JP2007302570A - Sustained release preparation containing thioctic acid - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a preparation that sustains a concentration of thioctic acid or derivatives thereof in the blood for many hours thereby to increase a biological coefficient of utilization by establishing a prescription design for delaying an elution time of thioctic acid or derivatives thereof. <P>SOLUTION: The preparation that permits delay of the elution time of thioctic acid or derivatives thereof is obtained in a sharply simplified manufacturing method compared to conventional known techniques by adjusting the compounding ratio of a lubricant incorporated with thioctic acid or derivatives thereof coated with a film of fats and oils. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a sustained-release preparation containing thioctic acid or a derivative thereof, and a method for producing the same.

Thioctic acid has the property of showing a maximum blood concentration 20 to 60 minutes after ingestion and then rapidly returning to the pre-intake concentration. For this reason, it is considered difficult to maintain blood concentration in the body for a long time with a normal preparation containing thioctic acid. Against this background, in recent years, pharmaceutical technologies that increase the bioavailability of thioctic acid have been studied.
As related prior art, Patent Documents 1 to 6 are known.

  Patent Document 1 discloses a delayed form containing (a) one or more cationogen polymers, (b) α-lipoic acid and / or a derivative thereof, and (c) at least one acid different from (b). is there. As an example, a production method is disclosed in which (a) component is swollen with chitosan and (c) component is glacial acetic acid swollen in mineral-free water, and then α-lipoic acid is mixed and wet granulated. However, such a production method is troublesome and there is a concern that the stability of α-lipoic acid itself may be lowered. In addition, chitosan is slightly less versatile because it contains the allergen “crab”. Furthermore, since the dissolution test solution is water, the conditions are not appropriate for discussing absorption in the body. Therefore, it cannot be determined from this result whether the gastric juice is resistant.

  Patent Document 2 discloses a delayed form containing an aqueous cellulose acetate phthalate dispersion and microcrystalline cellulose as excipient materials, and the conditions for the release time of α-lipoic acid are described in detail in the claims. However, the data to prove them are not disclosed.

  Patent Document 3 discloses a dosage form for oral application characterized by containing a solid salt of thioctic acid. However, there are problems in that the production method is complicated and the cost is high. In addition, data on gastric juice resistance is not disclosed.

  Patent Documents 4 and 5 disclose the content of hydrophilic polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyethylene oxide, sodium carboxymethylcellulose, etc., but the content of lubricant and oil film amount and sustained release are disclosed. There is no disclosure regarding sex.

  In Patent Document 6, there is a problem in that the control of the particle size of the nano fine particles is complicated and the cost is high. In addition, there is no disclosure regarding the content of lubricant and the amount of oil film and the sustained release property.

Special table 2003-510358 Special Table 2002-516270 JP-A-8-104629 JP2004-30149 JP2004-123738 JP2005-508939

The present invention provides a formulation that maintains the blood concentration of thioctic acid or its derivative in the body for a long time and increases the bioavailability by establishing a formulation design that delays the elution time of thioctic acid or its derivative. To do.

The present inventor has found that a preparation capable of controlling the elution time of thioctic acid can be obtained by adjusting the blending ratio of the lubricant to thioctic acid or a derivative thereof to which an oil film is applied. That is, the present invention is based on the following means.
(1) A preparation containing thioctic acid or a derivative thereof and a lubricant, wherein the elution time of thioctic acid or a derivative thereof is controlled.
(2) The preparation according to (1), wherein an oil film is applied to thioctic acid or a derivative thereof.
(3) The preparation according to (1) or (2), wherein the lubricant is one or more selected from carium stearate, magnesium stearate, and stearic acid.
(4) The preparation according to (1) to (3), wherein the blending amount of the lubricant is 5 to 10% by mass.
(5) The preparation according to (1) to (4), wherein the amount of the oil film is 5 to 50% by mass relative to thioctic acid or a derivative thereof.
(6) The preparation according to (1) to (5), wherein the dosage form is a hard capsule.

By carrying out the method of the present invention, a preparation capable of delaying the elution time of thioctic acid or a derivative thereof can be obtained by a production method greatly simplified as compared with conventionally known techniques. At the same time, significant cost reductions can be expected in manufacturing. Furthermore, since the elution time in the gastric juice can be delayed, it can be expected that the blood concentration of thioctic acid or its derivative in the body is maintained for a long time and the bioavailability is increased.

The present invention is described in detail below.
Thioctic acid is a short having a unique 1,2-diothyrane ring, also known as α-lipoic acid, 1,2-diothylan-3-pentanoic acid, and 1,2-diotyran-3-valeric acid. It means a chain fatty acid derivative. Because of the chiral center at the C3 carbon atom of the 1,2-dithiolane ring, it has an enantiomer, ie R-(+) thioctic acid or S-(-) thioctic acid. Unless otherwise stated, in addition to racemic mixtures, pure enantiomers or mixtures thereof are included. The molecular formula is C ₈ H ₁₄ 0 ₂ S ₂ .

Hard capsules are generally capsules composed of caps and bodies based on pullulan, HPMC, gelatin, etc., filled with powder, granules, or liquid. There are eight types of capsules from No. 000 to No. 5 with standardized capacities, and the larger the number, the smaller the capsule. The capsules currently in use are structured so that they are locked when fitted so that the cap and body are not easily separated after powder filling.
A general hard capsule filling method is shown below.
A method in which the powder in the Auger hopper is pushed directly from above into the body of the hard capsule in the holder.
When the holder loaded with the body of the disc type hard capsule passes under the powder layer, the filled powder is naturally dropped into the body by its own weight and filled.
Compressed filling powder is forcibly filled into the body from the powder layer by a compression plunger pin.
Press the tube into which the plunger pin is inserted into the powder layer of the pressure type content medicine, and fill the tube with the filling powder. Next, the tube moves to the top of the holder loaded with the capsule body, and the filled powder pushed out by the plunger pin is filled into the body.

The hard capsule of the present invention is not affected by the filling method, shape, weight, etc., and these are produced according to a general production method. For example, a mixture of thioctic acid or a derivative thereof and one or more selected from calcium stearate, magnesium stearate, and stearic acid is filled in a hard capsule according to the above-described filling method. Alternatively, it is produced by filling hard capsules according to the above-mentioned filling method by mixing thioctic acid or a derivative thereof coated with an oil and fat and one or more selected from calcium stearate, magnesium stearate, and stearic acid. it can.

In general, the lubricant is blended for the purpose of preventing adhesion of the filled powder to each part of the hard capsule filling machine or promoting fluidization of the filled powder when filling the powder into the hard capsule. Examples of the lubricant in the present invention include “calcium stearate” and “magnesium stearate” as food additives. Other “stearic acid” can also be used. “Calcium stearate” is a mixture of calcium salts of higher fatty acids mainly composed of calcium stearate and calcium palmitate. Similarly, “magnesium stearate” is a higher fatty acid mainly composed of magnesium stearate and magnesium palmitate. Consisting of a mixture of magnesium salts. In terms of properties, both are white, bulky powders with a smooth feel. On the other hand, “stearic acid” is mainly composed of stearic acid and palmitic acid, and is white waxy or crystalline lump or powder and has a slight fat smell.

Lubricants are usually used to prevent adhering to the mortar during tablet production and to make the fluidity of the formulation uniform when filling capsules in about 2% by weight in the formulation. 3 to 20% by mass, preferably 4 to 15% by mass, and particularly preferably 5 to 10% by mass in the powder. When the blending amount of the lubricant exceeds 20% by mass, thioctic acid or a derivative thereof does not elute even if the elution time is 24 hours. Moreover, if the blending amount of the lubricant is less than 3% by mass, the thioctic acid or its derivative is eluted within 60 minutes, and the blood concentration cannot be maintained in the body for a long time. It is desirable to be within.

Further, as the oil film material, an oil powder having a melting point of 40 ° C. or higher is preferable. Specifically, for example, animal oil such as beef tallow and fish oil, vegetable oil such as soybean oil, coconut oil, rapeseed oil, and the like Although it is hardened oil of fats and oils, it is not limited only to these, You may select 1 type or more. It should be noted that oil processing such as purification, deodorization, curing, and transesterification may be performed.

The method of applying the oil / fat coating is to use thioctic acid or its derivative as the core material, contact and collide with the oil / fat powder, and adhere / coat the oil / fat powder on the entire surface of the thioctic acid or its derivative. A method of forming a film by suspending thioctic acid or its derivative and then spray-cooling and solidifying using a spray or rotating disk, and letting thioctic acid or its derivative flow by wind from the bottom and dissolving from the top There is a method of forming a film by spraying the coating agent of the oil and fat powder, but it is not limited thereto.
At this time, when the melting point of the fats and oils to be used is less than 40 ° C., the film becomes non-uniform.

In the present invention, for the purpose of enhancing the production suitability, in addition to thioctic acid or a derivative thereof, calcium stearate, magnesium stearate, and stearic acid, the following inactive components can be contained. Inactive ingredients in the present invention include wheat starch, rice starch, corn starch, potato starch, pregelatinized starch, partially pregelatinized starch, lactose, maltose, reduced lactose, reduced maltose, sorbitol, mannitol, erythritol, xylitol, sucrose, Glucose, guar gum, xanthan gum, sodium alginate, gum arabic, tragacanth gum, pullulan, agar, gelatin, soy dietary fiber, crystalline cellulose, methylcellulose, ethylcellulose, low substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, Hydroxypropyl methylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate phthalate, hydroxyethylcellulose, hydroxypropy Lustach, polyvinylpyrrolidone, carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, carboxymethyl starch sodium, hardened oil powder, oil powder, carnauba wax, cacao oil powder, sucrose fatty acid ester, silicon dioxide, talc, silicic acid Examples include commercially available products such as aluminum and calcium hydrogen phosphate.

[Example 1]
Examples of the present invention are shown below.

“Thioctic acid” with a 50% oil film, “crystalline cellulose” and “calcium stearate” were put into a V-type mixer and mixed for 10 minutes. 10 kg of the obtained mixed powder was used as a filling powder to produce a hard capsule. The prescription is as shown in Table 1. For the preparation thus prepared, 900 mL of the first solution (Japanese Pharmacopoeia) with 0.1 w / v% surfactant added as the test solution, and the number of rotations according to the dissolution test method (Japanese Pharmacopoeia) Absorbance at 100 rpm and wavelength of 333 nm was measured. As the surfactant, polyoxyethylene sorbitan monooleate was used. In addition, elution rate is as follows: thioctic acid is dissolved in 0.1 w / v% polyoxyethylene sorbitan monooleate first solution at a concentration of 50 mg / 900 mL, and the absorbance value at a wavelength of 333 nm of the solution is taken as 100% elution rate. Calculated. The results up to 4 hours after the start of the test are shown in FIG.
[Example 2]

The formulation shown in Table 2 was produced in the same manner as in Example 1, and a dissolution test was performed. The results up to 4 hours after the start of the test are shown in FIG.
[Example 3]

The formulations shown in Table 3 were produced in the same manner as in Example 1 and subjected to a dissolution test. The results up to 4 hours after the start of the test are shown in FIG.
[Comparative Example 1]

The prescription is as shown in Table 4. A hard capsule was prepared in the same manner as in Example 1 except that “sucrose ester” was used instead of “calcium stearate”, and a dissolution test was performed in the same manner as in Example 1. The results up to 4 hours after the start of the test are shown in FIG.

The time point of 4 hours from the start of the test in this test substantially corresponds to the residence time in the stomach.
Therefore, if the dissolution rate has already reached 100% at that time, it means that most of the test preparation is absorbed in the stomach without reaching the intestine. That is, almost no sustained release is expected.
In the comparative example, the dissolution rate at the start of the test for 2 hours reached almost 100%, and it was revealed that the sustained release effect could not be expected simply by subjecting thioctic acid to the oil coating treatment.
On the other hand, in Examples 1 to 3, the dissolution rate after 4 hours from the start of the test was in the range of 30 to 80%. Furthermore, in this example, since the dissolution after 2 hours from the start of the test is very slow, the barrier function of calcium stearate gradually works in the gastric acid environment even after the capsule film dissolves in the stomach, and the dissolution is gentle. I found out that I was doing something.
From this result, it was found that the preparations of Examples 1 to 3 did not all elute in the stomach. That is, it is possible to relax the absorption of thioctic acid, which is the main objective of the present invention in the blood, quickly and uniformly from the stomach to the small intestine, and to keep the active ingredient in the body as much as possible. It means to do.
In the present invention, a singular point was found by using calcium stearate as a “lubricant” for the oil-coated thioctic acid outside the normal range.
As described above, in a preparation containing thioctic acid using “calcium stearate” as a lubricant, delaying the elution time in the first solution of thioctic acid (gastric acid model) depending on the blending ratio of “calcium stearate” I was able to.

The graph which shows the elution rate by the elution test method (Japanese Pharmacopoeia) in Examples 1-3 and a comparative example

Claims (6)

A preparation containing thioctic acid or a derivative thereof and a lubricant, wherein the elution time of thioctic acid or a derivative thereof is controlled. The preparation according to claim 1, wherein an oil film is applied to thioctic acid or a derivative thereof.  The preparation according to claim 1 or 2, wherein the lubricant is one or more selected from carium stearate, magnesium stearate, and stearic acid. The preparation according to claim 1, wherein the blending amount of the lubricant is 5 to 10% by mass. The preparation according to claims 1 to 4, wherein the amount of the oil film is 5 to 50% by mass relative to thioctic acid or a derivative thereof. The preparation according to claim 1, wherein the dosage form is a hard capsule.