DE19839443A1 - Pharmaceutical and dietetic product contains quaternary ammonium compound and/or S-adenosyl-methionine, useful for treatment of oxygen deficiency and energy metabolism disorders and NSAID side effects - Google Patents

Abstract

Pharmaceutical and/or dietetic product contains a quaternary ammonium compound and/or S-adenosyl-methionine. Pharmaceutical and/or dietetic product, especially for the prevention and treatment of disorders and damage caused by a deficient oxygen supply or of side effects of anti-inflammatory drugs as well as for the prevention and treatment of energy metabolism disorders, contains: (A) at least one compound (I) containing at least one quaternary ammonium functional group of formula (a); and/or: (B) S-adenosyl-methionine.

Description

The invention relates to an orally ingestible drug containing a non-steroidal anti-inflammatory Active ingredient.

Consumption of nonsteroidal anti-inflammatory drug neimitteln (anti-inflammatory drugs) with active ingredients such as acetylsa licylic acid, ibuprofen u. a. is effective compared to other classes of substances due to their good effect against pain, fie and inflammation very high. The already widespread Use of these drugs will continue to increase in the future since they are used to treat inflammatory diseases such as game rheumatism are very suitable and always a big increasing proportion of the population in an age range comes in which these diseases occur more often.

The beneficial effects of nonsteroidal inflammatory inhibitory agents are based on their influence on the enzyme Cyclooxygenase-2. The cyclooxygenase-2 is u. a. through oxida active stress or injury and is responsible for inflammation, pain and fever. Most conventional non-steroidal anti-inflammatory agents bloc temporarily reduce the enzyme cyclooxygenase-2 like the complaints. Acetylsalicylic acid is the only nonsteroidal anti-inflammatory drug that cyclooxygenase-2 covalently modified by acetylation and so blocks the enzyme.

Since the inflammatory diseases are often chronic in nature, must be treated with these anti-inflammatory agents usually take place over a long period of time. especially the non-steroids used in such long-term treatment Anti-inflammatory drugs show undesirable side effects the gastrointestinal tract such as gastrointestinal bleeding and Ma  ulcers, which are from Y. H. Lee at al in Arch. Int. Pharmaco dyn. 191, 370-377, (1971) and by K.D. Rainsford in Agents and Actions 1977, 7 (5/6), 573-77, and by A. R. Cooke in Drugs 1976, Vol. 11, pp. 36-44.

These side effects have been caused by two different ones so far Mechanisms of action described.

On the one hand, the side effects arise from the inhibition of Biosynthesis of the gastrointestinal tract protective prostaglan din EN. Lichtenberger et al. ([1983], Science 219, 1327-1329) describes prostaglandins locally in the stomach mucous membrane are synthesized. This hormone causes one Increase in the surface active phospholipids in the stomach mucus lining the stomach. The phospholipids in turn protect the gastric mucosa episode from aggressive substances zen like stomach acid. The side effects of nonsteroidal Anti-inflammatory agents are created by taking one whose enzyme, cyclooxygenase-1, blocks what is under which leads to the inhibition of biosynthesis of prostaglandin. Prostaglandin lowers the concentration of phospholipids in the gastric mucus and thus a reduction protection.

One way, like the side effects of nonsteroidal anti-inflammatory agents can be countered by Kalgutkar et al. ([1998] Science, 280, 1268-1270) Darge poses. He describes a group of new derivatives not steroids daler anti-inflammatory agents compared to Acetylsalicylic acid made cyclooxygenase-2 much more efficient block, while the cyclooxygenase-1 we much is inhibited. With these substances come true apparently in the future have pharmaceuticals manufactured that described prostaglandin-dependent side effects exhibit.  

Another way to reduce side effects from Arz drugs, the non-steroidal anti-inflammatory agent Fe was already included in DE 28 56 333 C2 The reduction in side effects is already here thereby achieved that these anti-inflammatory agents were appropriately combined with phospholipids. The Medicines described there contain these anti-inflammatory drugs stika together with phospholipids in a molar mixture ratio of 1: 0.1 to 1: 20. The phospholipids have compared to the be so far in the literature for this purpose substances written the advantage that it is the body's own sub punching, which are easily broken down in the body, none Show side effects of long-term treatment and none itself have analgesic or anti-inflammatory effects.

The addition of phospholipids causes a reduction such side effects of nonsteroidal anti-inflammatory active ingredients that have a prostaglandin-independent Mechanism arise. This prostaglandin-independent Me Chanism was described by Lichtenberger et al in 1995 in Natur Medici ne 1 (154-158) clarified. Accordingly, they are stored orally ingested nonsteroidal anti-inflammatory effect molecules to the zwitterionic phospholipids, which Lining your stomach, on. Through this intermolecular interaction kung is the surface activity of the phospholipids ge weakens and / or the stability of extracellular phospho lipid layer reduced. This leads to an anti phlogistics induced reduction in the hydrophobic eigen gastric mucus and a loss of it Protective effect.

However, these nonsteroidal anti-inflammatory drugs Active substances together with phospholipids, as in the DE 28 56 333 proposed to administer in a drug  is enough, the active ingredient molecules are already through the ex tern phospholipids of the drug with phospholipids saturated in terms of binding. This binds the active ingredient moles no longer cool the phospholipi that builds up the gastric mucosa de. This reduces damage to the gastric epithelium.

The use of phospholipids in these drugs however, there are some serious disadvantages. So han phospholipids are very large molecules. Around reduce the side effects of the corresponding active ingredient to be able to, is in a formulation a molar ratio between For example, acetylsalicylic acid and phospholipids of 1: 1 necessary. However, due to the higher Molecular weight an approximately 8 × larger amount of weight Phospholipids as needed on acetylsalicylic acid. Thereby These drugs are very bulky in tablet form. Another disadvantage is that phospholipids are water insoluble are. Therefore, for example, no effervescent tablets can be used produce. The water insolubility and the molecular size of the Phospholipids cause drugs with this sub punching can be difficult and costly to formulate. Furthermore, phospholipids are not a uniform substance. This makes characterization difficult. Particularly disadvantageous is the high price of phospholipids since they are not industri ell can be produced. In addition, no salts can be found of phospholipids.

The technical task was to be a more tolerable doctor drugs with non-steroidal anti-inflammatory agents to provide fen, the side effects of which are reduced, however, the disadvantageous phospholipids do not ver must be applied.

This object is achieved by an orally ingestible medicament containing a nonsteroidal anti-inflammatory agent and S-adenosylmethionine and / or a substance with the functional group -N ⁺ - (CH ₃ ) ₃ , except surface-active substances as a single substance, or mixtures thereof.

In a further preferred embodiment, the substance with the functional group -N ⁺ - (CH ₃ ) _{3 is} selected from the group betaine, acetylcholine, choline, glycerophosphocholine, carnitine, acetyl-L-carnitine, sphingomyeline, their derivatives or mixtures the same or phosphatidylcholine in a mixture with the same, the fatty acid content of the substances in question may be different.

These substances are all known in the art. So For example, betaine is natural in plants and animals Lich occurring substance with a molecular weight of 117 g / mol. In pharmacy, betaine is used as an auxiliary used in medicinal products. Betaine dihydrogen citrate continues to be found as an active ingredient in medicines for hepato pathies use.

It has surprisingly been found that in particular Betaine or its derivatives, in the same way as phospholi pide the side effects of nonsteroidal anti-inflammatory reducing active ingredients, although betaine is completely different has physicochemical properties as phospholipids. This is so surprising because phospholipids in the counter betaine are surface active and the professional world based on the work of Lichtenberger described above assumed that a lining of the stomach with surface acti Ven substances are required to pre-gastric epithelium the non-steroidal anti-inflammatory agents protect. This prejudice is now out of date, as is betaine as a non-surface-active substance, protection against nonsteroidal anti-inflammatory agents.  

Furthermore, betaine is a very small Mo lekül, which is about 7 times smaller than a phospholipid. Wei betaine is also water-soluble. Because of this property it was surprising that betaine was the side effect of nonsteroidal anti-inflammatory anti-inflammatory drugs stika reduced.

In a particularly preferred embodiment, this is molar mixing ratio of the substance to the non-steroid len anti-inflammatory agent 0.5: 1 to 2: 1. Thereby the active ingredients are selected from the group Acetylsa licylic acid, diclofenac and indomethacin or combinations the same.

The use of betaine in the medicament according to the invention tel is particularly advantageous due to the small molecule size of betaine. This leads to smaller drugs formulations, d. H. it will be much smaller and better tablet sizes to be administered reached. Another before Part is water solubility, which is a formulation as Effervescent tablet allowed. It is particularly advantageous that betaine is a mono substance. This means that betaine is in contrast to phos Pholipids can be clearly characterized analytically. In addition is the production of salts of betaine is possible. Because of the These benefits can lower galenical formulations Costs are developed. It is particularly advantageous here that betaine due to its industrial manufacturability is eighty to a hundred times cheaper than phospholipids. In egg In a particularly preferred embodiment, derivatives of Betains selected from the group beta dihydrogen citrate, Be tainaspartate, betaine hydrochloride, betaine palmitate, betainsa licylate or mixtures thereof are used.  

The medicament according to the invention is used in particular for therapy of inflammatory diseases, osteoarthritic and / or general pain and fever.

The following examples are intended to explain the invention in more detail tern:

Examples example 1 Manufacture of the drug in tablet form with Acetylsalicylic acid (ASA) and betaine

The procedure for producing the drug in tablet form is as follows:

• 1. Betaine is in the form of betaine HCl or betaine dihydrogen citrate dry mixed with microcrystalline cellulose.
• 2. 10% of the dried starch given in Table 1A is suspended in the same amount of cold water then pour 30 to 35 l of boiling water over it and gelatinized with stirring.
• 3. The mixture from 1) is moistened with the paste from 2) granulated. The mass is so long with small amounts Add water until it is sufficiently moist plastic. On finally the mass is passed through a sieve with a mesh beaten width of 5 mm and dried at 50 ° C until a Residual moisture content of 2-3% is reached. After that it will dry granules through a sieve with a mesh size of Homogenized 1 mm.
• 4. The crystalline Ace is first of all the granulate from 3) tylsalicylic acid and finally as the outer phase the rest dried starch and the stearic acid powder mixes.  
• 5. The tablet-ready mixture from 4) is in tablet size appear into tablets with the brood shown in Table 1B toweights pressed.

Table 1A

The quantities of the components are given in kg

The tabletting mixtures of formulation a become tablet with a gross individual weight of 175 mg or 350 mg ta bletted. They then contain 50 mg acetylsalicylic acid (ASS) and 100 mg betaine or 100 mg acetylsalicylic acid and 200 mg Betaine. The amounts of active ingredients of the other formulation Examples can be found in Table 1B.  

Table 1B

Formulation examples (amounts in mg)

Example 2 Preparation of the drug in tablet form with diclofenac and betaine

The procedure for producing the drug is as follows:

• 1. Diclofenac-Na, betaine (betaine HCl or betaine dihydrogen citrate), citric acid and microcrystalline cellulose dry mixed in a blender.
• 2. The mixture from 1) is with a 6% gelatin solution or a 10% povidone solution wet granulated. Here the mass is supplemented with small amounts of water for as long until it is sufficiently moist plastic. Then will the mass through a sieve with a mesh size of 5 mm beat and dried at 65 ° C until a residual moisture content of 3-5% is reached. After that, the dry granules homogenized through a sieve with a mesh size of 1 mm.
• 3. The granules from 2) are first listed in Table 2A given strength and finally as an external phase the magnesi mixed with umstearate.  
• 4. The ready-to-tablet mixture from 3) is in tablet size appear into tablets with the brood shown in Table 2B toweights pressed.

Table 2A

The quantities of the components are given in kg

The tabletting mixtures of formulation a become tablet tablets with a single gross weight of 200 mg. she then contain 25 mg diclofenac-Na and 100 mg betaine. The Amounts of the active ingredients of the other formulation examples can table 2B.  

Table 2B

Formulation examples (amounts in mg)

The advantageous effectiveness of the new medic according to the invention The following pharmacological Versu shown:

Trial 1 Quantification of microvascular permeability changes after subacute gastritis

In the experiments, 10 Wi star rats (290-320 g) were used per dose and 5 controls per control. The rats were kept on a high-carbohydrate diet one day before the start of the experiments. In the experiment, a subacute gastritis was triggered in the animals, ie a test liquid was administered three times a day under anesthesia by flushing it directly into the stomach. This test liquid contained the following components:
First 200 mg acetylsalicylic acid / kg body weight (KGW) were administered, the concentration of acetylsalicylic acid dissolved in water being 66 mg / ml. A test liquid was then administered which contained either 5% lecithin or 5% lecithin and 100 mg betaine / kg body weight. The animals in the control group received a test liquid consisting of water and 5% lecithin.

On the third day of the study, the microvascular passage gastric mucosa with the Evens Blue method Right. This method is based on the principle that Evans Blue binds to albumin and makes it visible. This allows changes in the microvascular permeabi lity in favor of high molecular blood components make cash. The microvascular permeability of the stomach mucous membrane is called the permeability index PI and defines the ratio of the concentration of Evans Blue in the gastric mucosa to concentrate in the blood serum.

Four hours after the last test liquid administration, the Animals under Evans Blue anesthetic (40 mg / kg in a saline solution (20 ml / kg dissolved) by injection into the penil vein administered. 60 minutes after the injection Animals stunned again with ether and for measuring the Evans Blue concentration in blood 0.5 ml of blood from the left heart chamber removed. The right antechamber of the heart was pre parried. The animals were treated with 100 ml of heparin (10 U / ml) cold phosphate buffered saline through the left ventricle administered. The stomach was removed opened along the large envelope and its contents with 20 ml a phosphate buffered saline solution. The Ma gene mucosa was scraped off, further homogenized in formamide and incubated for 18 hours at room temperature. To centrifugation of the gastric mucosal samples at 100 g for 1 Hour was the concentration of Evans Blue with a shi matzu 1601 spectrophotometer measured at 610 nm.

Result

Fig. 1 describes the results of the experiment 1 after administration of 5% lecithin (control), 5% lecithin and 5% ASA and lecithin, aspirin and betaine. The diagram in Fig. 1 shows that the intragastric acetylsalicylic acid injections resulted in an increase in microvascular permeability, which was demonstrated by the PI measurements. This increase in permeability caused by acetylsalicylic acid was significantly prevented by betaine.

Trial 2 Histological examinations of the gastric mucosa using hematoxylin-eosin staining and light micro scopie

This experiment was carried out analogously to experiment 1. Each Thursday sis 10 and per control 5 Wistar rats (290-320 g) as in first attempt held, whereby the provocation of the bloody stomach ulcer by oral application of the active ingredient fes takes place. The application was carried out on part of the tie acute, d. H. the animals are given three times a day for a day administered a test liquid. Another part of the Animals were administered subacutely. Here the tie test liquid three times a day for 3 days. The animals are given acetylsalicylic acid preparations with or without Betaine administered by intragastric injection. After that was de The animals had their stomachs taken and along the long course vatur opened, carefully rinsed with a saline solution and stretched on a styrofoam plate. The samples were puffed finished formalin fixed, cut into 6 ml-wide strips and stained with hematoxylin eosin. The colored cuts were light microscopically twice with a computerized th image analysis system evaluated. There were mucous membranes samples from two different areas of the stomach (antrum and corpus) according to a semi-quantitative 0-5 step Ulcer index analyzed (Table 3). The ulcer index knows draws the degree of ulceration, the Value 0 no damage to the gastric mucosa and value 5 the perforation means.  

The Wilcoxon test was used for statistical analysis increase of the stochastic probability with group ver same used. For multiple comparison with the control The Friedmann test and the Dynnett test became a group applied. P values less than 0.05 were found to be si considered significant. Table 3 shows the results summarized. The concentration of acetylsa is licylic acid (ASA) 100 mg / kg body weight. The concentrations of Be tain are also given in mg / kg body weight.

Table 3

Evaluation of experiment 2 using the ulcer index

Result

The thickness of the gastric mucosa was in the area of the antrum significant reduction after acute acetylsalicylic acid treatment graces. In the acute experiments, the decrease was Gastric mucosa 28% compared to the control group. This The thickness of the gastric mucosa was reduced by too additional betaine administration was significantly prevented. The same time administration of acetylsalicylic acid and betaine resulted in ver only a 12% reduction compared to the control group.  

In the group with subacute acetylsalicylic acid Concentrations treated, the reduction was Thickness of the gastric mucosa approximately 33%. Also led here the additional betaine addition causes the reduction in thickness of the gastric mucosa after 3 days of acetylsalicylic acid Betain treatment was only 12%.

Claims (6)

1. Orally ingestible drug containing a non-steroidal anti-inflammatory agent and S-adenosylmethionine and / or a substance with the functional group -N ⁺ - (CH ₃ ) ₃ , except surface-active substances as a single substance, or mixtures thereof. 2. Orally ingestible medicament according to claim 1, characterized in that the substance with the functional group -N ⁺ - (CH ₃ ) _{3 is} selected from the group betaine, acetylcholine, choline, glycerophosphocholine, carnitine, acetyl-L-carnitine, sphingomyeline , their derivatives or mixtures of the same or surface-active substances in a mixture with the same, where the fatty acid content of the substances concerned may be different. 3. Medicament according to claims 1 or 2, characterized ge indicates that the molar mixing ratio of the Substance with a non-steroidal anti-inflammatory effect fabric is 0.5: 1 to 2: 1. 4. Medicament according to claims 1 to 3, characterized ge indicates that the non-steroidal anti-inflammatory de Active ingredient is selected from the group Acetylsa licylic acid, diclofenac, indomethacin or combinations the same. 5. Medicament according to claims 1 to 4, characterized ge indicates that betaine derivatives are selected from the group beta-dihydrogen citrate, betaine aspartate, Be tain hydrochloride, betaine palmitate, betaine salicylate, or Mixtures of the same are used.   6. Use of the medicament according to claims 1 to 5 for the manufacture of a medicament for the therapy of inflammatory diseases, osteoarthritic and / or general pain and fever.