KR980008219A - Pharmaceutical composition for stabilized injection - Google Patents

Abstract

The present invention relates to a stabilized injectable pharmaceutical composition comprising an active ingredient which is sparingly soluble in water and which can be degraded during storage, is suitably mixed with polyethylene glycol 660 12-hydroxystearate and an organic solvent as a solubilizer, A pharmaceutical composition prepared by adding an appropriate acid to adjust the pH of the solvent to a specific range minimizes the degradation of the active substance and loss of activity during use and prevents the formation of precipitates during dilution for formulation, And thus can be usefully used as an intravenous injection.

Description

[Title of the Invention]

A malignant composition for stabilized injection

DETAILED DESCRIPTION OF THE INVENTION [

The present invention relates to a stabilized pharmaceutical composition for injection, and more particularly, to a pharmaceutical composition for stabilized injection, which comprises an anticancer agent which has strong anticancer activity but is insoluble and easily decomposed during use, as an active ingredient, To improve the stability, toxicity and side effects by properly mixing and admixing them.

In order to administer a pharmaceutical composition to a patient as an injection, the active ingredient must be suspended or prepared in the form of a suspension or solution in a suitable solvent. The conditions of the solvent for preparing an effective injection should be such that it can dissolve or suspend an effective amount of the active ingredient in an effective amount, be compatible with the active ingredient, and exhibit no toxicity or adverse side effects.

However, there are many active ingredients that are not sufficiently soluble in one solvent, so it is often the case that two or more solvents are mixed and used. Such a co-solvent system is suitable as a method for solubilizing many medicaments that can not be dissolved or suspended in various systems.

Illustrative examples of the co-solvent system may be a case where a mixture of a polar solvent and a non-ionic surfactant, such as a mixture of polyethylene glycol and polyoxyethylated castor oil federated (Cremophor EL ^TM). Castor oil (castor oil) and BASF (Germany) (g) product Crescent blanket EL ^TM as a condensation product of ethylene oxide is standing multidrug resistance of cancer cells without changing the drug sensitivity of the original cell line when used as a solvent of an anticancer agent (multi- drug resistance, and is known to exhibit hematopoiesis during chemotherapy or radiation isotope treatment. (WO91 / 012531)

Other co-solvent systems include a 50:50 mixture of Kremopo EL ^™ and ethanol. However, this cosolvent system is effective in solubilizing various insoluble drugs, but has disadvantages such as formation of precipitates when diluted to be administered to a patient and fibrous precipitates during storage. These precipitates are generally known as decomposition products produced by the reaction between the solvent and the active component.

Examples of the pharmaceutical composition using such a cosolvent system include a composition obtained by solubilizing paclitaxel having anticancer activity in a 50:50 mixed solution of ethanol and Kremopo EL ^™ . Paclitaxel is a natural substance first isolated from the Pacific tree (Taxus brevifolia) by Wani (J. Am. Chem. Soc., 93, 2325 - (1971)) and is currently used as a treatment for metastatic ovarian cancer and breast cancer Clinical trials are also underway for woody cancer, head cancer, lung cancer, melanoma, and lymphoma.

Of ethanol and crushers blanket ah EL ^TM co-solvent system has a problem that the winning effective in solubilizing sufficient amounts of the paclitaxel, but it can be are limited to the period the potency or activity of the active ingredient during the retention period, reduced to less than 60% . CREMOPHOIA EL ^™ has been reported to cause severe hypersensitivity in animal and clinical trials, including dyspnea, hypotension, angioedema and systemic dementia. These adverse effects were fatal to patients receiving this drug in Phase I trials, especially in the short-term infusion, so Phase 2 and Phase III trials in the United States were performed 24 hours . In order to minimize the occurrence of severe hypersensitivity reactions, the patient should be pretreated with corticosteroids and antihistamines. This pretreatment reduced the hypersensitivity to less than 5%. However, 30% Side effects are reported. (Cancer Research, 53, 5877-5881 (1993)).

Paclitaxel, teniposide, camptothecin, and the like have strong anticancer activities and are used in various kinds of cancer treatment in clinical practice. They are usually administered intravenously in the form of injections, which are poorly soluble in water, so large amounts of non-ionic surfactants are used for complete dissolution. In addition, since such a large amount of additives may cause side effects such as hypersensitivity reaction during intravenous injection, it is necessary not only that the pretreatment process must be accompanied with the treatment but also the stability is poor during storage period, There is a problem that a very small amount of precipitate must be removed.

Among these drugs, paclitaxel has shown good results in the treatment of ovarian cancer and breast cancer patients, which have not been effective in the treatment of car alkaloids or cisplatin for many years, but also have been used for treatment of lung cancer, head cancer, carcinoma, melanoma and lymphoma And also shows a preferable effect. Therefore, the recent development of effective semisynthetic and synthetic processes for paclitaxel, the synthesis of paclitaxel, which has excellent resistance to cancer cells and high solubility in water, and the development of injectable drugs that can increase and stabilize the solubility of kaklipothel Research has been concentrated, but the above problems have not yet been fully resolved.

[Technical Problem]

Accordingly, an object of the present invention is to provide a pharmaceutical composition for injections which effectively solubilizes an anticancer substance having a strong anticancer activity but is poorly soluble in water and low in stability, thereby improving stability and reducing toxicity and side effects.

In order to achieve the above object, the present invention provides a pharmaceutical composition for injections, which comprises an anticancer agent resistant to water, polyethylene glycol 660 12-hydroxystearate, an acid and an organic solvent.

[Structure and operation of the invention]

The solvent system used in the pharmaceutical composition may have poor stability due to the influence of the active ingredient when a large amount of impurities are contained, so that the impurity content of the solvent should be low enough to exhibit a sufficient stabilizing effect. In addition, when a pharmaceutical composition is formulated with an injection preparation, it is diluted with a carrier or a diluent. It is to be considered that a precipitate may be formed to lower the activity of the active ingredient.

In the present invention, an active ingredient such as an anticancer agent which is insoluble in water and degradable in storage period is mixed with a specific solubilizing agent and an organic solvent, and an appropriate acid is added thereto to form a solution having a pH within a specific range. Not only minimizes the degradation of the active substance and loss of activity, but also prevents the formation of a precipitate upon dilution for formulation, thereby improving the stability and side effects of the composition.

The pharmaceutical composition of the present invention includes at least one active ingredient which reacts with ethanol, promotes the decomposition reaction by the kerbose ion, and is easily decomposed during storage. Such anions may include paclitaxel, tenifoside, camptothecin, and analogs thereof.

The Taclitaxel is a compound having excellent anticancer activity sold under the trade name Taxol by Bristol-Myers Squibb, USA, and Ternifoside is a semisynthetic derivative of vincroproloxin, 4'-demethyl epipidophyllotoxin O- (4, 6-O-terenylidene-D-glucopyranoside, which can be produced by the method described in U.S. Patent No. 3,524,844.

Camptothecin is a 4-ethyl-hydroxy-1H-pyrano- [3,4 ': 6,7] indolizino [1,2-b) quinolin- [3,14 (4H, 12H) dione, which exhibits anti-leukemia and anticancer activity.

Solvent systems for use in the compositions of the present invention are mixtures of co-solvents comprising at least one solvent and solubilization, the solvent includes an alcohol such as anhydrous ethanol and a polyol such as polyethylene glycol.

Solubilizing agents include polyethylene glycol 660 12-hydroxystearate (e.g., Solutol HS 15 ^TM , BASF), biological and chemical analogs and derivatives thereof. Solutol HS 15 ^TM is a nonionic surfactant developed by BASF in Germany in 1982 with Kremopo Addis, which is a condensation product of 70% of 12-hydroxystearic acid polyglycol ester and 30% of polyethylene glycol. This solution toll ^TM HS 15 ah toxic emissions test results histamine on the body's mast cells, rats, mice and beagle dock Crescent blanket EL ^TM , Respectively. (International Symposium on Histamine H2-Receptor Antagonists, Deltakos London, 151-168 (1973)). Lorentz et al reported that Solutol HS 15 ^TM was 10-20 times lower in toxicity when compared directly with CREMOPOIA EL ^TM . (Lorentz et al., Agents Actions, 12, 64-80 (1982)). In view of this point, solution toll ^TM HS 15 is determined to be superior in terms of side effects is lower than the formulation using a Crescent blanket ah EL ^TM known in the clinical data to the present.

As the solvent system of the composition of the present invention, a solvent mixed with an organic solvent and the solubilizing agent Solutol HS 15 ^TM in a volume ratio of 40:60 to 60:40 is preferable. A particularly preferred co-solvent is a mixture of anhydrous ethanol and Solutol HS 15 ^{TM in} a ratio of about 50:50.

Examples of the solubilizing agent that can be used in the solvent system of the present invention include ethylene oxide-treated fatty acid, hydroxyated fatty oil, Polysorbate 80 known as Tween 80, polyethoxylated 12-hydroxystearic acid, Polyoxyethylene sorbitan fatty acid esters, polyethylene glycol esters, polyethylene fatty acid esters, block copolymers of ethylene oxide and propylene oxide, ethylated fatty acid alcohol ethers, and octyl-phenoxy polyethoxy ethanol associates. Other condensates of alkylene oxides may also be used as solubilizing agents, but alkylene oxide-treated fatty acids are preferred, including, for example, polyethylene glycol 400 and polyethylene glycol 40 castor oil. These non-ionic solubilizations can be prepared by a method known in the art or commercially available.

The composition of the present invention can improve the stability by adding an appropriate amount of an acid to the solvent to reduce the action of the carboxy ion that catalyzes the decomposition of the active ingredient, thereby adjusting the pH of the solution. The acid may be added to the solvent before or after the addition of the active ingredient and may be added in a solvent such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, succinic acid, tartaric acid, maleic acid, ascorbic acid, glutamic acid, lactic acid, fumaric acid, Propionic acid, galacturonic acid, aspartic acid, gluconic acid, and the like.

In order to improve the stability of the composition of the present invention, it is preferable to add an acid to adjust the pH range to 3.0 to 5.0, preferably 3.5 to 4.5 when diluted 10-fold.

When paclitaxel is used as the active ingredient, Solutol HS 15 ^TM is preferably used as a solubilizing agent and a cosolvent mixed with ethanol. In order to increase the stability of paclitaxel in the preparation, it is preferable that the range of pH is 3.0 to 5.0 when diluting the pH by 10 times by adding the above-mentioned acid. The taxol formulation using Kremopo EL ^™ mentioned in the Taxol clinical data revealed so far has a pH of 6.8 (10-fold dilution).

Injections formulated with the malignant composition of the present invention have improved stability and do not degrade the components or decrease the activity of the active substance during the use period and do not cause a slight sedimentation even when diluted unlike the conventional taxane injections, , And toxicity.

Hereinafter, the present invention will be described in more detail based on the following examples. It is to be understood, however, that these examples are for illustrative purposes only and are not intended to limit the scope of the invention.

[Example 1: Preparation of pharmaceutical composition containing paclitaxel]

Citric acid was added to absolute ethanol at a ratio of 1 ml of citric acid to 12 ml of absolute ethanol, mixed, and shaken for 15 minutes to prepare solution 1. 250 ml of polyethylene glycol 612 12-hydroxystearate (Solutol HS 15 ^TM ) was added to the mixing vessel (solution 2), and the solution 1 was added thereto. The solution 1 was rinsed with a minimum amount of anhydrous ethanol, Solution 3 was prepared. After nitrogen gas was blown into the flask for 15 minutes, a slurry prepared in a ratio of 4 ml of anhydrous ethanol per gram of paclitaxel was added. At this time, the container in which the paclitaxel was dissolved was also washed with a minimum of anhydrous ethanol and then added to the solution 3 again. The resulting mixture was stirred with anhydrous ethanol to about 75% of the final volume of 500 ml and at least 45 minutes until completely dissolved. Once it was confirmed to be dissolved, anhydrous ethanol was further added to a final volume of 500 ml and mixed well for 5 minutes. The pH of the prepared solution was 3.72.

[Example 2]

A solution having a pH of 3.72 was obtained by following the procedure of Example 1 except that 0.5 ml of Solutol HS 15TM, 6.0 mg of paclitaxel and 2.0 mg of citric acid (anhydrous) were used and ethanol was added to make a final volume of 1 ml.

[Example 3]

The procedure of Example 1 was followed except that 1.0 M acetic acid was added without using citric acid to adjust the pH to 4.20 to prepare a solution containing paclitaxel.

[Comparative Example 1]

According to Example 1, 6.0 ml of paclitaxel was added to 0.5 ml of Solutol HS 15 ^TM without using citric acid, and anhydrous ethanol was added to make a final volume of 1 ml to obtain a solution of pH 5.18.

[Comparative Example 2]

To prepare a solution toll ^TM HS 15 instead Crescent blanket ah ^TM EL 0.5 ml and is in the same way as in Comparative Example 1 except for using the solution to obtain a pH of 6.79 car replicon containing paclitaxel injections as the solubilizing agent.

The solutions prepared in Examples 2 and 3 and Comparative Examples 1 and 2 were placed in a transparent 5 ml vial, sealed with a rubber cap and an aluminum cap, and stored in an incubator at 50 ° C for 3 weeks. Respectively. The results are shown in Table 1 below.

Table 1

As can be seen from the figure, the formulations of Examples 2 and 3, in which Solutol HS 15 ^TM was used and the pH was adjusted to a range of 3.0 to 5.0 by addition of acid, showed the best stability, and as a solubilizer, formulations with EL ^TM was significantly decreased the potency of the active ingredient.

[Effects of the Invention]

As described above, the active ingredient, which is insoluble in water and can be decomposed during storage, is appropriately mixed with a pharmaceutically acceptable solubilizing agent and an organic solvent, and an appropriate acid is added thereto to control the pH of the solvent to a specific range The pharmaceutical composition of the present invention minimizes the degradation of the active substance and loss of activity during use and prevents the formation of precipitates when diluted to improve the stability and side effects of the composition, .

Claims (12)

A water-insoluble anticancer agent, polyethylene glycol 660 12-hydroxystearate, an acid, and an organic solvent. The composition according to claim 1, wherein the anticancer agent is at least one selected from the group consisting of paclitaxel, tenposide, camptothecin, and derivatives thereof. 3. The composition according to claim 2, wherein the anticancer agent is paclitaxel. The composition of claim 1, wherein the organic solvent is an alcohol or a polyol. The composition of claim 1, wherein the polyethylene glycol 660 12-hydroxystearate and the organic solvent are mixed in a volume ratio of 40:60 to 60:40. 6. The composition of claim 5, wherein the volume ratio of polyethylene glycol 660 12-hydroxystearate to organic solvent is 50:50. The method of claim 1, wherein the acid is selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, succinic acid, tartaric acid, maleic acid, iscorbic acid, glutamic acid, lactic acid, fumaric acid, citric acid, methanesulfonic acid, propionic acid, galacturonic acid, Lt; RTI ID = 0.0 > citric acid. ≪ / RTI > 8. The composition of claim 7 wherein the acid is citric acid. The composition of claim 1, wherein the pH is in the range of 3.0 to 5.0. The composition according to claim 9, wherein the pH is 3.5 to 4.5. 7. The composition of claim 1, wherein the composition comprises paclitaxel, polyethylene glycol 660 12-hydroxystearate, citric acid and ethanol and has a pH of 3.0 to 5.0. 14. An injectable formulation of the composition of any one of claims 1 to 11. ※ Note: It is disclosed by the contents of the first application.