6. The preparation according to claim 3 or 4, which comprises 0.1 to 1.0 part by weight of polyethylene glycol with respect to 1 part by weight of nilvadipine. 7. The preparation according to claim 3 or 4, wherein the surfactant is used in a proportion of 0.01 to 0.1 part by weight relative to 1 part by weight of nilvadipine. 8. The preparation according to claim 1 or 4, which is coated with a coating agent. 9. A method for producing a solid preparation containing nilvadipine, hydroxypropyl cellulose, and polyvinylpyrrolidone by granulating by a fluidized bed method or a kneading method, wherein hydroxypropyl cellulose 0.1 part by weight of hydroxypropyl cellulose is used. A method for producing a readily soluble solid formulation of nilvadipine, which comprises granulating 5 to 10 parts by weight and 0.5 to 10 parts by weight of polyvinylpyrrolidone in an organic solvent as a binder solution. 10. Granulation by a fluidized bed method or a kneading method,
A method for producing a solid preparation containing nilvadipine, hydroxypropylcellulose and polyvinylpyrrolidone, wherein nilvadipine, hydroxypropylcellulose and polyvinylpyrrolidone are dissolved in an organic solvent, and a solution obtained by further adding polyethylene glycol or a surfactant is prepared. , A method for producing an easily soluble solid preparation of nilvadipine, which is granulated by using as a binder solution. 11. A fluidized bed method in which a solution of nilvadipine, hydroxypropylcellulose and polyvinylpyrrolidone dissolved in an organic solvent is sprayed on an inert additive to dry, or the solution is kneaded with the inert additive. The method according to claim 9, wherein the granulation is performed by a kneading method of drying. 12. A fluidized bed method in which nilvadipine, hydroxypropylcellulose and polyvinylpyrrolidone are dissolved in an organic solvent, and a solution in which polyethylene glycol or a surfactant is further added is sprayed on an inert additive to dry, or The production method according to claim 10, wherein the solution is kneaded with an inert additive, and granulated by a kneading method of drying.