Pharmaceutical compositions of 3-substituted 2-oxindole-1 - carboxamide, the method of inhibiting activation of collagenase, the way you call analgesic reaction, a method of treating inflammatory diseases

 

(57) Abstract:

The invention relates to medicine. The pharmaceutical composition comprises at least one triglyceride or a complex of propylene glycol ester of fatty acids fractionated coconut oil and at least one compound of the formula

< / BR>
where R1, R2and R3each independently represents hydrogen, fluorine, bromine or chlorine, or a pharmaceutically acceptable salt. Proposed methods of inhibiting collagenase, call analgesic response and treatment of inflammatory diseases by introducing the composition in an effective amount. The proposed compositions have excellent safety and long shelf life. 4 N. and 15 C.p. f-crystals, 2 tab.

The present invention relates to pharmaceutical compositions containing certain 3-substituted 2-oxindole-1-carboxamide, triglycerides and complex of propylene glycol diesters of fatty acids with medium chain length (C8-C10). These carboxamide suitable for use as analgesics for mammals such as man, and to remove or relieve pain after surgery or other trauma, or to relieve the symptoms of such is provided in U.S. patent 4556672 and 5047554. Carboxamide also useful for the treatment of diseases and painful conditions associated with collagenase, such as diseases associated with bone resorption, lesions of the cornea, periodontal diseases, inflammatory diseases and wounds and burns in mammals, which are disclosed in U.S. patent 5008283.

Disclosed in the claims carboxamide formula I is chemically unstable in water. It is known that the rate of hydrolytic decomposition (hydrolysis) can be reduced, protecting labile drugs, for example, through the conclusion in the hydrophobic core of the micelles, or by compositions with the media based on non-aqueous solvents, inactive in water, for example, in essential oils. In addition to the hydrolytic instability carboxamide also susceptible to oxidative degradation in aqueous media, for example in water and nonaqueous carriers, such as oils. Oxidative instability can be reduced in saturated oils, for example, by the inclusion of antioxidants or by creating compositions of unsaturated oils that protect drugs from their significant autoxidation. However, carboxamide described in formula I, it is not easy to stabilize the oils, which are usually ispolzuem oil.

Summary of the invention

The present invention relates to pharmaceutical compositions containing:

A) at least one triglyceride or a complex of propylene glycol fluids fatty acids fractionated coconut oil;

B) at least one compound of the formula I

where R1, R2and R3each independently represents hydrogen, fluorine, bromine or chlorine, or their pharmaceutically acceptable salts; where the weight ratio of A to B is in the range from 5.6 to 999.

The pharmaceutical compositions comprise from 85 to 99 wt.% A and from 0.1 to 15 wt.% B.

Preferably, each of R1, R2and R3independently represented fluorine or chlorine.

Preferred compounds of formula I include 5-chloro-2,3-dihydro-2-oxo-(2-thienylboronic)-indolocarbazole, 6-chloro-5-fluoro-2,3-dihydro-2-oxo-3-(2-thienylboronic)-indolocarbazole; and 6-chloro-5-fluoro-2,3-dihydro-2-oxo-3-[2-(4-chloro)- thienylboronic]indolocarbazole.

The present invention also includes a method of inhibiting activation colonnesi.

The present invention also includes a method of treating inflammatory diseases.

The present invention also includes a method is prohibited, the pharmaceutical compositions containing carboxamide formula I, and triglycerides and a complex of propylene glycol diesters C8-C10saturated fatty acids have excellent safety and long shelf life. The use of such compositions carboxamide less susceptible to hydrolysis and oxidation, which could damage them and thereby make them ineffective. Stabilization of these carboxamido in such preparations do not require the addition of an antioxidant or other auxiliary stabilizers.

Triglycerides, which are used in the claimed invention are neutral oils, which are composed of esters of fatty acids with medium chain length (C8-C10), also known as fractionated coconut oil. These fatty acids atrificial either glycerin or propylene glycol and sold under the trademark MIGLYOL(for example, MIGLYOL810, MIGLYOL812 and MIGLYOL840). MIGLYOL describe as triglycerides of fatty acids fractionated coconut oil or triglycerides of Caprylic acid /capric acid. Fractionated coconut oil is obtained from fiksirovany selected fatty acids, and transesterification glycerin or propylene glycol. It consists of a mixture of saturated fatty acids with short or medium length chains, mainly octane and decanoas acids. Miglyolis a trademark for fractionated coconut oil or triglycerides of Caprylic acid/capric acid from Dynamit Nobel Ltd Germany and UK. These carriers showed stability against oxidation and rancidity (damage), as well as excellent stability and biocompatibility. Moreover, since they use only saturated fatty acids, oils do not create peroxides or other free radicals, which could destabilize contained in medicinal preparations. Low water content also minimizes the hydrolysis of carboxamides. In preferred compositions carboxamide formula I is dispersed in an oil carrier containing Migliol812 and other oil-soluble additives described below, under stirring to obtain a homogeneous suspension of the medicinal substance in an oil carrier.

Other additives that may be present in the pharmaceutical preparations can also include agents that prevent obrazovaniia aluminum. The amount of agent that prevents the formation of sludge, can be from about 0.05 to 5 wt.%. The pharmaceutical composition may also contain a preservative in an amount of from 0.5 to 2.0 wt.%. Such preservatives may include, for example, phenol, benzyl alcohol, parabens, chlorobutanol and benzyl benzoate. Such gelling agents as aluminum monostearate, may also be included in pharmaceutical compositions in amounts of from 0.5 to 3.0% by volume. The stability of these pharmaceutical compositions can be evaluated,for example,tightened storage conditions after the suspension of carboxamido (6 wt.% medicinal substances), placed in a glass ampoule, is subjected to high temperatures of up to 70oC for up to 9 weeks. During stability tests level interchnage drug remaining in the drug, as well as the content of products of hydrolytic and oxidative decomposition, determine quantitatively by high performance liquid chromatography (HPLC). For analysis, the suspension is diluted with a mixture of methanol/triethylamine 100/1/volume/volume to obtain a final concentration of drugs from 0.6 to 1.2 mg/ml of This solvent dissolves the suspension medicines to recip which is a mixture of methanol/water 90/10 vol/vol + 1% triethylamine; the column is converted phase of octadecadiene, and the flow rate is 1 ml/min. Medication detects due to UV absorption at 246 nm. This analysis shows that during the nine weeks is practically no decomposition carboxamide.

If the compound of formula I or its salt is used for people, the daily dose is usually determined by the practitioner. Moreover, the dose will vary depending on age, weight and response of the individual patient and the severity of the patient's symptoms and the effectiveness of specific compound that is administered. However, for introduction in acute attacks of pain effective dose in most cases ranges from 0.01 to 0.25 g of necessity (for example, 1-4 times per day). For receiving chronic patients, in most cases, the effective dose is from 0.01 to 0.5 g/day and preferably from 0.1 to 0.25 g per day in single doses or in a single dose. On the other hand, sometimes it may be necessary to use dosages outside these limits.

Preferred pharmaceutical compositions of the present invention are parenteral pharmaceutical composition. The pharmaceutical compositions of the present invention can IU. Some examples of unit dosage forms are sterile suspension for intramuscular, subcutaneous, intra-articular injection, sterile ophthalmic suspension for surface application to the eye, capsules for oral administration, rectal suppositories or lotions for surface application on the skin or on the area of the hairline.

An example of a suitable pharmaceutical dosage forms for oral administration can serve as gelatin capsules. Suspension for oral administration can be supplied, for example, after encapsulating the suspension of the compounds of formula I in the oil, such as Miglyol 812, in soft gelatin capsules. Rectal suppositories can be obtained dispersive carboxamid neutral oil, along with compatible bases suppositories, such as coconut oil or Wlutepsol W35, melting point above body temperature. Products for surface application to the skin must contain carboxamide as an active ingredient dispersed in a neutral oil, such as Miglyol 812, and also contain one or more of the pharmaceutically inactive ingredients, such as: cetyl alcohol, stearic acid, the material composition preferably represent a suspension carboxamide neutral oil, and may also contain other inactive pharmaceutical ingredients such as benzyl alcohol as preservative, aluminum monostearate as a gelling agent and propylene glycol as a dispersing agent.

The following examples illustrate how it is possible to prepare pharmaceutical compositions. Commercial reagents can be used without additional purification.

Example 1. 800 mg of Miglyol 812 heated to 45oC in the mixer, equipped with a stirrer and a homogenizer. To the oil add 10 g of benzyl alcohol under stirring (about 60-80 rpm). The oil solution is sterile filtered into a sterile mixer equipped with a stirrer and a homogenizer. 120 g of sterile micronized powder carboxamide is dispersed in the oil phase with stirring. The suspension is homogenized with a high shear for 10 minutes and then allowed to cool at room temperature under moderate stirring (60-80 rpm). The suspension is adjusted to the full amount of 1000 g, adding the required number of Miglyol 812 g to the suspension to obtain the final composition. This suspension is aseptically filled into 50 cm3, type 1, printglossaries ampoules, using the above closed aluminum casing.

Example 2. 800 ml of Miglyol 812 heated to 45oC in the mixer, equipped with a stirrer and a homogenizer. To the oil add 10 g of benzyl alcohol under stirring (60-80 rpm). The oil solution is sterile filtered into a sterile mixer equipped with a stirrer and a homogenizer. To the oil suspension is added 20 g of sterile powder aluminum monostearate separate portions with stirring to obtain a gel oil. Generowanie the oil is allowed to cool to room temperature and left to stand for 6 hours without stirring. Then gel the oil was dispersed with stirring, 120 g of sterile micronized powder carboxamide. The total weight of the suspension was adjusted to 1000 g, adding the right amount of sterile generovanou suspension Miglyol 812 to obtain the final concentration of 12 weight. % carboxamide in the final composition. This suspension is aseptically filled into 50 cm3type 1 printglossaries capsules using automatic apparatus for filling. Vials closed with rubber caps with Teflon coating and the top cover aluminum casing.

Example 3. 800 ml of Miglyol 812 heated to 45oC in the mixer, equipped with a stirrer and a homogenizer. To malout 120 g of sterile micronized powder carboxamide. The suspension is homogenized with a high shear for 10 minutes, then leave to cool to room temperature under moderate stirring (60-80 rpm). The total weight of the suspension was adjusted to 1000 g with stirring, adding the required number of Miglyol 812 to the suspension to obtain a final concentration of 12 weight. % carboxamide in the final composition. The suspension is filled into soft gelatin capsules for oral administration, using an automated apparatus for filling capsules.

Example 4. 200 g of Miglyol 812 and 800 g Whitepsol W35 heated to 60oC in the mixer, equipped with a stirrer and a homogenizer. Powder carboxamide was dispersed in the resulting oil solution with stirring. Suspension fill forms for suppositories and cooled to room temperature.

Use Migliol provides the most stable suspension.

Data on the biological activity of compounds I.

The ability to inhibit the activation of collagenase and inhibit myeloperoxidase activity was determined by methods described below.

Whole human blood from healthy volunteers was obtained by venipuncture in getparametervalue syringes. Greater density over giacomin picollo. The fraction with a high content of neutrophils were washed and the remaining erythrocytes were removed by hypotonic lysis in accordance with the methodology described Brackburn W. D., and others, Arthritis Rheum. 30: 1006-1014 (1987). Thus obtained neutrophils used in the following tests and was convinced of the viability of the cells by determining their ability to exclude tepnovy blue. In each test cell viability was usually more than 95%.

In order to assess the inhibition of the selection of the activated neutrophil collagenase, was conducted the following test. Suspension of neutrophilic cells were incubated at 37oC for 15-30 minutes in the presence of different concentrations tenidap or other investigational compounds. Tenidap was dissolved, diluted with water and added directly to cells. Other test compounds were first dissolved in 0.1 M NaOH, and then diluted with water before adding to the cells. After cells were incubated in the presence tenidap or other investigational compounds, the cell suspension (5106cells/ml, 125 μl/well) was added to the coated IgG and blocked bovine serum albumin (BSA) wells titration microplate and incubated them is of IgG. After incubation, the suspension of cells was centrifuged (750g) for 5 minutes at 4oC. Supernatant was removed and added DFF (diisopropylfluorophosphate) to a final concentration of 10-3M to inactivate semipretioase.

After it was determined the activity of collagenase in the treated DFF supernatant by incubating three aliquot 200 μl of the supernatant with labeled3H restored fibrils of collagen type 1 in 7-mm flat-bottomed holes for tissue culture ( Lindbro, Cat #76-032-05, Flow Laboratories, McLean, Va) as described by Johnson-Wint, B, Anal. Biochem., 104: 175-181 (1980). Restored fibrils in each well contained 75 μg of a mixture of labeled3H and its collagen activity 7,000 impulses per minute. In order to determine the total radioactivity that could potentially be emitted from fibrils in each experiment, the recovered fibers are also incubated with a mixture clostridial collagenase (250 mg/ml SSR (balanced salt solution, Henk, GIBCO, Grand Island, N. Y.)). To maximize the sensitivity and specificity of the analysis, three samples were incubated for eighteen hours at 37oC. At the end of the incubation period of each hole uberlndia with bacterial collagenase, received more than 99% of the radioactivity deposited in each well. The average number of pulses per minute of the fibrils incubated only with buffer (SRH), subtracted from the number of pulses per minute, measured for each supernatant. Three obtained values for each supernatant were averaged and divided by the average number of pulses per minute, secreted bacterial collagenase, in order to determine the percentage of lysis of fibrils occurring in each supernatant. Then counted the total number of activated collagen released by incubation for eighteen hours, and it was divided into the incubation time to obtain the values of the activity of collagenase (ng decomposed collagen/min) in each supernatant.

In parallel experiments determined the allocation of the entire collagenase in supernatant by activation of latent collagenase in supernatant using 1.0 mm mersalyl (Harris, E. D., and Vater, C. A., Methodology of collagenase research: substrate purification, enzyme yctivation and purification. Collagenase in Normal Pathological Connective Tissues. Edited by D. E. Woolley, J. M. Evanson, Chichester, John Wiley & Sons, 1980) before adding supernatant to labeled radioactive label the collagen fibrils. To avoid underestimating the total collagenase, vyd the activation of neutrophils, used for these definitions supernatant received from activated neutrophils in the presence of 1.0 mm of sodium azide (an inhibitor of myeloperoxidase). Incubation and calculation of the activity of collagenase in treated marshallom supernatant was carried out as described above.

Using the above test with tenidap, piroxicam, indomethacin, ibuprofen and naproxeno, with maximum concentrations of drug obtained data are shown below in table. 2.

As shown in the table.2, ibuprofen and naproxen, which are both inhibitors of cyclooxygenase, had no inhibitory effect on the secretion of the activated neutrophil collagenase. Piroxicam and indomethacin, which are also inhibitors of cyclooxygenase, have some inhibitory action on secretion of activated collagenase, but at concentrations above physiological data connections. Tenidap at concentrations relevant clinical, significantly inhibited the secretion of activated collagenase from neutrophils.

1. Pharmaceutical composition comprising 3-substituted 2-oxindole-1-carboxamide and a pharmaceutically acceptable carrier, arid or complex of propylene glycol fluids fatty acids fractionated coconut oil (A) and as 3-substituted 2-oxindole-1-carboxamide, at least one compound of formula I (B)

< / BR>
where R1, R2and R3each independently represents hydrogen, fluorine, bromine or chlorine,

or its pharmaceutically acceptable salt, where the weight ratio of A and B is in the range from 1 : 5.6 to 1 : 999.

2. The composition according to p. 1, wherein the composition comprises from 85 to 99 wt.% component A and from 0.1 to 15 wt.% component B.

3. The composition according to p. 1, wherein each of R1, R2and R3independently represents fluorine or chlorine.

4. The composition according to p. 1, characterized in that the compound of formula I is chosen from the group consisting of 5-chloro-2,3-dihydro-2-oxo-3-(2-thienylboronic)-indocarbocyanine, 6-chloro-5-fluoro-2,3-dihydro-2-oxo-3-(2-thienylboronic)-indocarbocyanine and 6-chloro-5-fluoro-2,3-dihydro-2-oxo-3-[2-(4-chloro)-thienylboronic] indocarbocyanine.

5. The composition according to p. 1, characterized in that the compound of formula I is 5-chloro-2,3-dihydro-2-oxo-3-(2-thienylboronic)-indolocarbazole.

6. The composition according to p. 1, characterized in that the compound of formula I is 6-chloro-5-fluoro-2,3-dihydro-2-oxo-3-(2-thienylboronic)-indolocarbazole.

7. The composition according to p. 1, characterized in that the compound of formula I is 6-chloro-5-fluoro-2,3-dihydro-2-Oka fatty acids of coconut oil include C8- C10fatty acid.

9. The composition according to p. 8, characterized in that the said fatty acids of coconut oil include Caprylic acid, capric acid, lauric acid and linoleic acid.

10. The composition according to p. 1, characterized in that it further contains from 0.05 to 5 wt.% agent that prevents the formation of sludge.

11. The composition according to p. 10, characterized in that the specified agent that prevents the formation of sludge is a propylene glycol, polyethylene glycol, glycerin, sorbitol, benzyl alcohol, lecithin, or stearic aluminum.

12. The composition according to p. 10, characterized in that it further comprises from 0.5 to 2.0 wt.% the preservative.

13. The composition according to p. 12, characterized in that the preservative is a phenol, benzyl alcohol, parabens, chlorobutanol or benzyl benzoate.

14. The composition according to p. 1, characterized in that the pharmaceutical composition is presented in a form suitable for oral, local, ophthalmic, parenteral or rectal administration.

15. The composition according to p. 1, wherein the pharmaceutical composition comprises from 0.01 to 1.0 g of the compounds of formula I.

the uly I.

17. Method of inhibiting activation of collagenase in a mammal in need of it, including the introduction of a pharmaceutical composition containing 3-substituted 2-oxindole-1-carboxamide, characterized in that it includes an introduction to the specified mammal a pharmaceutical composition according to p. 1 in an effective amount.

18. The way you call analgesic response in a mammal, comprising the introduction of a pharmaceutical composition containing 3-substituted 2-oxindole-1-carboxamide, characterized in that it includes an introduction to the specified mammal a pharmaceutical composition according to p. 1 in an effective amount.

19. A method of treating inflammatory diseases in mammals, including the introduction of a pharmaceutical composition containing 3-substituted 2-oxindole-1-carboxamide, characterized in that it includes an introduction to the specified mammal a pharmaceutical composition according to p. 1 in an effective amount.

 

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