JPS63310827A - Sustained release pharmaceutical containing nicotinic aid derivative as principal agent - Google Patents

Abstract

PURPOSE:To obtain the titled sustained release pharmaceutical with markedly low manifestation ratio of side effects, such as flush, and severity thereof and remarkably high bioavailability, by using a water-soluble high polymer substance as a sustainedly releasing carrier. CONSTITUTION:A sustained release pharmaceutical obtained by adding a water- soluble high polymer substance selected from hydroxypropyl cellulose, CMC, methyl cellulose, pullulan, PVA, glucomannan, etc., as a sustainedly releasing carrier to a principal agent consisting of a nicotinic acid derivative selected from nicotinamide, nicomol, hepronicate, niceritrol, inositol hexanicotinate, tartaric acid nicotinic alcohol and nicotinic acid dl-alpha-tocopherol, as necessary, blending a lubricant, excipient, etc., and preparing the pharmaecutical by a conventional method. The water-soluble high polymer substance is preferably selected so as to prolong residence time in the stomach and the amount thereof contained is 10-99wt.%, especially 25-90wt.% based on the total weight of the pharmaceutical.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to sustained release preparations, and particularly to sustained release preparations containing nicotinic acid derivatives as a main ingredient.

(Prior art) Nicotinic acid has an antihyperlipidemic effect, but when it is formulated and administered orally, it causes side effects such as severe flushing, gastrointestinal disorders, decreased glucose tolerance, and decreased liver function. Occur. For this purpose, nicotinic acid derivatives such as nicomol, heprodicato, niceritrol, inositol hexanicotinate, nicotinic alcohol tartrate, di-α-tocopherol nicotinate, etc. have been developed as prodrugs.

However, even when these prodrugs are formulated using conventional methods and administered orally, the degree of administration is weaker than when using nicotinic acid itself as the main ingredient and depends on the constitution of the patient. There was a problem in that a flash may occur after a short period of time. Furthermore, by substituting nicotinic acid with a prodrug that is a nicotinic acid derivative, the incidence and severity of flushing were significantly reduced, suggesting that flushing is caused by a rapid increase in blood nicotinic acid concentration. Therefore, in order to suppress flushing, it has become essential to suppress the rapid increase in blood nicotinic acid concentration.

In general, to suppress the rapid increase in blood concentration of drugs,
It is possible to formulate a sustained release formulation, but in relation to nicotinic acid derivatives, the solubility pn range of nicomol, hebronicate, niceritrol, inositol hexanicotinate, etc. is 4.0 or less, and pal 4. If it is more than 0, it will hardly dissolve, and the absorption site will be limited to the duodenum and upper small intestine. Release control methods using matrices such as molecular substances and wax, and dual-dissolution formulation methods that combine gastric and enteric properties do not allow the absorption site of the drug to be limited to the duodenum and upper small intestine, resulting in flushing. Although it can be prevented, it cannot be applied because it significantly reduces the bioavailability of the drug.
Other sustained-release formulation methods that are presumed to be applicable for allowing the drug containing the above nicotinic acid derivative as a prodrug as a main ingredient to remain in the stomach and gradually release it include, for example, tablets and capsules. A method for suppressing early passage through the pylorus in the stomach by increasing the diameter of
Vol. 9, No. 477, 1983), and a method of forming into a hollow shape and coating the outer layer with a drug (Japanese Unexamined Patent Publication No. 58
-57315 Publication), a method for forming expandable microcapsules (Japanese Patent Application Laid-open No. 52-76418), a method for encapsulating fine voids with a gel-forming substance and oil (Japanese Patent Application Laid-open No. 61-1999)
43108 Publication) etc.

(Problems to be Solved by the Invention and Objectives of the Invention) The preparation obtained by the sustained release method disclosed in the above-mentioned magazine "Pharmaceutical Factory" has a large side diameter, so it is expected that it will be difficult to take it. In addition, the sustained-release formulation method disclosed in JP-A-58-57315 and other publications requires complicated operations, strict manufacturing conditions, and a large number of steps. The problem is that the manufacturing cost increases and therefore it is impractical.

Therefore, the basic object of the present invention is that it is easy to manufacture;
Therefore, it is an object of the present invention to provide a sustained release preparation containing a nicotinic acid derivative as a main ingredient, which is excellent in practicality including economical efficiency.

A specific object of the present invention is to provide a sustained-release preparation that meets the above-mentioned basic objectives, which has an extremely low incidence and severity of side effects such as flushing, and has an extremely high bioavailability.
The object of the present invention is to provide a sustained release preparation containing a nicotinic acid derivative as a main ingredient.

(Means and effects for solving the problem and achieving the object) According to the present invention, the above problem can be solved by using a nicotinic acid derivative as the main ingredient, which is characterized by using a water-soluble polymer substance as a sustained release carrier. This problem is solved by a sustained release formulation that
The above objectives are achieved.

The water-soluble polymeric substance used as a sustained drug release carrier is at least one substance selected from hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, methylcellulose, ethylcellulose, pullulan, polyvinyl alcohol, polyvinylpyrrolidone, glucomannan, and gum arabic. can be. These water-soluble polymer substances have the property of swelling while gradually absorbing water, in this case gastrointestinal fluid, especially gastric fluid, and then gradually dissolving. When using a combination of two or more species, it is preferable to select them in consideration of specific gravity, swelling properties, stickiness, etc., so as to prolong the residence time in the stomach. The content of this water-soluble polymeric substance is preferably 10-99% by weight, particularly 25-90% by weight, based on the total weight of the preparation.

The nicotinic acid derivatives that are the main ingredients include the aforementioned nicomol, hepronicate, niceritrol, inositol hexanicotinate, nicotinic alcohol tartrate, and nicotinic acid d1-, which are already known as nicotinic acid amide or nicotinic acid prodrugs. Examples include α-tocopherol. The content of this main ingredient is preferably about 90-1% by weight, particularly about 75-10% by weight, based on the total weight of the preparation. The sustained-release preparation according to the present invention may contain a lubricant, an excipient, a coloring agent, a flavoring agent, etc., if necessary, in addition to the above-mentioned main ingredient and sustained-release carrier. Examples of lubricants include talc, stearic acid, stearate salts, waxes, etc., excipients include starch, dextrin, lactose, mannitol, propylene glycol, polyethylene glycol, oils, etc., and flavorings. Examples of the agent include citric acid, fumaric acid, tartaric acid, menthol, peppermint, and citrus flavoring agents.

The sustained-release preparation according to the present invention is prepared by adding a sustained-release carrier to the main ingredient and mixing the mixture, and adding the above-mentioned lubricants, excipients, colorants, flavorings, etc. to this mixture as necessary. It can be prepared by mixing and then formulating according to a conventional method. Preferred dosage forms include tablets, powders, fine granules, granules, and capsules.

(Manufacturing Examples, etc.) Next, the present invention will be described in further detail in relation to comparative examples, manufacturing examples, and test examples. In addition, the abbreviations mentioned in the comparative examples and manufacturing examples and their meanings are as follows.

) IPC: Hydroxypropylcellulose + 1PMc
Hydroxypropyl methylcellulose Comparative Example 1 Formula: Diceritrol 250.0 (g) Lactose 240.0 Light anhydrous silica P15
．． 0 Magnesium stearate 5.0500.0 (
g) Lactose was added to niceritrol and mixed, light silicic anhydride and magnesium stearate were added and mixed to this mixture, and then processed by a capsule filling machine to obtain capsules (each capsule was made of niceritrol). 125B
).

Le Umugi 1 Formula: Niceritrol 250.0 (g) Refined white sugar (24-32mesh) 250.0) IPc
・Ethanol solution l060 Eudragit
-YULL-1 560.0 (g) Niceritrol and purified white sugar were put into a centrifugal fluid granulator, and granulated by spraying an HPC/ethanol solution to obtain granules. Using a centrifugal flow granulation device, the granules are coated with a film of Eudragi Nto (RL: RS 3Nia) to obtain sustained release granules, and then processed by a capsule filling machine to obtain capsules. Capsules contain 125mg of Niceritrol).

1st production.

Prescription: Niceritrol 250.0 (g)) I
PMc 100.0 Magnesium stearate 2.5352.5 (g) Add IPMc (to niceritrol) and mix, add magnesium stearate to this mixture and mix, then process by capsule filling machine to make capsules Each capsule contains 125 mg of niceritrol).

1L prescription: Niceritrol 250.0 (g) HP
MC8θ, O Glucomannan 20.0 Magnesium stearate 2.5352.5 (g) HPMC and glucomannan are added to niceritrol and mixed, magnesium stearate is added to this mixture and mixed, then capsule filling machine to obtain capsules (each capsule contains 12 pieces of niceritrol).
Contains 1g of 5I).

Prescription: Niceritrol 250.0 (g) Glucomannan 250.0 Magnesium stearate 2.5502.5 (g) Glucomannan is added to niceritrol and mixed, and magnesium stearate is added to this mixture. and then processed through a capsule filling machine to obtain capsules (each capsule containing 125 mg of niceritrol).

11 Salmon 1 Prescription: Niceritrol 250.0 (g)) I
PMc ♂0.0 Polyvinyl alcohol 20.0 Magnesium stearate 2.5352.5 (g) HPMC and polyvinyl alcohol are added to Niceritrol and mixed, magnesium stearate is added to this mixture and mixed, and the mixture is prepared in a conventional manner. Granules were obtained by wet granulation. The granules were processed by a capsule filling machine to obtain capsules (each capsule contained 125 mg of niceritrol).
).

Squeeze test (base agent release test) a) Sample Capsules obtained in Production Example 1 and Comparative Examples 1 and 2 were used as test samples.

b) Test method "Diurnal cycle" Conforms to "Dissolution test method" of the 11th revised general test methods.

Test method: Paddle method, 100rp ■ Sample fixing position: Place the sample in a sinker and sink to the bottom of the dissolution tester Dissolution test solution: Disintegration test method first solution, pi (1,2C) quantitative method After starting the test, eluate Weighed 51 over time, added the elution test solution to make the total amount 251, and set the wavelength to 261.
The absorbance at nm is measured and compared with a calibration curve prepared in advance to determine the amount of released diceritrol, which is the main ingredient, and is converted into a release rate.

d) Results and discussion The results are as shown in the graph of Figure 1. From this graph, it is clear that the formulation with the conventionally widely used formulation (Comparative Example 1) has a low sustained release effect, and that the main ingredient Regarding sustained release properties, it can be seen that there is no significant difference between the formulation according to the present invention (Manufacturing Example 1) and the formulation of a general sustained release formulation (Comparative Example 2).

(Absorption test in oral administration - animal experiment) a) Sample Capsules obtained in Production Examples 1 and 2 and Comparative Examples 1 and 2 were used as test samples.

b) Test method A sample 1 capsule was administered to a Pegle dog as an experimental animal,
Changes in nicotinic acid blood concentration are measured by GC/MS. That is, blood is collected over time, nicotinic acid-64 labeled substance is added to this blood sample, the nicotinic acid portion is collected by thin layer chromatography, and after methylation, GC/MS is performed.
(Nicotinic acid in plasma is determined using SIM>.

C) Results and discussion The results were as shown in Figures 2 and 3.

As inferred from the release test results of the base agent in Test Example 1, the formulation according to Comparative Example 1 (general formulation by conventional method)
The blood concentration of nicotinic acid rises rapidly after administration, reaches its highest level within 1 hour, and then falls relatively rapidly, i.e., this type of drug has the potential to cause flushing. It is also clear that the drug's efficacy cannot be expected to last very long. On the other hand, the formulation according to Comparative Example 2 (a general sustained-release formulation prepared by conventional methods) showed good results in the release test of the main ingredient in Test Example 1, but the blood concentration of nicotinic acid remained at a high level for a long time. that it does not reach
That is, it was found that sufficient biological utilization of the drug could not be achieved.

(preparation according to the invention), the blood concentration of nicotinic acid rises slowly, reaches the highest level 2-3 hours after administration, and then declines gently, i.e., in the preparation according to the invention, there is no flash. It was found that this drug was difficult to develop and the medicinal effect lasted for a long time.

q<Oral administration test on humans) The formulations according to Production Example 1 and Comparative Examples 1 and 2 (2 capsules, containing 250B as niceritrol) were orally administered to healthy volunteers after meals to investigate the type and frequency of flushing. Ta.

The results were as shown in the table below.

(Effects of the Invention) According to the preparation according to the present invention, a nicotinic acid derivative as a prodrug of nicotinic acid is used as a main ingredient, and this main ingredient is sufficiently dispersed in a state of being surrounded by a water-soluble polymer substance. When the preparation is taken orally, it remains in the stomach for a long time (1-6 hours) and the main agent can be gradually dissolved and released, resulting in a gradual increase in blood nicotinic acid concentration, which causes flushing, etc. The development of side effects can be significantly suppressed, and the drug can be maintained at a high level for a long period of time. If the same is acceptable, the drug content can be reduced, and therefore safety can be further improved.

[Brief explanation of drawings]

FIG. 1 is a graph showing changes over time in the release amount of the base agent in a formulation according to the present invention and a formulation according to the prior art when niceritrol is used as the base agent, and FIG. 2 is a graph showing the formulation of Production Example 1 according to the present invention and the prior art. Figure 3 is a graph showing the change in blood concentration of nicotinic acid from the base drug niceritrol over time when the formulations of Comparative Examples 1 and 2 were orally administered to dogs. 3 is a graph showing the case of a formulation according to Production Example 2 and a formulation according to Comparative Example 1. Patent Applicant: Sanwa Kagaku Institute Co., Ltd. 2, Attorney, Patent Attorney Isao Sasaki
,J,:,\:,',Hr,-

Claims (6)

[Claims] (1) A sustained-release preparation containing a nicotinic acid derivative as a main ingredient, which is characterized by using a water-soluble polymeric substance as a sustained-release carrier. (2) The water-soluble polymeric substance is at least one substance selected from hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, methylcellulose, ethylcellulose, pullulan, polyvinyl alcohol, polyvinylpyrrolidone, glucomannan, and gum arabic. A sustained release preparation containing the nicotinic acid derivative according to claim 1 as a main ingredient. (3) The nicotinic acid derivative as the base agent is at least one substance selected from nicotinamide, nicomol, hepronicate, niceritrol, inositol hexanicotinate, nicotinic alcohol tartrate, and dl-α-tocopherol nicotinate. A sustained release preparation containing the nicotinic acid derivative according to claim 1 or 2 as a main ingredient. (4) Any one of claims 1 to 3, characterized in that the content of the water-soluble polymeric substance is 10-99% by weight, especially 25-90% by weight based on the total weight of the preparation. A sustained release preparation containing the nicotinic acid derivative described in item 1 as a main ingredient. (5) Any of claims 1 to 4, characterized in that the content of the nicotinic acid derivative as the main ingredient is 90-1% by weight, particularly 75-10% by weight, based on the total weight of the preparation. A sustained release preparation containing the nicotinic acid derivative according to any one of the above as a main ingredient. (6) A sustained-release preparation based on the nicotinic acid derivative according to any one of claims 1 to 5, which is in the form of a powder or a capsule.