EA027680B1 - Stable pharmaceutical composition in the form of a nasal spray containing ketorolac - Google Patents

Abstract

The invention is related to a novel stable pharmaceutical composition in the form of a nasal spray containing a theurapeutically effective amount of ketorolac in the form of an acid or its salt, water as a solvent and targeted additives, characterized in that it further contains dexpanthenol as an antioxidant. The technical result of the invention is provision of a preparation that is stable in storage both before and after opening the vial.

Description

The invention relates to the field of pharmaceuticals and is a pharmaceutical composition in the form of a nasal spray containing a therapeutically effective amount of ketorolac in the form of an acid or its salt, water as a solvent and target additives, characterized by the content of dexpanthenol as an antioxidant.

State of the art

Ketorolac refers to non-steroidal anti-inflammatory drugs (NSAIDs), has analgesic and moderate anti-inflammatory activity. By the degree of analgesic effect, it is noticeably distinguished among NSAIDs, comparable with strong opioid analgesics, in particular with morphine and codeine.

Ketorolac is more often used in the form of intramuscular and intravenous injections. It is also used in the form of tablets, eye drops and rectal suppositories. The new dosage form of ketorolac, which in some cases may turn out to be a more convenient and safe alternative to parenteral administration, has become the recently registered in the USA and Western Europe nasal spray ZRK4X (Kokhgo Ragta) [Voueg KS but! A1., A poe1 Γοπηιιίαΐίοη oG ke1ogoas Tsoteyattte Gog 1n1 band 1 abtiziZayon: Przegnts1 5aGe1u eu1ia1yup. Ιηΐ. I. Tox1co1. 2010, 29 (5), 467-478]. The intranasal form of ketorolac and the benefits of its use were first described in 1991 in patent FROM 6333044. Ketorolac is rapidly and completely absorbed into the systemic circulation through the mucous membrane of the nasal cavity, which allows to obtain a therapeutic effect equivalent to that obtained by injection or oral administration. In this case, there are no gastrointestinal disorders, and disorders associated with the effect on the central nervous system are significantly reduced both in frequency and intensity of manifestation.

Application \\ 'O 2009/0042968 shows that ketorolac tromethamine is successfully combined with a local anesthetic, such as lidocaine hydrochloride, in order to reduce the burning sensation experienced by some patients with the intranasal use of ketorolac tromethamine without an anesthetic.

Application \\ 'O 2009/152369 proposes a nasal spray composition with a higher concentration of ketorolac tromethamine (alone or in combination with lidocaine) compared to IZ 6333044, which reduces the volume of the drug injected into the nostril to 50-100 μl.

In most known dosage forms, ketorolac is contained in the form of tromethamine salt, which, in comparison with ketorolac as an acid, is better soluble in water.

Ketorolac tromethamine is a compound of racemic 5-benzoyl-2,3-dihydro-1Hyrrolysin-1-carboxylic acid with 2-amino-2- (hydroxymethyl) propane-1,3-diol in a 1: 1 molar ratio and has the following structure:

It is known [KazUar K. \\ abekag a! A1., Eua1ia! td Ιιηριιπίίο ΐη Ogidz (Pag1 ΙΙΙ oG III). Pagantaseis 1 1 espododu, 2012, 36 (4), 76-86; Cie Leo a! A1., 1 ld1 and Bedgabon OG ke1ogoas P'otebytt. Ιηΐ. I. Pag. 1988, 41 (1-2), 105-113; Cie Leo a! a1. Keynes apb tesztz oG! B aktbabon oG ke1ogoas p'otebytte ΐη atsieoiz zl1i1yup. Ιηΐ. I. Pag. 1988, 41 (1-2), 95-104] that undesired decomposition products are formed during storage of an aqueous solution of ketorolac tromethamine. The rate of their formation is affected by temperature, pH of the solution, the presence of light and oxygen in the air. The decomposition proceeds according to the decarboxylation mechanism, followed by oxidation to 1-keto analog and / or 1-hydroxy analog. The chemical structure of oxidation impurities is given in table. one.

Table 1

Ketorolac oxidation admixtures

5-benzoyl-2,3-dihydro-1 H-pyrrolysin-1-one (ketorolac 1-keto analog) (1 KZ) -5-benzoyl-2,3-dihydro-1-H-pyrrolisin-1-ol (ketorolac 1-hydroxy analog) ABOUT

Stability studies of the original ZRKEX | 1111 spray [y \ y \ y \ u.aseeszs1a1aGs1a.do \ s1p1dza11s1a s1oezlk1a-2010-0223820pd1z000R11appk. [X.1G | showed that the content of these degradation products increases over time, especially 1-keto analog and to a lesser extent 1-hydroxy analog.

In order to slow down the oxidation of ketorolac in an aqueous solution, it is recommended to store the original ZRKEX spray at a temperature of 2-8 ° C for two years. The drug is sold in two packaging options: one bottle in the package, in which 8 doses of the drug are 100 μl each (amount of spray for one day

- 1,027,680 applications) or in a package of 5 vials, each of which has 8 doses of the drug, 100 μl each. The last packaging option is designed for a five-day course of treatment, and an individual bottle for each day avoids oxidation of the drug after opening the bottle.

The authors of the application ϋδ 2013274650 to stabilize an aqueous solution of ketorolac suggest the use of carbon dioxide. A pillow made of heavy carbon dioxide, which is partially released from the solution saturated with it, excludes oxygen being thrown into the bottle at the time of closure.

According to the authors of the application AO 2010105042 (Κϋ 2011140749), which serves as a prototype, in order to prevent the oxidation of ketorolac in an aqueous solution, the bottles must be sealed in an inert gas atmosphere. It is necessary that in the free space of the bottle between the solution and the nozzle containing the spray system, the oxygen content should be no more than 10% vol./about. With this method of capping, the drug remains stable for at least two years at room temperature.

However, such stabilization principles work only until the bottle is opened or require the use of special primary packaging (systems with airless metering pumps and bottles with an internal bag of the SOMOE and APP 360 type). In addition, this package also has air permeability. In this regard, it is necessary to introduce antioxidants into an aqueous solution of ketorolac to reduce the rate of formation of oxidation products during storage.

SUMMARY OF THE INVENTION

We found that the addition of dexpanthenol significantly reduces the formation of ketorolac oxidation products in solution. Dexpanthenol has the following chemical structure:

Its antioxidant effect is determined by the presence of hydroxyl groups and a secondary amino group. Secondary amines belong to the class of antioxidants, also called proton donors and free radical scavengers. Compounds of this type are a sedentary molecule with a mobile easily cleaving hydrogen atom that reacts with a free radical.

At the same time, dexpanthenol is used in many nasal forms as an auxiliary and / or active substance. Dexpanthenol is a precursor of pantothenic acid (vitamin B ₅ ), an integral part of acetyl coenzyme A, which is necessary for normal metabolism in all cells, especially in the cells of the skin and mucous membranes. Dexpanthenol accelerates epithelialization and granulation, reduces itching, irritation and inflammation of the skin and mucous membranes, relieves burning, acts as a moisturizer, reduces transepidermal water loss and maintains softness and elasticity of the skin and mucous membranes.

The objective of the invention is to obtain pharmaceutical compositions of ketorolac for intranasal administration, with storage stability independent of the opening of the vial. The solution to the problem is achieved by the introduction of an aqueous solution of ketorolac dexpanthenol, which prevents the oxidation of ketorolac, and other targeted additives.

The content of ketorolac tromethamine in the proposed compositions is 2.5-22.5 wt.% (1.7-15.3% in terms of ketorolac acid), preferably about 15 wt.% (10.2% in terms of ketorolac acid) , the content of dexpanthenol is 0.1-4.0 wt.%, preferably 0.5-1.5 wt.%.

An important aspect of the invention is that the amount of dexpanthenol with respect to ketorolac should not exceed 25% in order to prevent the absence of its effect on the effectiveness of the drug.

The active ingredient contained in these compositions can be selected from ketorolac as a racemic mixture of one of the optically active ketorolac isomers or a mixture of two ketorolac isomers, which can be either in the form of an acid or in the form of a pharmaceutically acceptable salt.

The preferred solvent for the compositions is water, and other solvents may be used if necessary.

Optimal from the point of view of the stability of the drug, the pH of the composition should be in the range of 4-8, preferably 6.0-7.5. It can be achieved, for example, using tromethamine, phosphate and other buffers.

A preferred composition with a concentration of ketorolac tromethamine of about 15 wt.% And a concentration of dexpanthenol of 0.5-1.5 wt.% Is hypertonic, that is, has an osmotic pressure of 500-700 mOsm, which is greater than in biological fluids. If the concentration of ketorolac is lower, an isotonic agent used in pharmaceuticals, such as sodium chloride or glucose, must be added.

To ensure the stability of the active ingredient, it is advisable to introduce complexing agents into the composition of the drug, which will bind heavy metal ions, which are known to

- 2 027680 are catalysts for redox reactions or any other ions, such as calcium and magnesium ions, which contribute to the decomposition of ketorolac. A preferred complexing agent is ethylenediaminetetraacetic acid disodium salt (EDTA).

To ensure microbiological stability, it is advisable to introduce preservatives into the composition of the drug. Suitable preservatives include, but are not limited to, methyl paraben, propyl paraben, sodium benzoate, benzyl alcohol, benzalkonium chloride and chlorobutanol.

Preferably, in order to improve the stability of the active ingredient, the capping of the vials should be carried out in an inert gas atmosphere.

The implementation of the invention

The preparation of the proposed compositions is described in the following examples. The stability of the compositions was determined under conditions consistent with the guidance of 1CH O1 A. Stability tests of new drugs and preparations. According to clause A.2.1.7.2. 1CH E1 AL Medicines intended for storage in the refrigerator long-term tests were carried out at (5 ± 3) ° С for two years, accelerated - at (25 ± 2) ° С and relative humidity (60 ± 5)% for 6 months . Additionally, the stability of the drug after opening the bottle and extracting 95% of the contents of the bottle was determined. As a control experiment, the composition of the drug without dexpanthenol and data on its stability are given.

The content of the main substance in the compositions was determined by HPLC. Ketorolac trometamino EP SK8 was used as a standard. The chromatography process was carried out on a column of size 4.6 x 150 mm, filled with C8 silica gel with a particle size of 5 μm. Mobile phase: a mixture of 55 volume parts of methanol with 44 volume parts of water and 1 volume part of glacial acetic acid. Flow rate 1 ml / min; column temperature 25 ° C. Detection: spectrophotometric detector at a wavelength of 254 nm.

The rationing of impurities in the compositions corresponds to the guidance of 1CH 03 B Impurities in new drugs. The maximum daily dose of ketoroloc in the form of a spray is 126 mg. At such a dose, impurities, the content of which is higher than 0.2%, must be identified; toxicological studies with rationale for rationing should also be given for them. For 1 keto analogue impurity, the norm of which is not more than 0.9%, toxicological studies confirming safety are given in the RIA dossier for the original 8ΡΚΙΧ spray.

Foreign impurities were determined by HPLC. For the identification of impurities, we used keiogo1 as 1gosh1asho1 Gog reagent 1bPezeo-Tsop SK8 (containing impurities A, B, C, Ό). Impurities A, B, C, Ό correspond to the impurities described in the monograph EP 7.0 01/2008: 1755. Admixture A: (1K8) -5benzoyl-2,3-dihydro-1-H-pyrrolysin-1-ol (hydroxy admixture), impurity B: 5-benzoyl-2,3-dihydro-1Hpyrrolysin-1-one (keto admixture), impurity C: (1K8) -6-benzoyl-2,3-dihydro-1-H-pyrrolysin-1-carboxylic acid, impurity Ό: (1K8) -5-benzoyl-1-methoxy-2,3-dihydro-1H pyrrolisin-1-carboxylic acid. The chromatography process was carried out on a 4.6 x 250 mm column filled with C8 silica gel. Mobile phase: a mixture of 30 volume parts of tetrahydrofuran and 70 volume parts of a solution prepared as follows: 5.75 g of ammonium dihydrogen phosphate is dissolved in 900 ml of water, the pH is adjusted with phosphoric acid to 2.7 ± 0.2 and the volume is adjusted with water to 1000 ml . The flow rate of 1.5 ml / min, column temperature 40 ° C. Detection: spectrophotometric detector at a wavelength of 313 nm. The relative retention time at the peak of ketorolac (retention time is about 10 minutes): impurity C is about 0.5, impurity A is about 0.6, impurity Ό is about 0.7, impurity B is about 0.9.

Example 1

Ketorolac Tromethamine 157.5 g EDTA 0.5 g Potassium dihydrogen phosphate 6.8 g 2M sodium hydroxide to pH 7.2 Methylparaben 1 g Purified water up to 1000 ml

157.5 g of ketorolac tromethamine, 6.8 g of potassium dihydrogen phosphate, 0.5 g of EDTA and 1 g of methyl paraben were dissolved in a container into which 800 ml of purified water was pre-loaded. Then, with stirring, the pH of the solution was adjusted to 7.2 with a 2M sodium hydroxide solution. After that, the volume of the solution was adjusted to 1000 ml with purified water and mixed.

The resulting solution was poured into dark glass bottles and sealed with nasal metering pumps. Some of the corked vials were opened, and a 95% ketorolac solution was removed using a metering pump, which was replaced by air, respectively. Opened and unopened vials were stored for determination of drug stability (see Tables 2 and 3).

- 3 027680

The stability of the drug obtained in example 1 (storage in an unopened bottle)

table 2

Quantitative content ketorolac tromethamine in a single dose Impurity content Impurities Any other unit impurity Amount impurities BUT from ϋ IN Norm 14.96 to 16.54 mg no more than 0.2% no more than 0.9% no more 0.2% no more than 2.0% Long-term tests (5 ± 3) ° С 0 month 15,64 - 0.02 0.02 0.01 0.01; 0.04 0.10 3 month 15.67 - 0.02 0.02 0.18 0.02; 0.04 0.28 6 months 15.47 0.01 0.02 0.02 0.33 0.01; 0.03; 0.04 0.46 12 months 15.50 0.01 0,03 0.02 0.52 0.05; 0.04 0.67 18 months 15.46 0.01 0.02 0.02 0.65 0.01; 0.08; 0.04 0.83 24 months 15.44 0.01 0.02 0.02 0.71 0.09; 0.05 0.90 Accelerated tests (25 ± 2) ° С / (60 ± 5)% 0 month 15,64 - 0.02 0.02 0.01 0.01; 0.04 0.10 3 month 15,58 0.01 0.02 0.02 0.41 0.01; 0.04; 0.04 0.55 6 months 15.39 0.01 0.02 0.02 0.64 0.01; 0.09; 0.04 0.83

The stability of the drug obtained in example 1 (storage in an opened bottle)

Table 3

Quantitative content ketorolac tromethamine in a single dose Impurity content Impurities Any other unit impurity Amount impurities BUT from ϋ IN Norm 14.96 to 16.54 mg no more than 0.2% no more than 0.9% no more 0.2% no more than 2.0% Long-term tests (5 ± 3) ° С 0 month 15,64 - 0.02 0.02 0.01 0.01; 0.04 0.10 3 month 15.68 0.01 0,03 0.02 0.19 0.02; 0.04 0.31 6 months 15.65 0.01 0.02 0.02 0.36 0.03; 0.04 0.48 12 months 15,56 0.01 0.02 0.02 0.65 0.01; 0.05; 0.04 0.80 18 months 15.45 0.01 0.02 0.02 0.87 0.08; 0.04 1,04 24 months 15.42 0.01 0,03 0.02 1,03 0.10; 0.05 1.24 Accelerated tests (25 ± 2) ° С / (60 ± 5)% 0 month 15,64 - 0.02 0.02 0.01 0.01; 0.04 0.10 3 month 15,56 0.01 0.02 0.02 0.53 0.01; 0.05; 0.04 0.68 6 months 15.35 0.01 0,03 0.02 0.96 0.09; 0.04 1.15

As can be seen from the stability reports, after opening the bottle, the drug is not stable during storage.

Example 2

Ketorolac Tromethamine

Dexpanthenol

EDTA

Potassium dihydrogen phosphate 2M sodium hydroxide Methylparaben Purified water

157.5 g 0.75 g

0.5 g 6.8 g to pH 7.2 1 g to 1000 ml

157.5 g of ketorolac tromethamine, 0.75 g of dexpanthenol, 6.8 g of potassium dihydrogen phosphate, 0.5 g of EDTA and 1.0 g of methyl paraben were dissolved in a container into which 800 ml of purified water was pre-loaded. Then, with stirring, the pH of the solution was adjusted to 7.2 with a 2M sodium hydroxide solution. After that, the volume of the solution was adjusted to 1000 ml with purified water and mixed.

The resulting solution was poured into dark glass bottles and sealed with nasal metering pumps. Some of the corked vials were opened, and a 95% ketorolac solution was removed using a metering pump, which was replaced by air, respectively. Opened and unopened flagons were placed in storage to determine the stability of the drug (see Tables 4 and 5).

Table 4

The stability of the drug obtained in example 2 (storage in an unopened bottle)

Quantitative content ketorolac tromethamine in a single dose Impurity content Impurity Any other unit impurity Amount impurities BUT from ϋ IN Norm 14.96 to 16.54 mg no more than 0.2% no more than 0.9% no more 0.2% no more than 2.0% Long-term tests (5 ± 3) ° С 0 month 15.87 - 0.02 0.02 0.01 0.01; 0.01; 0.04 0.11 3 month 15.77 0.01 0.02 0.02 0.17 0.02; 0.04 0.28 6 months 15.77 0.01 0.02 0.02 0.31 0.01; 0.03; 0.04 0.44 12 months 15.82 0.01 0,03 0.02 0.50 0.05; 0.04 0.65 18 months 15.75 0.01 0.02 0,03 0.61 0.08; 0.04 0.79 24 months 15.71 0.01 0.02 0.02 0.67 0.01; 0.11; 0.89 0.05 Accelerated tests (25 ± 2) ° С / (60 ± 5)% 0 month 15.87 - 0.02 0.02 0.01 0.01; 0.01; 0.04 0.11 3 month 15.74 0.01 0.02 0.02 0.37 0.01; 0.06; 0.04 0.53 6 months 15.73 0.01 0.02 0.02 0.59 0.01; 0.10; 0.04 0.79

Table 5

The stability of the drug obtained in example 2 (storage in an opened bottle)

Quantitative content ketorolac tromethamine in a single dose Impurity content Impurity Any other unit impurity Amount impurities BUT from ϋ IN Norm 14.96 to 16.54 mg no more than 0.2% no more than 0.9% no more 0.2% no more than 2.0% Long-term tests (5 ± 3) ° С 0 month 15.87 - 0.02 0.02 0.01 0.01; 0.01; 0.04 0.11 3 month 15.85 0.01 0.02 0.02 0.17 0.02; 0.04 0.28 6 months 15,80 0.01 0.02 0.02 0.31 0.03; 0.04 0.43 12 months 15.76 0.01 0.02 0.02 0.55 0.04; 0.04 0.68 18 months 15.78 0.01 0.02 0.02 0.73 0.01; 0.08; 0.04 0.91 24 months 15.70 0.01 0.02 0.02 0.88 0.01; 0.10; 0.05 1.09 Accelerated tests (25 ± 2) ° С / (60 ± 5)% 0 month 15.87 - 0.02 0.02 0.01 0.01; 0.01; 0.04 0.11 3 month 15.75 0.01 0,03 0.02 0.49 0.01; 0.05; 0.04 0.65 6 months 15.71 0.01 0,03 0.02 0.83 0.09; 0.04 1,02

Example 3

Ketorolac Tromethamine 157.5 g Dexpanthenol 15.0 g EDTA 0.5 g Potassium dihydrogen phosphate 6.8 g 2M sodium hydroxide to pH 7.2 Methylparaben 1 g Purified water up to 1000 ml

157.5 g of ketorolac tromethamine, 15.0 g of dexpanthenol, 6.8 g of potassium dihydrogen phosphate, 0.5 g of EDTA and 1.0 g of methyl paraben were dissolved in a container into which 800 ml of purified water was pre-loaded. Then, with stirring, the pH of the solution was adjusted to 7.2 with a 2M sodium hydroxide solution. After that, the volume of the solution was adjusted to 1000 ml with purified water and mixed.

The resulting solution was poured into dark glass bottles and sealed with nasal pumps - 5,027,680 dispensers. Some of the corked vials were opened, and a 95% ketorolac solution was removed using a metering pump, which was replaced by air, respectively. Opened and unopened vials were stored for determination of drug stability (see Tables 6 and 7).

Table 6

The stability of the drug obtained in example 3 (storage in an unopened bottle)

Quantitative content ketorolac tromethamine in a single dose Impurity content Impurity Any other unit impurity Amount impurities BUT from ABOUT IN Norm 14.96 to 16.54 mg no more than 0.2% no more than 0.9% no more 0.2% no more than 2.0% Long-term tests (5 ± 3) ° С 0 month 15.79 - 0.02 0.02 0.01 0.01; 0.04 0.10 3 month 15.74 0.01 0.02 0.02 0.15 0.02; 0.04 0.26 6 months 15.67 0.01 0,03 0.02 0.27 0.01; 0.03; 0.04 0.41 12 months 15.72 0.01 0,03 0.02 0.44 0.05; 0.04 0.59 18 months 15.72 0.01 0.02 0,03 0.54 0.01; 0.08; 0.04 0.73 24 months 15.70 0.01 0.02 0,03 0.59 0.10; 0.05 0.80 Accelerated tests (25 ± 2) ° С / (60 ± 5)% 0 month 15.79 - 0.02 0.02 0.01 0.01; 0.04 0.10 3 month 15.75 0.01 0.02 0.02 0.33 0.01; 0.05; 0.04 0.48 6 months 15.74 0.01 0,03 0.02 0.52 0.09; 0.04 0.71

Table 7

The stability of the drug obtained in example 3 (storage in an opened bottle)

Quantitative content ketorolac tromethamine in a single dose Impurity content Impurity Any other unit impurity Amount impurities BUT from about IN Norm 14.96 to 16.54 mg no more than 0.2% no more than 0.9% no more 0.2% no more than 2.0% Long-term tests (5 ± 3) ° С 0 month 15.79 - 0.02 0.02 0.01 0.01; 0.04 0.10 3 month 15.78 0.01 0.02 0.02 0.15 0.01; 0.03; 0.04 0.28 6 months 15.69 0.01 0.02 0.02 0.27 0.03; 0.04 0.39 12 months 15.73 0.01 0,03 0.02 0.48 0.01; 0.04; 0.04 0.63 18 months 15.67 0.01 0,03 0,03 0.64 0.08; 0.04 0.83 24 months 15.65 0.01 0,03 0.02 0.77 0.11; 0.05 0.99 Accelerated tests (25 ± 2) ° С / (60 ± 5)% 0 month 15.79 - 0.02 0.02 0.01 0.01; 0.04 0.10 3 month 15.71 0.01 0,03 0.02 0.43 0.06; 0.04 0.59 6 months 15.68 0.01 0,03 0,03 0.73 0.01; 0.10; 0.04 0.95

Example 4

Ketorolac Tromethamine 157.5 g Dexpanthenol 39.0 g EDTA 0.5 g Potassium dihydrogen phosphate 6.8 g 2M sodium hydroxide to pH 7.2 Methylparaben 1 g Purified water up to 1000 ml

157.5 g of ketorolac tromethamine, 39.0 g of dexpanthenol, 6.8 g of potassium dihydrogen phosphate, 0.5 g of EDTA and 1.0 g of methyl paraben were dissolved in a container into which 800 ml of purified water was pre-loaded. Then, with stirring, the pH of the solution was adjusted to 7.2 with a 2M sodium hydroxide solution. After that, the volume of the solution was adjusted to 1000 ml with purified water and mixed.

The resulting solution was poured into dark glass bottles and sealed with nasal metering pumps. Part of the corked bottles was opened, from them using a metering pump removed

- 6,027,680

A 95% solution of ketorolac, which is accordingly replaced by air. Opened and unopened vials were put into storage to determine the stability of the drug (see tables. 8 and 9).

Table 8

The stability of the drug obtained in example 4 (storage in an unopened bottle)

Quantitative content ketorolac tromethamine in a single dose Impurity content Impurity Any other unit impurity Amount impurities BUT from Ts IN Norm 14.96 to 16.54 mg no more than 0.2% no more than 0.9% no more 0.2% no more than 2.0% Long-term tests (5 ± 3) ° С 0 month 15.68 - 0.02 0.02 0.01 0.01; 0.04 0.10 3 month 15.65 0.01 0.02 0.02 0.12 0.01; 0.02; 0.04 0.24 6 months 15.69 0.01 0,03 0.02 0.22 0.01; 0.03; 0.04 0.36 12 months 15,59 0.01 0.02 0.02 0.35 0.01; 0.05; 0.04 0.50 18 months 15,58 0.01 0.02 0.02 0.43 0.01; 0.08; 0.04 0.61 24 months 15,52 0.01 0.02 0,03 0.47 0.11; 0.05 0.69 Accelerated tests (25 ± 2) ° С / (60 ± 5)% 0 month 15.68 - 0.02 0.02 0.01 0.01; 0.04 0.10 3 month 15,55 0.01 0.02 0.02 0.26 0.05; 0.04 0.40 6 months 15,57 0.01 0,03 0.02 0.42 0.09; 0.04 0.61

Table 9

The stability of the drug obtained in example 4 (storage in an opened bottle)

Quantitative content ketorolac tromethamine in a single dose Impurity content Impurity Any another single impurity Amount impurities BUT from c IN Norm 14.96 to 16.54 mg no more than 0.2% no more than 0.9% no more 0.2% no more than 2.0% Long-term tests (5 ± 3) ° С 0 month 15.68 - 0.02 0.02 0.01 0.01; 0.04 0.10 3 month 15.66 0.01 0.02 0.02 0.12 0.01; 0.04 0.22 6 months 15.65 0.01 0.02 0.02 0.22 0.03; 0.04 0.34 12 months 15,57 0.01 0.02 0.02 0.39 0.04; 0.04 0.52 18 months 15,54 0.01 0.02 0,03 0.51 0.01; 0.08; 0.04 0.70 24 months 15,55 0.01 0.02 0,03 0.62 0.01; 0.10; 0.04 0.83 Accelerated tests (25 ± 2) ° С / (60 ± 5)% 0 month 15.68 - 0.02 0.02 0.01 0.01; 0.04 0.10 3 month 15.71 0.01 0.02 0.02 0.34 0.01; 0.06; 0.04 0.50 6 months 15.60 0.01 0,03 0.02 0.58 0.11; 0.04 0.79

CLAIM

Claims (3)

CLAIM 1. A pharmaceutical composition in the form of a nasal spray, containing a therapeutically effective amount of ketorolac, water as a solvent and targeted supplements, characterized in that it additionally contains dexpanthenol in an amount of 0.5-25% of the amount of ketorolac. 2. The pharmaceutical composition according to claim 1, in which ketorolac may be in the form of a racemic mixture of one of the optically active isomers or a mixture of two isomers of ketorolac, while ketorolac may be either in the form of an acid or in the form of a pharmaceutically acceptable salt. 3. The pharmaceutical composition according to claim 1, characterized in that dexpanthenol is used as an antioxidant.