DE3200766A1 - Product with excellent absorption property - Google Patents

Abstract

Product containing an absorption-promoting substance from specific classes of water-soluble compounds with chelate-forming activity, preferably in the presence of a salt in a concentration which shows a higher osmotic pressure than an isotonic sodium chloride solution, and a pharmaceutical or medicine for promoting the absorption of the pharmaceutical by an organ in the gastrointestinal tract, such as colon, rectum, or through the vagina.

Description

Preparation with excellent absorption properties

Claimed priorities: 1t. January 1981, Japan, No. 3263/81, 6. March 1981, Japan, No. 32951/81, November 11, 1981, Japan, No. 181508/81 and 17. November 1981, Japan, No. 184861/81.

The invention relates to a new preparation with excellent absorption properties, that to improve the absorption of a drug or remedy poor or poor absorption through the rectum or other digestive organs is determined in the body, with such a drug or remedy in the Rectum or other organs simultaneously with a water-soluble substance that has a shows higher osmotic pressure than an isotonic sodium chloride solution, such as a water soluble compound with chelating activity. Further concerns the invention a preparation with good absorption properties with a content of a water-soluble macromolecular compound with chelating activity and a drug that has the absorption property for the drug itself has a low absorption property, can improve to a great extent and one for a long time too high concentration of the drug sustains in the blood.

It has hitherto generally been considered that absorption of a drug or remedy through a digestive organ, regardless whether it is stomach, small intestine, large intestine, rectum or mouth, according to the pH distribution theory runs (see. "Modern Pharmaceutics", Marcel Dekker, INC., pages 31-49). Thereafter a drug or remedy easily dissociates in the relevant organs at absorption sites or tends to be a drug or remedy with low lipophilicity to be poorly absorbed. Such hard-to-absorb drugs or remedies are administered as injections in the current circumstances. To improve the absorption properties of a drug or medicinal product Numerous studies have been carried out on how to use the medicines in the form of precursors or softened agents, the application of ions pair or a complex formation. However, these suggestions are specific to individuals Medicinally effective, and no generally applicable method is known to date (see Nogami in "Pharmaceutics"). There are now numerous investigations has been carried out with the result that the mechanism of membrane absorption through digestive organs or other organs believed to be according to the foregoing pH distribution theory to proceed, a compound with chelating activity, which can bind at least calcium ions or magnesium ions, a change in terms of the membrane permeability causes, reducing the membrane absorption of a drug or drug Remedy can be improved in order to promote its absorption successfully. It has also been found that a water-soluble macromolecular compound with a chelating activity containing at least calcium ions and magnesium ions able to bind, also as a connection with such an absorption-promoting Effectiveness is useful. Furthermore, it has been found that the membrane absorption by adding a water-soluble substance to a Concentration, which exhibits a higher osmotic pressure than an isotonic sodium chloride solution, can be improved in a remarkable way to m the preparation under the Be condition a higher tonicity than the osmotic pressure of the body fluid. In addition to these findings, it has also been found that a preparation which by using a vehicle, desired selected additives and an objective one Medicinal or therapeutic agent, such as one that can be inserted into the rectum or vagina Suppository, is a good suppository that passes through the membranes can be absorbed in an excellent manner and high for a long time Can maintain concentration of the drug or remedy. The according to the present Medicines or remedies that can be used according to the invention are very important. in the h csu n der e s in d so-called water-soluble drugs or remedies with good solubility in water, for example those with partition coefficients of 50 or less in chloroform / water, or drugs or remedies that can easily be dissociated into ions useful. Furthermore, it was found that drugs or remedies that were previously only could be used as injection solutions, in a simple manner as preparations such as suppositories, can be made excellently absorbable. It has further been found that even drugs or remedies of high molecular weight, such as polypeptide ormones, according to the invention in the form of a preparation such as a suppository, effectively absorbable be made.

The present invention has been accomplished based on these findings been. The object of the present invention is therefore to provide a good preparation with which a medicine or remedy can be improved to a possessing remarkably increased absorption property.

Show in the drawing Fig. 1 fading curves for different osmotic pressures of cefmetazole when cefmetazole sodium is used as a drug is used, the percentages of cefmetazole disappearing through absorption plotted against time, Figures 2, 3 and 4 show various curves of percentages with regard to the loss of cefmetazole sodium versus the osmotic pressure, Fig. 5 shows a shrinkage curve of cefoxitin sodium versus osmotic pressure, and FIG. 6 shows a corresponding shrinkage curve Samples (A, B, C, D and E) according to Example 4, FIG Samples (A, B, C, D, E, F and G) according to Example 7, FIG. 8 shows the calcium concentration curve in serum when elcitonin drug is used, Fig. 9 is the fading curve of Cephalothin sodium versus osmotic pressure and FIG. 10 the curve of the calcium concentration in the serum when elcitonin is used as medicine.

The present invention is therefore a preparation with excellent absorption property containing a water-soluble compound having chelating activity and a drug.

Preferred is a preparation excellent in absorption property containing a water-soluble substance in a concentration that exhibits a higher osmotic pressure than an isotonic sodium chloride solution, a water-soluble compound having chelating activity and a drug or remedies.

Another preferred embodiment of the present invention is a preparation excellent in absorption property containing one water-soluble macromolecular compound with chelating activity and a drug or remedies.

The invention is further elucidated below.

First, we will discuss the water-soluble substances that are used after a preferred embodiment in the present invention in one concentration used that have a higher osmotic pressure than an isotonic sodium shows chloride solution. It can preferably be such a connection that considered as a whole is harmless and in the smallest possible amount can exhibit high osmotic pressure.

As such water-soluble substances, water-soluble salts are used and includes water soluble sugars.

Sodium chloride is particularly popular among the water-soluble salts preferred because it is safe and easily controllable with regard to its osmotic pressure and continues to be soluble in water at a high rate of dissolution.

Also among the water-soluble sugars are mannitol and glucose preferred. Generally speaking, water-soluble salts can be, for example, halides, Sulfates, phosphates or carbonates of alkali metals, such as sodium, potassium or lithium, in particular the aforementioned sodium chloride, sodium sulfate, disodium hydrogen phosphate, Sodium dihydrogen phosphate, sodium dihydrogen phosphate, sodium phosphate, sodium hydrogen carbonate, Sodium carbonate, potassium chloride, potassium sulfate, potassium hydrogen phosphate, potassium carbonate, Lithium chloride and the like. These salts can be based on concentrations which have a higher tonicity than the osmotic pressure of an isotonic Show sodium chloride solution depending on its osmotic characteristics. in the In the case of sodium chloride, for example, it can generally be used in one concentration of 1 wt. m or higher, based on the total content. The upper concentration limit is not particularly limited, but is a concentration about 2 to 30 wt. M preferred. Examples of preferred water-soluble sugars can be one monosaccharides or disaccharides, which are often used to adjust the osmotic Used in pharmaceutical technology, such as glucose, mannitol, Sorbitol, xylitol, lactose, maltose and sucrose. Such a sugar can be in a concentration with higher tonicity than isotonic sodium chloride solution is used which is generally 0.25 molar or higher. These water-soluble substances can be used in combination of 2 or 3 ways to adjust the osmotic pressure be used, which is preferably 1.5 to 6 times the osmotic pressure, shown by an isotonic sodium chloride solution.

In connection with the osmotic pressure, this is used in the present Description compared to an isotonic sodium chloride solution, but is one such description with the use of an isotonic sodium chloride solution as a comparison substance only as an example for the comparison between osmotic Press, and therefore it may also be possible to use other body fluids or other solutions of salts with a tonicity equal to an isotonic sodium chloride solution to be used for comparison.

Next are the compounds with chelating activity discussed which are used as absorption promoters according to the present invention will. You are by adding, for example, isctonic preparations for a rectal application with a content of a medicament or therapeutic agent for examination the increase or decrease in membrane absorption of the drug or therapeutic agent studied to carry out the present invention. The mechanism of the promotional effect is not entirely clear, but it seems likely that the membrane absorption mechanism is changed by the chelating activity and affinity for the membrane that them through this absorption accelerator on the structures of the Cell membranes or the spaces between the epithelial cells possesses to thereby promote absorption. Although the mechanism of action of the absorption promoter to increase membrane absorption by the rectum or by other organs such as mentioned above is one such mechanism action nothing more than a mere opinion, and all that is needed is a connection to use with chelating activity that binds at least calcium ions or magnesium ions is capable. Specifically, they can be used as chelating ligands for an effective chelating activity are mentioned, for example, acid groups, such as the carboxyl group, the sulfonic acid group, the phosphoric acid group, the phenolic group Hydroxyl group, the hydroxyl group, the imino group, the carbonyl group, the amino group and the like. Further examples of compounds having chelating activity therewith chelating ligands include organic compounds with at least one acid group, for example organic compounds with acid groups, such as carboxyl groups, thiocarboxyl groups, Sulphonic acid groups or phosphoric acid groups, organic compounds with acid groups and phenolic hydroxyl groups or organic compounds having at least two Carbonyl groups. As organic compounds with at least one carboxyl group, Sulfonic acid group or phosphoric acid group can contain numerous compounds with carboxyl groups, Sulfonic acid groups or phosphoric acid groups are included, such as monocarboxylic acids, Sulphonic acids, phosphoric acid compounds or keto-carboxylic acids, sulphonic acids with Carbonyl groups, phosphoric acid compounds with carbonyl groups, hydroxycarboxylic acids or aminocarboxylic acids, iminocarboxylic acids, hydroxyl or aminophosphoric acid compounds and polyacid compounds having two or more carboxyl groups, sulfonic acid groups and phosphoric acid groups. These compounds can also be placed in the appropriate groups the aliphatic compounds, the alicyclic compounds, the aromatic Compounds and the heterocyclic compounds classified will. Furthermore, tautomeric isomers of the keto-enol type can be used either as compounds with Carbonyl groups or as compounds with hydroxyl groups.

Furthermore, connections with several types of these groups, such as the carboxyl group, hydroxyl group, amino group and imino group, not necessarily uniquely selected for each of these groupings. For example, you can Polyacid compounds include oxalic acid, malonic acid, succinic acid, glutaric acid, Maleic acid, glutaconic acid, adipic acid, fumaric acid, aconitic acid, pimellic acid, Sebacic acid, suberic acid, azelaic acid, acridic acid, allylmalonic acid, mesaconic acid, Brassylic acid, dodecanolic acid, methylmalonic acid, ethylmalonic acid, phthalic acid, terephthalic acid, Homophthalic acid, phenylsuccinic acid, phenylmalonic acid, phenylenediacetic acid, 1,3-naphthalenedicarboxylic acid, Iminodiacetic acid, ß-alaninediacetic acid, hydrochelidonic acid, 1,2-cyclohexanedicarboxylic acid, Anthranilinoacetic acid, oxanilic acid-o-carboxylic acid, tricarballylic acid, 1,3-diamino-propanetetraacetic acid, Hydroxyethyl-iminodiacetic acid, ethylenediaminediacetic acid, ethylenediaminedipropionic acid, Hydroxyethyl-ethylenediaminetriacetic acid, ethylenediaminetetraacetic acid, ethylene glycol bis (ß-aminoethyl ether) -N, N'-tetraacetic acid, trans-cyclohexanediaminetetraacetic acid, diaminopropanol tetraacetic acid, diethylenetriaminepentaacetic acid, Ethylenediamine-di-o-hydroxyphenylacetic acid, triethylenetetraminehexaacetic acid, nitrilotriacetic acid, Nitrilotripropionic acid and the like. Examples of hydroxy acid compounds or acid compounds with a phenolic hydroxyl group are lactic acid, citric acid, isocitric acid, Malic acid, glyceric acid, tartaric acid, oxyacetic acid, dihydroxyethylglycine pantothenic acid, Panto acid, mevalonic acid, iduronic acid, saccharic acid, phenolpyruvic acid, 2-phosphorus glyceric acid, 3-phosphorus glyceric acid, glycero-3-phosphoric acid, glucose-l, 6-diphosphoric acid, Fructose-1,6-diphosphoric acid, & -oxybutyric acid, α-oxybutyric acid, gluconic acid, - Oxyi snbtj t t e rs; iu r e, Glucuronic acid, galacturonic acid, leucic acid, Oxyglutamic acid, diethooxalic acid, atrolactic acid, phenyllactic acid, naphthylglycolic acid, Benzilic acid, mandelic acid, salicylic acid, 2,5-dihydroxybenzoic acid, 2,3-dihydroxybenzoic acid, 2,6-dihydroxybenzoic acid, tetraoxyhexahydrobenzoic acid, shikimic acid, melilotic acid, Hexahydrosalicylic acid, o-, m-, p-phenolsulfonic acid, 1,2-hydroxybenzene-3,5-disulfonic acid, l-naphthol-2-sulfonic acid, l-naphthol-3,6-disulfonic acid, 4-aminophenol-2-sulfonic acid and the like .. Examples of carbonyl carboxylic acid compounds are glyoxalic acid, glyoxyl acetic acid, Acetoacetic acid; Oxaloacetic acid, d-ketobutyric acid, acetobyruvic acid, pyruvic acid, d-ketoglutaric acid, p-ketoglutaric acid, i-ketomalonic acid, d-ketovaleric acid, ß-ketovaleric acid, Benzoylformic acid, benzoylglycolic acid, benzoylpropionic acid, benzoylbutyric acid, Levulinic acid, ß-ketocapric acid, phenylpyruvic acid, oxanilic acid, and the like. Typical examples of monoacid compounds are butyric acid, isovaleric acid, Caproic acid, caprylic acid, capric acid, undecylic acid, lauric acid, myristic acid, Palmitic acid, stearic acid, eicosanoic acid, arachidonic acid, linoleic acid, linolenic acid, Phenylthioacetic acid, phenylpropionic acid, d-phenylbutyric acid, acetylsalicylic acid, Anisic acid, anisilic acid, phenylphosphoric acid, and the like. A compound with phenolic Hydroxyl groups can be, for example, salicylic acid, as mentioned above. Amino acid compounds can include amino acids such as quinaldic acids, kynurenic acid, glycine, alanine, Proline, hydroxyproline, phenylalanine, phenylglycine, tyrosine, cystine, cysteic acid, <-Aminocaproic acid, aspartic acid, glutamine, glutamic acid, leucin, isoleusin, Serine, valine, threonine, methionine, p-hydroxy phenylglycine, alginine, tryptophan, Hystidine, lysine, t-carboxyglutamic acid, kynurenine and the like. Furthermore, as organic compounds with at least two carbonyl groups are preferably used are enamine derivatives between amino acids (e.g. glycine, lysine, leucine, serine, Phenylalanine, glutamic acid, tyrosine, phenylglycine, p-hydroxyphenylglycine, proline, Hydroxyproline) and diketo compounds (for example Acetylacetone, Propionylacetone, Butyroylacetone, 3-Phenylacetylacetone, Methylacetoacetate, Ethylacetoacetate, Ethyl diacetoacetate, propylacetoacetate, methoxyethyl acetoacetate, ethoxyethyl acetoacetate, Ethoxymethylene malonic acid diethyl ester and dibutyl ester and the like.). Also can the aforementioned diketo compounds used per se as absorption promoters will. These absorption promoters are generally in the form of the alkali metal salts, such as the sodium salts, potassium salts or ammonium salts, but they can can also be esterified to such an extent that the water solubility is not is adversely affected. With some absorption enhancers, for example Polyacid compounds such as ethylenediaminetetraacetic acid (EDTA) or ethylene glycol bis (ß-amine ethyl ether) -N, N'-tetraacetic acid (EGTA), some of the acid groups can be protected by esterification or the like, so that they are converted into derivatives. In the case of EDTA in particular, a of the carboxyl groups in the ethyl ester are converted to a derivative with a better effect to promote the absorption of a drug or medicinal product to have.

Furthermore, as water-soluble macromolecular compounds with chelating activity for binding at least calcium ions or magnesium ions any water-soluble macromolecular compound with two or more chelating agents Ligands are used. Typical examples are water-soluble polysaccharide compounds, water-soluble cellulose derivatives, dextran derivatives, water-soluble starch derivatives, water-soluble synthetic polymers, water-soluble peptide compounds or their water soluble derivatives with two or more chelating ligands. These connections can also be esterified to such an extent that the chelating activity is not lost.

These compounds can be at least two of one or more Contain types of chelating ligands that are selected from the carboxylic acid groups, sulfonic acid groups, Phosphoric acid groups, phenolic hydroxyl groups, hydroxyl groups, Imino groups, Carbonyl groups and amino groups are selected. You can either of course occurring, semi-synthetic or synthetic products. Examples of this naturally occurring, semi-synthetic or synthetic water-soluble macromoleculars Compounds with chelating activity are listed below, however the present invention is not limited to these compounds.

Water-soluble polysaccharides containing uronic acid: alginic acid, pectic acid, Chondroitin sulfate, hyaluronic acid, arabinic acid; water-soluble cellulose relatives Compounds: carboxymethyl cellulose, carboxyethyl cellulose, carboxypropyl cellulose, Cellulose acetate phthalate; water-soluble starch-related compounds carboxymethyl starch, Carboxyethyl starch; Dextran-related compounds carboxymethyl dextran, dextran sulfate; Polypeptide compounds: polyglutamic acid, poly-gca rboxyg lu tarninsäu re, Polyaspartic acid, polylysine, polyalginine and copolymers of these amino acids; Water soluble synthetic polymers polyacrylic acid, polymethacrylic acid, methacrylic acid-acrylic acid copolymers, Acrylamide-acrylic acid copolymers, polyphosphoric acid Farther can use these compounds or water-soluble base polymers that are not detectable Show chelating activity with a chelating agent and low molecular weight associated with a chelating activity to convert them into water-soluble macromolecular To convert compounds with chelating activity as a whole.

In this case the base polymer can have any water solubility and are exemplified by synthetic polymers such as polyvinyl alcohol, Polyäthyienoxid and the like. Or by zatil rich naturally occurring polymers.

Preferably, a polymer that is harmless to the living body is used, and such a polymer may have functional groups in the side chain for the introduction of chelating groups, such as hydroxyl groups, carboxyl groups, Amino groups or imino groups.

The polymer has a molecular weight that is not particularly limited is, as long as it is soluble in water or able to form a hydrogel, but lies the molecular weight generally in the range from 1,000 to 1,000,000.

Typical examples of such water-soluble base polymers are below listed, but the present invention is not limited thereto.

Typical examples of water-soluble base polymers are polysaccharides Contains uronic acid: chondroitin sulfate, heparin, arabinic acid, pectin, tragacanth, Traganthic acid, pectic acid; other polysaccharides: carrageenan, ß-gulcan, galactomannan, Konj akamannan, galactan, fucan, inulin, levan; Cellulose-related Compounds hydroxyethyl cellulose, hydroxypropyl cellulose, cellulose, methyl cellulose, Ethyl cellulose, hydroxypropyl methyl cellulose, agarose; Starch-related compounds soluble starch, phosphoric acid starch, acetyl starch, hydroxyethyl starch, dextrin, Amylose, amylopectin; Dextran-related compounds dextran, diethylaminoethyldextran, Aminoethyldextran; Polypeptides gelatin, casein, albumin, globulin; Synthetic Polymers polyethylene glycol, polyvinyl alcohol, polyethylene oxide, vinyl acetate-maleic acid copolymer, Vinyl acetate-crotonic acid copolymer, vinyl acetate-acrylic acid copolymer, polyvinyl alcohol-maleic acid copolymer, Polyacrylamides, polyvinylactal diethylaminoacetate, 2-methyl-5-vinylpyridine / methyl acrylate / methacrylic acid copolymer.

As chelating agents that can be incorporated into these water-soluble base polymers Means one can use a compound with calcium ions or magnesium ions allows chelation and which are introduced into the polymer side chain can and still has chelating activity after introduction.

One can use a chelating agent that has a grouping of atoms having a ring containing ligands between central metal ions able to form. This chelating Agent can be in the polymer side chain introduced and coordinated with two or more molecules per metal ion.

In particular, the chelating agent can be a compound which contains three types of ligands or functional groups.

namely a ligand (I) having a proton as a chelating functional Group that is substituted by this metal ion (for example, a hydroxyl group, Carboxyl group, imino group and the like), a ligand (II) having a coordinative Able to form a compound with the metal ion, e.g. 8. the carbonyl group, amino group and the like) and a functional group (III) for chelating to the polymer side chain by forming bonds such as an amide bond, ester bond or ether bond by reaction of the side chains of the aforementioned polymers (e.g. the amino group, Carboxyl group, hydroxyl group, halogen and the like). The chelating agent has such a structure that the chelating ligands (I) and / II) through a bond with one or two basic atoms are separated or that the ligands (I) and (II) are separated by the ligand (III) that binds to a Polymer by an organic radical with 1 to 10 carbon atoms, such as an aliphatic or an aromatic radical.

Typical examples of such compounds are given below, however, the present invention is not limited thereto.

Aliphatic polycarboxylic acid compounds: oxa] -, malon, amber, Maleic, fumaric, aconitic, pimellic, sebacic, allylmalonic, ethylmalonic acid; Aliphatic Oxycarboxylic acid compounds citric, malic, glyceric, tartaric, mevalonic, oxyglutaric acid; Aliphatic keto-polycarboxylic acid compounds: oxaloacetic acid, 6-keto-glutaric acid, β-ketoglutaric acid, C -ketomalonic acid; Uronic acid compounds: glucuronic, Galacturonic, mannuronic acid; Amino acid compounds: aspartic acid, glutamic acid, Glycine, alanine, lysine, hystidine, alginine, cysteine, ε-aminocaproic acid, phenylalanine, Phenylglycine, p-hydroxyphenylglycine, p-aminophenylalanine, t-carboxyglutamic acid; Aminopolycarboxylic acid compounds iminodiacetic acid, hydroxyethyliminodiacetic acid, Ethylenediaminediacetic acid, ethylenediaminetetraacetic acid, trans-cyelohexanediamine tetraacetic acid, Diethylenediaminepentaacetic acid, ß-alaninediacetic acid, diaminopimellic acid; Aromatic Carboxylic acid compounds phthalic acid, terephthalic acid, homophthalic acid, phenylsuccinic acid, Phenylmalonic acid, oxanilic acid-ocarboxylic acid, anthralininoacetic acid, 2,4-dihydroxybenzoic acid, p-aminosalicylic acid, phthalylglutamic acid, kynurenine; Aliphatic and aromatic Sulfonic acid compounds 1,2-hydroxybenzene-3,5-disulfonic acid, 4-aminophenol-2-sulfonic acid, Cysteic acid; Phosphoric acid compounds: 2-phosphoglyceric acid, glycero-3-phosphoric acid, Glucose-1,6-diphosphoric acid, fructose-1,6-di-phosphoric acid.

To incorporate such a chelating agent into a water-soluble one Base polymer will be the chelating agent and incorporation methods to be used expediently depending on the side chains of the water-soluble one used Base polymer selected. The bond formed as a result of implementation is also determined by their combination, as detailed in JA-OS No. 16979/1979 or in US Pat. No. 4,024,073.

The effect of the promoting absorption of a drug or medicinal product by means of a water-soluble macromolecular compound with chelating activity, obtained according to the present invention is made using, for example of an Elcitonin preparation with a content of Lysir-dextran T 150, which according to Example 1 of the aforementioned JA-OS No. 16979/1979 and US-PS 4024073, respectively by intrarectal 1 nj ec tion in rats in vivo and measuring the decrease the calcium concentration in the serum is checked.

It has been found that this preparation has a significant absorption-promoting effect in comparison with the control experiment without use of lysine-dextran T-150 shows. This macrcmolecular adsorption becomes generally in the alkali metal salts formed, such as sodium salts or potassium salts or Ammonium salts are used.

The water-soluble low molecular compound and the macromolecular Compound having chelating activity or the water-soluble polymer with a incorporated chelating agents of the present invention is used as a membrane absorption promoter used. These absorption promoters can be used in quantities of 0.05 wt. generally in the range from 0.1 to 50% by weight, preferably 1.0 to 30% by weight, ° Ó, be applied. As a vehicle used in the manufacture of a suppository containing on the above-mentioned absorption promoter, a medicament or remedy and preferably a water-soluble salt added to increase the tonicity one can conveniently choose from the oily vehicles and water-soluble vehicles choose commonly used in the manufacture of suppositories or rectals Injections are used. Optionally, you can also use a surface-active Use connection. Of course, two or more absorption conveyors can also be used use together.

Oily Vhicel or as a water-soluble vehicle can expediently use such as those described in "The Theory and Practice of Industrial Pharmacy," pages 245-269 (1976).

The drugs or remedies made according to the present invention are not particularly limited, but common pharmaceuticals, so-called water-soluble medicaments are particularly preferably used which are excellently soluble in water, like water-soluble drugs with a Partition coefficient of 50 or less in chloroform / water or pharmaceuticals, which easily dissociate into ions. For example, numerous drugs can be included like hypnotics, sedatives, antiepileptics, antipyretics, analgesics, Antidepressants, muscle relaxants, anti-inflammatory agents, antiallergics, immunosuppressants, Anti-inflammatory drugs, vasidilators, anti-hemorrhagic drugs, antihyposensives, antibiotics, antibacterial drugs Agents, urinary tract sterilants, anti-tumor agents, vitamins, hormones and galenic remedies.

in particular, typical examples are antibiotics of the penicillin type, such as ampicillin, hetacillin, amoxicillin, cyclacillin, cloxacillin, dicloxacillin, Oxacillin, Carindacillin, Sulbenicillin, Piperacillin, Apalcillin, Methicillin, etc. or combination preparations of ampicillin or amoxicillin with oxacillin, cloxacillin, Floxacillin or dichloxacillin; also antibiotics of the cephalosporin type such as cephalothin, Cephazolin, Cephaloridin, Cephacetoril, Cefoxitin, Cefadroxil, Cefatrizine, Cephaloglycine, Cephalexin, Cephapirin, Cephaclor, Ceftezol, Cefuroxime, Cefsulodin, Cefmetazol etc., as well as their non-toxic salts, such as the alkali metal salts (for example sodium salts or potassium salts), ammonium salts or benzylamine salts. Also to be mentioned Tetracycline type antibiotics such as doxycycline, oxycycline and the like; of other antibiotics of the aminosaccharide type, such as kanamycin, sisomicin, amikacin, Tobramycin, netromycin, gentamycin and the like; in addition antibiotics from Peptide type, such as tuberactinomycin N, actinomycin and so on or their non-toxic salts; also peptide hormones such as insulin, somatostatin, calcitonin, Angiotensin, kallikrein, secretin, gastrisin, parathyroid hormones and the like; and finally other drugs such as barbital, theophylline, aspirin, mizoribine, Bredinin, 5-fluoro-uracil, methotrexate, L-dopa and the like. The drug resp. Medicines can be used in an amount appropriately selected and can be designated. For example in the case of antibiotics, such as ß-lactam antibiotics, can contain 20 to 500 mg of active substance, generally 100 to 300 mg of active substance or in the case of peptide hormones such as insulin, 1 to 500 units per gram des Be included in the preparation. In general, the drug may be preferred in finely divided form with a diameter of 1 to 50 µm or as an aqueous solution be used.

The step for the formation of the preparations can be carried out according to conventional methods Manufacture of general preparations such as rectal, urethral or vaginal suppository bases or creams. For example, the selected absorption conveyor, a water-soluble substance in an amount that has a higher osmotic pressure as an isotonic sodium chloride solution, and a medicament or remedy to a vehicle, possibly in combination with a surface-active compound, are added and these ingredients are thoroughly mixed together to form of the preparations.

Furthermore, preservatives, such as methyl p-oxybenzoate or propyl ester, colorings, flavorings and Stabilizers are also added. The following examples illustrate the invention.

Example 1.

There will be the absorption effects under conditions with different Checked tonicities. Each sample solution is prepared by adding 0.1% by weight Cefmetazole sodium as a medicinal product together with sodium oxalate or sodium glyoxalate as an absorption promoter to a phosphate buffer of pH 7.0, which with Sodium chloride has been adjusted to a tonicity) that of isotonic to twice, three times, five times, six times and seven times hypertonic than isotonic (double tonicity, triple tonicity, fivefold tonicity, sixfold tonicity or seven times the tonicity) is varied.

This experiment is carried out in the following manner. It will male Sprague Dawleg rats weighing 200 to 300 grams with 50 mg / kg pentobarbital anesthetized (for 20 hours safely after the procedure). Then the Rats make a lower abdominal incision for the first cannula about 1.5 cm from the anus and 5 cm above it for a second cannula. Then the rectum Washed internally with about 50 ml of isotonic sodium chloride solution kept at 380C. 10 ml / samples are allowed to circulate through the rectum for 5 minutes (2 ml / minute), to make the concentration in the system constant. After that, 5 ml each Sample circulated therein at a flow rate of 2 ml / minute. Samples of are calculated at intervals of 10 minutes from the beginning 0.05 ml removed. Each sample is diluted with 5 ml of distilled water, and the The amount of the drug that has disappeared by absorption is measured by means of a UV spectrophotometer certainly.

The result is the decrease curve of cefmetazole sodium below the condition of 0.1 wt .- ° Ó sodium oxalate according to FIG. 1, in which the curve x - x the result under the isotonic condition, the curve h - b under twofold Tonicity, the curve A, -, S, under triple tonicity, the curve O - O-under five times the tonicity, the curve - below six times the tonicity and the curve q below shows sevenfold tonicity.

FiguI 2 also shows the absorption group of cefmetazole sodium under the aforementioned conditions of 0.1 wt. sodium oxalate against the osmotic Press.

Figure 3 shows the absorption curve of cefmetazole sodium under the Condition of 0.2% by weight of sodium oxalate against the osmotic pressures.

Furthermore, FIG. 4 shows the absorption curve of cefmetazole.

Sodium under the condition of 0.5 wt% sodium glyoxalate versus the osmotic pressures.

Example 2.

Using 0.1% by weight of Cefoxitin-Na as a drug and 0.5% by weight of sodium glyoxalate as an absorption promoter under appropriate osmotic pressure conditions (namely, two-fold, four-fold and six-fold Toni zi activities using sodium chloride) are performed according to the same procedure as in Example 1 the amounts of cefoxitin which have disappeared due to absorption are the same Way as determined in Example 1 using a UV spectrophotometer.

The results are given in Figure 5, in which the curve x ---- x the shrinkage curve due to the absorption of only cefoxitin under isotonic conditions without the use of sodium glyoxalate, the curve x - x the shrinkage curve of Ce fo xi t in using sodium glycolate under isotonic conditions that Curve - those under the dual tonic condition, the curve o - o the one under fourfold tonic condition and curve # - 0 that under sixfold tonic condition.

Example 3.

The quantities of 0.5 wt. ° Ó cefmetazole sodium that are produced by Absorption under isotonic and triple isotonic conditions disappears, determined using the sodium salts of malic acid, pyruvic acid, phosphenolpyruvic acid, 8-hydroxybutyric acid, the ß-hydroxyglutaric acid, and the 2-phospho-D-glyceric acid. The results are given in Table 1 below.

Table 1 (values after 60 minutes) sodium salts of the isotonic triple Condition condition condition malic acid 4.9% 10.2% pyruvic acid 5, 10.9 phosphenolpyruvic acid 7.3% 16.6% ß-oxybutyric acid 6.6% 14.0% ß-oxyglutaric acid 7.8% 16.5% 2-phospho-D-glyceric acid 5.4% 13.8% If no absorption enhancer is used, the amount is 0.1% by weight of cefmetazole sodium, which is obtained by absorption under isotonic conditions disappears, practically negligible.

Example 4 ..

Be using a 0.01% solution of Tuberact i nomycin the rectal circulation tests were carried out in the same manner as in Example 1. The tuberactinomycin concentrations in the perfusion solutions is measured by measuring the antimicrobial activities (according to the Japanese antimicrobial standard) determined over time. As a result, it is found that the absorptions through the rectum and the presence of ED tA disodium salt and sodium chloride can be increased, as can be seen from FIG.

Sample A (comparative): 0.01 tuberactinomycin 0.9% sodium chloride sample B (comparison): 0.01% tuberactinomycin 5% sodium chloride Sample C (Invention): 0.01 tuberactinomycin 5% sodium chloride 0.05 EDTA disodium salt sample D (invention): 0.01 tuberactinomycin 5% sodium chloride 0.1% EDTA disodium salt Sample E (Invention): 0.01 tuberactinomycin 5% sodium chloride 1% EDTA disodium salt (Each sample is dissolved in 0.1 molar Tris-HCl buffer solution, whose pH value is 7.5 is set).

Example 5.

Using a 1% solution of tuberactinomycin (ir 0.1 molar Tris-HCl buffer solution of pH 7.5) as a comparison, an injection medium is used Addition of 5% sodium chloride and 1.0% EDTA disodium salt to the solution. In each case 0.5 ml of these samples are injected into rats through the anus.

The concentration of tuberactinomycin in the blood is measured and it the drug was found to work at the concentrations given below disappears in the blood.

Concentration in blood. (Y / ml) 10 min. 20 min. 30 min. 45 min. 60 min. 90 min.

Comparison: - lower than the measurable limit of microbial activity Invention: 5γ 10γ 11γ 8γ 7γ 2γ Example 6.

Using a 2% solution of cephalotin.sodium (in 0.1 molar Tris-HCl buffer solution of pH 8.0) as a comparison, an injection medium is used Addition of 6% sodium chloride and 1.0% of the disodium salt of EDTA monoethylate prepared for solution. In each case 0.5 ml of these samples are in rats by the After injecting, and the levels of cephalothin in the blood are measured by the antimicrobial activity (according to the Japanese antimicrobial standard) certainly. You find that the concentration in the blood is remarkable increase.

Concentration in blood (y / ml) 10 min. 20 min. 30 min 45 min. 60 min. 90 min.

Comparison: - # <1γ siy - -invention: 8γ 12γ 14γ 5γ 3γ example 7.

Using a 0.04% solution of theophylline (in 0.1 molar Tris-HCl buffer solution from pH 8.0) the concentrations of the circulating liquids are determined by UV absorption (max = 270 nm) measured over time in the same way as in Example 1. It will found that absorption through the rectum was due to the presence of EDTA disodium salt and sodium chloride is increased as shown in FIG.

A (comparison): 0.04% theophylline, 0.9% sodium chloride B (comparison): 0.04% theophylline, 0.1% EDTA disodium salt, 0.8% sodium chloride C (invention): 0.04 ° Ó theophylline, 0.1% EDTA disodium salt, 2% sodium chloride D (invention): 0.04% theophylline, 0.1% EDTA disodium salt, 4% sodium chloride E (invention): 0.04 % Theophylline, 0.1% EDTA disodium salt, 8% sodium chloride F (invention): 0.04, ° Ó Theophylline, 1.0% EDTA disodium salt 4% sodium chloride G (invention): 0.04% theophylline, 4.0% EDTA disodium salt 4% sodium chloride (Each sample is in 0.1 molar Tris-HCl buffer solution dissolved, the pH of which is adjusted to 8.0 each time.) Example 8.

An intrarectal injection preparation is obtained by adding calcitonin (CT: 625 mu / ml, based on the total amount; 25 ng / 0.2 ml), sodium oxalate (0.2 wt .-, ° Ó, based on the total amount) and glucose (isotonic = 0.25 molar; triple-tonic = 0.75 molar; six-tonic = 1.5 molar) to a base of a carboxyvinyl polymers (CVP: "Wako Gel 105" by Wako Junyaku Co., Ltd.). 0.2 ml of this preparation are injected into 4 week old SD rats. After an hour, the calcium concentration will be measured. It shows the relative effects compared to the calcium concentration evaluated by CVP and C1, which are set equal to 1 as standard values. The results are given in Table 2 below.

Table 2 Drugs isotonic 3-fold tonic 6-fold tonic CT 1 1.05 1.67 CT + sodium oxalate 5.4 6.9 10.9 Example 9.

Soppositories of the summaries below become six male Beagles weighing 9.5 to 10.5 kg are introduced through the anus. The concentrations in the blood after 15 minutes, 30 minutes, 60 minutes, 120 minutes and Measured 180 minutes after administration. The results obtained are in the Table 3 given.

Comparison: suppository containing 100 mg of activity of the Sulphate of Tuberactinomycin N that has been pulverized to 50 ptm or below is, and 400 mg of cocoa butter; Invention: suppository with a content of 100 mg Activity of the sulfate of tuberactinomycin N, 50 mg sodium chloride, 10 mg EDTA disodium salt and 180 mg of cocoa butter.

Table 3 Beagle No. Concentration in blood (g / ml) 15 min. 30 min. 60 min. 120 min. 180 min.

Comparison 1 - 0.8 0 - -2 1.0 2.3 1.3 - -3 - 1.5 - - - 15th min. 30 min. 60 min. 120 min. 180 min.

4 - 0.9 0.7 - -5 -6 - - - - -Invention 1 3.9 12.0 7.6 4.2 2.2 2 9.7 11.7 5.4 3.5 2.7 3 9.2 10.0 8.1 4.8 3.0 4 5.6 7.7 7.4 3.2 1.9 5 10.8 9, 2 7.3 6.0 2.0 6 6.9 11.4 9.3 7.7 4.4 Example 10.

As a group of aliphatic polycarboxylic acids are used sodium oxalate, Malonic acid, maleic acid, fumaric acid, adipic acid, glutaric acid, pimellic acid, EDTA disodium salt, trans-cyclohexane-diamine-tetraacetic acid (CyDTA), iminodiacetic acid, nitrilotriacetic acid, Ethylmalonic acid, trans-aconitic acid, diaminopropanol tetraacetic acid (DTPA-OH) respectively in a concentration of 0.1% by weight per volume. There will be the amounts of by Absorption of cephalothin disappeared one hour after administration of 0.1% by weight / volume Cephalothin sodium among isotonic (X 1), doubly tonic (X 2) and quadruple tonic conditions (X 4) determined. The trials are done in the same way as carried out in Example 1, i.e. H. male Wistar rats weighing 250 to 300 g are anesthetized with 50 mg / kg pentobarbital. Then one lays for them first cannula an abdominal incision about 1.5 cm from the anus and for a second Cannula 5 cm above the first cannula. Then the rectum with about 20 ml of an isotonic sodium chloride solution kept at 380C. Every Sample will circulate for 5 minutes at a flow rate of 2 ml / minute relaxed in order to keep the concentration in the system constant. Then one leaves each Circulate 6 ml of each sample at a flow rate of 2 ml / minute. in the Samples of 9.05 ml each are collected every 10 minutes. Every sample will diluted. The amount of disappeared cephalothin is measured using a UV spectrophotometer or high speed liquid chromatography.

The results of the disappeared cephalontin when collecting the samples and after 1 hour are given in Table 4 below.

Table 4 aliphatic polycarbonate osmotic pressure acids X 1 X 2 X 4 none 1.2% 1.6% 3.1% sodium oxalate 6.6% 11.1% 18.3% malonic acid 4.5% 13.0% succinic acid 8.2% 13.1% 24.0% maleic acid 6.3% 10.6% 18.3% fumaric acid 5.5% - 17.3% adipic acid 7.5% 11.2% 20.0% glutaric acid 5.7% 9.3% 15.2% pimellic acid 5.1% 7.8% 15.0% EDTA.2NA 9.4% 17.1% 31.2% CydTA 8.1% 15.0% 32.3% iminodiacetic acid 7.1% 14.2% 17.0% nitrilotriacetic acid 4.4% -10.4% DTPA-OH 7.5% 13.7% 21.6 % trans-aconitic acid 10.5% 18.6% 27.8% ethylmalonic acid 12.3% 24.2% 36.9% Example 11.

The group of aliphatic keto-carboxylic acids used is the Sodium salts of gyloxalic acid, pyruvic acid, ketomalonic acid, i-ketoglutaric acid and oxaloacetic acid, such as the acids -ketobutyric acid, i-ketovaleric acid and a levulinic acid each in a concentration of 0.1% by weight by volume.

The amounts of cephalothin disappeared by absorption become one Hour after the administration of 0.1 wt. ° a / volume of cephalothin sodium under isotonic (X 1), doubly tonic X 2) and quadruple lonic conditions (X 4) determined. The results are given in Table 5 (the determination method was the same as Example 10, and the units in the table are percentages).

Table 5 Aliphatic keto-osmotic pressure carboxylic acids X 1 X 2 X 4 sodium glyoxalate 4.9-13.1 sodium salt of pyruvic acid 7.0 11.6 23.1 Sodium salt of ketomalonic acid 8.4 12.7 19.6% kotonic glutaric acid 7.1 - 25.6 sodium salt of oxaloacetic acid 13.8 17.5 22.2 α-ketone butyric acid 11.2 18.3 30.9 s-ketovaleranic acid 9.8 14.7 23.2 Lavulinic acid 11.9 21.1 34.3 none 1.2 1.6 3.1 Example 12.

Using citric acid, malic acid, lactic acid, glucuronic acid and galacturonic acid as a group of aliphatic hydroxycarboxylic acids in each case a concentration of 0.1 wt .-% / volume, the amounts of by absorption disappeared cephalothin one hour after administration of 0.1% by weight / volume Cephalothin sodium among isotonic (X 1), doubly tonic (X 2) and quadruple tonic (X 4) conditions. The results are given in Table 6 (the test method was the same as in Example 10, and the units in the table are percentages).

Table 6 aliphatic hydroxycarbo osmotic pressure acids X 1 X 2 X 4 Citric Acid 4, 5 11, 3 Malic Acid 7.2 12.3 18.8 Lactic Acid 4.3 - 13.5 Glucuronic acid 5.5 11.1 16.4 Xl X 2 X 4 galactouronic acid 5.8 10.5 16.1 none 1.2 1.6 X, l Example 13.

Using sodium salicylate, sodium sulfosalicylate.

Sodium phthalate and 2,6-dihydroxybenzoic acid as aromatic carboxylic acids in each case in a concentration of 0.5 wt. to / volume, the amounts of Absorption disappeared cephalothin one hour after the administration of 0.1 Wt .-, ° 0 / volume cephalothin. Sodium under isotonic (X 1), doubly tonic (X 2) and quadruple tonic (X 4) conditions determined.

The results are given in Table 7 (the investigation method was the same as Example 10, and the units in the table are percentages).

Table 7 aromatic carboxylic acids osmotic pressure X 1 X 2 X 4 Sodium salicylate 8.9 16.5 29.8 Sodium sulfosalicylate 10.4 - 19.7 sodium phthalate 7.1-18.9 2,6-Dihydroxybenzoic acid 9.5 15.3 22.9 Example 14.

There are 1,2-dihydroxybenzene-3,5-disulfonic acid as a group of aromatic sulfonic acids (DHBDS) and l-naphthol-3,6-disulfonic acid (NDS) each in a concentration of 0.1 wt% u / volume used. The experiments are carried out in the same way as in example 10 carried out. The results are given in Table 8 below, in which the units mean percentages.

Table 8 aromatic sulfonic acids osmotic pressure Xl X 2 X 4 DHRDS 9.8-22.0 12.6 19.8 31.6 Example 15.

Example 1 is repeated with the proviso that butyric acid, isovaleric acid and the sodium salts of caproic acid, caprylic acid, capric acid and lauric acid as aliphatic carboxylic acids each in a concentration of 0.1 wt. -%/Volume used.

The results obtained are given in Table 9 below, in which the units are percentages.

Table 9 fatty acids osmotic pressure X1 X 2 X 4 butyric acid 9.9 17.1 21.0 Isovaleric acid 7.7-14.4 Sodium salt of caproic acid 10.4 14.7 17.2 Sodium salt of caprylic acid 5.8-13.0 sodium salt of capric acid 5.2-8.6 sodium salt of lauric acid 3.9 - 6.5 Example 16.

Example 10 is repeated with the proviso that the aliphatic Carboxylic acids through ethyl acetoacetate and 3-phenylacetylacetone as diketo compounds be replaced. The results obtained are shown in Table 10 in which the units represent percentages.

Table 10 Diketo compounds, osmotic pressure X 1 X 2 X 4, ethyl acetoacetate 14.6 20.2 26.7 3-phenylacetylacetone 9.1 16.3 22.2 Example 17.

Example 10 is repeated with the proviso that the aliphatic Carboxylic acids through the following group of aminocarboxylic acids or iminocarboxylic acids, namely DL-glycine, DL-hydroxyproline (each 0.5 wt% / volume), DL-phenylalanine.

DL-phenylglycine, N-phenylglycine, DL-aspartic acid, Dl-glutamic acid, & -Methyl-DL-glutamate, DL-cysteic acid, £ -aminocaproic acid, N-dimethylphenylalanine, -Carboxyglutamic acid, glycyl-DL-aminobutyric acid and glycyl-DL-aspartic acid (respectively 0.1% by weight / volume). The results are in the table below 11, in which the units represent percentages.

Table 11 Amino-carboxylic acids and osmotic pressure of iminocarboxylic acids X 1 X 2 X 4 DL-Glycine 6.9 9.4 14.0 DL-Hydroxyproline 5.5-12.9 DL-Phenylalanine 6.6 15.6 DL-phenylglycine 11.5 19.8 29.3 N-phenylglycine 12.0 22.3 30.8 DL-aspartic acid 11.6 15.6 22.4 DL-glutamic acid 12.1-22.3 α-methyl-DL-glutamate 11.9-21.4 DL-cysteic acid 5.3 9.0 14.6 i-aminocaproic acid 7.1 11.8 17.0 N-dimethylphenylalanine 10.9-25.5 8-carboxyglutamic acid 13.1 24.6 31.4 glycyl-DL-aminobutyric acid 11.0 30.4 Glycyl-DL-aspartic acid 8.6-19.0 Example 18.

Example 10 is repeated with the proviso that other acids Glycero-3-phosphoric acid, fructose-1,6-diphosphoric acid and ethylene diamine tetrakis (methylene phosphoric acid) (EDTPO) in each case in a concentration of 0.1% by weight / volume instead of that in example 10 mentioned aliphatic carboxylic acids can be used.

The results are given in Table 12, in which the unit Represent percentages.

Table 12 Acid Osmotic Pressure X1 X 2 X 4 Glycero-3-phosphoric acid 4.0-11.5 fructose-1,6-diphosphoric acid 4.1 7.5 13.3 EDTPO 7.6-20.0 Example 19.

The sodium salt of cephaiothin (1 y effectiveness) as a medicinal product, 1 g of the sodium salt of d-ketoglutaric acid as an absorption promoter and 500 mg of sodium chloride as Hypertonicum is pulverized in each case and then mixed together. To the mixture obtained is a base of "Witepsol H-15", which was previously melted has been added up to a total amount of 10 g and a homogeneous dispersion from it manufactured. The dispersion is used at a dose of 50 mg / kg male Wistar rats weighing 250 to 300 g (4 animals per group) administered intrarectally. Then will 15 minutes, 30 minutes, 60 minutes, 120 minutes after the administration of blood samples taken to measure the cephalothin concentration in the serum according to the bio-analysis using Bacillus subtilis ATCC'6633. A Preparation containing sodium chloride without the use of the absorption promoter (Comparison 1) and a preparation containing the absorption enhancer without Using sodium chloride (comparison 2) obtained. Another will continue Preparation according to the present invention. Invention using 1 g of C-ketobutyric acid made instead of the aforementioned absorption conveyor and in the same Way examined as described above.

The cephalothin concentrations for the corresponding preparations are given in their results in Table 1 3 below.

Table 13 Preparation concentration in blood (t / ml) 15 min. 30 min. 60 min. 120 min.

Comparison 1 (NaCl) 0.2 0.5 - Comparison 2 (sodium salt of the α-ketoglutar 2.1 5.3 1.2 acid Invention sodium salt of <-ketoglutaric acid / NaCl 5.9 11.4 3.1 1.2 Invention (* -ketobutyric acid / NaCl) 7.9 13.0 4.5 1.4 Example 20.

Tuberactinomycin N sulfate (1 g effectiveness) as a medicinal product, 1 g of D-phenylglycine as an absorption promoter and 500 mg of sodium chloride as a hypertonicum are each pulverized individually and then thoroughly mixed together. to the mixture obtained is "Witepsol H-15", previously melted by heating has been added and a homogeneous dispersion is produced from the mixture obtained, to obtain a suppository mass for intrarectal administration. The procedure of Example 19 is repeated with the proviso that instead of D-phenylglycine 1 g of L-aspartic acid is used to make suppositories for intrarectal administration to obtain. For comparison, a preparation with the same composition as previously stated, made with the measure that no absorption promoter included is. Each of these preparations is given to rats, and then the Concentrations in blood were measured in the same manner as in Example 19. The received Results are given in Table 14.

Table 14 Preparation concentration in blood (γ / ml) 15 min. 30 min. 60 min. 120 min.

Comparison (NaCl) 0.9 1.8 0.3 Invention (D-phenylglycine / NaCl) 13.1 10.7 3.5 1.3 Invention (L-Aspartic Acid / NaCl) 8.4 10.3 2.8 0.9 Example 21.

Ten units of elcitonin (Asul 7-eel calcitonin) as a medicine, 20 mg of powdered EDTA.2Na as an absorption enhancer and 50 mg of powdered sodium chloride as Hypertonicum are dissolved in 5% gelatin solution to an amount of 1 g. The solution is then given to four-week-old rats each in an amount of 0.1 ml administered intrarectally. 15 minutes, 30 minutes, 60 minutes and 90 minutes after of administration, the calcium concentrations are determined according to the atomic absorption spec t roscopy measured. The same experiment is repeated with the proviso that instead of of EDTA-2Na 20 mg CyDTA can be used. A preparation is also used as a comparison manufactured without using the absorption conveyor and following the same process examined. The results are illustrated in FIG. 8, in which the curve e - X the calcium concentrations in the serum in the case of the preparation with a content on EDTA.2Na as an absorption promoter according to the invention, the curve d - the calcium concentrations in the serum in the case of the preparation containing CyDTA according to the present invention and also the curve o - o the calcium concentration in the serum in the case of the comparative preparation without showing an absorption promoter.

Example 22.

Add to a solution with a content of 0.1% by weight Cephalothin.Na 0.1% by weight of pectic acid and also mannitol in different amounts to an isotonic solution, a two-fold tonic solution, and a four-fold tonic solution Solution.

For comparison, an isotonic solution without the use of pectic acid is used manufactured. These samples are then used in Wistar rats in the same manner as described in Example 10 administered. The amount of by absorption is measured versr. sore Cepha 1 o t ti iris The results are shown in Figure 9, in which the curve - - # the shrinkage curve of cephalothin in the case of the comparison without Use of pectic acid, the curve a - n the - shrinkage curve in the case of isotonic Solution using pectic acid, the curve - a that of a twofold tonic solution using pectic acid and the curve # -that of the View quadruple tonic solution using pectic acid.

As can be seen from Figure 9, the use of pectic acid improves the absorption of cephalothin in a remarkable way. Another improvement is made by using in a combination pectic acid in hypertonic conditions achieved.

Example 23.

Instead of pectic acid in Example 22 above, sodium alginate, Sodium carboxymethyl cellulose, sodium polyacrylate, chondroitin sulfate, the sodium salt of polyaspartic acid and the sodium salt of polyglutamic acid in one concentration of 0.1% by weight each are used. This solution is made up by means of sodium chloride different tonicities set, namely one isotonic (X 1), one twofold tonic (X 2) and a quadruple tonic (X 4) solution.

The results showing the amounts of disappeared cephalothin 60 Minutes after circulation are shown in Table 15.

Table 15 Absorption promoters osmotic pressure X1 X 2 X 4 sodium alginate 6.3% 10.2% 22.4% sodium carboxymethyl cellulose 7.1% 10.2% 18.7% sodium polyacrylate 6.7% - 14.6% chondroitin sulfate 4.0% 6.7% 11.5% sodium polyaspartate 8.4% 11.5% 20.4% sodium polyglutamate 7.9% 15.0% 33.6% none 1.2% 1.6% 3.1% example 24.

Using absorption conveyors, which are after the further below described preparation examples have been obtained, namely of aspartic acid-carboxymethyl cellulose, Iminodiacetic acid-alginic acid, iminodiacetic acid-carboxymethyl starch, glycine starch, Glycine polyacrylic acid, ethylenediaminetetraacetic acid dextran and hydrochelidonic acid albumin, samples are obtained from preparations whose tonicity is isotonic (X 1), twofold tonic (X 2) and quadruple tonic (X 4). For each sample, in the amount of cephalothin which has disappeared is determined in the same way as in Example 10. The results that the amounts of disappeared cephalothin 60 minutes after Circulation are given in Table 16.

Table 16 Absorption promoter osmotic pressure X 1 X 2 X 4 Aspartic acid-carboxymethyl- 7.0% 10.4% 22.6% cellulose iminodiacetic acid-alginic acid 7.2% 10.5% 24.6% iminodiacetic acid-carboxymethyl starch 5.2% 9.8% 18.8% glycine starch 5.1% 8.8% 11.9% glycine polyacrylic acid 6.9% 10.1% 17.0% Xl X 2 X 4 ethylenediaminetetraacetic acid- 5.8% 9.2 % 16.7 Dextran Hydrochelidonic Acid Albumin 4.2% - 9.5 ° o Example 25.

One time 100 units and the other 10 units of elcitonin (Asu 1.7 -eel calcitonin), 50 mg sodium alginate and 50 mg sodium chloride are added in 1 ml of distilled water dissolved.

0.1 ml of each solution is given to four week old SD male rats administered intrarectally. The calcium concentrations in the serum are 30 minutes, 60 minutes and 90 minutes after administration by atomic absorption spectroscopy measured. For comparison, a solution containing no sodium alginate ( to 100 units of elcitonin). Furthermore, a similar experiment is presented below Use of 50 mg of pectic acid instead of sodium alginate was carried out.

The results can be seen from Figure 10, in which the curve x ---- x the calcium concentrations in serum in the case of the comparative example, the curve o - o those in the case of a solution containing sodium alginate and sodium chloride to 100 units of elcitonin, the curve - A those in the case of a solution with a content of pectic acid and sodium chloride per 100 units of elcitonin, the Curve e - e those in the case of a solution containing sodium alginate and sodium chloride to 10 units of elcitonin and the curve # - # those im Case of a solution containing pectic acid and sodium chloride to 10 units Show Elcitonin.

Example 26.

Using Ampicillin.Na (20 g effectiveness) as a medicine, 0.5 g sodium oxalate as an absorption enhancer and 4 g sodium chloride as water-soluble Substance For higher tonic conditions - with all ingredients powdered present - becomes a homogeneous dispersion by adding these ingredients to a Base produced from 50 9 peanut oil. Dir-; e Are dispersions diluted with peanut oil to a total of 100 g. The preparation is then in 1 g aliquots filled into soft gelatin capsules.

Example 27.

of 20 g of the sulfate tuberactinomycin N, 3 g of sodium chloride as water-soluble Substance for hypertonic conditions and 0.2 g of sodium oxalate as absorption Conveyors - each of the substances being pulverized - become an oily one Base of peanut oil added to a total of 100 g to rectal capsules to obtain.

Example 25.

For the production of suppositories of 1 g each, Cefazolin.Na (200 g activity), 50 g D-phenylglycine and 50 g sodium chloride each powdered and mixed together.

The resulting mixture becomes "Witepsol" melted by heating W-35 "is added up to a weight of 1 kg. A homogeneous dispersion is obtained. The dispersion is then compressed into suppositories.

Example 29.

For the preparation of suppositories of 1 g each, Ampicillin.Na (250 g activity), 200 9 D-phenylglycine and 50 g sodium chloride, each in powdered form Shape, mixed. The mixture obtained is made with "Witepsol. Melted by heating." H-15 "mixed up to an amount of 1 kg. The total mixture is dispersed homogeneously. The dispersion is pressed into suppository containers.

Example 30.

Finely powdered ampicillin 3H20 (250 g activity), 100 g i-ketobutyric acid and 50 g of finely powdered sodium chloride are mixed together. The received Mixture is made with "Witepsol W-35" melted by heating up to an amount of 1 kg is mixed and then dispersed homogeneously. The dispersion will pressed in suppository containers to form suppositories of 1 g each.

Example 31.

Finely powdered Cephalothin # Na (250 g effectiveness), 100 g ethyl acetate and 50 g of finely powdered sodium chloride up to an amount of 1 kg with Sesamril mixed.

to form a homogeneous dispersion. The dispersion is in appropriate Portions of 2 g each filled into plastic-based injection cylinders for intrarectal use To obtain injectables.

Example 32.

Tuberactinomycin N sulphate (500 g potency), 100 g oxaloacetic acid and 50 g of sodium chloride are each pulverized and mixed together. That Mixture is made with "Witepsol H-5" melted by heating up to an amount of 1 kg mixed and dispersed homogeneously. The dispersion is placed in suppository containers pressed to obtain suppositories of 2.5 g each. Example 33.

One hundred thousand units of elcitonin, 20 g of finely powdered CyDTA and 50 g of finely powdered sodium chloride are melted with heating "Witepsol H-15" added to an amount of 1 kg. The resulting mixture is aliquoted 1 g portions in suppository containers for making suppositories pressed by 1 g each.

Example 34.

One hundred thousand units of elcitonin, 30 g of finely powdered sodium salt the phenylpyruvic acid and 250 g of finely powdered Hannitol are through Dissolve in 0.1% carboxyvinyl polymer solution ("Wako Gel" from Wako Junyaku Co., Ltd.) to an amount of 1 kg. The dispersion is then in aliquots of 1 g each are injected into plastic applicators for intrarectal To make injection preparations available.

Example 35.

Gentamycin (200 g effectiveness), 50 g of the sodium salt of caproic acid and 50 g of sodium chloride are each finely pulverized and then mixed together. The mixture is melted by heating up to an amount of 1 kg with "Witepsol W-35 "mixed. The mixture obtained is pressed into suppository containers, to obtain suppositories of 1 g.

Example 36; Am ir'ic L'n-ryJ f'tt (200 q effectiveness), 50 g y-ketogiutamic acid and 50 g of sodium chloride are each finely pulverized and mixed together. The mixture is made with "Witepsol H-15" melted by heating to an amount offset by 1 kg. The resulting mixture is put into suppository containers for preparation squeezed from suppositories of 1 g.

Example 37.

Cephalothin.Na (200 g effectiveness), 50 g sodium alginate and 50 g sodium chloride are each finely pulverized and then mixed together. The resulting mixture is dissolved in 2% gelatin solution up to a volume of 1 liter. The solution will be then filled in aliquots of 1 ml each into injection cylinders for intrarectal To make injection preparations available.

Example 38.

Gentamycin (100 g potency), 50 g sodium pectinate and 250 g mannitol are each pulverized and mixed together.

The mixture is in 5 pointer gelatin solution up to a volume of 1 1 homogeneously dispersed. The dispersion is then made up in aliquots of each 1 ml placed in injection cylinder to provide intrarectal injection preparations to deliver.

Example 39.

thousands of units of leitonin, 50 g sodium pectinate and 2 50 g Mannitol are each pulverized and mixed together.

The resulting mixture is in 5, ° Óiger gelatin solution up to one Volume of 1 l dispersed homogeneously. The dispersion is then made up in aliquots of 1 ml each in injection cylinders for the production of injection preparations filled for vaginal suppositories.

Example 40.

One thousand units of elcitonin, 50 g of sodium pectinate and 250 g of mannitol are in "Witepsol H-15" melted by heating up to an amount of 1 kg homogeneously dispersed. The mass is then aliquoted into suppository containers In portions of 1 g each filled for the preparation of rectal suppositories.

Example 41.

One thousand units of elcitonin, 50 g of sodium alginate and 5 g of sodium chloride are dissolved in 100 ml of distilled water. The solution becomes "WitepsDl H-5" with a content of 1% sorbitan monosterarate added up to an amount of 500 g. A homogeneous emulsification then takes place. The emulsion is placed in suppository containers filled in aliquots of 1 g each for the preparation of rectal suppositories.

Example 42.

Cefoxitin.Na (200 g effectiveness), 50 g sodium alginate and 50 g sodium chloride are each pulverized and mixed together. The mixture is in by Heat melted "Witepsol H-5" dispersed up to an amount of 1 kg. the Dispersion is then placed in suppository containers in aliquots of each 1 g filled for the preparation of suppositories.

Example 43.

Example 42 is repeated with the proviso that instead of cefoxitin-Na Ct'phazolin.Na (200 q effectiveness) our production of suppositories is used.

Preparation Examples A) 10 grams of the commercially available sodium salt The caboxymethyl cellulose are in 400 ml of a 17.5 point sodium hydroxide solution solved. The solution is mercerized at 3 to 50 ° C. under a nitrogen atmosphere. That The product is diluted to 2 liters with completely deionized water and then with hydrochloric acid adjusted to pH 11. Then 100 ml of an aqueous solution are added to the solution given a content of 5 g of cyanogen bromide. The reaction is 5 minutes at room temperature carried out. After the reaction has ended, pieces of ice are used to cool the mixture added to below 50C, whereupon an aqueous solution of pH 10 with a Content of 150 mmol of aspartic acid and 1 mmol of ethylenediaminetetraacetic acid is added and the reaction is allowed to proceed overnight at 50C. After completion of the implementation the reaction mixture is neutralized with 6N hydrochloric acid, under reduced pressure The pressure was reduced and adjusted to pH 10.5 again with 5N sodium hydroxide solution, to dissolve insoluble matter formed during concentration. Then will the mixture was dialyzed against water and then against 0.01 N hydrochloric acid. The solution is then freeze-dried, and 8.5 g of aspartic acid-carboxymethyl cellulose are obtained.

B) 1.5 g of sodium alginate are dissolved in 100 ml of distilled water. The solution is adjusted to pH 8.0 and mixed with 10 mmol hydroxysuccinimide. The reaction is carried out at 50 ° C. for 60 minutes to give an activated ester obtain. After the reaction, 10 mmol of aminodiacetic acid are added to start the reaction perform. The reaction mixture is then applied to a "Sephadex G-200 column" given. The column is eluted with 10 mmol of pH 6.5 phosphate buffer solution. It eluted fractions are obtained which are lyophilized. 1.0 g is obtained Iminodiacetic acid-alginic acid.

C) The manufacturing process B is repeated with the measure that instead of sodium alginate used 1.5 g of the sodium salt of carboxymethyl starch will. 0.8 g of iminodiacetic acid carboxymethyl starch is obtained.

D) Activation is carried out in the same way as in preparation example A) commercially available soluble starch with glycine and contains 7.6 g of glycine starch.

E) In a manner analogous to Preparation Example B) is commercially available Available sodium polyacrylate activated by esterification. The reaction product allowed to react with glycine.

8.2 g of glycine polyacrylic acid are obtained.

F) A mixture of ethylenediaminetetraacetic acid and acetic anhydride and pyridine is allowed to react at 650C for 24 hours. The dianhydride is obtained of ethylenediaminetetraacetic acid. The product is then added to dimethylformamide and added dextran to carry out the reaction.

Distilled water is added to the reaction mixture and filtered the ethylenediamine-dextran formed.

G) Narhdem hydrochelidonic acid in an analogous manner as in the preparation example F) has been converted into active ester, the ester is allowed to react with albumin, to obtain hydrochelidonic acid albumin.

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Claims (1)

Claims Claim Preparation with excellent absorption properties containing a water soluble advertising binding with chelating activity and a drug. Claim 2 preparation with excellent absorption properties a content of a water-soluble substance in a concentration that a exhibits higher osmotic pressure than an isotonic sodium chloride solution, one water-soluble compound having chelating activity and a drug respectively. Remedies. Claim 3 Preparation according to Claims 1 and 2, d a d u r c h g e -Notice that the water-soluble compound with chelating agent Activity a low molecular weight water-soluble compound with one or more chelating ligand is. Claim 4 Preparation according to Claims 1 or 2, d a d u r c h g e -k e n n n e i c h n e t that the water-soluble compound with chelating agents Activity a water-soluble macromolecular compound with one or more chelating agents Ligand is. Claim 5 Preparation according to Claim 3, d a d u r c h g e k e n n -z e i c h n e t that the chelating ligand from the group carboxyl group, sulfonic acid group, Phosphoric acid group, phenolic hydroxyl group, hydroxyl group, carbonyl group, Amino group, imino group or combinations thereof is selected. Claim 6 Preparation according to Claim 4, d a d u r c h g e k e n n -z e i c h n e t that the water-soluble macromolecular compound with two or several chelating ligands is selected from the group of water-soluble Polysaccharide compounds, water-soluble cellulose derivatives, water-soluble Starch derivatives, dextran derivatives and water-soluble polypeptide compounds and water-soluble synthethiser polymers each with two or more chelating agents Ligands. Claim 7 Preparation according to Claim 4, d a d u r c h g e k e n n -z E i n e t that the water-soluble macromolecular compound is a compound with functional, chelating groups that are incorporated into a water-soluble base polymer are incorporated. Claim 8 Preparation according to Claim 3, d a d u r c h g e k e n n -z e i c h n e t that the low molecular weight water soluble compound with chelating Ligands a polycarboxylic acid, a hydroxycarboxylic acid, a ketocarboxylic acid or is a monocarboxylic acid. Claim 9 Preparation according to Claim 3, d a d u r c h g e k e n n -z e i c h n e t that the low molecular weight water-soluble compound is an aminocarboxylic acid, an iminocarboxylic acid, an aminopolycarboxylic acid or an iminopolycarboxylic acid is. Claim 10 Preparation according to Claim 3, d a d u r c h g e k e n n -z e i c h n e t that the low molecular weight water-soluble compound with chelating ligands is a sulfonic acid compound or a phosphoric acid compound. Claim 11 Preparation according to Claim 7, d a d u r c h q e k e n n -z It is noted that the water-soluble base polymer is selected from the group of water-soluble polysaccharides, water-soluble cellulose derivatives, water-soluble Starch derivatives, dextran derivatives, water-soluble polypeptides and water-soluble ones synthetic polymers. Claim 12 preparation according to claim 7, d a d u r c h q e k e n n -in the water-soluble base polymer to be incorporated shows that the compound with functional chelating groups one or more functional binding groups and has two or more chelating ligands. Claim 13 Preparation according to Claim 12, d a d u r c h g e R e n n - to be incorporated into the water-soluble crundrolvrner that the compound with functional chelating groups an aliphatic polycarboxylic acid, a aliphatic hydroxycarboxylic acid, a uronic acid, an amino acid, an aminopolycarboxylic acid, an aromatic carboxylic acid, an aliphatic sulfonic acid, an aromatic sulfonic acid, a phosphoric glyceric acid, a glycerophosphoric acid or a phosphoric acid ester of a sugar is. Claim 14 Preparation according to Claim 3, d a d u r c h g e k e n n -z E i c h n e t that the low molecular weight water-soluble compound with a chelating agent Ligand is selected from the group of succinic acid, ethylmalonic acid, adipic acid, trans-aconitic acid, pyruvic acid, & ketoglutaric acid, levulinic acid, oxaloacetic acid, Acetoacetic acid, butyric acid, salicylic acid, 2,6-dihydrobenzoic acid, phthalic acid, Phenylpyruvic acid, phenylmalonic acid, citric acid, malic acid, DL-aspartic acid, DL-glutamic acid, DL-phenylglycine, N-phenylglycine, γ-carboxyglutamic acid, N-phenylglycine ethyl ester, glycyl-L-aminobutyric acid, N-dimethylphenylalanine, ethylenediaminetetraacetic acid, trans-cyclohexanediaminetetraacetic acid, diethylenetriaminepentaacetic acid, ethylenediaminetetrakis (methylphosphonic acid ), l-naphthol-3,6-disulfonic acid, chromotropic acid 1,2-dihydroxybenzene-3,5-disulfonic acid, Ethyl acetoacetate or salts thereof. Claim 15 Preparation according to Claim 4, d a d u r c h g e k e n n -z e i c h n e t that the water-soluble macromolecular compound with two or more chelating ligands is selected from the group of alginic acid, pectic acid, Polyacrylic acid, polyaspartic acid and polyglutamic acid or their salts. Claim 16 Preparation according to Claim 2, d a d u r c h g e k e n n -z E i c h n e t that the water-soluble substance is in a concentration that a shows higher osmotic pressure than an isotonic sodium chloride solution, a water-soluble one Salt in an amount of 1 m or more by weight. Claim 17 Preparation according to Claim 16, d a d u r c h g e k e n n -z It is noted that the water-soluble salt is a water-soluble salt of an alkali metal is claim 18 Preparation according to claim 17, d u r c h g e k e n n -z e i c h n e t, dClß dns the water-soluble salt of an alkali metal a halogen, a sulfate, is a phosphate or a carbonate of sodium, potassium or lithium. Claim 19 Preparation according to Claim 2, d a d u r c h g e k e n n -z e i c h n e t that the water-soluble substance in a. Concentration that has a higher osmotic pressure than an isotonic one Sodium chloride solution shows a water-soluble saccharide in an amount of 0.25 molar or above is. Claim 20 Preparation according to Claim 19, d u r c h g e k e n n -z e i c h e t that the water-soluble saccharide sorbitol, glucose, mannitol, maltose, Is lactose or sucrose. Claim 21 Preparation according to Claim 2, d a d u r c h g e k e n n -z E i c h e t that the main ingredient of the drug or remedy is a is a water-soluble drug or remedy with good water solubility. Claim 22 Preparation according to Claim 21, d u r c h g e k e n n -z e i c h n e t that the water-soluble drug resp. Remedies have a partition coefficient of 50 or less in Has choroform / water. Claim 23 preparation with excellent absorption properties according to claim 1, characterized by a content of a water-soluble lactomolecular Connection with ch el atb ld ene r activity and a drug or remedies. Claim 24 Preparation according to Claim 23, d u r c h g e k e n n -z Note that the water-soluble compound has chelating activity a water-soluble macromolecular compound with two or more chelating agents Ligand is. Claim 25 Preparation according to Claim 24, d u r c h g e k e n n -z It is noted that the chelating ligands are selected from the group Carboxylic acid group, sulfonic acid group, phosphoric acid group, phenolic hydroxyl group, Hydroxyl group, carbonyl group, amino group, imino group or their combinations. Claim 26 Preparation according to Claim 24, d u r c h g e k e n n -z e i c h n e t that the water-soluble macromolecular compound with zt, ei or several chelating ligands is selected from the group of water-soluble Polysaccharide compounds, water-soluble cellulose derivatives, water-soluble starch derivative, Dextran derivatives and water-soluble polypeptide compounds and water-soluble synthetic ones Polymers with two or more chelating ligands. Claim 27 Preparation according to Claim 24, d a d u r c h y e k e ri n -z e i n e t that the water-soluble macromolecular compound with two or more chelating ligands combine with functional chelating ligands Is groups that are incorporated into a water-soluble base polymer. Claim 28 Preparation according to Claim 27, d u r c h g e k e n n -z It is noted that the water-soluble base polymer is selected from the group of water-soluble polysaccharides, water-soluble cellulose derivatives, water-soluble Starch derivatives, dextran derivatives, water-soluble polypeptides and water-soluble ones synthetic polymers. Claim 29 Preparation according to Claim 27, d u r c h g e k e n n -z e i h n e t that the compound with functional chelating groups that are to be incorporated into the water-soluble base polymer, one or more functional Has binding groups and two or more chelating ligands. Claim 30 Preparation according to Claim 29, d u r c h g e k e n n -z e i h n e t that the compound with functional chelating groups that are to be incorporated into the water-soluble base polymer, an aliphatic polycarboxylic acid, an aliphatic hydroxycarboxylic acid, a uronic acid, an amino acid, an aminopolycarboxylic acid, an aromatic carboxylic acid, an aliphatic sulfonic acid, an aromatic sulfonic acid, a phosphorus glyceric acid, a glycerophosphoric acid or a Phosphoric acid ester of a sugar is. Claim 31 Preparation according to Claim 24, d u r c h g e k e n n -z E i c h n e t that the wasorlösiiche macromoiekuiare connection with two or more chelating ligand is selected from the group of alginic acid, pectic acid, Polyacrylic acid, polyaspartic acid and polyglutamic acid or their salts. Claim 32 Preparation according to Claim 23, d a d u r c h g e k e n n -z E i c h e t that the drug or remedy is a water-soluble medicinal product or is a remedy with good water solubility. Claim 33 Preparation according to Claim 32, d u r c h g e k e n n -z e i c h n e t that the water-soluble drug resp. Remedies have a partition coefficient of 50 or less in chloroform / water Has.