CN1294912C - Itraconazole hydrochloride composition and freeze-dried powder injection thereof - Google Patents

Abstract

A composition of itraconazole hydrochloride and its lyophilized powder injection, comprising a therapeutically effective amount of itraconazole hydrochloride, a sufficient amount of cyclodextrin derivatives as a solubilizer, and Acids or bases with a pH in the range of 4-5. The invention has good formulation stability and does not contain alcoholic co-solvent. It is a composition preparation for intravenous injection of itraconazole which is convenient for marketing units to transport and store.

Description

Itraconazole hydrochloride composition and its freeze-dried powder injection

technical field

The invention relates to an itraconazole hydrochloride composition suitable for intravenous injection and its freeze-dried powder injection.

Background technique

The water solubility of azole antifungals such as itraconazole is rather small, thus greatly hindering the development of effective pharmaceutical compositions thereof, according to the method described in WO85/02767, US-4,764,604, the above compounds are derivatized with cyclodextrins Combination of compounds can increase the solubility and bioavailability of the compounds. However, in the preparation of itraconazole injection, it was found that in the accelerated test at 40°C, although the content, pH value and clarity of the injection were stable, the appearance color gradually deepened with the prolongation of storage time, and the related substances increased. The polysaccharide structure of the solvent hydroxypropyl-β-cyclodextrin is related to the thermal decomposition of the injection under acidic conditions. Therefore, itraconazole injection (Sporanox, Janssen Company) needs to be stored below 25°C. Moreover, the fragile and fragile injection solution brings a lot of inconvenience to the transportation and storage of marketing units.

The technical problem to be solved in the present invention is to disclose a freeze-dried powder injection of itraconazole hydrochloride composition suitable for injection, so as to overcome the above-mentioned defects in the prior art.

Said itraconazole hydrochloride composition suitable for injection includes a therapeutically effective amount of itraconazole hydrochloride, a sufficient amount of cyclodextrin derivatives as a solubilizer, and is used to adjust the pH of the composition at 4.5 Acid or alkali and solvent water within ±0.5.

Preferred components and levels include:

Itraconazole hydrochloride 1～11 g/L

Cyclodextrin derivatives 400～600 g/L

Acids or bases that adjust the pH of the composition within the range of 4.5 ± 0.5

Make up 1 liter of water.

The present invention also relates to a freeze-dried powder injection, comprising a therapeutically effective amount of itraconazole hydrochloride, a sufficient amount of a cyclodextrin derivative as a solubilizer, and an acid used to adjust the pH of the composition within the range of 4.5±0.5 Or alkali, preferred components and content include:

Itraconazole hydrochloride 0.2%～2.7%

Cyclodextrin derivatives 94.8%～97.3%

Water 0%～5.0%

The above are all based on the total weight of itraconazole hydrochloride and cyclodextrin derivatives;

An acid or base that adjusts the pH of the composition in the range of 4.5 ± 0.5.

The said itraconazole, namely (±)-cis-4-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-1,2 , 4-triazol-1-yl-methyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4 -Dihydro-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one is a broad-spectrum antifungal compound for oral, parenteral and topical administration, listed in US- 4,267,179 disclosed.

Said itraconazole hydrochloride is (±)-cis-4-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-1 , 2,4-triazol-1-yl-methyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2 , 4-dihydro-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one hydrochloride, its structural formula is:

Wherein: n=1～2, preferably n=2.

The present invention finds itraconazole hydrochloride, especially itraconazole dihydrochloride, i.e. (±)-cis-4-[4-[4-[4-[[2-(2,4- Dichlorophenyl)-2-(1H-1,2,4-triazol-1-yl-methyl)-1,3-dioxolane-4-yl]methoxy]phenyl] -1-piperazinyl]phenyl]-2,4-dihydro-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one dihydrochloride is stable Compound, compared with itraconazole, the water solubility of itraconazole hydrochloride is greatly improved, which is beneficial to the preparation of preparations.

Said itraconazole hydrochloride of the present invention is prepared like this:

Since itraconazole is a weak base, it is difficult to obtain its hydrochloride according to conventional preparation methods, or the obtained product is easy to absorb water and is unstable. Therefore, preferred preparation method comprises the steps:

Dissolve itraconazole in an organic solvent, pass through hydrogen chloride gas for a salt-forming reaction, and then cool and filter to obtain stable itraconazole hydrochloride.

The mentioned organic solvents include alcoholic solvents containing 1 to 4 carbon atoms, such as methanol and ethanol, and ketone solvents containing 3 to 5 carbon atoms, such as acetone and butanone.

The reaction temperature is room temperature to 100°C, preferably 60 to 80°C.

The most preferred cyclodextrin derivatives in the present invention are partially substituted β-cyclodextrin ethers or mixed ethers. They contain hydroxypropyl, hydroxyethyl, especially 2-hydroxypropyl and/or 2-(1-hydroxypropyl) substituents.

The most preferred cyclodextrin derivative is hydroxypropyl-beta-cyclodextrin with an M.S. in the range of 4-9, containing less than 0.1% unsubstituted beta-cyclodextrin. M.S. values determined by NMR or IR preferably range from 5.5 to 7.5.

M.S. represents the average molar degree of substitution, which is the average number of moles of alkoxy units per mole of glucoside.

Said acid or base for adjusting the pH of the composition within the range of 4.5±0.5 is hydrochloric acid and sodium hydroxide.

For the freeze-dried powder injection of the itraconazole hydrochloride composition suitable for intravenous injection, its pH value is very important. First, the pH of the injection should be equal to or close to that of blood, generally controlled within the range of 4 to 9, and the preferred dosage of the solubilizing agent hydroxypropyl-β-cyclodextrin should ensure that the preparation is stable within the pH range of 4.5±0.5.

The invention has good preparation stability, does not contain alcoholic co-solvent, and is a composition preparation for intravenous injection of itraconazole which is convenient for transportation and storage by marketing units.

Description of drawings

Figure 1 shows the equilibrium solubility of itraconazole and itraconazole hydrochloride in hydroxypropyl beta cyclodextrin solution (25°C/110rpm/24hours).

Detailed ways

The following examples are used to illustrate the present invention, but are not meant to limit the invention in any way.

Example 1

Preparation of itraconazole hydrochloride

Add 40 g of itraconazole and 600 ml of acetone into a 1 L reaction flask, and pass excess hydrogen chloride under stirring. After the reaction is complete, filter, wash with acetone, and dry to obtain 42 g of itraconazole hydrochloride. Yield 95%. Elemental analysis C ₃₅ H ₃₈ N ₈ O ₄ .2HCl: (found/calculated) C 53.70/53.99, H 5.20/5.18, N 14.46/14.39, Cl 18.20/18.22.

Table ¹ HNMR data of itraconazole hydrochloride (using DMSO-d6 as solvent) proton number Chemical shift δ(ppm) multiplicity proton number 35333421 22 20 2313113212325 2916 1891015 19 0.781.271.56～1.803.64～3.833.883.984.134.414.917.127.227.457.547.60 triplet doublet multiplet multiplet doublet doublet multiplet multiplet triplet doublet doublet doublet doublet doublet doublet doublet doublet 33282211222112 726 281312 7.687.948.318.419.08 doublet doublet singlet singlet singlet 12111

Example 2

Preparation of itraconazole hydrochloride

Add 2g of itraconazole and 20ml of ethanol into a 50ml reaction bottle, heat to reflux, pass in excess hydrogen chloride under stirring, after the reaction is complete, cool to room temperature, filter, wash with ethanol, and dry to obtain itraconazole Dihydrochloride 2.12g. Yield 96.4%. Elemental analysis and ¹ HNMR data are the same as above.

Example 3

Equilibrium solubility of itraconazole and itraconazole hydrochloride

Weigh hydroxypropyl-β-cyclodextrin respectively, dissolve in water to make a set concentration, and put them into 10ml stoppered test tubes. Add excess itraconazole or itraconazole hydrochloride, plug, and ultrasonicate in a water bath for 30 minutes, place in a SHZ-28 desktop water bath constant temperature shaker, and shake horizontally at 25°C and 110rpm. After reaching the solid-liquid equilibrium, filter through a 0.45 μm microporous membrane, take the subsequent filtrate and inject it directly or after appropriate dilution to measure the equilibrium solubility. The solubility of itraconazole hydrochloride in water is 0.016mM, which is 6 times that of itraconazole (0.0027mM). The solubility of the former in 0.323M hydroxypropyl-β-cyclodextrin solution is 77.10mM, which is The latter has 46 times the solubility (1.67mM). See Figure 1, the equilibrium solubility of itraconazole (1) and itraconazole hydrochloride (2) in hydroxypropyl beta cyclodextrin solution (25°C/110rpm/24hours).

Example 4

Preparation of itraconazole hydrochloride composition

Prescription: itraconazole hydrochloride 11 grams

Hydroxypropyl-beta-cyclodextrin 450g

Sodium Hydroxide Appropriate amount

Add water for injection to 1000ml

Preparation:

(a) Weigh the prescribed amount of hydroxypropyl-β-cyclodextrin, add 600ml of water for injection to dissolve.

(b) Add itraconazole hydrochloride and heat in a water bath to dissolve.

(c) Adjust the pH to 4.5±0.3 with 1mol/L NaOH.

(d) Add water for injection to volume.

Example 5

Preparation of freeze-dried powder injection of itraconazole composition

Prescription: itraconazole hydrochloride 3.67g

Hydroxypropyl-β-cyclodextrin 150g

Sodium Hydroxide Appropriate amount

Add water for injection to 1000ml

Preparation:

(a) Weigh the prescribed amount of hydroxypropyl-β-cyclodextrin, add 200ml of water for injection to dissolve.

(b) Add itraconazole hydrochloride and heat in a water bath to dissolve.

(c) Slowly add 650ml of water for injection under stirring.

(d) Adjust the pH to 4.5±0.3 with 1mol/L NaOH.

(e) Add water for injection to volume.

(f) Add 0.1% activated carbon for needles in total volume, keep warm at 52° C. for 30 minutes, absorb pyrogen, and filter.

(g) Fine filtration with a 0.22 μm microporous membrane.

(h) Freeze-drying in shallow pans.

Example 6

Stability of freeze-dried powder injection of itraconazole hydrochloride composition

The lyophilized powder of itraconazole hydrochloride composition has been subjected to 40°C, 75% RH accelerated test for 6 months and 25°C ± 0.2°C, humidity of 60% ± 2% in a constant temperature and humidity box for 18 months. The properties, acidity, clarity and color of the solution, loss on drying, content and related substances have no significant changes compared with 0 months. The results are shown in Table 2 and Table 3. Accelerated tests at 40 °C, 75% RH and 25 °C ± 0.2 °C, The long-term retention samples of the constant temperature and humidity box with a humidity of 60%±2% all show that the composition of the present invention has good stability.

Table 2. Accelerated test results at 40°C batch number time character acidity Clarity and color of the solution Labeled amount percentage (%) relative substance(%) Loss on drying (%) 020512 0 month 1 month 2 month 3 month 6 month white powder white powder white powder white powder white powder 4.54.44.54.54.4 <No. 2 turbidity, yellow No. 1 < No. 2 turbidity, yellow No. 1 < No. 2 turbidity, yellow No. 1 < No. 2 turbidity, yellow No. 1 < No. 2 turbidity, yellow No. 1 99.699.098.998.998.8 0.590.610.650.620.61 4.14.34.44.24.4 020515 0 month 1 month 2 month 3 month 6 month white powder white powder white powder white powder white powder 4.54.54.54.44.5 <No. 2 turbidity, yellow No. 1 < No. 2 turbidity, yellow No. 1 < No. 2 turbidity, yellow No. 1 < No. 2 turbidity, yellow No. 1 < No. 2 turbidity, yellow No. 1 99.699.199.098.898.7 0.590.600.660.590.61 4.44.34.44.44.5 020520 0 month 1 month 2 month 3 month 6 month white powder white powder white powder white powder white powder 4.54.54.54.44.4 <No. 2 turbidity, yellow No. 1 < No. 2 turbidity, yellow No. 1 < No. 2 turbidity, yellow No. 1 < No. 2 turbidity, yellow No. 1 < No. 2 turbidity, yellow No. 1 99.599.299.099.098.8 0.570.630.630.620.56 4.44.24.54.44.5

Table 3 Long-term test results batch number time character acidity Clarity and color of the solution Labeled amount percentage (%) relative substance(%) Loss on drying (%) 020512 0 month 3 month 6 month 9 month 12 month 18 month white powder white powder white powder white powder white powder white powder 4.54.54.54.44.44.4 <No. 2 turbidity, yellow No. 1 < No. 2 turbidity, yellow No. 1 < No. 2 turbidity, yellow No. 1 < No. 2 turbidity, yellow No. 1 < No. 2 turbidity, yellow No. 1 < No. 2 turbidity , Yellow No. 1 99.699.299.099.399.599.0 0.590.540.550.540.580.55 4.14.44.44.34.54.5 020515 0 month 3 month 6 month 9 month 12 month 18 month white powder white powder white powder white powder white powder white powder 4.54.44.44.54.44.5 <No. 2 turbidity, yellow No. 1 < No. 2 turbidity, yellow No. 1 < No. 2 turbidity, yellow No. 1 < No. 2 turbidity, yellow No. 1 < No. 2 turbidity, yellow No. 1 < No. 2 turbidity , Yellow No. 1 99.699.298.999.299.599.1 0.590.570.540.550.560.60 4.44.54.34.64.54.6 020520 0 month 3 month 6 month 9 month 12 month 18 month white powder white powder white powder white powder white powder white powder 4.54.54.54.44.54.4 <No. 2 turbidity, yellow No. 1 < No. 2 turbidity, yellow No. 1 < No. 2 turbidity, yellow No. 1 < No. 2 turbidity, yellow No. 1 < No. 2 turbidity, yellow No. 1 < No. 2 turbidity , Yellow No. 1 99.599.098.699.299.499.3 0.570.640.640.630.650.64 4.44.54.54.74.64.6

Claims (3)

1. itraconazole hydrochlorate compositions is characterized in that component and content comprise:

Itraconazole hydrochlorate 1～11 grams per liter

HP-400～600 grams per liters

Regulate acid or the alkali of pH in 4.5 ±-0.5 scopes of compositions

Water is supplied 1 liter;

Described itraconazole hydrochlorate is the itraconazole dihydrochloride;

The molar average substitution value of said HP-is 4～9.

2. itraconazole hydrochlorate compositions according to claim 1 is characterized in that, the molar average substitution value span of HP-is 5.5～7.5.

3. the freeze-dried powder of an itraconazole hydrochlorate compositions is characterized in that, component and content comprise:

Itraconazole hydrochlorate 0.2%～2.7%

HP-94.8%～97.3%

Water 0%～5.0%

More than all in the gross weight of itraconazole hydrochlorate and HP-;

Regulate acid or the alkali of pH in 4.5 ± 0.5 scopes of compositions;

Described itraconazole hydrochlorate is the itraconazole dihydrochloride;

The molar average substitution value of said HP-is 4～9.

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