KR20200006682A - An oral pharmaceutical composition comprising taxane having improved oxidation stability - Google Patents

Abstract

The present invention relates to an oral pharmaceutical composition containing taxane. Specifically, the present invention relates to an oral pharmaceutical composition containing taxane having improved oxidation stability by including an antioxidant. The oral pharmaceutical composition of the present invention can not only secure oxidative stability by including an antioxidant, but also improve the stability of a formulation.

Description

Oral pharmaceutical composition comprising taxane having improved oxidation stability

The present invention relates to oral pharmaceutical compositions containing taxanes. Specifically, the present invention relates to an oral pharmaceutical composition comprising taxane having improved oxidation stability by including an antioxidant.

Taxanes are diterpenes produced by the genus Taxus and are widely used as chemotherapy agents. Examples of taxanes include paclitaxel (Taxol ^® ), docetaxel (Taxotere ^® or Docecad), cabazitaxel, larotaxel, ortataxel, tecetaxel and the like.

Among these, paclitaxel, which has been widely prescribed for treating various tumors including ovarian carcinoma, breast cancer, head and neck cancer, non-small cell lung cancer, prostate cancer, and Kaposi's sarcoma, is one of the most effective antitumor agents. Have

[Formula]

Taxanes are known to have very low solubility in water, for example paclitaxel-containing formulation Taxol ^™ is currently formulated in the form of emulsion preconcentrates and is used diluted prior to injection. However, in order to overcome the problems such as patient compliance (patient compliance), the stability of the formulation, and the safety to the human body due to the use of the injection form is being studied for oral formulations.

On the other hand, oral administration of taxanes, such as paclitaxel, has been reported to exhibit low oral bioavailability due to outflow pump action (Walle et al., Drug Metabo. Disp. 26 (4): 343-346 (1998)). It has also been reported that paclitaxel is very poorly absorbed (less than 1%) upon oral administration (Eiseman et al., Second NCI Workshop on Taxol and Taxus (sept. 1992), Suffness (ed.) Et al., Taxol ^TM Science and Applications, CRC Press (1995). In an attempt to improve such low oral bioavailability, Korean Patent Laid-Open Publication No. 10-2004-0009015 uses a medium chain triglyceride such as triacetin, a monoglyceride compound such as monoolein, and a surfactant such as Tween. Oral taxane-containing solubilizing compositions formulated by the present disclosure have been disclosed. The composition is an oral taxane-containing solubilizing composition having increased bioavailability through high intestinal mucoadhesion by monoglyceride-based compounds such as monoolein.

In addition, Korean Patent Application Publication No. 10-2007-0058776 discloses an improved method for preparing the oral taxane-containing solubilizing composition, that is, paclitaxel using an organic solvent and a medium chain triglyceride, a monoglyceride compound, and a surfactant. It has been disclosed a preparation method comprising dissolving together.

The composition patent of Korean Patent Application Laid-Open No. 10-2014-0150173 relates to a pharmaceutical composition for oral administration containing taxane, the composition comprising medium chain glyceride, oleyl glycerol complex, and lipids of surfactant as excipients. Oral anticancer agents have been disclosed.

However, when the lipids of the surfactant is included as an excipient, oxidation of the lipids may occur depending on the storage conditions, and may be expected to affect the stability of the preparation. The present inventors have completed the present invention by studying the applicable antioxidant to ensure the oxidation stability of the formulation.

It is an object of the present invention to provide an oral pharmaceutical composition comprising taxane with improved oxidative stability. Specifically, the present invention provides a stabilized pharmaceutical composition further comprising an antioxidant to improve oxidation stability in a composition comprising taxane, medium chain triglycerides, oleoyl glycerol complex, and a surfactant.

In order to achieve the above object, the present invention comprises a taxane and an antioxidant, wherein the antioxidant is at least one selected from the group consisting of dibutyl hydroxy toluene, butylhydroxyanisole, propyl gallate and tocopherol It provides a pharmaceutical composition.

Specifically, the present invention provides oral pharmaceutical compositions comprising taxanes, antioxidants, medium chain triglycerides, oleyl glycerol complexes and surfactants.

In addition, the present invention

(Iii) dissolving taxane, antioxidant, medium chain triglycerides in an organic solvent;

(Ii) removing the organic solvent from the solution obtained in step (iii); And

(Iii) adding oleyl glycerol complex and surfactant to the mixture obtained in (ii);

It provides a method for producing an oral pharmaceutical composition comprising a.

The oral pharmaceutical composition of the present invention not only secures oxidative stability by including an antioxidant, but can also improve stability of the formulation, and prevents changes in the active ingredient and formulation during storage and distribution.

1 shows the solution properties of Example (A), Comparative Example 1 (B) and Comparative Example 5 (C).
Figure 2 shows the oxidation degree (%) according to the content of the antioxidant dibutyl hydroxy toluene (BHT).
Figure 3 shows the oxidation degree (%) according to the content of the antioxidant butylhydroxyanisole (BHA).
Figure 4 shows the oxidation degree (%) according to the content of the antioxidant propyl gallate (propyl gallate).
Figure 5 shows the oxidation degree (%) according to the content of the antioxidant tocopherol (tocopherol).
Figure 6 shows the oxidation degree (%) according to the content of the antioxidant ascorbic acid.
Figure 7 shows the oxidation degree (%) at the highest content of the daily intake allowance of each antioxidant.
Figure 8 shows the browning phenomenon with or without the antioxidant.

The present invention provides oral pharmaceutical compositions comprising taxanes and antioxidants.

The taxane is paclitaxel, docetaxel, 7-epipaclitaxel, t-acetylpaclitaxel, 10-desacetylpaclitaxel, 10-desacetylpaclitaxel. 10-desacetyl-7-epipaclitaxel, 7-xylosylpaclitaxel, 10-desacetyl-7-glutarylpaclitaxel, 7 At least one selected from the group consisting of -N, N-dimethylglycylpaclitaxel and 7-L-alanylpaclitaxel, preferably paclitaxel. However, the present invention is not limited thereto.

The antioxidant may be at least one selected from the group consisting of dibutyl hydroxy toluene (BHT), butyl hydroxyanisole (BHA), propyl gallate and tocopherol.

The antioxidant may include 0.001 to 1.0% by weight, preferably 0.01 to 0.2% by weight based on the total weight of the composition.

In addition, oral pharmaceutical compositions of the present invention may further comprise medium chain triglycerides, oleyl glycerol complexes and surfactants.

The medium chain triglycerides refer to a substance in which three molecules of saturated or unsaturated C ₂ -C ₂₀ fatty acids and one molecule of glycerol are connected by an ester bond. For example, the medium chain triglycerides are triacetin, tripropionin, tributyrin, trivalerin, tricaproin, tricaproline, tricapryline ( tricaprylin) [e.g., cap-Tex ^TM 8000 (Captex ^TM 8000), etc.], tri-capric (tricaprin), tri cyclohepta elderly (triheptanoin), teurino nano (trinonanoin), tri undead Kano of (triundecanoin), tri La Trilaurin, tritridecanoin, trimyristin, tripentadecanoin, tripalmitin, glyceryl triheptadecanoate and triolein triolein) may be one or more selected from the group consisting of, preferably tricapryline, but is not limited thereto.

The medium chain triglycerides may comprise 1 to 40% by weight based on the total weight.

The oleoyl glycerol complex refers to a complex obtained by partial glycerolysis of vegetable oil mainly containing triglycerol of oleic acid or by esterification of glycerol and oleic acid. . Partial glycerol degradation and / or esterification results in varying amounts of monooleyl glycerol, dioleyl glycerol, and trioleyl glycerol. Commercially available oleyl glycerol complexes, such as peceol (PECEOL ^™ , Gattefosse) or capmal (CAPMUL ^™ , Abitec), and the like, may be used, and preferably may be peseol, but is not limited thereto.

The oleyl glycerol complex may comprise 1 to 80% by weight based on the total weight.

Wherein the surfactant is polyoxyethylene-polyoxypropylene copolymers [e.g., poloxamer ^TM (Poloxamer ^TM)], sorbitan esters, for example, Span ^TM (Span ^TM)], polyoxyethylene sorbitan EXAMPLES for example, tween ^TM (tween ^TM)] and polyoxyethylene ethers [for example, Breeze ^TM (Brij ^TM)] with and be at least one selected from the group consisting of, preferably polyoxyethylene be sorbitan tanil However, this It is not limited.

The surfactant may include 1 to 70% by weight based on the total weight.

In addition, the present invention

(Iii) dissolving taxane, antioxidant, medium chain triglycerides in an organic solvent;

(Ii) removing the organic solvent from the solution obtained in step (iii); And

(Iii) adding an oleyl glycerol complex and a surfactant to the mixture obtained in step (ii);

It provides a method for producing an oral pharmaceutical composition comprising a.

The organic solvent may be at least one selected from the group consisting of halogenated alkyl compounds, alcohols and ketones. The halogenated alkyl compound may be a halogenated C ₁ to C ₅ alkyl compound, preferably methylene chloride or chloroform, more preferably methylene chloride.

Hereinafter, preferred examples are provided to aid in understanding the present invention. However, the following examples are merely provided to more easily understand the present invention, and the contents of the present invention are not limited by the examples.

[Examples 1 to 12]

Preparation of Oral Taxanes Formulation Containing Antioxidants

Paclitaxel, antioxidants and medium chain triglycerides were dissolved in methylene chloride and concentrated under reduced pressure at 40 ° C. to remove methylene chloride.

The oleyl glycerol complex and the surfactant were added to the mixture obtained above, followed by stirring at 40 ° C to prepare an oral taxane formulation.

The antioxidant content of each formulation was calculated based on the Acceptable Daily Intake (mg / kgbw / day).

In the preparation method, the taxane formulations of Examples 1 to 3 were prepared according to the antioxidant components and contents of Table 1 below. Taxane formulations prepared as shown in FIG. 1 (A) showed clear solution properties.

division Ingredient (% by weight) Example 1 Example 2 Example 3 Taxane Paclitaxel 1.02 1.02 1.02 Oxidation
Inhibitor Dibutyl hydroxy gallate
(BHT) 0.01 - - - 0.02 - - - 0.03 Excipient Medium chain
Triglycerides 27.00 27.00 27.00 Oleyl glycerol
Complex 53.55 53.54 53.54 Surfactants 18.42 18.42 18.42 Sum(%) 100.00

In the preparation method, the taxane formulations of Examples 4 to 6 were prepared according to the antioxidant components and contents of Table 2 below. Taxane formulations prepared as shown in FIG. 1 (A) showed clear solution properties.

division Ingredient (% by weight) Example 4 Example 5 Example 6 Taxane Paclitaxel 1.02 1.02 1.02 Oxidation
Inhibitor Butylhydroxyanisole
(BHA)  0.01 - - - 0.02 - - -  0.05 Excipient Medium chain
Triglycerides 27.00 27.00 26.99 Oleyl glycerol
Complex 18.42 18.42 18.41 Surfactants 53.55 53.54 53.53 Sum(%) 100.00

In the preparation method, the taxane formulations of Examples 7 to 9 were prepared according to the antioxidant components and contents of Table 3 below. Taxane formulations prepared as shown in FIG. 1 (A) showed clear solution properties.

division Ingredient (% by weight) Example 7 Example 8 Example 9 Taxane Paclitaxel 1.02 1.02 1.02 Oxidation
Inhibitor Profile gallate 0.04 - - - 0.07 - - - 0.14 Excipient Medium chain
Triglycerides 26.99 26.98 26.97 Oleyl glycerol
Complex 18.42 18.41 18.39 Surfactants 53.53 53.52 53.48 Sum(%) 100.00

In the preparation method, the taxane formulations of Examples 10 to 12 were prepared according to the antioxidant components and contents of Table 4 below. Taxane formulations prepared as shown in FIG. 1 (A) showed clear solution properties.

division Ingredient (% by weight) Example 10 Example 11 Example 12 Taxane Paclitaxel 1.02 1.02 1.02 Oxidation
Inhibitor α-tocopherol 0.05 - - -  0.10 - - - 0.20 Excipient Medium chain
Triglycerides 26.99 26.98 26.95 Oleyl glycerol
Complex 18.41 18.40 18.39 Surfactants 53.53 53.50 53.44 Sum(%) 100.00

Comparative Example 1

Preparation of Oral Taxanes Formulation Without Antioxidant

Paclitaxel and medium chain triglycerides were dissolved in methylene chloride and concentrated under reduced pressure at 40 ° C. to remove methylene chloride.

After adding an oleyl glycerol complex and surfactant to the mixture obtained above, it stirred at 40 degreeC conditions.

In the preparation method, the formulation of Comparative Example 1 containing no antioxidant was prepared according to the ingredients and contents of Table 5 below. As shown in FIG. 1 (B), the prepared taxane formulation showed clear solution properties.

division Ingredient (% by weight) Comparative Example 1 Taxane Paclitaxel 1.02 Excipient Medium chain triglycerides 27.00 Oleyl Glycerol Complex 53.55 Surfactants 18.42 Sum(%) 100.00

[Comparative Examples 2 to 5]

Preparation of Oral Taxanes Formulation Containing Antioxidants

Paclitaxel, antioxidants and medium chain triglycerides were dissolved in methylene chloride and concentrated under reduced pressure at 40 ° C. to remove methylene chloride.

After adding an oleyl glycerol complex and surfactant to the mixture obtained above, it stirred at 40 degreeC conditions.

In the preparation method, the formulations of Comparative Examples 2 to 5 containing antioxidants were prepared according to the ingredients and contents of Table 6 below. As shown in FIG. 1 (B), the prepared taxane formulation showed clear solution properties. However, at least 0.15% of ascorbic acid, the highest weight of the test, did not dissolve and was not formulated as shown in FIG. 1 (C).

division Ingredient (% by weight) Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Taxane Paclitaxel 1.02 1.02 1.02 1.02 Oxidation
Inhibitor Ascorbic acid 0.03 - - - - 0.05 - - - - 0.10 - - - - 0.15 Excipient Medium chain triglycerides 26.99 26.99 26.98 26.96 Oleyl Glycerol Complex 18.42 18.41 18.40 18.39 Surfactants 53.54 53.53 53.50 53.48 Sum(%) 100.00

[Test Example 1]

Antioxidant Effect Test

Formulations of Examples and Comparative Examples with different types and dosages of antioxidants were stored under severe conditions (stored at 70 ° C., and after 30 days, samples were checked for oxidation degree using the following analytical conditions using HPLC.

<HPLC Analysis Conditions>

HPLC: Agilent 1260

Detector: Ultraviolet detector

Detection wavelength: 227 nm

Column: 4.6 mm × 150 mm, 3um, YMC-Pack ODS-A

Column temperature: 35 ℃

Injection volume: 10 ul

The oxidation degree of Examples 1-12 and Comparative Examples 2-4 was confirmed using the oxidation degree of Comparative Example 1 as 100%, and is shown in FIGS.

As shown in FIG. 2, Examples 1 to 3 using dibutyl hydroxy toluene (BHT) as the antioxidant showed an oxidation degree of less than 20%. Accordingly, it was found from Examples 1 to 3 that all exhibited similar antioxidant effects of 80% or more regardless of the BHT content.

As shown in FIG. 3, Examples 4 to 6 using butylhydroxyanisole (BHA) as an antioxidant showed an oxidation degree of about 30%. Thus, it was found from Examples 4 to 6 that all exhibited similar antioxidant effects of about 70% regardless of the BHA content.

As shown in Figure 4, Examples 7 to 9 using propyl gallate as an antioxidant showed an oxidation degree of less than about 10%. Therefore, it can be seen from Examples 7 to 9 that as the content increases, the degree of oxidation decreases and the antioxidant effect increases.

As shown in Figure 5, Examples 10 to 12 using tocopherol (tocopherol) as an antioxidant showed an oxidation degree of about 40 to 70%, the oxidation degree is greatly reduced as the content is increased, the antioxidant effect is increased I could see that.

As shown in Figure 6, Comparative Examples 2 to 4 using ascorbic acid (L-ascorbic acid) as an antioxidant showed an oxidation degree of about 95 to 97%, it was confirmed that no antioxidant effect.

The oxidation degree at the highest content of the daily intake allowance of each antioxidant is shown in FIG. 7, and as shown in FIG. 7, the highest antioxidant effect was shown at 0.14% by weight of propyl gallate, and BHT, BHA and Both tocopherols showed excellent antioxidant effects.

[Test Example 2]

Browning Prevention Test

The formulations of Example 1 and Comparative Example 1 were stored under severe conditions (70 ° C., and then the browning of the formulations was confirmed by observing the properties of each sample at 0, 3, 6, and 12 months, and the results are shown in FIG. 8. Shown in

As shown in Figure 8, in Comparative Example (B) containing no antioxidant was confirmed browning of the appearance at the third month, it was confirmed that the browning gradually worsens over time.

In Example (A) containing an antioxidant, it was confirmed that browning did not occur until 12 months and the appearance was maintained. Therefore, the browning prevention effect of the formulation containing antioxidant BHT was confirmed.

In addition, according to the antioxidant type and content of all the antioxidants of Examples 2 to 12, the test for browning effect of the formulation was repeatedly performed, and as a result, the browning prevention effect of the formulation was confirmed in all the antioxidants.

After all, when the antioxidant is included in the formulation containing taxane may have an antioxidant effect and browning effect, among the antioxidants, dibutyl hydroxy toluene (BHT), butyl hydroxyanisole (BHA), propyl gallate (propyl gallate) and tocopherol (tocopherol) shows an excellent effect, but ascorbic acid does not show an excellent antioxidant effect, it can be seen that high content ascorbic acid is not well dissolved in the formulation.

Claims (11)

Contains taxanes and antioxidants,
Oral pharmaceutical composition, characterized in that the antioxidant is selected from the group consisting of dibutyl hydroxy toluene, butyl hydroxyanisole, propyl gallate and tocopherol.
The method according to claim 1, wherein the taxane is paclitaxel, docetaxel, 7-epipaclitaxel, t-acetylpaclitaxel, 10-desacetylpaclitaxel, 10-desacetyl-7-epipaclitaxel, 7-xylsilpaclitaxel, 10-desacetyl Oral pharmaceutical composition, characterized in that at least one selected from the group consisting of -7- glutaryl paclitaxel, 7-N, N- dimethyl glycyl paclitaxel, and 7-L-alanyl paclitaxel.
The oral pharmaceutical composition according to claim 2, wherein the taxane is paclitaxel.
The oral pharmaceutical composition according to claim 1, wherein the antioxidant comprises 0.001 to 1.0 wt% based on the total weight.
The oral pharmaceutical composition according to claim 4, wherein the antioxidant comprises 0.01 to 0.2 wt% based on the total weight.
The oral pharmaceutical composition of claim 1, further comprising a medium chain triglyceride, an oleyl glycerol complex, and a surfactant.
7. The medium according to claim 6, wherein the medium chain triglycerides are triacetin, tripropionine, tributyrin, trivalerine, tricaproin, tricapryline, tricaprine, triheptanoin, trinonanoin, tri At least one member selected from the group consisting of undecanoine, trilaurin, tritridecanoine, trimyristin, tripentadecanoin, tripalmitin, glyceryl triheptadecanoate, and triolein Oral pharmaceutical composition.
7. The oral pharmaceutical composition of claim 6, wherein the surfactant is selected from the group consisting of polyoxyethylene-polyoxypropylene copolymers, sorbitan esters, polyoxyethylene sorbitan and polyoxyethylene ethers. Composition.
(Iii) dissolving taxane, antioxidant and medium chain triglycerides in an organic solvent;
(Ii) removing the organic solvent from the solution obtained in step (iii); And
(Iii) adding an oleyl glycerol complex and a surfactant to the mixture obtained in step (ii);
Method for producing an oral pharmaceutical composition comprising a.
The method of claim 9, wherein the organic solvent is selected from the group consisting of halogenated alkyl compounds, alcohols and ketones.
The method of claim 10, wherein the organic solvent is methylene chloride.

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