JPS61275214A - Menatetrenone soft capsule for oral administration - Google Patents

Abstract

PURPOSE:To provide the titled orally administrable soft capsule having high stability, by compounding menatetrenone useful as a hemostatic agent with a vegetable oill and a surfactant (polysorbate 80, medium-chain glycerol fatty acid ester, soybean phospholipid, etc.) at specific ratios. CONSTITUTION:100pts.wt. of menatetrenone is compounded with (A) >=100pts.wt. of a vegetable oil and (B) at least one component selected from 0.01-40pts.wt. of monooleic acid polyoxyethylene sorbitan (polysorbate 80), 30-2,000pts.wt. of a medium-chain glycerol fatty acid ester and 10-200pts.wt. of soybean phospholipid. The soft capsule obtained by the above process is a safe oral capsule agreeable to take. The administration method of menatetrenone preparation having remarkable effect to hypoprothrombinemia, hemorrhage, etc., can be improved in the above soft capsule. It can be applied to a wide variety of patients.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to improvements in the route of administration of menatetrenone preparations that are effective against, for example, hypoprothrombinism and hemorrhage, and specifically relates to improvements in the route of administration of menatetrenone preparations for oral use. By re-recognizing the necessity from the perspective of all those involved in medical care, including patients and doctors, and resolving the problems that arise when planning oral preparations, we will be able to make oral administration possible, thereby making it clinically viable. The present invention relates to oral menatetrenone soft capsules that can contribute to the effectiveness, usefulness, and safety of menatetrenone.

[Prior Art] Menatetrenone is known as the common name for vitamin 2.

Menatetrenone (hereinafter sometimes referred to as vitamin 2) has the physiological effect of being strongly involved in hemostasis in the body, so it can cause hypoprothrombinism due to biliary atresia and bile secretion failure, neonatal hypoprothrombinism, and bleeding. It occupies an important position as a drug that improves the

A preparation containing such menatetrenone includes (1) menatetrenone, (2) a solvent for dissolving the menatetrenone,
(3) For example, surfactants such as polyoxyethylene sorbitan monooleate (hereinafter referred to as polysorbate 80) and polyoxyethylene hydrogenated castor oil (hereinafter referred to as HCO-60); (4) the above (1) to (3); It is generally composed of water, etc., which is a dispersion medium for dispersing in a suspension or emulsion.

When using this preparation, intravenous or intramuscular administration routes are selected, and the medical background for selecting such administration routes can be explained as follows.

(a) As is clear from the indications for menatetrenone preparations, it has been thought that they are mainly administered to inpatients and outpatients.

(b) When administering drugs to patients with severe injuries, newborns, etc., it is often necessary to rely on injections.

(c) There are many cases where prompt effects are required.

[Problems to be solved by the invention] When intramuscular or intravenous administration as described above is performed,
Menatetrenone has an extremely quick onset of efficacy, but there are quite a few problems when judged from the perspective of side effects. In other words, in the case of intramuscular injection, side effects such as delayed induration, hemolysis, myopathy, edema, and tissue necrosis may occur at the injection site due to the influence of the solvent (2) above or the surfactant (3) above. Intravenous administration can sometimes lead to serious crises such as shock symptoms depending on the injection speed.

Therefore, oral administration is being reconsidered as an alternative administration method to intravenous and intramuscular injections of menatetrenone. The necessity of oral administration is also supported by the fact that patients who can receive oral administration, such as outpatients, do not necessarily need to be limited to intravenous or intramuscular injection.

The present invention has been made in response to these demands, and enables oral administration by solving the problems that arise when planning oral menatetrenone preparations, thereby improving the clinical effectiveness and usefulness of the preparations. The present invention aims to provide a menatetrenone soft capsule for oral use that can contribute to safety and safety.

[Means for Solving the Problems] The oral menatetrenone soft capsules according to the present invention contain (A) vegetable oil:
Contains 100 parts by weight or more, and (B) polyoxyethylene rubitan heptanooleate 80:O, 1 to 40 parts by weight, medium chain glycerin fatty acid ester 30 to 2000 parts by weight, soybean phospholipid: 10 to 200 parts by weight at least l
The gist lies in the combination of different types.

[Effect] The present inventors have solved the above-mentioned problems with injections, and have developed an oral administration method that is easy and safe for patients to take, while not causing difficulties for doctors. Focusing on administration, since menatetrenone itself is fat-soluble, it can be mixed with vegetable oils (sesame oil, olive oil, cottonseed oil, peanut oil, wheat germ oil, etc.) and surfactants (polysorbate 80, medium-chain glycerin fatty acid ester, soybean phospholipid). etc.), and the surfactant is dispersed and dissolved, and the dispersed and dissolved medicinal solution is used to prepare oral metinatrenone soft capsules. The present invention has been completed as a result of intensive research from the viewpoints of stability and (B) pharmacological properties of menatetrenone associated with administration of the soft capsule preparation. The following will be explained separately in (A) and (B).

(A) Regarding the pharmaceutical stability of oral menatetrenone soft capsules: As a guideline for evaluating the pharmaceutical stability of the oral menatetrenone soft capsules, (a) focusing on the presence or absence of crystal precipitation near the low temperature storage temperature of menatetrenone. investigated. Furthermore, since menatetrenone itself is unstable to light, (b) capsule materials and additives were also included in the formulation stability evaluation.

Each will be explained below.

(a) Presence or absence of crystal precipitation near the low-temperature storage temperature of menatetrenone The crystal precipitation is, of course, affected by the types of vegetable oils and surfactants used to disperse and dissolve menatetrenone, and their blending ratio, among other things. It is largely influenced by the type of surfactant and its blending ratio.

Therefore, the present inventors prepared a solution in which the blending ratio of menatetrenone and vegetable oil was kept constant (specifically, 60, 80, 100° and 120 parts by weight of vegetable oil were blended with 100 parts by weight of menatetrenone). Various surfactants were added to the sample, and the mixing ratio of the surfactants was varied to examine the presence or absence of crystal precipitation. As a result, the following conclusions were obtained.

(a) Polysorbate 80 did not cause crystallization of menatetrenone if its blending ratio was 0.01 to 40 parts by weight, preferably 0.05 to 20 parts by weight, per 100 parts by weight of menatetrenone.

(0) For medium chain glycerin fatty acids, 30 to 200
If the amount was 0 parts by weight or more, preferably 50-1500 parts by weight or more, the crystallization did not occur.

(c) Regarding soybean phospholipid, 10 to 200 parts by weight, preferably 20 to 100 parts by weight, was molded.

Next, the material etc. of the capsule in (b) will be explained.

(b) Soft capsule material and additives As mentioned above, menatetrenone is a tamin that is unstable to light, so soft capsule material (
gelatin, concentrated glycerin, D-sorbitol, etc.), substances that absorb particularly short wavelength light, such as titanium oxide, and coloring agents, such as Food Yellow No. 4, No. 5, etc.1 Food Red No. 2, No. 3, 102 It is possible to add tar-based pigments such as No.

(B) Regarding the pharmacological properties of oral menatetrenone soft capsules: Oral menatetrenone soft capsules (301 g as menatetrenone) with the blending ratio specified in (4), (o), axis) and (b) above are described below. We compared the pharmacoefficacy index obtained by oral administration to pegle dogs and the results obtained when the same amount of menatetrenone was intramuscularly injected.
It has been found that if the formulation contains OO parts by weight or more, there will be no clinical disadvantage to the absorption ability of menatetrenone even if it is administered orally. This is because when the amount is less than 100 parts by weight, menatetrenone, vegetable oil, surfactant, water, etc. form micelles in the menatetrenone absorption site of the above sample, and as a result, the absorption ability of menatetrenone itself is inferior. .

This is because if the amount is 100 parts by weight or more, such formation of micelles will not occur, and therefore the absorption ability of menatetrenone will not be adversely affected.

The present invention will be made clearer by giving examples according to the present invention.

[Examples] First, four examples will be described regarding the method for producing soft capsules.

Example 1 Purified sesame oil was heated to 70 to 80°C in a hot bath, and menatetrenone, polysorbate) 80, medium chain glycerin fatty acid ester, and soybean phospholipid were added and dissolved, and after cooling to 50°C,
Soft capsules were prepared in a conventional manner using a separately prepared capsule base with 160 g of content to obtain orange soft capsules containing 30 mg of menatetrenone per capsule. The contents and the components and composition of the capsule base are summarized as follows.

(Contents) Menatetrenone 30g refined sesame oil
103mg polysorbate 80
2mg medium chain glycerin fatty acid ester 20
mg soy phospholipid 5+sg (capsule base) gelatin 79 mg concentrated glycerin 30.8 mg ethyl paraoxybenzoate 0.17 rag propyl paraoxybenzoate 0.08 layer g food yellow No. 5 trace purified water dosage meter
270■g example? Medium chain glycerin fatty acid ester in a hot bath at 70-80℃
Then, menatetrenone and polysorbate 80 were added and dissolved, and after cooling to 50° C., orange soft capsules containing 160 mg of contents and 10 mg of menatetrenone per capsule were obtained using a separately prepared capsule base. The ingredients and composition of the contents and capsule base are summarized below.

(Contents) Menatetrenone 10mg Refined sesame oil Sesame oil 10+g Polysorbate 80
2 liters of soybean phospholipid lon
g Medium chain glycerin fatty acid ester 138 mg (capsule base) Gelatin 79 g Concentrated glycerin 3o, 6 g Ethyl paraoxybenzoate 0.17 g Propyl paraoxybenzoate 0.
08 ■g Edible Red No. 3 Trace Purified Water Dosage Meter
270mg Example 3 Refined sesame oil was heated to 70-80°C in a hot bath, and menatetrenone, polysorbate 80, and soybean phospholipid were added.

After adding and dissolving medium-chain glycerin fatty acid ester and cooling to 50°C, the contents 16 were added using a separately prepared capsule base.
Menatetrenone 2011 in 1 capsule at 0g
Orange soft capsules containing g were obtained. The ingredients and composition of the contents and capsule base are summarized as follows.

(Contents) Menatetrenone 20+sg refined sesame oil 86mg polysorbate 80
4mg soy phospholipid 1
0mg medium chain glycerin fatty acid ester 40g fat (capsule base) Gelatin 85mg D-sorbitol liquid (70%) 8.5mg concentrated glycerin
17.0 mg ethyl hydroxybenzoate
0.17 mg Propyl paraoxybenzoate 0.0
8 rag food yellow No. 5 small amount purified water appropriate amount meter
Table 1 shows the observation results regarding the state of precipitation of menatetrenone crystals at 270 tmg and around the low temperature storage temperature.

Finally, we will show the results of an animal experiment using Peagle dogs.

The drug was administered to pegle dogs orally (oral menatetrenone soft capsules) and intramuscularly, and 15,30 days after administration.
45,60,90,120°180.240.360.
After 480 minutes, 7 ml of blood was collected from the jugular vein of the Peagle dog.
Their plasma was collected. Menatetrenone in the plasma was extracted with an organic solvent and then quantified by high performance liquid chromatography under the following conditions.

Liquid chromatography conditions> Column Tsubapak (5#LmX I Ocm) Mobile phase Methanol:water (99:l) Flow rate 1.0ml
/gin Detector Ultraviolet spectrophotometer 280 nm The results of tracking menatetrenone concentration in each plasma are shown in Figure 1, and from these results Cmax, Tmax, A
The results of determining UC are shown in Table 2.

[Effects of the Invention] Since the present invention is configured as described above, oral administration is possible by solving the pharmaceutical and pharmacological problems that arise when planning oral menatetrenone preparations, and it is possible to make oral administration possible. The drug can be administered to a wide range of patients, including hospitalized patients, and furthermore, the use of the preparation can also prevent symptomatic diseases, thereby contributing to the clinical effectiveness, usefulness, and safety of the preparation. Menatetrenone soft capsules for oral use can be provided.

[Brief explanation of the drawing]

FIG. 1 is a graph showing changes over time in plasma menatetrenone concentration in pegle dogs.

Claims (1)

[Scope of Claims] Contains (A) 100 parts by weight or more of vegetable oil based on 100 parts by weight of menatetrenone, and (B)
Polyoxyethylene sorbitan monooleate: 0.0
1 to 40 parts by weight, medium chain glycerin fatty acid ester: 30
A menatetrenone soft capsule for oral use, characterized in that it contains at least one or more of 10 to 200 parts by weight of soybean phospholipids.