JPS62194861A - Liquid drug package - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for stabilizing liquid pharmaceutical products filled in plastic containers. Furthermore, the present invention relates to a liquid pharmaceutical package manufactured based on such a stabilization method.

BACKGROUND OF THE INVENTION Over-the-counter medicines used in solution form, such as eye drops, nasal drops, and rut-preventing medicines, are often sold in relatively small plastic containers.

This is because plastic containers have less risk of breakage than glass containers, and their elasticity makes them extremely convenient for their intended use.

On the other hand, liquid pharmaceuticals have poor stability (in this specification, "
"Stability" means chemical stability), and various stabilization methods have therefore been attempted. One of the countermeasures is to put a pharmaceutical solution (hereinafter referred to as "chemical solution") into a glass ampoule.
Immediately after filling with nitrogen, melt and seal the mouth of the ampoule to prevent the chemical solution from coming into contact with air. By such a method, a chemical solution that is unstable depending on the type of drug solution can be kept stable for a long period of time.

Problems to be Solved by the Invention Although the nitrogen filling method described above is extremely effective in stabilizing chemical solutions, it is generally believed that this method cannot be applied when plastic containers are used. Ta. That's because plastic containers usually consist of a main body and an attached nozzle and screw-on cap.
Nitrogen gas was expected to leak from the joint between the two in a short period of time, and plastic materials generally have good breathability, so it was thought that it would be impossible to contain nitrogen gas for a long period of time. It is.

Means for Solving the Problems The present inventors have discovered that even if the plastic container is closed with a screw-type cap, gas leakage at the fitting part is surprisingly negligible. Therefore, it has been discovered that when a non-breathable plastic container selected from polyethylene terephthalate and polyarylate is used, the chemical solution can be sufficiently stabilized by filling with an inert gas such as nitrogen, and the present invention has been developed. completed.

That is, the present invention provides a method for stabilizing a drug solution filled in a plastic container made of a screw-type cap and a main body, which are most commonly used. and a liquid pharmaceutical packaging body filled with an inert gas.

The plastic container that can be used in the present invention is not limited to the above-mentioned containers, but may be any plastic container that has air permeability equivalent to or lower than these. In this specification, such containers with poor air permeability are referred to as non-air permeable plastic containers.

Nitrogen is generally the most convenient inert gas to use, but other gases that do not adversely affect the chemical solution can also be used. In this specification, an inert gas is defined as a substance that is gaseous at room temperature and does not cause undesirable interactions with components in the drug solution.

Liquid pharmaceutical packaging is a liquid product obtained by dissolving or dissolving the active ingredient and optionally added auxiliary drugs in a suitable solvent, as seen in commercially available eye drops, nasal drops, etc. A type of pharmaceutical preparation that is conveniently filled in a suitable container for long-term storage and/or divided administration over a relatively long period of time, and is a combination of a liquid pharmaceutical and a container.

Detailed Disclosure of the Invention The present invention will be described in detail below, taking as an example an aqueous solution of sodium guaiazulene sulfonate used as eye drops.

Guaiazulene sulfonic acid and its salts have anti-inflammatory effects,
It is a drug that has a wide range of effects such as antiallergic effects and promotion of epithelial regeneration and granulation formation, and is a useful drug that has been used in pharmaceuticals such as gastrointestinal medicines, rutting agents, nasal sprays, and eye drops since ancient times.

Eye drops and nasal drops made of an aqueous solution of guaiazulene sodium sulfonate (hereinafter abbreviated as GAS) have extremely poor stability and are easily decomposed by light or heat. G.A.
Table 1 shows the results of evaluating the stability of commercially available products (eye drops) containing S. Among the commercially available products stored at room temperature for 3 years, there are no formulations that exhibit a residual rate of GAS of 90% or more.

Surface soil Stability of GAS-containing eye drops The decomposition of GAS in aqueous solutions mainly occurs through oxidation and desulfonation, but the factors that influence the decomposition are the hydrogen ion concentration (pi-1) and dissolved oxygen in the solution. is possible. Generally, GAS is stable on the alkaline side, but the upper limit of pH at which a GAS aqueous solution can be used as a pharmaceutical is '8.
．． Even if it is maintained at a temperature of 5, it cannot maintain its stability against light and heat for a long period of time.

In addition, in the stabilization of GAS, addition of polymer compounds (JP-A-57-108012) and formation of complexes with GAS (JP-A-56-30927, JP-A-5L-1)
25713), etc., but none of these methods can maintain stability over a long period of time.

The present inventors have discovered that dissolved oxygen plays a major role in the decomposition of GAS in an aqueous solution, and have attempted to stabilize it for practical use by lowering its dissolved rate using the method described below. succeeded in. In this case, being practical means that the content of the active ingredient is maintained at 90% or more for three years, which is the expiration date for ordinary pharmaceuticals or quasi-drugs in the market, or longer.

In order to examine the influence of dissolved oxygen on the stability of GAS aqueous solutions, the present inventors prepared in advance GAS aqueous solutions containing various concentrations of dissolved oxygen according to the following formulations and evaluated their stability. The results are shown in Table 2.

Prescription! Sodium guaiazulene sulfonate 0010% boric acid 0.500 borax
0067NaCQ
O,390KCσ
o, o s.

Sterile purified water, suitable pH 7,
6 Red Stability of GAS aqueous solutions with various dissolved oxygen concentrations (residual rate %) As shown in Table 2, even a slight reduction in the amount of dissolved oxygen can be expected to be sufficient to improve the stability of GAS aqueous solutions. There was found. Furthermore, since the ratio of oxygen concentration in the air and in the liquid is very large, by reducing only the oxygen concentration in the air layer in the packaging container filled with the GAS aqueous solution, the GAS aqueous solution can be sufficiently stabilized. It was expected that it would be possible.

The present inventors used plastic containers made of polyethylene terephthalate (PET) and polyarylate materials in the production process of eye drops, etc., and excluded the final step of air cleaning before filling the main body with the drug solution. G
The AS aqueous solution could be kept sufficiently stable for a long period of time.

In the present invention, the purpose can be sufficiently achieved by replacing the gas phase within the container with nitrogen after filling the container with nitrogen, and then closing the container with a cap instead of nitrogen cleaning.

Examples will be given below to show the results of stability evaluation of GAS aqueous solutions using containers of the same shape but different materials.

Example I The shapes are the same (capacity B t 3 mQ), and the materials are polyethylene terephthalate (PET) and polyarylate (PET).
A), polycarbonate (PC), polypropylene (
A container made of polyethylene (PP) and polyethylene (PE) was aseptically cleaned for 10 seconds with 2.4 Q/min of nitrogen, filled with 7 Q of a GAS aqueous solution of Formulation 2 shown below, and closed aseptically. On the other hand, instead of nitrogen cleaning, conventional air cleaning was performed, and a package sample that underwent the same process was prepared as a control.

Table 3 shows the results of evaluating the stability of GAS at 50°C for the above samples.

Formulation 2 Sodium guaiazulene sulfonate 0.02 boric acid I, 20 cavus
0.3011CO-60o
0.10 Henzalkonium chloride
0. O1 sterilized purified water suitable m
pH 7,6 E1 Differences in GAS stability due to different container materials As shown in Table 3, polyethylene terephthalate (PET)
When using containers made of polyarylate and polyarylate (PA), the effect of nitrogen filling can be maintained for a long period of time.

Next, we investigated to what extent differences in the amount of filling liquid, in other words, differences in the amount of nitrogen filling in the container, would affect the stability of the GAS aqueous solution. The results are shown in Example 2 below.

Odoriferous carp l In the same manner as in Example 1, a 13m (PET container was cleaned with nitrogen, and the GAS aqueous solution of formulation 2 was poured into 6*Q, 8*Q, 10
*Q and 12*Q are filled aseptically and then closed aseptically. As a control, 61 and 12 m12 were added to the air-washed container.
G filled with S aqueous solution was used.

Table 4 shows the results of evaluating the stability of the GAS aqueous solution at 50° C. for these packaged samples.

Table 1: Filling amount of chemical liquid and stability of GAS (PET container: capacity: 3 units) It can be seen that if the filling amount is 12 m9 or less, it can be stabilized for a long period of time. In addition, the GAS residual rate in the case of nitrogen filling and air filling was 9 at 50℃ and 30 days, respectively.
4% and 86%, and this difference seems small, but this difference actually means that the product can be stably guaranteed for more than 3 years, or that it cannot be guaranteed and the drug must be recorded as a product with an expiration date. This is the turning point in whether or not it becomes necessary, and from that point of view, this difference is extremely large from an economic point of view.

The above study was about the thermal stability of the GAS aqueous solution, but the present inventors further investigated the stability against photodecomposition when nitrogen filling and an appropriate container material were combined. The results are shown in Example 3 below.

Tomoshiki Koi 1 +3 A MQPET container was cleaned with nitrogen or air, and a package sample prepared in the same manner as in Example 1 was placed under a fluorescent lamp (50001
The stability of the GAS aqueous solution was evaluated. The results are shown in Table 5. In addition, prescription 2 was used as the S aqueous solution for G, and 7*Q was used as the filling liquid m.

25°C, 75%, under fluorescent light (50001 ux) As shown in Table 5, the GAS aqueous solution when filled with nitrogen has sufficiently increased stability against light, and is suitable for manufacturing processes such as container closure and packaging. , or can have sufficient stability against light that is expected to be exposed during the subsequent distribution process.

Although the above explanation has been given by taking an aqueous solution of sodium guaiazulene sulfonate as an example, it will be easily understood that the present invention can be applied to all liquid pharmaceuticals. However, particularly suitable pharmaceuticals for the application of the present invention include vitamin A and its esters, vitamin C, vitamin B, and glutathione.

Claims (6)

[Claims] (1) A liquid pharmaceutical package consisting of a non-breathable plastic container filled with a medicinal solution and an inert gas. (2) The package according to item (1), wherein the non-breathable plastic container is made of a material selected from polyethylene terephthalate and polyarylate. (3) The package according to item (2), wherein the chemical solution is an aqueous solution of sodium guaiazulene sulfonate, and the inert gas is nitrogen. (4) After cleaning the non-breathable plastic container with an inert gas, immediately fill it with a chemical solution and close it, or replace the gas phase inside the container with an inert gas after filling it with a chemical solution and close it. , a method for stabilizing drug solutions in plastic containers. (5) The method according to item (4), wherein the non-breathable plastic container is made of a material selected from polyethylene terephthalate and polyarylate. (6) The method according to item (4), wherein the chemical solution is an aqueous solution of sodium guaiazulene sulfonate, and the inert gas is nitrogen.