Liposomal pharmaceutical composition for intravenous

 

(57) Abstract:

The invention relates to medicine, in particular to pharmacology relates to liposomal pharmaceutical composition for intravenous administration containing insoluble lipophilic active substance in the form of liposomes, at least one phospholipid, distilled water, and targeted supplements, and additionally contains at least one cretaceou fatty acid formula: H3C-(CH2)n-COOH, where n = 4-8, or its salt, at a certain ratio of components. Liposomal pharmaceutical composition for intravenous administration has the best chemical-physical stability. 5 C.p. f-crystals.

The invention relates to a liposomal pharmaceutical compositions, in particular to the liposomal pharmaceutical composition for intravenous administration.

Known liposomal pharmaceutical composition for intravenous administration containing insoluble lipophilic active substance in the form of liposomes, in particular a derivative of dihydropyridines, phospholipids, distilled water and special additive selected from the group containing antifreeze, antioxidants and regulators pH, and actin (see European application N 0 560138 A1, MCI: A 61 K 9/127, 1993).

The disadvantage of liposomal pharmaceutical composition is that its chemical-physical stability is not always entirely satisfactory.

The objective of the invention is the creation of a liposomal pharmaceutical composition for intravenous administration with the best chemical-physical stability.

This object is achieved offer liposomal pharmaceutical composition for intravenous administration containing insoluble lipophilic active substance in the form of liposomes, at least one phospholipid, distilled water and additives target, due to the fact that it further contains at least one cretaceou fatty acid of the formula (I)

H3C-(CH2)n-COOH (I)

where n means the number of 4 - 8,

or its salt, in the following proportions, wt. hours at 100 weight. including distilled water:

Lipophilic, poorly soluble active substance is 0.001 to 2.0

The phospholipid - 0,02-40

Target additive is 0.0001-100

moreover, the weight ratio of the active substance and the phospholipid is 1: (20 to 200), and the weight ratio of cratchet and phospholipid is preferably 1: (30 - 80), in particular 1:(30 - 50). The weight ratio gracciano fatty acids or its salts and phospholipid is preferably 1:(4 - 50). The concentration of gracciano fatty acids in the proposed composition is 0.3-10 mg/ml to give a composition.

As gracciano fatty acids, the compositions preferably contains Caprylic acid or its salt, in particular its sodium or potassium salt.

As insoluble lipophilic active substances, the compositions preferably contain derivatives of dihydropyridines of General formula (II)

< / BR>
where R is methyl, R1- methoxyethyl, R2group-COOC3H7-image and R3is phenyl, substituted by a nitro-group in the meta-position, or

R is amino, R1is lower alkyl, R2is cyano and R3group of the formula

< / BR>
where R4means hydrogen, halogen, cyano, deformity, lower alkyl or alkoxy,

or (R)-ethyl-(-methylbenzyl)-imidazoledicarboxylic or ester (2aR, 4S, 4aS, 6R, 9S, 11S, 12S, 12aR, 12bS) - a 1,2, 3,4, 4a, 6, 9, 10, 11, 12, 12a, 12b, dodecahydro-4, 6, 9, 11, 12, 12b - hexahydroxy - 4a, 8, 13, 13-tetramethyl-7, 11-methane-5H - cyclodina[3,4] ,benzo[1,2-b]oxet-5 he-6, 12b-diacetyl-9-[(2R, 3S)- N-benzoyl-3-phenyl-is ibidi, which are uncharged outside phosphoglyceride, which can form intramolecular amphoteric ions and correspond to the General formula (III)

< / BR>
where R2and R3the same or different and are saturated or unsaturated acyl group with 8-24 carbon atoms that may be branched and/or substituted.

In addition to the phospholipids of the formula (II) can also be used in a small amount of phospholipids of another type, such as, for example, phosphatidylethanolamine, synthesised, sphingomyelin, phosphatidylserine and/or phosphatidic acid. Used phospholipids can be obtained by purification of substances from natural sources, such as soy lecithin or raw egg lecithin. Preferably use purified egg lecithin.

Target additives are, for example, antifreeze agents, antioxidants, regulating the pH of a substance, and osmotically active agents. As antifreeze suitable, for example, a polyalcohol, such as, for example, glycerol, monosaccharides, such as glucose, disaccharides, such as sucrose, lactose or trehalose, proteins or amino acids. The ratio of antifreeze and phospholipid composition is to manage reconstituirea the means to achieve isotonic pressure, are, for example, glycerol, mannitol and glucose, in particular glycerol.

Suitable antioxidants are, for example, butylacetamide, butylacetyl, alpha-tocopherol and their salts, ascorbic acid and its salts and esters, preferably ascorbic acid and their salts. Regulating the pH of the substances are buffers, acids or bases, in particular ascorbic acid and sodium hydroxide.

Offer liposomal composition can be obtained by usual methods, for example, by homogenization under high pressure extrusion through pores, dialysis, dilution, and ultrasonic dispersion, preferably by homogenization under high pressure, as, for example, microfluidizer.

The proposed composition preferably get so that 1 weight. including lipophilic active substances and 20-200 weight. including phospholipids pre-dispersed in water using a stirrer at a temperature of 10-90oC, preferably 50-80oC, if necessary in the presence of the antioxidant and, if necessary, in an atmosphere of nitrogen, and then homogenized by means of nozzles high pressure at temperatures of 20-80oC and a pressure of 400 to 1500 bar to the middle led is useprivatekey General formula (I) or its salt in the ratio, equal to 1: (2-60), and thus obtained dispersion was subjected to freeze drying.

According to a variant of the method described above active substance and/or antifreeze can also be added already during the pre-dispersion or homogenization by means of nozzles high pressure. In addition, kratkocasijo fatty acids can also be added to reconstituirea tool, so that they come into contact with liposomes only during the process of reconstitution, that is bringing money in ready to use form. In both cases, prevents flocculation ready to use liposomes for more than 24 hours, and at a time is the average particle diameter of liposomes and provides chemical stability of the active substance.

When exceeding the concentration of fatty acids, equal to 10 mg/ml, there is a destabilization of the liposomes and release of active substances from liposomes, as shown by comparative example b Without additives kratkocasijo fatty acid dispersion coagulates within 24 hours, as evidenced by comparative example Century.

The following examples illustrate the obtaining of the proposed composition and its advantage over isfet for 30 minutes with nitrogen, then dissolve in water 16.2 g of sodium ascorbate and then add 580,5 g of purified egg lecithin (phosphatidylcholine > 94%). The resulting mixture was dispersed using a rapidly rotating stirrer at a temperature of 65oC for 30 minutes. After refilling evaporated water, the resulting dispersion is filtered through a membrane filter having a pore size of 8 μm, and served in a high-pressure homogenizer.

The dispersion is homogenized 5 times at a temperature of 65oC and a pressure of 800 bar. Then add 145g complex isopropyl ether 2-amino - 1,4-dihydro-5-cyano-6-methyl-4-(3-phenylindolin-5-yl)pyridine-3-carboxylic acid, which are distributed uniformly in the dispersion at low pressure (25 bar). Then homogenize 20 times at a temperature of 65oC and a pressure of 800 bar. The resulting liposomes are cooled to room temperature.

On 1 g of the obtained product homogenization add and dissolve 168,2 mg sucrose and 0.11 mg of ascorbic acid. The variance add up to pH value of 6.5 by the addition of 0.1 n sodium hydroxide solution and sterile filtered over a membrane filter (the size of pores of 0.2 μm). 2.5 ml of the resulting filter is filled in a brown glass bottle and podvergali adding 10 ml of an aqueous solution, containing 0,0495% kaprilat sodium and 1,51% glycerol, the average size of liposomes is 57 nm. After 24-hour storage of ready-to-use dispersion average size of liposomes is 57 nm. For the specified retention period flocculation and/or sedimentation does not occur.

According to gelchromotography active substance included at 100% in liposomes.

Example 2.

In 638,33 g of distilled water, which is pre-treated with nitrogen for 10 minutes, dissolved 1,8561 g of sodium ascorbate. To the resulting solution add 66,9 g of purified egg powder (the content of phosphatidylcholine > 94%). The mixture was dispersed by using a rapidly rotating stirrer at a temperature of 60oC for 30 minutes. Then recharge the treated nitrogen water to 706,2 g and type of 1.65 g of the active substance according to example 1. For uniform distribution of the active substance is again dispersed in 3 minutes. The resulting dispersion was transferred to a high-pressure homogenizer and homogenize 25 times at a temperature of 60oC and a pressure of 800 bar. In the resulting liposomal dispersion is dissolved 637,19 g of sucrose and the pH of the dispersion was adjusted to 6.5 by the addition of 0.1 G. of a solution of the hydroxide naturalista on 2.64 g fill in a brown glass bottle and subjected to freeze drying.

After three months of storage freeze dried liposomes at a temperature of 40oC the active substance is 98.5% and within 24 hours after adding 10 ml of an aqueous solution containing 0,0495% kaprilat sodium and 1,51% glycerol, flocculation and/or sedimentation does not occur.

Example 3.

of 12.53 g of ascorbic acid and 2.85 g of sodium hydroxide are dissolved with stirring in 4868,18 g of water and then add 504,8 g of purified egg lecithin (phosphatidylcholine > 94%). The resulting mixture is dispersed in a rapidly rotating mixer. The dispersion is filtered over a membrane filter having a pore size of 8 μm, and the obtained filtrate 25 times homogenized in a high-pressure homogenizer at a pressure of 800 bar. In the resulting liposomal dispersion is dissolved 908,70 g of sucrose and the pH was adjusted to 6.5 by dissolving 0.6 g of ascorbic acid and the corresponding titration a solution of 0.1 G. of sodium hydroxide. For protection against oxidation, the entire process is carried out in nitrogen atmosphere. Type of 12.6 g of (4R)isopropyl-2-methoxyethyl-4-(2-chloro-3 - cyano-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3,5-in primary forms and the resulting dispersion is stirred for 12 hours until rastvoreniya in bottles of 50 ml Lyophilized product lead in ready to use form by addition of an aqueous solution containing 0,725 g glycerol 0,02375 g kaprilat sodium and 47,184 g of distilled water.

Example 4.

4,6583 kg of distilled water is treated with nitrogen for 10 minutes and then it is dissolved in 5.7 mg of ascorbic acid and 852,8 g glucose. The resulting solution is brought to a pH value of 6.5 by adding 66 g of a 0.5 molar solution of arginine. Then add 9,502 g of the active substance nimodipina and 473,8 g of purified egg lecithin (phosphatidylcholine > 80%). The resulting mixture was dispersed using a rapidly rotating stirrer at a temperature of 75oC for 60 minutes in nitrogen atmosphere. The resulting dispersion was filtered (pore size 5 μm) and then homogenized in a homogenizer high pressure at a temperature of 75oC and a pressure of 800 bar, and then cooled to a temperature below 30oC. the resulting dispersion is filtered sterile membrane filter having a pore size of 0.2 μm, and it is filled in quantities at 15,30 ml in a brown glass bottle and subjected to freeze drying. Liposomes result in ready-to-use form by addition of an aqueous solution, the content is Persia is not observed any sediment, no flocculation.

Example 5.

171,6 g of distilled water is treated with nitrogen for 20 minutes and then add 200 mg of sodium ascorbate and 10 g of purified egg lecithin (phosphatidylcholine > 94%) and 200 mg of active substance of etomidate [(R)-ethyl-( -methylbenzyl)-5 - imidazolecarboxamide]. The resulting mixture was dispersed using a high speed stirrer for 20 minutes at a temperature of 60oC in nitrogen atmosphere. After refilling evaporated water, the resulting dispersion is served in a high-pressure homogenizer and homogenize 25 times at a temperature of 60oC and a pressure of 800 bar. Then 1 g of the product of homogenization when dissolved add the 98.9 mg sucrose and 1.8 mg kaprilat sodium, after which the pH of the dispersion was adjusted to 6.5 by adding 1 N. sodium lye. After sterile filtration (membrane filter with a pore size of 0.2 μm) dispersion in the quantity of 20.0 g fill in a brown glass bottle and subjected to freeze drying.

The average size of the liposomes before freeze drying is 56 nm. After bringing in ready-to-use form by adding 17,16 g (5%) glucose solution, the average size of the liposomes is 61 nm. For CLASS="ptx2">

Example 6.

1.4 g of sodium ascorbate dissolved in 425 g free from oxygen distilled water. Then add 50 g of purified egg powder (the content of phosphatidylcholine > 80%) and 1.5 g of paclitaxel (a mixture of alkaloids from needles and berries Tisa) and the resulting mixture was dispersed using a rapidly rotating stirrer at a temperature of 65oC for 30 minutes. Thus obtained dispersion is homogenized 25 times in the high-pressure homogenizer at a temperature of 60oC and a pressure of 725 bar.

To 382,32 g this homogenized dispersion added 72 g of sucrose and 80 mg of ascorbic acid, the pH was adjusted to 6.5 by addition of 0.1 n sodium hydroxide solution and the resulting dispersion fill with water up to 480, Then the dispersion is filtered and portions of 12,32 g (corresponding to 30 mg of paclitaxel +2,67% reseed) fill in bottles of 50 ml and subjected to freeze drying. Dried by freezing the product bring in ready-to-use form by adding and 29.7 g of a solution containing 0,725 g glycerol 0,02375 g kaprilat sodium and 47,187 g of distilled water. 30 ml of the resulting dispersion contains 30 mg of paclitaxel.

Comparative examples

Comparative examples oraut 49,1 g glucose and 0,345 g of ascorbic acid, then the pH was adjusted to 6.5 by the addition of 3.9 g of a 0.5 M solution of arginine. To the resulting solution add 27,25 g of purified egg lecithin (phosphatidylcholine > 80%), 0,345 g of the active substance according to example 1 and treated with nitrogen water to a total weight of 345 g of the Obtained mixture was dispersed by using a rapidly rotating stirrer at a temperature of 75oC for 30 minutes. After filtration (membrane filter size 5 μm) dispersion is carried out in a high-pressure homogenizer and homogenize 25 times at a temperature of 75oC and a pressure of 800 bar.

Ready liposomal dispersion is subjected to sterile filtration (membrane filter with a pore size of 0.2 μm), the number of 2.1 ml fill in a brown glass bottle and subjected to freeze drying.

After 2-week storage freeze dried liposomes at a temperature of 40oC the active substance is of 89.7%.

The average particle diameter of liposomes is 45 nm after homogenization under high pressure. After bringing in ready-to-use form freeze dried liposomes by the addition of 9.5 ml of distilled water, the average diameter of the liposomes is 47 nm2">

Comparative example B (concentration of fatty acids > 10 mg/ml)

Obtained analogously to example 1 liposomes result in ready-to-use form by adding 10 ml of an aqueous solution containing 5% of kaprilat sodium and 1,51% glycerol. Liposomes destabiliziruetsya. In liposomes has only 5.3% of the active substance.

Comparative example B5 (without fatty acids)

Obtained analogously to example 1 liposomes result in ready-to-use form by adding 10 ml of an aqueous solution containing 1,51% glycerol. When this dispersion is observed flocculation within 24 hours. A precipitate.

1. Liposomal pharmaceutical composition for intravenous administration containing insoluble lipophilic active substance in the form of liposomes, at least one phospholipid, distilled water and additives target, characterized in that it further contains at least one cretaceou fatty acid of the formula I

H3C - (CH2)n- COOH

where n = 4 - 8,

or its salt, in the following proportions, wt. hours at 100 weight.h. distilled water:

Lipophilic, poorly soluble active substance is 0.001 to 2.0

The phospholipid- 0,02 - 40< 1 : (20 - 200), and the weight ratio gracciano fatty acids or its salts and phospholipid is 1 : (2 - 60).

2. Liposomal pharmaceutical composition for internal injection under item 1, characterized in that it as the active substance contains a derivative of dihydropyridines of General formula II

< / BR>
where R is methyl;

R1- methoxyethyl;

R2group - SOOS3H7-out;

R3is phenyl, substituted by a nitro-group in the meta-position, or chlorine in position 2 and cyano in position 3,

or R is amino, R1is lower alkyl, R2is cyano and R3group of the formula

< / BR>
where R4means hydrogen, halogen, cyano, deformity, lower alkyl or alkoxyl.

3. Liposomal pharmaceutical composition for intravenous injection under item 1, characterized in that the active substance contains (R)-ethyl - methylbenzyl)-imidazoledicarboxylic.

4. Liposomal pharmaceutical composition for intravenous injection under item 1, characterized in that the active substance contains an ester of (2aR, 4S, 4aS, 6R, 9S, 11S, 12S, 12aR, 12bS) - a 1,2, 3,4, 4a, 6,9,10,11,12,12 a, 12b-dodecahydro-4,6,9,11,12,12 b-hexahydroxy-4A, 8, 13, 13-tetramethyl-7, 11-methane-5H-cyclodina [3,4] , benzo[1,notice for intravenous injection by p. 1, wherein it as the target of the additive contains at least one antifreeze in the amount of 0.8 to 4.0 per 1 weight.h. phospholipid.

6. Liposomal pharmaceutical composition for intravenous injection under item 1, characterized in that it as the target of the additive contains an antioxidant in an amount of 0.0001 to 2.0 per 100 weight.h. of distilled water.

 

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