Pharmaceutical composition with special 1,2-diacyl-glycero-3-phosphocholines for the treatment of diseases of the stomach and the intestines

The present invention relates to the use of special 1,2-diacyl-glycero-3-phosphocholine, optionally in a mixture with other 1,2-diacyl-glycero-3-phosphates, with 75 to 86% by weight of unsaturated fatty acid residues a chain length of C₁₆, C₁₈ and / or C₂₀ for the manufacture of pharmaceutical preparations for the treatment of diseases in the gastrointestinal area.

DE-A-2 907 778 discloses the use of phosphatidylcholine derivatives and phosphatidylethanolamine derivatives in medicaments for combating perception and consciousness disorders.

About 10% to 20% of people develop a peptic ulcer of the stomach, duodenum or other inflammatory changes in the gastrointestinal area once or more in their life. The causes are varied, e.g. B. including endogenous cytotoxic substances, such as gastric and bile acids, or exogenous noxae, such as ethanol or pharmaceuticals. The gastrointestinal tract is one of the most common organ systems affected by drug side effects. In particular, non-steroidal anti-inflammatory drugs lead to erosions and ulcerations of the stomach.

The therapy of mucosal damage (ulcers) of the stomach and duodenum is based today primarily on the removal of aggressive factors such as<ul id="ul0001" list-style="none"><li>- Elimination of acid and pepsin by acid neutralization (antacids, such as aluminum hydroxides, calcium carbonate, hydrotalcite, magnesium hydroxide, sodium bicarbonate, etc.), inhibition of secretion (anticholinergics, H₂Antagonists, such as Cimetidine or ranitidine, vagotomy or distal gastric resection) or accelerated elimination (metoclopramide, sulpiride);</li><li>- Prevention of a cytotoxic effect of certain components (bile acids, lysolecithin) of the duodenal juice in the stomach through absorption (cholestyramine, antacid) or accelerated elimination (metoclopramide, sulpiride).</li></ul>

In addition, film formers such as sulfated disaccharides (sucralfates) are used.

The previous therapy is primarily based on a reduction in the activity of gastric acid and pepsin. This is to prevent the "breakthrough" of the mucosal barrier. However, this therapy has the consequence that food digestion is also impaired, which in turn results in further disorders and stress on the gastrointestinal tract.

A number of other disadvantages of these therapeutic agents used today are known. So the acid gastric juice itself also has protective functions, e.g. B. in the defense against bacteria. This natural protection is lost. Depending on their composition, antacids can also have an constipating, stone-forming or absorption-inhibiting effect on minerals and pharmaceuticals. Anticholinergics and the recently used H have similar effects and more extensive disorders₂Antagonists. They are resorbable and therefore systemically active drugs that are associated with a multitude of side effects. Anticholinergics cause z. B. Dry mouth and accommodation disorders; H₂-Antagonists cause headache, diarrhea, joint and muscle pain, fatigue, dizziness, hair loss, disturbance in sexual behavior, liver damage, etc.

EP-A-092 121 also proposed coating the gastric mucosa with an amphoteric phospholipid surfactant in order to avoid damage. These considerations are based on the protective effect of natural surfactants in the lungs. The nature of such 'surfactants' has been extensively studied, e.g. E.g .: BH Hills et al., J. Appl. Physiol .: Environ Exercise Physiol. 1982.53 (1). 119 - 123; 1982, 53 (2), 463-469; 19B3, 54 (2), 420-426; Respiration Physiology 1983, 51, 79-93; LM Lichtenberger, Science 219 (1983), 1327-1329.

The most important components were identified:<ul id="ul0002" list-style="none"><li>Dipalmitoylphosphatidylcholine (DPPC),</li><li>Dipalmitoylphosphatidylglycerol (DPPG),</li><li>Dipalmitoylphosphatidylethanolamine (DPPE) and</li><li>Sphingomyelin (SP).</li><li>Combinations such as e.g. B.</li><li>DPPC: DPPE: DPPG: SP (5: 2: 2: 1)</li><li>DPPC: DPPE: DPPG (5: 2: 2)</li><li>DPPC: DPPE (1: 1)</li><li>DPPC: DPPG (1: 1) or</li><li>DPPC: DPPE: SP.</li></ul>

However, in order to enable film formation, it is important (BA Hills et al., AJ Physiol. 244 (Gastrointest. Liver Physiol 7), G561-G568, 1983) that the fatty acid residues in the phospholipids can be aligned. Only saturated fatty acid residues, in particular palmitic acid, are therefore suitable.

However, the use of such 'surfactants' for the therapy of mucosal damage shows a number of problems:<ul id="ul0003" list-style="none"><li>- Obtaining such natural, complex surfactants is very complex.</li><li>- When such surfactants are used therapeutically, the predominantly saturated fatty acid residues in the phospholipid are extremely problematic because of their unfavorable influence on the fat metabolism and the resulting risk of atherosclerosis (M. Rosseneu et al., Atherosclerosis 32 (1979) 141-153).</li><li>- The formation of a protective film in the stomach is very problematic. The transfer of the function of the surfactants in the pulmonary alveoli to the mucosa of the gastrointestinal tract is not possible due to anatomical and physiological differences between the two organ systems.</li></ul>

The pulmonary alveoli are lined with a non-eroding single-layer flat endothelium, which forms a good basis for a stable molecular lipid film. In functional terms, only the exchange of small gas molecules takes place there (0₂, C0₂) instead, which diffuse through the lipid film without any problems.

In contrast, intensive secretion and resorption processes take place in the gastrointestinal area. The latter also relate in particular to large water-soluble molecules, so that film formation is hardly possible.

Current ulcer therapy is symptomatic, but by no means curative therapy. It heals the ulcer at most, but not ulcer disease.

An alternative therapeutic goal would therefore be to seek therapy that increases the protective properties of the mucosa. Carbenoxolone was the first active ingredient to stimulate the protective properties of the mucosa. However, due to pronounced side effects (sodium and water retention, hypokalaemia), the use is only possible to a limited extent.

The experimentally well documented properties of prostaglandins, such as an increase in bicarbonate and mucus secretion, mucosal blood flow and the promotion of epithelial cell maturation as well as gastric emptying, indicate that the therapeutic principle of cytoprotection would be ideally fulfilled by administration of this group of active substances.

The clinically proven long-life PGE₂Analogs, however, suffered from significant systemic side effects.

The natural prostaglandins counteract, as in other organs, also in the digestive tract as so-called local hormones. This means that they do not reach their place of action via the bloodstream, but are formed in the immediate vicinity or even directly in the tissues in which they exert their short-lived effect.

It is therefore worth striving for a therapeutic option of treatment that favors the physiological synthesis of the mucosa-protective prostaglandins locally in the intestinal mucosa. For theoretical reasons, substrates of prostaglandin synthesis are particularly suitable for this purpose, which accumulate quickly and permanently in the gastrointestinal mucosa when taken orally.

The object of the present invention is to provide pharmaceutical preparations for the treatment of diseases in the gastrointestinal area which accumulate quickly and permanently in the gastrointestinal mucosa when taken orally and can thus serve as a substrate for the synthesis of mucosa-protective prostaglandins.

The object is achieved by using 1,2-diacylglycero-3-phosphocholine in the<ul id="ul0004" list-style="none"><li>75 up to 36% by weight of the acyl residues are unsaturated fatty acid residues and a mixture of fatty acid residues</li><li>10th up to 20% by weight of palmitic acid</li><li>4th up to 5% by weight of stearic acid</li><li>10th up to 12% by weight oleic acid</li><li>62 up to 68% by weight of linoleic acid</li><li>3rd up to 6% by weight of linolenic acid for the manufacture of a pharmaceutical preparation for the treatment of diseases in the gastrointestinal area.</li></ul>

It has surprisingly been found that special 1,2-diacylglycero-3-phosphocholines, in which acyl stands for predominantly unsaturated fatty acid residues with 16 and / or 18 and / or 20 carbon atoms, are outstandingly suitable for the treatment of diseases of the gastrointestinal area. The suitable special 1,2-diacyl-glycero-3-phosphocholines have 75 - 86% unsaturated fatty acid residues.

The 1,2-diacylglycero-3-phosphocholines in which the 1- and 2-acyl radical consists of different mixtures of fatty acid radicals are very particularly preferred.

In these preferred 1,2-diacylglycero-3-phosphocholines, the acyl radical in the 1-position consists of the following mixtures of fatty acids<ul id="ul0005" list-style="none"><li>22 - 26% by weight palmitic acid</li><li>6 - 9% by weight of stearic acid</li><li>8th - 12% by weight oleic acid</li><li>50 - 54% by weight linoleic acid</li><li>4th - 6% by weight linolenic acid</li><li>and the acyl residue in the 2-position consists of the following mixtures of fatty acids</li><li>1 - 2% by weight palmitic acid</li><li>0 - 1% by weight of stearic acid</li><li>8th - 12% by weight oleic acid</li><li>75 85% by weight linoleic acid</li><li>5 8% by weight of linolenic acid, the individual contents being selected so that they each give 100%.</li><li>The 1,2-diacyl-glycero-3-phosphocholines correspond to the general formula<chemistry id="chem0001" num="0001"><img file="EP0147741B1_D0001.tif" /></chemistry>where R¹ and R² can be the same or different and the residues<chemistry id="chem0002" num="0002"><img file="EP0147741B1_D0002.tif" /></chemistry>wherein<maths id="math0001" num=""><img file="EP0147741B1_D0003.tif" /></maths><maths id="math0002" num=""><img file="EP0147741B1_D0004.tif" /></maths><maths id="math0003" num=""><img file="EP0147741B1_D0005.tif" /></maths>mean, such as B. the following residues<chemistry id="chem0003" num="0003"><img file="EP0147741B1_D0006.tif" /></chemistry><chemistry id="chem0004" num="0004"><img file="EP0147741B1_D0007.tif" /></chemistry><chemistry id="chem0005" num="0005"><img file="EP0147741B1_D0008.tif" /></chemistry><chemistry id="chem0006" num="0006"><img file="EP0147741B1_D0009.tif" /></chemistry><chemistry id="chem0007" num="0007"><img file="EP0147741B1_D0010.tif" /></chemistry></li><li>The pharmaceutical preparations with special 1,2-diacyl-glycero-3-phosphocholines can if necessary. Up to 20% further 1,2-diacyl-glycero-3-phosphates or mixtures thereof, such as. B. 1,2-diacyl-glycero-3-phosphoethanolamine, 1,2-diacyl-glycero-3-phosphoinositol, 1,2-diacyl-glycero-3-phosphoserine, 1,2-diacyl-glycero-3- phosphoglycerol, but especially 1,2-diacyl-glycero-3-phosphoethanolamine,<ul id="ul0006" list-style="none"><li>where the acyl radicals have the same composition as indicated for the 1,2-diacylglycero-3-phosphocholines,</li></ul></li></ul>

These 1,2-diacylglycero-3-phosphocholines can be obtained by processes known per se (EP-A-54 770, EP-A-54 768, EP-A-54 769), in particular from soybeans.

The special 1,2-diacyl-glycero-3-phosphocholines, as whole animal autoradiographs show, are quickly and permanently enriched in the gastric and intestinal mucosa after oral administration. Animal experiments have shown that pretreatment with special 1,2-diacyl-glycero-3-phosphocholines impressively protects the test animals against gastric mucosal damage caused by agents that irritate the mucous membrane.

Clinical examinations were carried out in 9 patients. Seven characteristic, subjective parameters (heartburn, pain in the epigastrium, feeling of fullness, loss of appetite, nausea, nausea, singultus), which occur in connection with mucosal erosions and ulcers in the gastric duodenal area, were examined before and after treatment with 1,2- Diacyl-glycero-3-phosphocholine detected. The documentation was semi-quantitative, taking into account the intensity of the complaints. In 8 of the 9 patients (including 4 taking non-steroidal anti-inflammatory drugs, 1 taking cytostatics, 1 with gastric stump gastritis, 1 with bilious reflux, 1 with chronic recurrent ulcer disease), significant, sometimes dramatic improvements were achieved within 1 - 4 days of treatment of complaints registered. There were no side effects or impairment of other drug therapy. As the animal and clinical studies show, oral and parenteral treatment with special 1,2-diacyl-glycero-3-phosphocholine leads to lasting protection of the gastric mucosa. The cytoprotective effect can be explained as a local stimulation of prostaglandin synthesis due to an accumulation of 1,2-diacyl-glycero-3-phosphocholine in the mucous membrane. Systemic, increased effects of prostagland, such as when testing long-lived PGE₂- Analogues observed could not be found.

As the studies show, oral and parenteral administration of the special 1,2-diacyl-glycero-3-phosphocholines leads to lasting protection of the gastric mucosa. This is particularly surprising and, to the knowledge of EP-A-092 121, was not to be expected, since the highly unsaturated 1,2-diacylglycero-3-phosphocholines are not able to form a useful protective film under the physiological conditions. In addition, it was by no means to be expected that parenteral administration would lead to long-term protection of the gastric mucosa, since film formation is completely excluded here. The special 1,2-diacyl-glycero-3-phosphocholines to be used according to the invention can be administered orally and parenterally in doses of 0.2 to 150 mg, in particular 10-50 mg per kg of body weight, once or several times a day. They can be administered prophylactically or therapeutically. In addition, administration during therapy with drugs which cause erosions and ulcerations of the stomach is possible. To prevent or eliminate gastric mucosal damage caused by drugs, the 1,2-diacyl-glycero-3-phosphocholines can be administered before, during or after therapy with these drugs. Pre-treatment is preferably carried out by administration of 1,2-diacyl-glycero-3-phosphocholine or by simultaneous administration of medicaments in order to avoid possible gastric mucosal damage from the medicament.

In the treatment of severe ulceration, one can reduce or eliminate the aggressive factors Ulcus Therapeutica, such as. B. H₂Antagonists, and then switch to therapy with 1,2-diacyl-glycero-3-phosphocholines. This has the advantage that the side effects of ulcer therapy are reduced.

Especially in the treatment of diseases with gastrointestinal aggressive agents, e.g. B. with cytostatics such as methohexate; Antihyertonica, such as reserpine; Tuberculostatic drugs such as rifampicin; or p-aminosalicylic acid; Antibiotics such as penicillin; or analgesics or antiphlogistics, such as pyrazolones (phenylbutazone, oxyphenbutazone), salicylic acid derivatives (salicylic acid, salicylic acid amide, acetylsalicylic acid, benorilat, diflunisal); Phenylalkanoic acids, such as. B. Ibuprofen, Naproxen, Alclofenac, Ketoprofen, Diclofenac, Fenoprofen, Tolmetin, Flurbiprofen, Suprofen, Indoprofen, Carprofen, Pirprofen, Fenclofenac, Sulindac, Indometacin, Piroxicam, Acemetacin, Pimetacin, uaindind /, Advantageous with and vorum treatment with and numeton or simultaneous administration in one dose or separate doses with the special 1,2-diacyl-glycero-3-phosphocholine.

For the administration of the special 1,2-diacyl-glycero-3-phosphocholines, these are converted into a suitable form, such as, for. B. capsules, solutions, emulsions, tablets, powders, chewable capsules, drinking ampoules or aqueous emulsions and in conventional parenteral forms.

The special 1,2-diacyl-glycero-3-phosphocholines can be made in soft gelatin capsules or more advantageously in hard gelatin capsules, e.g. B. according to the method described in DE-A-3 022 136, if necessary. With the addition of suitable auxiliaries and fillers. The soft or hard gelatin capsules can be swallowed whole or chewed.

To produce the hard gelatin chewable capsules, the phospholipids are mixed with pharmaceutically inert carriers, such as. B. waxes, hydrogenated oils, natural, semi-synthetic or synthetic triglycerides and their mixtures, such as cocoa butter, and conventional suppository compositions, e.g. B. based on triglycerides such. B. Witepsol suppository masses (see HP Fiedler, Lexicon of auxiliary substances for pharmacy, cosmetics and related areas, 1971, Vol. 9, p. 548 - 50 and 632 - 634); Fatty alcohols; solid hydrocarbons such as petroleum jelly or paraffin solidum; saturated fatty acids such as lauric acid, myristic acid, palmitic acid, stearic acid; Emulsifiers such as ethoxylated triglycerides, polyethoxylated vegetable oils; Fatty acid sugar esters; Silicones; Gelatin; Methyl cellulose; Hydroxypropoxy cellulose; Hydroxypropyl cellulose; Polyethylene glycols; Polyvinyl pyrrolidone; Polyvinyl alcohol; Mixed polyacrylic acid and its salts. Ethanol is added to the masses in such an amount that a flowable filling material is obtained at room temperature or slightly elevated temperature under pressure, i. That is, that the product at this temperature has a viscosity which is just sufficiently low or slightly less for transport under pressure, and this product on the known filling plants with an additional device for liquid filling and with a heatable filling nozzle analogous to that described in DE-A-3 022 136 Method can be filled.

The 1,2-diacyl-glycero-3-phosphocholines can also be processed together with other ulcer therapies or with medicinal products which show side effects damaging to the mucosa by the method, e.g. B. be incorporated into the viscous 1,2-diacylglycero-3-phosphocholine masses before filling, or after filling the 1,2-diacylglycero-3-phosphocholines in powder or tablet form, the ratio of 1.2 -Diacyl-glycero-3-phosphocholine and other active ingredients can vary from 0.1: 1 to 1:20.

For the production of tablets and powder mixtures, the 1,2-diacyl-glycero-3-phosphocholines have to be converted into a solid form, which is extremely difficult because of the viscous properties of these substances. Solid preparations can be obtained by adding 2-10% by weight calcium chloride.

To prepare the solid preparations, the special 1,2-diacyl-glycero-3-phosphocholines are added with the addition of customary auxiliaries in water or an organic solvent such as B. alcohols, such as methanol, ethanol or isopropanol, in hydrocarbons, such as hexane, chloride hydrocarbons or mixtures thereof, dissolved or emulsified, the calcium chloride added and stirred with gentle heating and then the solvent removed again, whereby a dry powder is obtained. The calcium chloride is added in amounts of 1 to 20%, but in particular 2 to 10%, based on the amount by weight of 1,2-diacyl-glycero-3-phosphocholine.

Preferred solvents for processing 1,2-diacyl-glycero-3-phosphocholines are alcohols, especially ethanol. Slurries are water or alcohols, such as methanol or ethanol.

Usual methods are suitable for drying, such as vacuum roller drying, spray drying, freeze drying. The dried, comminuted 1,2-diacylglycero-3-phosphocholine-calcium chloride mixtures can optionally be comminuted or granulated by customary methods. To stabilize the products, 0.1-2% by weight, based on the amount of 1,2-diacylglycero-3-phosphocholine used, of a stabilizer or stabilizer mixture, such as toxopherol acetate and / or ascorbic acid palmit, is advantageously used.

The special 1,2-diacyl-glycero-3-phosphocholines can also be processed together with drugs that show side effects that damage the mucosa. Medicines include e.g. For example: cytostatics, chemotherapeutics, antibiotics, steroids, especially steroidal and non-steroidal anti-inflammatory drugs.

The solid, oral dosage forms, consisting of drug or non-steroidal anti-inflammatory drugs and special 1,2-diacyl-glycero-3-phosphocholine, can be produced by various methods:<ul id="ul0007" list-style="none"><li>Powder mixtures:</li><li>The medicinal products, which have been comminuted to the appropriate grain size, and a special 1,2-diacyl-glycero-3-phosphocholine-calcium chloride mixture are mixed with the addition of conventional pharmaceutical auxiliaries and pressed into tablets or filled into capsules.</li></ul>

Spray embedding:<ul id="ul0008" list-style="none"><li>The solution or dispersion of the drug in organic solvents or water are mixed with a solution or emulsion of the special 1,2-diacylglycero-3-phosphocholine in organic solvents or water and the solution of calcium chloride in organic solvents or water, and if necessary, mixed other conventional pharmaceutical auxiliaries and spray dried. The spray embedding obtained can either be pressed into tablets or filled into capsules with the addition of other pharmaceutical auxiliaries.</li></ul>

Servings:<ul id="ul0009" list-style="none"><li>The solution or emulsion of the special 1,2-diacyfi-.glycero-3-phosphocholine in organic solvents or water is mixed with a solution of calcium chloride in organic solvents or water and applied in a fluidized bed to the medicinal product which has previously been comminuted to the desired particle size . The powdery, free-flowing product obtained is either compressed into tablets or filled into capsules with the addition of pharmaceutical auxiliaries.</li></ul>

The ratio of drug to 1,2-diacyl-glycero-3-phosphocholine / calcium chloride can vary in a weight ratio of 1: 0.1 to 1:20, depending on the therapeutic requirements. Advantageously, 50-250 mg, in particular 100 mg, of the 1,2-diacyl-calcium chloride mixture are used per dosage of the drug.

The advantage of solid, oral forms of administration, consisting of drugs and a special 1,2-diacyl-glycero-3-phosphocholine-calcium chloride mixture, over formulations consisting of drugs and phospholipids, such as z. B. are described in DE-B-2 856 333, can be determined as follows: It is the proportion of emulsified phospholipid or 1,2-diacyl-glycero-3-phosphocholine from a solid, oral dosage form, consisting of drug and Phospholipid or Drug and 1,2-diacyl-glycero-3-phosphocholine / calcium chloride, determined in the gastric juice according to the USP dissolution test (rotating basket method, 100 rpm, 900 ml gastric juice, pH 1.2), material:<ul id="ul0010" list-style="none"><li>AS = phenylbutazone</li><li>PL = phosphatidylcholine</li><li>PC / CaC1₂ = 1,2-diacyl-glycero-3-phosphocholine / calcium chloride (content: 6.43% CaCl₃)</li><li>Capsules of 200 mg AS and 100 mg PL or PC / CaCE2<img file="EP0147741B1_D0011.tif" /></li></ul>

As a further advantage of the preferred preparations, consisting of drug and 1,2-diacylglycero-3-phosphocholine / calcium chloride, over drug forms consisting of drug and phospholipid, there is the possibility that according to the method high and necessary amounts of 1 , 2-diacyl-glycero-3-phosphocholine in the form of mixtures with CaC1₂ and drug can be combined. For example, according to the known fluid bed process acetylsalicylic acid with phosphatidylcholine, only maximum mixing ratios of 1: 0.2 can be obtained, whereas acetylsalicylic acids with the special 1,2-diacylglycero-3-phosphocholine / calcium chloride can be produced in mixtures of over 1: 0.5 to let.

Another great advantage is the powder technology properties of the pharmaceutical preparations made with the special 1,2-diacyl-glycero-3-phosphocholine / calcium chloride.<tables id="tabl0001" num="0001"><img file="EP0147741B1_D0012.tif" /></tables><ul id="ul0011" list-style="none"><li>ASS = acetylsalicylic acid</li><li>PL = phosphatidylcholine</li><li>PC = 1,2-diacylglycero-3-phosphocholine</li></ul>

The advantage of the powder technology properties of the medicinal forms produced with mixtures of 1,2-diacyl-glycero-3-phosphocholine / calcium chloride is the advantageous physical properties of the 1,2-diacyl-glycero-3-phosphocholine-calcium chloride mixture compared to the pure 1 , Attributing 2-diacyl-glycero-3-phosphocholine.<tables id="tabl0002" num="0002"><img file="EP0147741B1_D0013.tif" /></tables><ul id="ul0012" list-style="none"><li>PC1 = 1,2-diacyl-glycero-3-phosphocholine</li><li>PC2 = mixture of</li><li>80 % 1,2-diacyl-glycero-3-phosphocholine</li><li>20 % 1,2-diacyl-glycero-3-phosphoethanolamine</li></ul>

If the special 1,2-diacyl-glycero-3-phosphocholines are to be administered together with other drugs, drug cores can also be coated with the 1,2-diacyl-glycero-3-phosphocholine. Combination packs are also possible which contain the medicament to be administered and the preparation of special 1,2-diacylglycero-3-phosphocholine.

example 1

The following tests were carried out to demonstrate effectiveness:<ul id="ul0013" list-style="none"><li>Enrichment of special 1,2-diacyl-glycero-3-phosphocholine in the gastrointestinal mucosa.</li></ul>

Rats received 70 mg / kg ³H radioactively labeled phosphocholine (1,2- / 9,10,12,13-³H_4/-Dilinolyl-sn-glycero-3-phosphocholine) by gavage. The radioactivity was 4.4 x 10 per animal⁶ dpm ³H. The rats became 1.5; 3; 6; 24 hours after application in deep ether anesthesia, immersed in an acetone-dry ice mixture (-72 ° C). Whole body cuts were made. The dry sections, together with 2 standards of different radioactivity, were brought into contact with the photographic emulsion under uniform pressure and exposed at -20 ° C. The duration of exposure was 47 days. It could be shown by this autoradiography picture that the administered 1,2-diacylglycero-3-phosphocholine quickly and long-lasting leads to an accumulation in the gastrointestinal mucosa, which is caused by a pronounced blackening of the gastric wall on the picture is expressed.

Example 2

Chemical mucosal damage.

An ulcerogenic dose of phenylbutazone (200 mg / kg, 5 ml / kg) was orally administered to male rats that were fed white bread for 3 days and then had 24 hours of food-free diet. Immediately afterwards, the test substance was administered orally. After 3.5 hours, the animals were killed by ether anesthesia and the stomachs were examined macroscopically. The ulceration was used according to Takagi and Okabe (Jap. J. Pharmacol. 18, 9-18 (1968) using an index number.<tables id="tabl0003" num="0003"><img file="EP0147741B1_D0014.tif" /></tables><ul id="ul0014" list-style="none"><li>PPC = 1,2-diacyl-glycero-3-phosphocholine (acyl residues approx. 62 - 68% linoleic acid) acc. Claim 3</li><li>DPPC = Dipalmitoylphosphatidylcholine</li><li>DPPG = Dipalmotoylphosphatidylglycerol</li><li>OPPI = Dipalmitoylphosphatidylethanolamine</li><li>Sph = sphingomycline</li></ul>

The mixture DPPC / DPPE / DPPG / DPPI / Sph (9: 1: 1: 1: 1) corresponds to the most effective mixture from EP-0 092121.

As can be seen from the table, the special ones

1,2-Diacylglycero-3-phosphocholine clearly shows the greatest inhibition of ulcer provocation.

Example 3

<tables id="tabl0004" num="0004"><img file="EP0147741B1_D0015.tif" /></tables>

The 1,2-diacyl-glycero-3-phosphocholine is emulsified in the water containing the preservatives while stirring, and the dry glucose and flavorings are then mixed in. The viscous emulsion is filled into tubes.

Example 4

Hard gelatin capsules

<tables id="tabl0005" num="0005"><img file="EP0147741B1_D0016.tif" /></tables><ul id="ul0015" list-style="none"><li>b) Filled in hard gelatin capsules. The mass described under a) is filled into hard gelatin capsules on a hard gelatin capsule machine with a filling station for liquid contents at 60 ° C. Capsule size 0 elongated, dosage 658 mg.</li></ul>

Example 5

Drinking ampoules

<tables id="tabl0006" num="0006"><img file="EP0147741B1_D0017.tif" /></tables>

The 1,2-diacyl-glycero-3-phosphocholine is dispersed in 1.4 l of water with stirring and then homogenized with a gap homogenizer. After adding an aqueous solution of the combination syrup and the aromas, make up to 2 l with water and filter sterile. The solution is then filled into injection vials (5 ml) under aseptic conditions.

Example 6

98 g 1,2-diacyl-glycero-3-phosphocholine are dissolved in ethanol with heating and mixed with a solution of 2 g calcium chloride (anhydrous) in 50 ml methanol. The solvents are removed under vacuum and the product obtained is reduced to a particle size of &lt;100 μm with the addition of 1% Aerosil® 200. The powder obtained is filled into capsules.

The mixture can also be pressed into tablets with the addition of suitable auxiliaries.

Example 7

90 g 1,2-diacyl-glycero-3-phosphocholine are dissolved in 200 ml chloroform and with a solution of 10 g CaC1₂ mixed anhydrous in 200 ml of methanol and dried by means of a spray dryer, type Büchi 190. The product obtained is comminuted to a grain size of &lt;100 μm with the addition of 1% Aerosil® 200 and can then be filled into capsules or compressed into tablets.

Example 8

94 g of a mixture of 80 wt .-% 1 2-diacyl-glycero-3-phosphocholine and 20 wt .-% 1,2-diacyl-glycero-3-phosphoethanolamine are dissolved in ethanol and with a solution of 6 g CaC1₂ (anhydrous) mixed in 120 ml ethanol. The solvents are removed under vacuum and the product obtained is processed as in Example 6.

Example 9

90 g 1,2-diacyl-glycero-3-phosphocholine are distilled in 500 ml aqua. emulsified and with a solution of 10 g CaC1₂ anhydrous in 50 ml aqua dest. mixed and processed analogously to Example 6.

Example 10

Aqueous dispersion.<tables id="tabl0007" num="0007"><img file="EP0147741B1_D0018.tif" /></tables>

To prepare the ready-to-drink aqueous dispersion, 12.5 g of powder mixture are added to 100 ml of water immediately before use and shaken briefly.

Example 11

ASA tablets:<tables id="tabl0008" num="0008"><img file="EP0147741B1_D0019.tif" /></tables>

The ingredients listed are mixed, pressed and in a similar manner with known tablet coating agents, e.g. B. cellulose acetate phthalate or hydroxypropyl methyl cellulose phthalate.

Example 12

ASS capsules:

<tables id="tabl0009" num="0009"><img file="EP0147741B1_D0020.tif" /></tables>

A solution consisting of 90 g 1,2-diacylglycero-3-phosphocholine / CaCL₂, 200 ml chloroform and 10 g CaC1₂-water-free and 200 ml of methanol, is sprayed on ASS, ground &lt;100 µ, in a fluid bed. The free-flowing powder obtained is filled into hard gelatin capsules of 300 mg ASA capsules.

Example 13

Phenylbutazone tablets:<tables id="tabl0010" num="0010"><img file="EP0147741B1_D0021.tif" /></tables>200 g of phenylbutazone are dissolved in 500 ml of chloroform, 93.5 g of phospholipid and 6.5 g of CaCl₂dissolved in 100 ml of methanol. The mixture obtained is spray-dried, mixed with the remaining components, comminuted, pressed to give 200 mg of phenylbutazone tablets and coated as in Example 11.

Example 14

Indomethacin capsules:

<tables id="tabl0011" num="0011"><img file="EP0147741B1_D0022.tif" /></tables>

A solution consisting of 90 g 1,2-diacyl-glycero-3-phosphocholine in 500 ml isopropanol and 10 g CaC1₂ in 100 ml of methanol, is sprayed onto the ground indomethacin in a fluidized bed. The powder obtained is treated as described in Example 6.

Example 15

Ibuprofen tablets:

<tables id="tabl0012" num="0012"><img file="EP0147741B1_D0023.tif" /></tables>

Example 16

Ibuprofen capsules:

<tables id="tabl0013" num="0013"><img file="EP0147741B1_D0024.tif" /></tables><tables id="tabl0014" num="0014"><img file="EP0147741B1_D0025.tif" /></tables>

Example 17

Sulindac tablets:

<tables id="tabl0015" num="0015"><img file="EP0147741B1_D0026.tif" /></tables>

Example 18

Naproxen capsules:

<tables id="tabl0016" num="0016"><img file="EP0147741B1_D0027.tif" /></tables>

Example 19

Diclofenac sodium tablets:

<tables id="tabl0017" num="0017"><img file="EP0147741B1_D0028.tif" /></tables>

Example 20

Tablets containing diclofenac:<tables id="tabl0018" num="0018"><img file="EP0147741B1_D0029.tif" /></tables>

The mixture is pressed into domed tablets of 150 mg diclofenac sodium each and then coated with a coating<tables id="tabl0019" num="0019"><img file="EP0147741B1_D0030.tif" /></tables>

Example 21

Capsules containing diclofenac:<ul id="ul0016" list-style="none"><li>a)<img file="EP0147741B1_D0031.tif" /></li><li>b) Filling compound:<img file="EP0147741B1_D0032.tif" />The mixture is mixed homogeneously in a kneader at 60 ° C.</li><li>c) 350 mg of the mixture per hard gelatin capsule of size 0 are dosed from the filling compound described under b) on a hard gelatin capsule machine with an additional part for liquid filling. 150 mg of the powder mixture described under a) are then added per capsule on the same hard gelatin capsule filling system with the aid of a filling station for powder and the capsule is closed.</li></ul>

The capsules contain 50 to 1500 mg of 1,2-diacyl-glycero-3-phosphocholine and 10 - 250 mg of non-steroidal anti-inflammatory drugs, the ratio of anti-inflammatory drugs to 1,2-diacyl-glycero-3-phosphocholine advantageously being 1: 01 to 1: Is 10.

Example 22

Capsules containing diclofenac:<ul id="ul0017" list-style="none"><li>a)<img file="EP0147741B1_D0033.tif" />The substances are mixed homogeneously and pressed into 150 mg tablets with a diameter of 6.5 mm.</li><li>bl filling compound<img file="EP0147741B1_D0034.tif" />are mixed homogeneously in a kneader at 60 ° C.</li><li>c) 500 mg of the filling compound described under b) are filled into a size 0 hard gelatin capsule on a hard gelatin capsule machine with a filling station for liquids. A compact of the composition described under a) is then placed in the capsule on the same machine with the aid of a filling station for tablets and the capsule is closed.</li></ul>

Example 23

Prednisolone tablets:

<tables id="tabl0020" num="0020"><img file="EP0147741B1_D0035.tif" /></tables><tables id="tabl0021" num="0021"><img file="EP0147741B1_D0036.tif" /></tables>

Example 24

<tables id="tabl0022" num="0022"><img file="EP0147741B1_D0037.tif" /></tables>

Example 25

<tables id="tabl0023" num="0023"><img file="EP0147741B1_D0038.tif" /></tables>

Example 26

p-Aminosalicylic acid tablets:

<tables id="tabl0024" num="0024"><img file="EP0147741B1_D0039.tif" /></tables>