KR920006911B1 - Stable Pyroxycam Injectable Composition and Preparation Method Thereof - Google Patents

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Description

Stable Pyroxycam Injectable Composition and Preparation Method Thereof

The present invention is useful as an anti-inflammatory analgesic agent, 4-hydroxy-2-methyl-N-2-pyridinyl-2H-1,2-benzothiazine-3-carboxamide 1, 1-dioxide, That is, the present invention relates to a stable aqueous injection composition containing pyoxycamp and a method for producing the same.

Pyroxycam represented by the above structural formula is a compound useful as a nonsteroidal anti-inflammatory and analgesic agent, and is a known compound generally used to treat rheumatoid arthritis, ankylosing spondylitis, low back pain, menstrual pain, trauma and post-extraction pain. Such a method for producing pyroxicam is described in US Pat. No. 3,591,584, and German Federal Patent No. 1,943,265.

However, in spite of excellent anti-inflammatory and analgesic effect, such phyroxicam may cause side effects such as peptic ulcer due to gastrointestinal disorders when orally administered in the form of tablets or capsules containing it as an active ingredient. The administration to patients such as the weak elderly has been considerably limited.

Therefore, many studies have been conducted to improve these problems, and these studies have been divided into two directions as follows.

First of all, in order to minimize gastrointestinal disorders, there is a method of converting and administering the active ingredient pyoxycham to a form of pyoxycam salt by reacting with another compound which is harmless to the human body and is pharmaceutically acceptable. In this way, for example, Korean Patent Publication No. 87-3783 discloses a method for preparing pyroxicam salt by reacting pyroxicam with 5'-guanylic acid or N-acetyl-L-methionine. No. 66,459 describes a process for preparing mono (di) ethanolamine salts of pyroxicam and mixing them with a carrier to tablet them.

As a second method, in order to prevent gastrointestinal disorders, a method of using a gel ointment instead of orally administering phyroxicam is applied to the pain area or by dissolving phyroxicam in water or a suitable solvent as an injection. As a technique for developing pyroxam as an injection, U.S. Patent No. 4,434,163 and European Patent No. 66,458 can be exemplified. According to these techniques, pyrocampam is reacted with L-arginine to produce an arginine salt of pyroxicam. After the preparation, a vial filled powder injection was prepared by mixing with sodium dihydrogen phosphate. Such injections should be used after dissolving in distilled water when administering to patients.

However, these powder injections have some improvement in absorption rate than oral tablets prepared by the first method.However, the powder injections cannot be stored for a long time after dissolving the powder injection in distilled water for re-preparation in use. have. This is because the aqueous solution of pyoxycham is very unstable in solution state, so that crystals are precipitated when stored for 1 day at 10 ° C. and at least 3 days at 20 ° C., and thus there is a critical problem in that they cannot be stored for a long time in solution state.

Accordingly, the present invention aims to develop a stable injection solution which does not need to be re-prepared in use by improving the problem of the use of pyroxicam injection. That is, it is an object of the present invention to prepare a stable aqueous pyroxicam injectable composition which does not precipitate crystals even after long-term storage by preparing pyroiccam insoluble in water using a specific dissolution aid and stabilizer. It is.

Hereinafter, the present invention will be described in detail.

The present invention is characterized in that it contains one of the dibasic amino acids and propylene glycol, and a stabilizer, povidone, selected from the group consisting of pyroxicam as an active ingredient, L-arginine, L-lysine, and other amino acids having two amino groups as dissolution aids. It relates to a phyroxicam injection liquid composition.

In the injection solution composition of the present invention, the amino acid as a dissolution aid is contained in an amount of 1.1 to 1.2 moles per 1 mole of pyroxicam, propylene glycol is contained in 10 to 30 W / V% in the total injection solution, povidone is stabilizer 1 in the total injection solution To 2 W / V%.

In addition, the concentration of pyroxycam in the injection liquid composition of the present invention is about 2 W / V%.

Referring to the present invention in more detail as follows.

Specifically, the method for preparing the pyricampam injection solution composition according to the present invention is dissolved in distilled water for injection at 60 ° C to 80 ° C with an amino acid having two amino groups as a dissolution aid and propylene glycol. After adding povidone which is a stabilizer to the resulting solution, a pyroxicam injection solution is prepared according to the method for preparing a general injection solution. The pyroxycam concentration in the thus prepared pyroxycam injection solution composition may be about 2 W / V%.

As a dissolution aid in the injection solution composition of the present invention, propylene glycol and one dibasic amino acid selected from L-arginine, L-lysine and other amino acids having two amino groups are used together. It can be increased or decreased by complementary action with povidone, a stabilizer.

In the present invention, the dibasic amino acid per mole of pyroxicam is used at a ratio of 1.1 to 1.2 moles, and propylene glycol is used in combination so as to be 10 to 30 W / V% in the total injection solution. At this time, the stabilizer povidone is preferably used in an amount of 1 to 2W / V% in the total injection solution. More preferably, 1.1 mole of amino acid and 20 W / V% of propylene glycol per mole of pyroxicamp, and the pH of the injection solution is 8.0 to 8.4.

On the other hand, since the dissolution aid and stabilizer used in the present invention may be precipitated as crystals of the active ingredient in the injection, pyroxicam, depending on the type and the amount used, it is very appropriate to select the type and amount of the dissolution aid and stabilizer. It is important.

In other words, when the amino acid is used in an amount of 1.1 to 1.2 moles as a dissolution aid and propylene glycol is used at an optimum amount of 20 W / V%, the povidone as a stabilizer is used in an amount less than lW / V% in the total injection solution. Pyroxycam crystals are precipitated when stored at 10 ℃ for more than 2 months. On the contrary, propylene glycol is used in amounts less than 10W / V% while using amino acids in amounts of 1.1 to 1.2 mol and povidone in lW / V%. Even when it was found, the pyroxycam crystal was found to precipitate.

In addition, when only 1.1-1.2 mol of dibasic amino acids which have two amino groups are used without using propylene glycol as a dissolving aid, pyroxycam does not dissolve completely even if it is suspended in distilled water and dissolved while heating. Therefore, more than about 1.5 moles of amino acids should be used. In addition, even when used in such an excess, if the prepared injection solution is stored for only one month at 10 ° C., the crystals are precipitated again, and the pH of the injection solution is increased to 8.6 or higher, which is not suitable for administration as an injection.

Therefore, by using a certain amount of dibasic amino acid and propylene glycol as described above, it is possible to prepare the most ideal injection solution composition while reducing the amount of amino acid added.

The most preferable composition of the phyroxicam injection composition according to the present invention is as follows.

[Composition ratio in ml of phyroxicam injection solution]

In the composition, other additives generally used in the preparation of injectables may be added, in particular, analgesic agents such as benzyl alcohol.

As described above, the stabilized pyroxicam injection composition prepared according to the present invention has a very desirable effect of maintaining a stable state in which crystals do not precipitate even when stored at 10 ° C. for 4 months or more.

Hereinafter, the present invention will be described in detail based on examples.

In the following examples, all of the cases in which the preferred injection solution composition ratio according to the present invention and the composition ratio outside of the range were carried out as examples, but the present invention is not limited thereto.

In addition, the pyricampam injections prepared in Examples 1 to 6 were compared to determine whether the crystals were deposited while being stored at 10 ° C. to confirm their storage stability, and the results are shown in Table I below.

Example 1

20 g of pyoxycham, 12 g of L-arginine and 200 g of propylene glycol were added to 700 ml of distilled water for injection at 70 ° C. and stirred for 30 minutes to dissolve all. Then, 10 g of povidone (polyvinyl pyrrolidine K-30) and 10 g of benzyl alcohol were added. do.

After stirring for 10 minutes, the mixture was cooled to room temperature, the volume was adjusted to 1 L as distilled water for injection, followed by stirring well, followed by sterile filtration. The filtered injection solution was filled in a 5 ml brown ampoule, sealed, autoclaved and sterilized and stored at 10 ° C to observe the precipitate state of the crystals.

Example 2

20 g of pyoxycam, 12 g of L-arginine and 200 g of propylene glycol are added to 700 ml of distilled water for injection at 70 ° C., stirred for 30 minutes to dissolve, and then 5 g of povidone and 10 g of benzyl alcohol are added.

After stirring for 10 minutes, the mixture was cooled to room temperature, the volume was adjusted to 1 L as distilled water for injection, prepared according to the method of Example 1, and stored at 10 ° C to observe the precipitated state of the crystal.

Example 3

20 g of pyoxycam, 12 g of L-arginine and 100 g of propylene glycol are added to 700 ml of injectable distilled water at 70 ° C to dissolve, and 10 g of povidone and 10 g of benzyl alcohol are added thereto. After stirring for 10 minutes, the mixture was cooled to room temperature and the volume was adjusted to 1 L as distilled water for injection, followed by well stirring. Then, the precipitated state of the crystal was observed while preparing according to the method of Example 1 and storing at 10 ° C.

Example 4

20 g of pyoxycam, 10 g of L-lysine and 200 g of propylene glycol are added to 700 ml of injectable distilled water at 70 ° C to dissolve, and 10 g of povidone and 10 g of benzyl alcohol are added. After stirring for 10 minutes, the mixture was cooled to room temperature, the volume was adjusted to 1 L as distilled water for injection, followed by stirring well, and then prepared according to the method of Example 1 and the crystallization state was observed while storing at 10 ° C.

Example 5

20 g of pyroxycam and 12 g of L-arginine are added to 900 ml of distilled water for injection at 70 ° C., followed by stirring for 30 minutes. Then, 3.8 g of L-arginine is further added and stirred for 30 minutes. After dissolving all the pyricampam, 10 g of benzyl alcohol was added, stirred, cooled, adjusted to 1 L as distilled water for injection, prepared according to the method of Example 1, and stored at 10 ° C. to observe the precipitation state of the crystals.

Comparative Example 1

Suspend 50 g of pyroxycam in 4 L of water and add 27.7 g of L-arginine. The suspension is heated to dissolve and the insolubles are filtered off and the filtrate is concentrated under reduced pressure. A mixed solvent of chloroform and 1500 ml of ethyl acetate was added to the viscous residue, and stirred for 24 hours at room temperature under a stream of nitrogen. Precipitated crystals were filtered and dried under reduced pressure to obtain 49.3 g of an pale yellow arginine salt of pyroxicam. Pyroxycam content is 64.8%. Mix 30.9 g of arginine salt of pyroxycam (20 g as pyroxycam) with 77.3 g of sodium monohydrogen phosphate, and fill an amount corresponding to 100 mg of pyroxycam per vial. The vial was sealed and dissolved by adding 5 ml of distilled water for injection, and then compared with the sample of another example for storage at 10 ° C. to determine whether crystals were precipitated.

[Table I 20 samples each, pyroxham concentration 2W / V%]

* 1) The amount of L-arginine and L-lysine is the molar concentration for 1 mole of pyruxicam

2)% of povidone and propylene glycol is W / V% of total injection solution

Claims (2)

Pyricam as an active ingredient: A mixture of 1.1 to 1.2 mol of L-arginine or L-lysine per mol of pyroxicam as a dissolution aid, and a mixture of 15 to 25 W / V% propylene glycol of the total injection composition and a total injection solution A stable pyoxycham injection composition comprising 1 to 2 W / V% of povidone of the composition. The active ingredient pyoxycam is dissolved in distilled water for injection with a dissolution aid, L-arginine or L-lysine, and propylene glycol, and povidone, a stabilizer, is added to the resulting solution. A method of preparing a stable pyroxyl injection solution composition.