KR20070076769A - Injectable composition of amlodipine and preparation method thereof - Google Patents

Abstract

An amlodipine composition for one-shot injection having improved amlodipine solubility and stability is provided to be administered to patients who have problems on digestive duct when taking medicines orally or cannot take medicines orally. The amlodipine composition for one-shot injection comprises 3.0-10.0mg of amlodipine selected from the group consisting of amlodipine besylate and amlodipine maleate, 0.9 wt.% of NaCl, 5.0-50.0 wt.% of a dissolution supplement selected from the group consisting of ethylalcohol, propyleneglycol, polyethyleneglycol300 and a mixture thereof, 0.1-1.5 wt.% of an additive selected from the group consisting of a stabilizer such as sodium sulfite, sodium metabisulfite, sodium pyrosulfite and a mixture thereof, a preservative such as methyl paraben, propyl paraben and a mixture thereof, and a chelating agent such as disodium ethylene diamine tetraacetate.

Description

Injectable Formulation Containing Amlodipine and Preparing Method Thereof}

The present invention relates to amlodipine injectable compositions capable of one-shot intravenous administration and methods for preparing the same. More specifically, the present invention includes amlodipine having a besylate or maleate salt as an active ingredient, and includes a dissolution aid and other additives selected from the group consisting of ethyl alcohol, propylene glycol, polyethylene glycol 300 or a mixture thereof. By providing a one-shot intravenous composition is made of amlodipine injectable composition and a method for preparing the same that can be used for the purpose of emergency blood pressure lowering.

Amlodipine, a compound of the present invention, is 3-ethyl-5-methyl-2- (2-aminoethoxy-methyl) -4- (2-chlorophenyl-)-6-methyl-1,4-dihydro-3, It is the generic name of 5-pyridine-dicarboxylate and is a calcium channel blocker that acts for a long time in the human body, and this compound is mainly useful for treating angina and hypertension. This compound can reduce the migration of calcium into cells, thereby delaying or preventing cardiac contractions caused by the accumulation of intracellular calcium in the ischemic state. Excessive infusion of calcium in ischemia can lead to many additional side effects that further damage the ischemic myocardial layer.

This reduces the amount of oxygen required for ATP production and activates the oxidation of fatty acids of the mitochondria, possibly promoting cell necrosis. Thus, the compound is effective for the treatment or prevention of various heart diseases such as angina pectoris, cardiac arrhythmia, heart attack and cardiac hypertrophy. In addition, the compound of the present invention can prevent the influx of calcium to the cells of the vascular tissue has a vasodilation action, it is also effective as a therapeutic agent for hypertension and coronary vessel contraction.

When used in pharmaceutical applications, amlodipine is administered in the form of a salt with a pharmaceutically acceptable acid because the free base form is advantageous but there is a problem in stability. In fact, amlodipine besylate was developed commercially as a prescription drug by Feature, and was marketed in the United States under the trade name NORVASC. Subsequently, prescription drugs with maleate salts and camsylate salts have been marketed by several pharmaceutical companies.

However, these commercial oral drugs have a side effect of oral drugs such as burden on the stomach and liver metabolism. In addition, amlodipine drug has a disadvantage that it is difficult to use in patients in an emergency situation that is slow to lower blood pressure because of the slow release. In addition, oral medications have a disadvantage in that they are difficult to take oral medications.

In order to overcome the above problems, when the formulation is prepared in an injectable composition, not only can the rapid drug effect be expected, but also can be effectively administered to patients who are difficult to take oral drugs.

Meanwhile, Korean Patent Publication No. 95-7228 describes a method for preparing a sterile aqueous solution of amlodipine besylate salt. However, the composition of the invention disclosed in this patent is a conventional application of only amlodipine besylate salt to the general method used to prepare a sterile aqueous solution, there is no particular problem, the manufacturing method is also administered slowly over a long time It is a manufacturing method for the purpose of drip settlement.

In addition, the administration method of the antihypertensive injection formulation which is commercially available is the method by the drip instillation mostly. One of the existing emergency blood pressure medications that can be settled (one-shot) drugs of the Nicardipine hydrochloride-based Dong-A drug Ferdipine. However, this drug has a short half-life.

Accordingly, the present invention is to solve the problems of the various oral medications described above and the inconvenience of patients who are not easy to take, the injection composition according to the present invention is not a method of instillation which is slowly administered for a long time. The purpose of this method is to replace oral amlodipine drugs in patients with oral medications who have adverse gastrointestinal side effects or who have difficulty in taking oral medications.

In order to achieve the above object, the one-shot injectable composition according to the present invention is based on the total weight of the composition: (a) amlodipine, an antihypertensive agent selected from amlodipine besylate salt or amlodipine maleate salt as active ingredient 3.0 mg to 10.0 mg as this single dose, (b) sodium chloride as an isotonic agent, 0.9 weight% with respect to the total weight of the composition, and (c) ethyl alcohol, propylene glycol, polyethylene glycol 300 or a mixture thereof as a dissolution aid. Group 2 selected from the group can comprise 5.0% to 50% by weight relative to the total weight of the composition, 0.1% to 1.5% by weight as an additive.

Stabilizer selected from the group consisting of sodium sulfite, sodium metabisulfite, sodium pyrosulphite or mixtures thereof; Preservatives selected from the group consisting of methyl paramen, propyl paraben or mixtures thereof; And a chelating agent composed of disodium ethylene diaminetetraacetate (EDTA).

The one-shot injectable composition may be amlodipine besylate as an active ingredient.

The one-shot injectable composition may be amlodipine maleate as an active ingredient.

Hereinafter, the present invention will be described in detail.

A common method of injection preparation is to dissolve the main medicine and other additives in distilled water for injection, filter the solution with a bacterial filter, aseptically, fill the vial in a sterile state and then seal it.

In the present invention, as an active ingredient, amlodipine, an antihypertensive agent selected from amlodipine besylate salt or amlodipine maleate salt, may contain 3.0 mg to 10.0 mg as a single dose. Containing more than 10.0mg side effects such as headache, peripheral edema, flushing, palpitations due to excessive blood pressure drop, and less than 3.0mg can not achieve the expected blood pressure lowering effect.

In the present invention, in order to dissolve the amlodipine component, each salt containing the amlodipine component (the besylate salt, the maleate salt) was dissolved in isotonic distilled water containing two kinds of dissolution aids, and then an injection composition was prepared with various additives. In particular, in order to help dissolve each salt of amlodipine, ethyl alcohol, prepropylene glycol, and polyethylene glycol 300 were used as dissolution aids. Each salt of amlodipine is soluble in water but does not have great solubility in small amounts of water, so it was dissolved using the above dissolution aids.

The dissolution aid according to the present invention may be included 5.0 wt% to 50.0 wt% with respect to the total weight of the composition according to the present invention. Preferably 8.0% to 30.0% by weight more preferably 10.0% to 21.0% by weight may be included.

When it contains more than 50.0% by weight, a negative effect occurs on the blood pressure drop, and there is a problem of causing harmful effects on the administered patient. When included less than 5.0% by weight there is a difficulty in solubilizing the main component, there is a problem that the main component is precipitated over time after manufacture.

As the additive, stabilizers, preservatives, chelating agents and other pharmaceutically acceptable conventional additives can be used.

As the stabilizer, sodium sulfite, sodium metabisulfite, sodium pyrosulfite, or the like can be used to prevent oxidation. Methyl paraben, propyl paraben, etc. are used as a preservative. Meanwhile, disodium ethylene diaminetetraacetate (EDTA) or the like is used as a chelating agent for removing trace metals.

The additive according to the present invention may comprise 0.1 wt% to 1.5 wt% with respect to the total weight of the composition of the present invention. Preferably from 0.15% to 1.0% by weight, more preferably from 0.2% to 0.5% by weight.

When added in excess of 1.5% by weight, it causes an allergic reaction caused by some components in the human body, and increases the toxicity due to preservatives. When added less than 0.1% by weight, the degree of microbial contamination is increased, there is a problem such as side effects due to the trace metals do not prevent the chemical reaction between oxygen and the drug in the air.

The desired final volume of the amprodpin injectable composition according to the present invention can be adjusted by the addition of sterile distilled water for injection.

On the other hand, the injection solution prepared according to the present invention is treated by bubbling nitrogen gas and filled in vials under nitrogen atmosphere. In other words, when preparing an injection solution in a general atmosphere, oxygen dissolved in air or distilled water may cause an oxidation reaction, and thus nitrogen gas must be saturated in the solution to remove oxygen dissolved in the injection solution. The operation of saturating the nitrogen gas is applied to bubbling nitrogen gas having a purity of 99.9% or more into the solution.

The temperature at the time of bubbling is performed at room temperature, and the bubbling time is adjusted according to the amount of solution. In addition, the injection solution obtained by the composition according to the present invention is filled in a unmanned automatic device system using an automatic filling sealer in a sterile chamber of aseptic state, that is, a vial filled with a silicate glass, and commercialized. The vial is preferably a brown glass container to prevent photochemical reactions from direct sunlight.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are merely examples and the scope of the present invention is not limited thereto.

[Examples 1 and 2 and Comparative Example 1]

According to the composition of Table 1 below, an amlodipine injectable composition comprising a besylate salt (Example 1) or a maleate salt (Example 2) was prepared.

Table 1

ingredient content Amlodipine Besylate (Example 1) or Amlodipine Maleate (Example 2) 6.42mg 6.944mg Sodium chloride 18.0mg Ethyl alcohol 400.0mg Sodium Metabisulfite 3.0mg Methyl paraben 0.8mg Profile paraben 0.1mg Disodium ethylene diaminetetraacetate 0.1mg Distilled water for injection Add 2mL final

According to each of the above compositions, drugs and additives were dissolved in distilled water. There was no significant difference in the preparation method according to each salt, and each injection solution was filtered through a membrane filter and sterilized, and then filled into vials under a nitrogen atmosphere in an aseptic state to prepare an injection.

[Test Example 1]

For Examples 1 and 2 it was confirmed that the stability over time under the conditions of room temperature, refrigeration and acceleration, the results are shown in Table 2.

[Table 2]

Example 1 Content (%) Example 2 Content (%) Preservation Room temperature cold storage Acceleration Room temperature cold storage Acceleration Week 0 100 100 100 100 100 100 1 week 100 99.3 96.6 99.9 99.8 96.1 4 Weeks 99.7 99.4 95.0 99.4 99.2 94.2 9 Weeks 99.7 99.1 91.0 99.5 99.3 91.3

(Content was converted into% compared to 0 weeks)

As can be seen in Table 2, when the one-shot injection composition of Examples 1 and 2 according to the present invention was prepared, it was confirmed that the composition was stable at room temperature and refrigerated conditions.

[Test Example 2]

For Examples 1 and 2 according to the present invention, the blood concentrations of the rats when injected subcutaneously were compared with the group (control) administered with amlodipine besylate tablets at 8 mg / kg and the results are shown in Table 3 below. Shown in

Table 3

Minutes 0 15 30 60 90 Example 1 Administration Group 0 1496.8 227.2 32.1 5.1 Example 2 Administration Group 0 1675.5 311.2 22.8 4.8 Control 0 28.1 118.3 272.1 451.1

(Concentrations were subcutaneously injected at 4 mg / kg in ng / ml, and 5 rats in each group were used to determine an average value.)

As can be seen from the results of Table 3, the amlodipine besylate salt (Example 1) and amlodipine maleate salt (Example 2) reached the highest blood concentration within 15 minutes when prepared as an injectable composition, It can be seen that the blood pressure lowering effect is faster than the control group).

[Test Example 3]

For Examples 1 and 2 according to the present invention, changes in blood pressure were observed when the rats were injected subcutaneously, compared with the control group, and the results are shown in Table 4 below.

Table 4

Dosage 4 mg / kg (S.C) Measuring time 0min 15min 30min 45min 1hr 2hr 3hr 4hr 6hr 24hr unit mmHg mmHg mmHg mmHg mmHg mmHg mmHg mmHg mmHg mmHg Example 1 Administration Group 123.9 67.0 58.9 57.9 56.6 48.8 92.3 95.1 96.9 108.0 Example 2 Administration Group 121.3 65.8 62.7 58.7 60.4 51.4 93.5 98.4 97.5 109.9 Control 123.3 118.1 117.4 103.9 87.4 71.2 63.5 58.2 65.5 107.1

(An average value was applied using 5 rats in each group.)

As can be seen in Table 4, the amlodipine besylate salt (Example 1) and the amlodipine maleate salt (Example 2) showed a blood pressure lowering effect within 15 minutes when prepared as an injectable composition, which was compared with Comparative Example 1 It can be seen that it has an early blood pressure lowering effect when compared. This is in agreement with the results of Table 3 above.

[Examples 3 and 4]

As shown in Table 5, a one-shot injection was prepared in the same manner as in Example 1 with propylene glycol and ethyl alcohol added as a dissolution aid.

Table 5

ingredient content Amlodipine Besylate (Example 3) or Amlodipine Maleate (Example 4) 6.42mg 6.944mg Sodium chloride 18.0mg Propylene glycol 180.0mg Ethyl alcohol 60.0mg Sodium Metabisulfite 3.0mg Methyl paraben 0.8mg Profile paraben 0.1mg Disodium ethylene diaminetetraacetate 0.1mg Distilled water for injection Add 2mL final

[Examples 5 and 6]

As shown in Table 6, a one-shot injection was prepared in the same manner as in Example 1, with the addition of polyethylene glycol 300 as a dissolution aid.

Table 6

ingredient content Amlodipine Besylate (Example 5) or Amlodipine Maleate (Example 6) 6.42mg 6.944mg Sodium chloride 18.0mg Polyethylene Glycol 300 400.0mg Sodium Metabisulfite 3.0mg Methyl paraben 0.8mg Profile paraben 0.1mg Disodium ethylene diaminetetraacetate 0.1mg Distilled water for injection Add 2mL final

With respect to Examples 3 to 6 according to the present invention, the stability test at room temperature, refrigeration and accelerated state was carried out under the same conditions as in Test Example 1, and all of the test results showed excellent stability at room temperature and refrigerated state.

In addition, in Examples 3 to 6 according to the present invention, the results of blood pressure change administered to the rat at a dose of 4 mg / kg as a subcutaneous injection in the same conditions as in Test Example 3, showed a distinct blood pressure drop within 15 minutes, about 24 The effect was maintained even after time.

As can be seen in the test examples, the amlodipine injectable composition had no significant difference in blood pressure lowering effect according to the besylate salt, the maleate salt or the salt, and the effect was faster than that of the oral composition. Seemed. This is expected to be faster than the oral drug by using a drug that has a stable stability of amlodipine, and it can be said that the oral drug can be substituted for patients who can not administer.

Injectable preparations of the present invention include amlodipine, an active pharmacological ingredient, and contain a besylate salt or a maleate salt as salts to exhibit a fast and stable effect on antihypertensive symptoms and to prevent oral administration of the oral drug or to the digestive tract for oral drugs. It has a good therapeutic effect for patients with side effects. In addition, it is manufactured in the form of one-shot dosing rather than drip dosing, greatly improving the convenience of patients by greatly reducing the drug administration time when administered by injection. It is also an injectable composition that has the advantage that there is no change in properties and the content is not reduced even when stored using suitable additives.

While the invention has been described in detail with reference to the specific examples described, it will be apparent to those skilled in the art that various modifications and variations are possible within the scope and spirit of the invention, and such modifications and modifications are within the scope of the appended claims. It is natural to belong.

Claims (4)

As a single-dose composition for amlodipine injection (a) 3.0 mg to 10.0 mg of amlodipine, an antihypertensive agent selected from amlodipine besylate salt or amlodipine maleate salt as the active ingredient, as a single dose; (b) 0.9% by weight sodium chloride as a tonicity agent, based on the total weight of the composition; (c) 5.0 to 50.0% by weight of the total weight of the composition of the group selected from the group consisting of ethyl alcohol, propylene glycol, polyethylene glycol 300 or a mixture thereof as a dissolution aid; And (d) 0.1% to 1.5% by weight of the total weight of the composition as an additive; A one-shot injectable amlodipine composition comprising a. The method of claim 1, wherein the additive is a stabilizer selected from the group consisting of sodium sulfite, sodium metabisulfite, sodium pyrosulfite or mixtures thereof; Preservatives selected from the group consisting of methyl paramen, propyl paraben or mixtures thereof; And Chelating agents consisting of disodium ethylene diaminetetraacetate (EDTA); Amlodipine composition for one-shot injection, characterized in that consisting of. The one-shot injectable amlodipine composition of claim 1, wherein the active ingredient is an amlodipine besylate salt. The one-shot injectable amlodipine composition of claim 1, wherein the active ingredient is an amlodipine maleate salt.