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

0001The present invention relates to new pharmaceutical preparations for the treatment of diseases in the gastrointestinal area, consisting of special 1,2-diacyl-glycero-3-phosphocholine, possibly in a mixture with other 1,2-diacyl-glycero-3-phosphates, with 75 - 86 wt .-% unsaturated fatty acid residues with a chain length of C₁₆, C₁₈ U.N^d/O^dhe ^C.₂₀.

0002About 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 diverse, for example endogenous cytotoxic substances such as gastric and bile acids, or exogenous noxious substances such as ethanol or pharmaceuticals. The gastrointestinal tract is one of the most common of drug side effects^Gaffected organ systems. In particular, non-steroidal anti-inflammatory drugs lead to erosions and ulcerations of the stomach.

0003The 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). In addition, film formers such as sulfated disaccharides (sucralfates) are used.</li></ul>

0004The 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.

0005A number of other disadvantages of these therapeutic agents used today are known. The acidic gastric juice itself also has protective functions, for example 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 in the whole organism, which have a variety of side effects. Anticholinergics cause, for example, dry mouth and accommodation disorders; H₂Antagonists

0006cause headache, diarrhea, joint and muscle pain, fatigue, dizziness, hair loss, disturbances in sexual behavior, liver damage, etc.

0007EP 92 121 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 investigated, for example: BH Hills et al., J. Appl. Physiol .: Environ Exercise Physiol. 1982, 53 (1), 119-123; 1982, 53 (2), 463-469; 1983, 54 (2), 420-426; Respiration Physiology 1983, 51, 79-93; LM Lichtenberger, Science 219 (1983), 1327-1329.

0008The most important components were identified: Dipalmitoylphosphatidylcholine (DPPC),<ul id="ul0002" list-style="none"><li>Dipalmitoylphosphatidylglycerol (DPPG),</li><li>Dipalmitoylphosphatidylethanolamine (DPPE) and</li><li>Sphingomycein (SP).</li><li>Combinations such as, for example, are particularly advantageous</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. 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.</li></ul>

0009However, 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 the anatomical and physiological differences between the two organ systems. 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 tract. The latter also relate in particular to large water-soluble molecules, so that film formation is hardly possible.</li></ul>

0010Current ulcer therapy is symptomatic, but by no means curative therapy. It heals the ulcer at most, but not ulcer disease.

0011An alternative therapeutic goal would therefore be to strive for the protective properties of the mucosa. Carbenoxolone became 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.

0012The 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 met by administration of this group of active substances.

0013The clinically proven long-life PGE₂Analogs, however, suffered from significant systemic side effects.

0014In contrast, as in other organs, the natural prostaglandins also act in the digestive tract as so-called local hormones. That means that they don't have the bloodstream on

0015reach the place of their effect, but are formed in the immediate vicinity or even directly in the tissues in which they develop their short-lived effect.

0016It 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.

0017The 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.

0018The object is achieved by the pharmaceutical preparations according to the patent claims.

0019It 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. 1,2-Diacyl-glycero-3-phosphocholines are preferred which contain linoleic acid or fatty acid mixtures of the following composition as fatty acid residues:<ul id="ul0004" list-style="none"><li>10th - 14% by weight palmitic acid</li><li>3rd - 5% by weight of stearic acid</li><li>8th - 12% by weight oleic acid</li><li>62 - 68% by weight linoleic acid</li></ul>

00204th 6% by weight of linolenic acid, the individual contents being selected so that they each give 100%,

0021The 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.

0022In 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 of oleic acid</li><li>50 - 54% by weight linoleic acid</li><li>4th - 6% by weight linolenic acid</li></ul>

0023and the acyl residue in the 2-position consists of the following mixtures of fatty acids.<ul id="ul0006" list-style="none"><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>, 78-85% 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></ul>

0024The 1,2-diacyl-glycero-3-phosphocholines correspond to the general formula<chemistry id="chem0001" num="0001"><img file="EP0147741A2_D0001.tif" /></chemistry>where R¹ and R² can be the same or different and the residues<chemistry id="chem0002" num="0002"><img file="EP0147741A2_D0002.tif" /></chemistry>where 1 = 1, 4, 7, 8 or 10<ul id="ul0007" list-style="none"><li>m = 0, 1, 2, 3 or 4</li><li>n = 2 or 6, such as the following radicals<chemistry id="chem0003" num="0003"><img file="EP0147741A2_D0003.tif" /></chemistry><chemistry id="chem0004" num="0004"><img file="EP0147741A2_D0004.tif" /></chemistry><chemistry id="chem0005" num="0005"><img file="EP0147741A2_D0005.tif" /></chemistry><chemistry id="chem0006" num="0006"><img file="EP0147741A2_D0006.tif" /></chemistry><chemistry id="chem0007" num="0007"><img file="EP0147741A2_D0007.tif" /></chemistry><chemistry id="chem0008" num="0008"><img file="EP0147741A2_D0008.tif" /></chemistry></li></ul>

0025The pharmaceutical preparations with special 1,2-diacyl-glycero-3-phosphocholines can, if necessary, up to 20% more 1,2-diacyl-glycero-3-phosphates or their mixtures, such as 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, contain wherein the acyl radicals have the same composition as specified for the 1,2-diacyl-glycero-3-phosphocholines. However, 1,2-diacylglycero-3-phosphocholines with the following fatty acid composition are preferred<tables id="tabl0001" num="0001"><img file="EP0147741A2_D0009.tif" /></tables>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 residue in the 1-position consists of the following mixtures of fatty acid residues<tables id="tabl0002" num="0002"><img file="EP0147741A2_D0010.tif" /></tables>and the acyl residue in the 2-position consists of the following fatty acid residue mixtures<tables id="tabl0003" num="0003"><img file="EP0147741A2_D0011.tif" /></tables>the individual contents are selected so that they each add up to 100%.

0026These 1,2-diacylglycero-3-phosphocholines can be obtained by processes known per se (EP 54 770, EP 54 768, EP 54 769), in particular from soybeans.

0027The whole 1,2-diacyl-glycero-3-phosphocholine, as whole animal autoradiographs show, is quickly and permanently enriched in the stomach 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 from gastric mucosal damage caused by agents that irritate the mucous membrane.

0028Clinical examinations were carried out in 9 patients. Seven characteristic, subjective parameters (heartburn, pain in the epigastrium, fullness, loss of appetite, nausea, nausea, singultus), which occur in connection with mucosal erosions and ulcerations in the gastric duodenal area, were measured 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 jaundice disease), significant, sometimes dramatic improvements were achieved within 1 - 4 days of treatment the complaint 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 were observed, could not be found.

0029As 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 E 0 092 121, was not to be expected since the highly unsaturated 1,2-diacylglycero-3-phosphocholines according to the invention were not under the physiological conditions

0030are able to form a useful protective film. In addition, it was not at all to be expected that parenteral administration would also lead to lasting protection of the gastric mucosa, since film formation is completely ruled out here.

0031The 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 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 To remove 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.

0032In the treatment of severe ulcerations, one can reduce or eliminate the aggressive factors Ulcus Therapeutica, such as 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.

0033In particular in the treatment of diseases with gastrointestinal aggressive agents, for example 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 Ibuprofen, Naproxen, Alclofenac, Ketoprofen, Diclofenac, Fenoprofen, Tolmetin, Flurbiprofen, Suprofen, Indoprofen, Carprofen, Pirprofen, Fenclofenac, Sulindac, Indometacin, Piroxicam, Acemetacin, Pimetacin, uaindind /, advantageous with an / numeton treatment with and numeton or simultaneous administration in one dose or separate doses with the special 1,2-diacyl-glycero-3-phosphocholine.

0034For the administration of the special 1,2-diacylglycero-3-phosphocholines, these are converted into a suitable form, such as, for example, capsules, solutions, emulsions, tablets, powders, chewable capsules, drinking ampoules or aqueous emulsions and

0035in common parenteral forms.

0036The special 1,2-diacyl-glycero-3-phosphocholines can be prepared in soft selatine capsules by methods known per se or more advantageously in hard gelatine capsules, for example in accordance with the method described in DE-OS 30 22 136, optionally with the addition of suitable auxiliaries and fillers, be filled. The soft or hard gelatin capsules can be swallowed whole or chewed.

0037To produce the hard gelatin chewable capsules, the phospholipids are mixed with pharmaceutically inert carriers, such as waxes, hydrogenated oils, natural, semi-synthetic or synthetic triglycerides and their mixtures, such as cocoa butter, and conventional suppository compositions, for example based on triglycerides, such as Witepsol suppository compositions (see HP F , Lexicon of auxiliaries 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.

0038Ethanol 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 bottling plants with an additional device for liquid filling and with a heatable filling nozzle analogous to the method described in DE-OS 30 22 136 can be filled.

0039The 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, for example by are incorporated into the viscous 1,2-diacyl-glycero-3-phosphocholine masses before filling, or after filling the 1,2-diacyl-glycero-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.

0040For 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.

0041To 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, for example, 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, are advantageously used.

0042The special 1,2-diacyl-glycero-3-phosphocholines can also be processed together with drugs that show side effects that damage the mucosa. Medicaments include, for example: cytostatics, chemotherapeutics, antibiotics, steroids, especially steroidal and non-steroidal anti-inflammatory drugs.

0043The solid, oral dosage forms, consisting of pharmaceutical or non-steroidal anti-inflammatory drugs and special 1,2-diacyl-glycero-3-phosphocholine, can be produced by various methods:<ul id="ul0008" list-style="none"><li>Powder mixtures:</li><li>The medicinal substances 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>

0044Spray embedding:<ul id="ul0009" 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>

0045Servings:<ul id="ul0010" list-style="none"><li>The solution or emulsion of the special 1,2-diacyl-glycero-3-phosphocholine in organic solvents or water is mixed with a solution of calcium chloride in organic solvents or water and in a fluidized bed to the medicinal product which has previously been reduced to the desired particle size. no substance applied. The powdery, free-flowing product obtained is either compressed into tablets or filled into capsules with the addition of pharmaceutical auxiliaries.</li></ul>

0046The ratio of drug to 1,2-diacylglycero-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.

0047The advantage of solid, oral forms of administration, consisting of drugs and special 1,2-diacyl-glycero-3-phosphocholine-calcium chloride mixture, over formulations consisting of drugs and phospholipids, as described, for example, in DE-PS 28 56 333 , can be determined as follows: 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, in gastric juice determined according to the USP dissolution test (rotating basket method, 100 rpm, 900 ml gastric juice, pH 1.2), material:<ul id="ul0011" list-style="none"><li>AS = phenylbutazone</li><li>PL = phosphatidylcholine</li><li>PC / CaC1₂= 1,2-diacyl-glycero-3-phos</li><li>phocholine / calcium chloride (content: 6.43% CaC1₃)</li><li>Capsules of 200 mg AS and 100 mg PL or PC / CaC1₂<img file="EP0147741A2_D0012.tif" /></li></ul>

0048As a further advantage of the preferred preparations according to the invention, consisting of drug and 1,2-diacyl-glycero-3-phosphocholine / calcium chloride, compared to drug forms consisting of drug and phospholipid, there is the possibility that high and required amounts of can be obtained by the process 1,2-diacyl-glycero-3-phosphocholine in the form of mixtures with CaCl₂ 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.

0049Another 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="tabl0004" num="0004"><img file="EP0147741A2_D0013.tif" /></tables>

0050The advantage of the powder technology properties of the pharmaceutical 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="tabl0005" num="0005"><img file="EP0147741A2_D0014.tif" /></tables><tables id="tabl0006" num="0006"><img file="EP0147741A2_D0015.tif" /></tables>

0051If 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

0052The following tests were carried out to demonstrate effectiveness:<ul id="ul0012" list-style="none"><li>Enrichment of special 1,2-diacyl-glycero-3-phosphocholine in the gastrointestinal mucosa.</li><li>Rats received 70 mg / kg ³H radio-labeled phosphocholine (1,2- / 9,10,12,13-3H4 / -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;</li><li>24th Hours after application in deep ether anesthesia, by immersing 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.</li></ul>

Example 2

Chemical mucosal damage.

0053An 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="tabl0007" num="0007"><img file="EP0147741A2_D0016.tif" /></tables>

0054The mixture DPPC / DPPE / DPPG / DPPI / Sph (9: 1: 1: 1: 1) corresponds to the most effective mixture from EP 0 092 121.

0055As can be seen from the table, the 1,2-diacylglycero-3-phosphocholines according to the invention clearly led to the greatest inhibition of ulcer provocation.

Example 3

0056<tables id="tabl0008" num="0008"><img file="EP0147741A2_D0017.tif" /></tables>

0057The 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

0058Hard gelatin capsules<ul id="ul0013" list-style="none"><li>a) Recipe and production of the filling material<img file="EP0147741A2_D0018.tif" />are mixed homogeneously in a kneader.</li><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

0059<tables id="tabl0009" num="0009"><img file="EP0147741A2_D0019.tif" /></tables>The 1,2-diacyl-glycero-3-phosphocholine is dispersed in 1.4 l of water under Rüchren and then homogenized with a gap homogenizer. After adding an aqueous solution of the combination syrup and the aromas, make up to 2 1 with water and filter sterile. The solution is then filled into injection vials (5 ml) under aseptic conditions.

Example 6

006098 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 comminuted to a particle size of &lt;100 p with the addition of 1% Aerosil 200. The powder obtained is filled into capsules.

0061The mixture can also be pressed into tablets with the addition of suitable auxiliaries.

Example 7

006290 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 particle size of &lt;100μ with the addition of 1% Aerosil 200 and can then be filled into capsules or compressed into tablets.

Example 8

006394 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

006490 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

0065<tables id="tabl0010" num="0010"><img file="EP0147741A2_D0020.tif" /></tables>are mixed homogeneously in a powder mixer. 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

0066ASA tablets:

0067<tables id="tabl0011" num="0011"><img file="EP0147741A2_D0021.tif" /></tables>The ingredients listed are mixed, pressed and provided in a similar manner with known tablet coating agents, for example cellulose acetate phthalate or hydroxypropylmethyl cellulose phthalate.

Example 12

0068ASS capsules:<tables id="tabl0012" num="0012"><img file="EP0147741A2_D0022.tif" /></tables>

0069A solution consisting of 90 g 1,2-diacylglycero-3-phosphocholine / CaCL₂, 200 ml chloroform and 10 g CaCl₂-water-free and 200 ml of methanol, is sprayed onto ASS, ground &lt;100 p, in a fluid bed. The free-flowing powder obtained is filled into hard gelatin capsules of 300 mg ASA capsules.

Example 13

0070Phenylbutazone tablets:<tables id="tabl0013" num="0013"><img file="EP0147741A2_D0023.tif" /></tables>

0071200 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

0072Indomethacin capsules:<tables id="tabl0014" num="0014"><img file="EP0147741A2_D0024.tif" /></tables>

0073A solution consisting of 90 g 1,2-diacyl-glycero-3-phosphocholine in 500 ml isopropanol and 10 g CaCl₂ 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

0074Ibuprofen tablets:<tables id="tabl0015" num="0015"><img file="EP0147741A2_D0025.tif" /></tables>

0075Production analogous to example 6.

Example 16

0076Ibuprofen capsules:<tables id="tabl0016" num="0016"><img file="EP0147741A2_D0026.tif" /></tables>

0077Production analogous to example 12.

Example 17

0078Sulindac tablets:<tables id="tabl0017" num="0017"><img file="EP0147741A2_D0027.tif" /></tables>

0079Production analogous to example 11.

Example 18

0080Naproxen capsules:<tables id="tabl0018" num="0018"><img file="EP0147741A2_D0028.tif" /></tables>

0081Production analogous to example 12.

Example 19

0082Diclofenac sodium tablets:<tables id="tabl0019" num="0019"><img file="EP0147741A2_D0029.tif" /></tables>

0083Production analogous to example 11.

Example 20

0084Tablets containing diclofenac:<tables id="tabl0020" num="0020"><img file="EP0147741A2_D0030.tif" /></tables>

0085The mixture is pressed into curved tablets of 150 mg of diclofenac sodium each and then coated with a top coating<tables id="tabl0021" num="0021"><img file="EP0147741A2_D0031.tif" /></tables>

0086coated in amounts of approx. 100 mg per tablet.

Example 21

0087Diclofenac-Haltiqe capsules:<tables id="tabl0022" num="0022"><img file="EP0147741A2_D0032.tif" /></tables><ul id="ul0014" list-style="none"><li>b) Filling compound:<img file="EP0147741A2_D0033.tif" />The mixture is mixed homogeneously in a kneader at 60 ° C.</li><li>c) 350 mg of the mixture per size 0 hard gelatin capsule 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>

0088The 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:

0089<tables id="tabl0023" num="0023"><img file="EP0147741A2_D0034.tif" /></tables>The substances are mixed homogeneously and pressed into 150 mg tablets with a diameter of 6.5 mm.

0090b) filling compound<tables id="tabl0024" num="0024"><img file="EP0147741A2_D0035.tif" /></tables>are mixed homogeneously in a kneader at 60 ° C.

0091c) 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.

Example 23

0092Prednisolone tablets:<tables id="tabl0025" num="0025"><img file="EP0147741A2_D0036.tif" /></tables>

0093Production analogous to example 13.

Example 24

0094Dexamethasone tablets (9-fluoro-16-methylprednisolone)<tables id="tabl0026" num="0026"><img file="EP0147741A2_D0037.tif" /></tables>

0095Production analogous to example 13.

Example 25

0096Methotrexate tablets<tables id="tabl0027" num="0027"><img file="EP0147741A2_D0038.tif" /></tables>

0097Production analogous to example 13.

Example 26

0098p-Aminosalicylic acid tablets:<tables id="tabl0028" num="0028"><img file="EP0147741A2_D0039.tif" /></tables>

0099Production analogous to example 12.