JPH0867638A - Injection solution containing erythritol - Google Patents

Abstract

PURPOSE: To provide an injection solution which contains erythritol as a medicinal additive such as an isotonic agent or an analgesic agent, thus is markedly improved in pain relief on injection with safety increased. CONSTITUTION: Erythritol is added to an injection solution as an active ingredient as well as a medicinal additive in an amount of 0.5-7wt.%, optimally so that the osmotic pressure of the injection solution becomes equal to or higher than that of body fluid. Erythritol is a tetrahydric sugar alcohol and a sweetener of extremely low calorie, and has 122 molecular weight, 119 deg.C melting point in a crystalline or powdery form, and is soluble in water, more resistant to diarrhea than other sugar alcohols such as sorbitol, noncariogenic, causes no browning reaction with amino acids and protein medicines. It is not metabolized in vivo and rapidly excreted into urine without adverse effect on the living body. Since it is very high hydration-accelerating action and moisture retention, the solution is excellent in moderation of the stimulation to the skin layer on injection.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an injection containing erythritol as a pharmaceutical additive such as a tonicity agent and a soothing agent.

[0002]

2. Description of the Related Art Orally administered drugs are those which, after being taken, are absorbed from the digestive system and transferred to the blood before being distributed in the body to exert their drug effects. It often takes more than enough time. Therefore, injections that directly deliver the drug into the blood have been developed for the purpose of urgently exhibiting the action. Injectables are also effective for drugs that are poorly absorbed from the digestive system and are difficult to obtain effective blood concentrations. Injectables have a rapid onset of action and some are superior in effect to oral agents, but since they are generally aqueous solutions, sufficient consideration must be given to their stabilization. In addition, injectables, etc., which continue to have a medicinal effect, have been developed, including efforts to make an oily drug an aqueous solution, and various pharmaceutical additives have been developed and used for these purposes.

Thus, injections are very useful and have excellent therapeutic effects, but their safety must be clear, and as a problem that often appears especially in subcutaneous and intradermal injections. The drawback is that it is accompanied by pain. As for the safety of injections, not only the main drug but also the additives are naturally required to have high safety. Pain during injection is caused when there is a large difference in osmotic pressure between the injection and body fluid, the pH value, or local irritation. Therefore, to relieve pain during injection, an isotonicity agent that reduces the difference in osmotic pressure is used, and the pH value is generally adjusted to near neutral. To alleviate irritation, additives exhibiting a hydration promoting effect and pharmaceutical additives such as soothing agents are used. The pH of injections is important for pain and irritation, but also for the solubility and stability of the main drug, and it is not always optimal to adjust the pH value of blood, that is, 7.4. is not. Too strong acids and strong alkalis are out of the question, but due to solubility and stability, they may be unavoidable as weakly acidic or weakly alkaline injections. In such cases, some pain and irritation cannot be avoided.

Conventionally, inorganic salts such as sodium chloride, sugars such as glucose and sugar alcohols such as sorbitol have been used for the purpose of making isotonic injections. Of these, unlike chemically-synthesized products, there are almost no problems in safety, and normally sugars such as fructose and glucose, which are easy to handle as crystals or powders and dissolve in water, are often used. However, these sugars, in the coexistence of amino acid and protein drugs, and drugs with amino groups, acid, alkali,
Since it contains problems such as coloring and changes in components due to heat, there is no choice but to be restricted in its use. Alternative isotonic agents to sugars include sugar alcohols such as xylitol, sorbitol and mannitol. However, since these sugar alcohols are all metabolized in the liver after injection, there is a concern that metabolites may affect diabetic patients and the like. Therefore, materials that are not metabolized in vivo after injection are desired.

[0005] Conventionally, as an example of using erythritol as a drug additive in a drug, a meso-method is used on the surface of a solid drug.
A coated solid drug formed by forming a coating layer of a coating material containing erythritol (erythritol) as a main component (Patent Document 1)
-268628) and a drug component immobilized between erythritol crystals and / or eutectic crystals (Japanese Patent Laid-Open No. 1-268627).
Further, a cerebral pressure and intraocular pressure lowering agent containing erythritol as an active ingredient is known (Japanese Patent Laid-Open No. 63-230627). However, until now, no example has been known in which erythritol is used as an injection as a pharmaceutical additive.

[0006]

DISCLOSURE OF THE INVENTION The present invention does not have the above-mentioned drawbacks, that is, has both isotonic action and stimulative alleviation action, which is capable of relieving pain during injection, and has amino acid and protein system. It is to find a very safe material for sugar-based pharmaceutical additives, which does not cause browning with other drugs and is not metabolized in vivo.

[0007]

As a result of earnest research, the present inventor has found that erythritol is preferable as a material having such properties and characteristics, and has further researched to complete the present invention. . That is, the present invention relates to the use of erythritol as an injection, a tonicity agent, a soothing agent, and other pharmaceutical additives, and specifically, an injection containing a medicinal component and erythritol. is there.

The medicinal components of the injection in the present invention include thioctic acid, follinate calcium, pralidoxime methyl iodide, insulin, dacarbazine, thioinosine, ancitabine hydrochloride, technetium dimercaptosuccinate, technetium hydroxymethylenediphosphonate, and cephalo. Lysine, cefotetan, ceftazidime, sodium cefminox, oleandomycin phosphate, minocycline hydrochloride, dibekacin sulfate, miconazole, midazolam, tolazoline hydrochloride, scopolamine hydrobromide,
Diponium bromide, papaverine hydrochloride, dopamine hydrochloride, dobutamine hydrochloride, etilefrine hydrochloride, trans pie oxocamphor, bucladesine sodium, propranolol hydrochloride dipyridamole, meclofenoxate hydrochloride,
Ozagrel sodium, citicoline, cytochrome C,
Lobeline hydrochloride, doxapram hydrochloride, dextromethorphan hydrobromide, noscapine hydrochloride, berberine hydrochloride, oxytomine, vasopressin, dexamethasone sodium phosphate, betamethasone acetate, prednisolone sodium succinate, plasterone sulfate sodium, dinoprosttromethamine, thiamine disulfide, Riboflamin sodium phosphate and the like can be mentioned.

The content of erythritol in the present invention is usually 0.5 to 7% by weight in the injectable solution, preferably 0.5.
5 to 5% by weight, and more preferably, the osmotic pressure of the injection is almost the same as or higher than that of body fluid. If it is less than 0.5%, the effect of the present invention is difficult to be exhibited. In addition, if it exceeds 7%, it becomes too hypertonic, which is not preferable, and when the amount of the injection solution to be administered is large, cerebral pressure and intraocular pressure lowering action due to osmotic pressure may appear. The injectable composition of the present invention is produced by a conventional method using erythritol instead of or as a part of the conventionally used sugar or sugar alcohol. At this time, erythritol alone may be used as a pharmaceutical additive, but in general, it is often used in combination with other additives such as stabilizers.

Erythritol in the present invention is a tetravalent sugar alcohol, which is an ultra-low energy sweetener which has recently begun to appear on the food market, and has a molecular weight of 122 and a melting point of 1.
Crystals or powder at 19 ℃, soluble in water, having high-quality sweetness, less prone to diarrhea than other sugar alcohols such as sorbitol, non-cariogenic, amino acids,
It is a sugar-based material that does not cause browning reaction with protein-based drugs. Erythritol is found in the natural world in fruits such as pears, grapes, watermelons, and melons, as well as in lichens, mushrooms, and in fermented foods such as wine, sake, and soy sauce. Is a highly safe material that has been used as food.

Like saccharides and other sugar alcohols, erythritol has an isotonic action and has a small molecular weight, so that the amount added to the injection may be reduced accordingly. Erythritol is not only physically and chemically stable, but when administered into blood, it is not metabolized at all in the body and is rapidly excreted in the urine in its original form. Since it has no adverse effect, it is highly preferable as a pharmaceutical additive that is required to have no effect on the living body. On the other hand, since other sugar alcohols such as xylitol and sorbitol are metabolized in the liver, there is concern about the influence of metabolites. In addition, since erythritol has extremely high hydration promoting action and moisturizing action, it has an excellent ability to alleviate irritation to the skin layer at the time of injection, and this action is far superior to other sugar alcohols.

[0012]

EXAMPLES The present invention will be described in more detail below with reference to examples and test examples, but the present invention is not limited thereto. Example 1 Bovine insulin crystals were suspended in distilled water for injection, diluted hydrochloric acid was added and dissolved, and then erythritol was added and dissolved,
100 ml of an aqueous solution containing 40 units of insulin and 30 mg of erythritol in 1 ml was prepared. Then, this aqueous solution was passed through a low protein adsorption Millipore filter having a pore size of 0.45 μm, dispensed into an ampoule of 1 ml, melted, and then heat sterilized at 115 ° C. for 30 minutes to produce an insulin injection. As a control, 30m glucose in 1ml instead of erythritol
An injection containing g was prepared in the same manner as above. The glucose-containing injection was colored by heating,
The injection containing erythritol was stable without any coloration even after 30 days from heating.

Example 2 1 g of thiamine hydrochloride and 5 g of erythritol were dissolved in 900 ml of water for injection, the pH was adjusted to 3.5 with hydrochloric acid, and the total amount was 1000 ml.
And The solution is passed through a 0.45 μm membrane filter. Dispense 1 ml of this into ampoules, and after sealing 1
It was sterilized at 15 ° C for 30 minutes to prepare an injectable solution of thiamine hydrochloride. Separately, in the same manner as above, thiamine hydrochloride
Five types of injections were prepared by adding 10, 20, 35, 50, 70 g of erythritol to 1 g of each. As a control, an injectable solution of thiamine hydrochloride without addition of erythritol was prepared by the same method.

Test Example 1 Using the thiamine hydrochloride injection prepared in Example 2, a pain test for rabbits was carried out. Test method is test solution 0.2 ml
Was injected subcutaneously into the auricles of unrestrained rabbits, and the degree of escape of the rabbits during injection and the behavior after injection were observed.
As a result, the injection without addition of erythritol showed a very strong escape reaction at the time of injection, and exhibited behavior such as violent shaking of the neck after injection. In contrast, erythritol was added to 20,35,50
The g-added injection showed almost no pain reaction. In addition, the injection containing 5,10,70 g of erythritol showed a slight pain reaction at the time of injection, and exhibited behavior such as slight shaking of the neck after the injection.

[0015]

INDUSTRIAL APPLICABILITY According to the present invention, erythritol, which is highly stable and has an isotonic action, a hydration promoting action and a moisturizing action, is used as a pharmaceutical additive for injections, and thus has high stability and It is possible to provide an injectable drug in which pain during injection is remarkably relieved.

Claims (2)

[Claims] 1. An injection containing a medicinal component and erythritol as a pharmaceutical additive. 2. The injectable composition according to claim 1, which contains 0.5 to 5% by weight of erythritol in the injectable composition.