Pharmaceutical compositions based on non-steroidal anti-inflammatory drugs

 

(57) Abstract:

The invention relates to medicine and relates to pharmaceutical compositions containing non-steroidal anti-inflammatory compound, at least one connection, reinforcing its pharmacological action, selected from dibasic carboxylic acids, ammonium succinate, amino acids, salts, vitamins, polyphenolic compounds and products containing animal and vegetable origin, as well as the target additive, representing a carbohydrate or sorbent. The songs have a more pronounced pharmacological effect and low toxicity with prolonged use. 8 C.p. f-crystals, 9 PL.

The invention relates to medicine, specifically to pharmacology, and relates to non-steroidal anti-inflammatory drugs (NSAIDs).

In medical practice, widely used NPVS of different chemical structure. In particular, derivatives of salicylic acid (acetylsalicylic acid, diflunisal), derivatives of acetic acid (indomethacin, sulindac, tolmetin, diclofenac), propionic acid derivatives (ibuprofen, naproxen, Ketoprofen, surgam), derivatives of Anthranilic acid (mefenamovaya acid, voltaren), production is the IKI), etc. For typical NSAIDs anti-inflammatory, analgesic, antipyretic actions, as well as the ability to inhibit platelet aggregation (to reduce blood clotting). The main side effects of NSAIDs include ulcerogenic (ulceration of the gastric mucosa) and toxic effects of drugs /1, 2, 3/.

Known combination of NSAIDs, acetylsalicylic acid with ascorbic acid (Aspirin), in which ascorbic acid helps increase the body's resistance and decrease capillary permeability /4/, however, the effect of ascorbic acid in this combination is not considered from the point of view of increasing the anti-inflammatory activity of NSAIDs, through effects on vitamin a metabolism in inflammation. Also known combination of acetylsalicylic acid with giammarino salt of succinic acid to increase the efficiency and reduce the toxicity of the drug /5/, however, the introduction of ammonium succinate in this combination is not considered from the point of view of enhancing the pharmacological activity of NSAIDs dicarboxylic acids by affecting metabolism in inflammation, furthermore, provides an example of the inefficiency of succinic acid in the potentiation of protivokislotnoe, preserving, however, the adverse properties of the drug /20/.

The aim of the invention is to increase the pharmacological activity and the reduction of toxic effects of NSAIDs and their combinations with other biologically active compounds.

This goal is achieved using pharmaceutical compositions containing non-steroidal(s) anti-inflammatory(s) tool(a) and at least one connection, reinforcing its pharmacological action, selected from the group of dibasic carboxylic acids, and their salts, amino acids, and their salts, polyphenolic compounds, containing products of vegetable or animal origin, compounds having vitamin a activity, as well as at least one of the target additive, representing a carbohydrate or sorbent.

This set of distinctive features is not obvious to a person skilled in the art. Thus, the technical solution meets the criteria of the invention of "novelty", "inventive step". This solution can be used in clinical practice as NSAIDs. Thus it meets the criterion of industrial applicability.

and lower toxicity in comparison with prototypes, especially with long-term use of the drug. This allows to obtain previously unknown positive effect.

As NSAIDs can be used a variety of connection groups specified above. Single dose varies from 10 mg, for example, to piroxicam, up to 500 mg, such as aspirin, and depends on the type of drug, disease severity, age, weight of the patient.

As an agent for enhancing the pharmacological activity NPRC part introduces various pharmacologically acceptable carboxylic acid, such as, for example, succinic, fumaric, maleic, malic, potassium, sodium, ammonium and other salts, amino acids, preferably glycine, taurine, glutamic acid, and their salts, compounds having vitamin a activity, such as ascorbic acid, b vitamins, retinol and other polyphenolic compounds of vegetable or animal origin isolated in pure form, such as quercetin, baicalein, or in the form of extracts, such as extracts of motherwort five-bladed, bergenia tolstolistnogo, Thistle, licorice. Increased activity of the agents administered in effective amounts, which vary depending on their PR is RAM. The number of amino acids may be from 0.1 mg, such as taurine, 500 mg, such as glutamic acid. The vitamins included in their biologically active dose comprising from 2 mg, such as Riboflavin, up to 500 mg, such as ascorbic acid. Phenolic compounds, as a rule, included in the composition in an amount of 2 mg, for example, for routine, up to 300 mg, for example, extract of Scutellaria baicalensis.

The composition includes as a special additive carbohydrates and sorbents. As carbohydrates are used in a variety of mono-, di - or polisher, such as, for example, glucose, fructose, sucrose, lactose, stachyose and others. As the sorbent can be used such substances as, for example, activated carbon, silica gel, hydroxyapatite, aluminum hydroxide, wheat bran, starch, MKC.

The above specific substances are intended to illustrate the invention but do not restrict it.

In addition to these components, the compositions may optionally contain other conventional pharmaceutical auxiliary substances, allowing you to choose one or another preferred route of administration of the composition. This can be consid="ptx2">

The composition can be a different shape, preferably for oral administration such as solutions, syrups, powders, tablets, capsules.

One of the preferred embodiments of the invention is the following composition of pharmaceutical compositions, wt.%:

Acetylsalicylic acid - 25-80

The ammonium succinate - 5-30

Bergenia crassifolia and/or licorice - 5-20

Ascorbic acid - 5-20

Glucose - Rest

The claimed properties of the proposed compositions have been proven in animal experiments and in clinical practice.

Example 1. Strengthening anti-inflammatory action of NSAIDs. Investigated the effect on anti-inflammatory activity of NSAIDs:

A) extracts with a high content of polyphenolic compounds - Baikal skullcap (ESB) and bergenia tolstolistnogo (ESTs), polyphenolic compounds flavonoid patterns of silibinin (SB), quercetin (KB)

B) carboxylic acids - malic (Apple withdraws), fumaric (FUM), amber (UC) and its ammonium salt (YAK-NH4)

B) amino acids - glutamic (GLU), glycine (GLI), cysteine (CYS), taurine (TAU),

D) substances with vitamin - vitamins C, b6E, lipoic acid (La).

Experiments carried out on outbred white mice - males weighing 22-24, the study drugs were administered to the animals through a tube into the stomach once a day for 5 days in the form of a suspension in 1% starch mucus or aqueous solution. ASA is used in an optimal anti-inflammatory dose of 200 mg/kg /5/, other NSAIDs used in proportional to ask doses to balance their therapeutic doses/1, 2, 3, 6/, namely (in parentheses indicate the dose in mg/kg): N.A (10), NP (100), VL (10), NC (100), bn (60), PC (8).

Dose of carboxylic acids was: YAK-Na (100), YAK-NH4(100), APPLE WITHDRAWS THE (100), FUM(100) /7, 8/.

Doses of amino acids was as follows: GLU (100), GLI (100), CYS (50), TAU(50) /6, 9-12/.

Dose of polyphenolic compounds or containing extracts were ASB - 150 mg/kg /13/, ESTs - 100 mg/kg /14/, quercetin 50 mg/kg /6, 15/, silibinin - 50 mg/kg /6, 16/.

Doses of vitamins were: Vit. From (50), Vit. IN6(10), Vit. E (20), lipoic acid(20) /6, 17, 18/.

One hour after the last injection the mice were injected with 0.05 ml of 1% solution carragenine in isotonic sodium chloride solution under the aponeurosis of the right hind La is the mass of swollen and healthy paws and determined the degree of suppression of edema in experimental groups compared with the control formula

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The results were processed statistically using the nonparametric Wilcoxon criterion /19/.

In table. 1 presents the results of the separate steps of the studied drugs. You can see that all NSAIDs significantly limit the development of inflammatory responses, and the remaining components of the composition did not show glagoliceskij activity.

As can be seen from the table. 2-5, polyphenolic compounds and containing plant extracts, carboxylic acids, amino acids, vitamins to increase anti-inflammatory activity of NSAIDs. In table. 6 presents data showing the increase in anti-inflammatory activity of the composition containing NSAIDs and vitamin or carboxylic acid, or amino acid.

Example 2. Evaluation of the effect of carbohydrates and substances having absorption properties, toxicity ASC. Experiments carried out on outbred white mice-males weighing 22-26 g Acute toxicity ASC was assessed by the magnitude of LD50the compositions containing the ASC + carbohydrate or sorbent in the ratio of 4:1 compared to LD50The ASC. The drugs were injected intragastrically once in the form of water suspension at doses of 350-3000 mg/kg to groups of 6 mice. Observations were carried out over 14 days. As Vee hydroxide, magnesium trisilicate, hydroxylapatite, microcrystalline cellulose (MCC). As carbohydrates used the monosaccharides glucose and fructose, gisagara - sucrose and lactose and polysaccharide - starch potato. The experimental results are processed according to the method of Lichfield-Wilcoxon /19/. LD50the compositions are designed to ASC (PL. 7, 8).

According to the data obtained, compounds having absorbent properties, and carbohydrates combined with NSAIDs acetylsalicylic acid, reduce its toxicity.

Example 3. Evaluation of the effect of carbohydrates and substances having absorption properties in doses of 100 mg/kg, on the pharmacological activity of NSAIDs in combination with the connection, reinforcing its action, selected from the group of dibasic carboxylic acids, and their salts, amino acids, polyphenolic compounds, containing products of vegetable or animal origin, vitamins. Doses used compounds indicated in the table and are expressed in mg/kg of Experiments carried out on outbred white mice-males weighing 22-26 g

The results are given in table. 9.

The study indicates an increase in pharmacological activity of the investigated combinations of NSAIDs with diversified extracts under the influence of carbohydrates and nutrients, having absorptive properties.

Example 4. Clinical study of the effects of carbohydrates and substances having absorption properties, the manifestation of side effects of NSAIDs and their combination with vitamins, carboxylic acids, flavonoids or containing plant extract. The study was conducted on 14-and outpatients aged of both sexes 32-68 years, receiving NSAIDs in the form of a course of treatment (4-5 weeks) about exacerbation of chronic inflammatory diseases; 10 patients received acetylsalicylic acid in combination with ammonium succinate to reduce blood clotting after myocardial infarction. The ammonium succinate was part of the combination for recovery of energy metabolism in the myocardium.

Some patients (6 people) took ortofen (0.05 g) in conjunction with vitamins P and C (0.1 g) regarding the exacerbation of rheumatoid arthritis (3 times a day for 5 weeks). The drugs were given in the form of a powder. Three of the examined patients received a mixture of drugs with potato starch (1:1). All patients receiving combination with starch, better tolerated drug. They were less pronounced dyspepsia, headaches, head"Kars" about gout (2 persons), thrombophlebitis (4 people) and rheumatoid arthritis (2 people). As in the previous case, the drug was given in the form of a powder (0.05 g of indometacin and 0.25 g of Kars 3 times a day the first week, and then 4 weeks on 4 times a day). Half the group received the drug together with microcrystalline cellulose in a weight ratio of 1: 2. All patients treated together with combination drug NSAID and bioflavonoid sorbent - MCC, to a lesser extent were expressed side effects of indomethacin, in particular, dyspepsia, dizziness, headache. Whereas in the group not treated with the sorbent 1 patient had at the end of 3 weeks to stop taking the drug because of severe pain in the epigastrium, vomiting; one patient required the use of antihistamines for relief of allergic phenomena.

Half of the patients out of 10 people treated with acetylsalicylic acid as antiplatelet agents along with ammonium succinate (0.25 g and 0.1 g, respectively), and the second half of the specified combination with activated charcoal (0.35 g), 2 times a day for 8 weeks. Four out of five treated sorbent noted better portability mix ASC and succinate Ammon the Oia.

Thus, the obtained data testify to reduce side effects joint use of NSAIDs in combination with other biologically active compounds and carbohydrates or substances having absorption properties.

Example 5. Give examples of rational combinations NPRC with substances that increase the biological activity, as well as sorbents or carbohydrates.

Recipe 1

Acetylsalicylic acid, 0.5 g

Vitamin C is 0.1 g

Glucose 0.5 g

(this recipe is adaptable to production)

Recipe 2

Acetylsalicylic acid, 0.5 g

Rutin - 0.1 g

Starch - 0.01 g

Glucose 0.5 g

(the drug is easy to manufacture and highly effective)

Recipe 3

Indomethacin - 0,025-0,05 g

Silymarin - 0.01 g

Activated carbon is 0.02 - 0.5 g

(the drug in all combinations maintains high efficiency and low toxicity)

Recipe 4

Acetylsalicylic acid, 0.25 g

The ammonium succinate - 0.1 g

Bergenia crassifolia - 0.1 g

CMC - 0.05 g

Recipe 5

Acetylsalicylic acid 0.4 g

The ammonium succinate - 0.1 g

Bergenia crassifolia - 0.03 g

Ascorbic acid 0.03 g

Glucose - 0.04 g

the Ascorbic acid 0.05 g

Glucose - 0.1 g

Recipe 7

Ortofen - 0.05 g

Vitamin P - 0,1 g

Vitamin C is 0.1 g

Starch - 0.25 grams

Recipe 8

Phenylbutazone - 0.05 g

Glutamic acid 0.1 g

Lactose - 0.2 g

Starch - 0.1 g

Magnesium stearate - 0,05 HS

1. A pharmaceutical composition comprising a non-steroidal anti-inflammatory compound, characterized in that it additionally contains at least one compound enhancing its pharmacological action selected from the group comprising dibasic carboxylic acid, ammonium succinate, amino acids, and their salts, polyphenolic compounds, containing products of animal and vegetable origin, and at least one target additive, representing a carbohydrate or sorbent.

2. The pharmaceutical composition under item 1, characterized in that as non-steroidal anti-inflammatory compounds it contains aspirin.

3. The pharmaceutical composition under item 1 or 2, characterized in that, as specified amplifier it contains succinic acid.

4. The pharmaceutical composition under item 1, characterized in that it contains as polyphenolic compounds extract modestmouse points, characterized in that it additionally contains at least one substance having vitamin a activity.

6. The pharmaceutical composition under item 1, characterized in that as the target additives it contains glucose.

7. The pharmaceutical composition according to p. 5, characterized in that it contains, wt%:

Acetylsalicylic acid - 25-80

The ammonium succinate - 5-30

Bergenia crassifolia - 5-20

Ascorbic acid - 5-20

Glucose - Rest

8. The pharmaceutical composition according to any one of the preceding paragraphs, characterized in that further comprises a pharmaceutically acceptable carrier suitable for oral administration.

9. The pharmaceutical composition according to any one of the preceding paragraphs, characterized in that it is in the form of tablets or capsules.

 

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