CA1184492A - Preparation having excellent absorption property - Google Patents
Preparation having excellent absorption propertyInfo
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- CA1184492A CA1184492A CA000394029A CA394029A CA1184492A CA 1184492 A CA1184492 A CA 1184492A CA 000394029 A CA000394029 A CA 000394029A CA 394029 A CA394029 A CA 394029A CA 1184492 A CA1184492 A CA 1184492A
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0031—Rectum, anus
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F25/00—Flow mixers; Mixers for falling materials, e.g. solid particles
- B01F25/80—Falling particle mixers, e.g. with repeated agitation along a vertical axis
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Abstract
Abstract PREPARATION HAVING EXCELLENT ABSORPTION PROPERTY
A preparation containing an absorption promoter selected from specific classes of water-soluble compounds having chelating activity, preferably in the presence of a salt at a concentration exhibiting higher osmotic pressure than isotonic sodium chloride solution, and a medicine is found to promote absorption of the medicine through a gastrointestinal organ such as the colon and rectum, and through the vagina.
A preparation containing an absorption promoter selected from specific classes of water-soluble compounds having chelating activity, preferably in the presence of a salt at a concentration exhibiting higher osmotic pressure than isotonic sodium chloride solution, and a medicine is found to promote absorption of the medicine through a gastrointestinal organ such as the colon and rectum, and through the vagina.
Description
PREPARATION HAVING EXCELLENT ABSORPTION PROPERTY
This invention relates to a novel preparation having excellent absorption property which is intended for improvement of absorption of a medicine poor in absorption property through the rectum or other digestive organs in a body by administration of such a medicine into the rectum or others simultaneously with a water-soluble substance exhibiting higher osmotic pressure than isotonic sodium chloride solution and a water-soluble compound having chelating action. Further, it also pertains to a prepa-ration having good absorption property comprising a water-soluble macromoleeular compound having chelating activity and a medicine, which can improve absorption property to a great e~tent of a medicine, which is itself poor in absorp-tion property, and also maintain a high concentration thereof in blood for a long time.
Absorption of a medicine through a digestive organ, irrespective of whether it may be the stomach, small intestine, large intestine, rectum or mouth, has heretofore been generally believed to proceed according to pH Partition theory (Modern Pharmaceutics, Marcel Dekker, INC., p. 31 ~
49). Hence, a medicine readily dissociated in respective organs at absorption sites or a medicine having poor lipophilicity tends to be poorly absorbed. Such difficultly absorptive medicines are administered as injections under the present circumstances. For improvement of absorption property of a medicine, there have been made various investigations such as Prodrug, Sofdrug, utilization of ion pairs or complex formation. But any of these proposals is effective specifically for individual medicines, and no universally applicable method is known in the art ("Pharma-ceutics" wr-.tten by Nogami).
The present inventors have made various ~`
r ~
~ ., investigations and consequently found that in the mechanlsm of membrane absorption through digestive organs or others, which is believed to proceed according to the pH Partition theory as mentioned above, a compound having a chelating action capable of bonding at least calcium ions or magne-sium ions causes a change in membrane permeability, whereby membrane absorption of a medicine can be improved to promote successfully absorption thereof. It has also been found that a water-soluble macromolecular compound having a chelating action capable of bonding at least calcium ions or magnesium ions is also useful as a compound having such an absorption promoting action. Further, it has also been found that membrane absorption can be markedly improved by addition of a water-soluble substance at a concentration exhibiting higher osmotic pressure than isotonic sodium chloride solution to make the preparation under condition of higher tonicity than the osmotic pressure of a body fluid. In addition to these findings, it has further been found that a preparation obtain~d by use of a vehicle, addi-tives selected as desired and an objective medicine, forexample, a suppository to be inserted into the rectum or vagina is a good suppository which can excellently be absorbed through membranes and maintain a high concentration of the medicine in blood for a long time. A very broad range of medicines may be used in the present invention. In parti-cular, the so called water-soluble medicines having good solubility in water, for example, those with partition coefficients of 50 or less in chloroform/water or medicines readily dissociated into ions, are us~ful. Further, medi-cines applicable only as injections in the prior art arealso found to be made excellently absorbable easily as preparations such as suppositories. Even a medicine with a high molecular weight such as polypeptide hormones is also found as the result of this invention to be made efficiently absorbable in the form of a preparation such as a suppository.
The present invention has been accomplished based on the above ~indings, and the object of the present inven-tion is to provide a good preparation in which a medicine can be improved to have a markedly enhanced absorption property.
In the accompanying drawings, Fig. 1 shows disappearance curves for various osmotic pressures of Cefmetazole when using Cefmetazole Na as medicine, in which the percentages of Cefmetazole disappeared by absorption are plotted versus measuremen~
time;
.
Figs. 2,3, and 4 are variation curves of percentages of disappearance of Cefmetazole-Na versus osmotic pressure, respectively;
Fig. 5 is a disappearance curve of Cefoxitin-Na versus osrnotic pressure;
Fig. 6 shows disappearance curves of respective samples (A,B,C,D and E) in Example 4;
Fig. 7 shows disappearance curves of respective samples [A,B,C,D,E,F and G) in Example 7;
Fig, 8 is a curve of calcium concentration in serum when using Elcitonin as medicine;
Fig. g is a disappearance curve of Cephalothin-Na ~ersus osmotic pressure; and Fig. 10 is a curve of calcium concentration in serum when using Elcitonin as medicine.
According to the present invention, a preparation is provided which comprises a water-soluble substance at a concentration exhibiting an osmotic pressure higher than iso-tonic sodium chloride solution, a water-soluble compound having chelating ac-tivity and a medicine.
According to the present invention, there is also provided a preparation, which comprises a water~soluble macromolecular cornpound having chelating activity and a medicine.
To speak first of a water-soluble substance to be used in the present invention at a concentration exhibiting higher osmotic pressure than isotonic sodium chloride solu-tion, it may preferably be one which is harmless as a whole and can exhibit high osmotic pressure with an amount as small as possible.
As such a water-soluble substance, there may be included water-soluble salts and water-soluble sugars.
Particularly among water-soluble salts, sodium chloride is preferred since it is safe and readily control-lable of its osmotic pressure, and further soluble in water rapidly at a high dissolving rate. Further, mannitol or glucose is preferred among water-soluble sugars. Generally speaking, wa-ter-soluble salts may include, for example, halides, sulfates, phosphates or carbonates of alkali metals such as sodium, potassium or lithium, more specifi-cally the aforesaid sodium chloride, sodium sulfate, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium phosphate, sodium hydrogen carbonate, sodium carbonate, potassium chloride, potassium sulfate, potassium hydrogen phosphate, potassium carbonate, lithium chloride, etc. These salts may be adjusted to concentrations exhibit-3S ing higher tonicity than osmotic pressure of isotonic sodiumchloride solution depending on the osmotic characteristic thereof. For example, in the case of sodium chloride, it may generally be adjusted to a concen~ration of 1 W/W % or higher for whole content~ The upper limit of the concen-tration is not particularly limited, but preferably the concentration is about 2 to 30 W~W %. As preferred water-soluble sugars, there may be employed monosaccharides or disaccharides frequently used for adjustment of osmotic pressure in pharmaceutical technology, including, for example, glucose, mannitol, sorbitol, xylitol, lactose, maltose and sucrose. Such a sugar may be used at a concen-tration with higher tonicity than isotonic sodium chloride solution, which is generally 0.25 M or higher. These water soluble substances may be used in combination of two or more kinds for adjustment of osmotic pressure, which is preerably 1.5 to 6-fold of-the osmotic pressure exhibited by isotonic sodium chloride solution.
In connection with osmotic pressure, description is herein made by comparison with isotonic sodium chloride solution, but such a description with the use of isotonic sodium chloride solution as Control is merely exemplary for comparison between osmotic pressures, and therefore may also be possible with the use of body fluids or other solutions of sal~s with tonicity equal to such isotonic sodium chloride solution.
Referring now to the compounds having chelating action to be used as absorption promoters in this invention, they were investigated by adding to, for example, isotonic preparations for rectal application containing a medicine for examination o increase or decrease of membrane absorption o the medicine to accomplish the present invention. The mechanism of promotion effect has not so far been clarified, but it seems likely that the membrane absorption mechanism may be changed through the chelating action and affinity to the membrane possessed by~these %
absorption promoters on the structures of cell membranes or the spaces between the epithelial cells ~hereby to promote absorption. Although the mechanism o action of the absorption promoter for increase of membrane absorption through the rectum or other organs may be speculated as men-tioned above, such a mechanism action is still no more than mere estimation and it is only sufficient to employ a com-pound having chelating action capable of bonding to at least calcium ions or magnesium ions. More specifically, as the chelating ligands for effective chelating action, there may be mentioned, for example, acid groups such as a carboxylic acid group, sulfonic acid group, phosphoric acid group, phenolic hydroxyl group, etc., hydroxyl group, imino group, carbonyl group, amino group, etc. Further, as the compounds having chelating action with these chelating ligands, there may be included organic compounds having at least one acid group , as exemplified by organic compounds having acid groups such as carboxylic acid groups, thiocarboxylic acid groups, sulfonic acid groups or phosphoric acid groups, organic acid compounds having acid groups having phenolic hydroxyl groups or organic compouncls having at least 2 carbonyl groups. As the organic compourlds having at least one carboxylic acid group, sulfonic acid group or phosphoric acid group, there may be included various compounds having carboxylic acid groups, sulfonic acid groups or phosphoric acid groups such ~s monocarboxylic-, sulfonic- phosphoric-compounds or keto-carboxylic-, sulfonic-, phosphoric-compounds having carbonyl groups, hydroxy- or amino-carboxylic~, imino-carboxylic-, sulfonic-, phosphoric-compounds having hydroxyl groups or amino groups and polyacid compounds having two or more carboxylic acid groups, sulfonic acid groups or phosphoric acid groups. These compounds may also be classified into respective groups of aliphatic compounds, alicyclic com-pounds, aromatic compounds and heterocyclic compounds.
Further, keto-enol type tautomeric isomers may be classi-fied either as compounds having carbonyl groups or as 1~ , compounds having hydroxyl groups. Further, compounds having plural kinds of groups such as a carboxyl group, hydroxyl group, amino group and imino group are not necessarily clearly selected for each grouping. To set forth examples of these groups, polyaci~ compounds may 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, acridinic acid, allylmalonic acid, mesaconic acid, brassylic acid, dodecanoic acid, methylmalonic acid, ethylmalonic acid, phthalic acid, terephthalic acid, homophthalic acid, phenylsuccinic acid, phenylmalonic acid, phenylenediacetic acid, 1,3-naphthalenedicarboxylic acid, iminodiacetic acid, ~-alaninediacetic acid, hydrochelidonic acid, 1,2-cyclo-hexanedicarboxylic acid, anthranylinoac~tic acid, oxanylicacid-o-carboxylic acid, tricarballylic acid, 1,3-diamino-propanetetraacetic acid, hydroxyethyliminodiacetic acid, ethylenediaminediacetic acid, ethylenediaminedipropionic acid, hydroxyethylethylenediaminetriacetic acid, ethylene-diaminetetraacetic acid, ethyleneglycol-bis(~ aminoethyl ether)N,N'~tetraacetic acid, trans-cyclohexanediamine-tetraacetic acid, diaminopropanoltetraacetic acid, diethylenetriaminepentaacetic acid, ethylenediamine-di-o-hydroxyphenylacetic acid, triethylenetetraminehexaacetic acid, nitrilotriacetic acid, nitrilotripropionic acid and the like. Examples of hydroxy-acid compounds or phenolic hydroxyl group-acid compounds are lactic acid, citric acid, isocitric acid, malic acid, glyceric acid, tartaric acid, oxyacetic acid, dihydroxylethylglycinepanthotenic acid, pantoic acid, mevalonic acid, iduronic acid, saccharic acid, phosphenolpyruvic acid, 2-phosphoglyceric acid, 3-phosphoglyceric acid, glycero-3-phosphoric acid, gl.ucose-1,6-diphosp~oric acid, fructose-1,6-diphosphoric acid, ~-oxybutyric acid, ~oxybutyric acid, gluconic acid, ~-oxyisobutyric acid, glucuronic acid, galacturonic acid,leusinic acid, oxyglutamic acid, diethooxalic acid, ~.`
atrolactinic acid, phenyllactic acid, naphthylglycolic acid, phenylhydroacrylic acid, benzylic acid, mandelic acid, salicylic acid, 2,5-dihydroxybenzoic acid, 2,3-dihydroxybenzoic acid, 2,6-dihyd~oxybenzoic acid, tetra-oxyhexahydrobenzoic acid, shikimic acid, melilotic acid,hexahydrosalicylic acid, o-, m-, p-phenolsulfonic acid, 1,2-hydroxybenzene-3,5-disulfonic acid, 1-naphthol-2-sulfonic acid, l-naphthol-3,6-disulfonic acid, 4-amino-phenol-2-sulfonic acid, and the like. Exemplary carbonyl-acid compounds are glyoxylic acid, glyoxylylacetic acid,acetoacetic acid, oxaloacetic acid, ~-ketobutyric acid, acetopyruvic acid, pyruvic acid~ ~-ketoglutaric acid, ~-ketoglutaric acid, ~-ketomalonic acid, ~-ketovaleric acid, ~-ketovaleric acid, benzoylformic acid, benzoylglycolic acid, benzoylpropionic acid, benzoylbutyric acid, levulinic acid, ~ ketocapric acid, phenylpyruvic acid, oxanylic 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, eicosanic acid, arachidonic acid, linoleic acid, linolenic acid, phenylthioacetic acid, phenylpropionic acid, ~-phenylbutyric acid, acetylsalicyllc acid, anisic acid, phenylphosphoric acid and the like. A
compound containing phenolic hydroxyl groups may be, for example, salicylic acid as mentioned above. Amino-acid compounds may include amino acids such as quinaldic acid, kynurenic acid, glycine, alanine, proline, hydroxyproline, phenylalanine, phenylglycine, thyrosine, cystine, cysteic acid, -aminocaproic acid, aspartic acid, glutamine, glutamic acid, leucine, isoleucine, serine, valine, threo-nine, methionine, p-hydroxyphenylglycine, arginine, tryptophan, histidine~ ly~ine, y-carbo~yglutamic acid, kynurenine and the like. Further, as the organic compounds having at least two carbonyl groups, there may be prefer-ably employed enamine derivatives between amino acids(e.g. glycine, lysine, leucine, serine, phenylalanine, z _ 9 _ glutamic acid, thyrosine, phenylglycine, p-hydroxyphenyl-glycine, proline, hydroxyproline) and diketo compou~ds ~e.g. acetylacetone, propionylacetone, butyroylacetone, 3-phenylacetylacetone, methylacetoacetate, ethylacetoacetate, ethyldiacetoacetate, propylacetoacetate, methoxyethylaceto-acetate, ethoxyethylacetoacetate, diethyl ethoxymethylene~
malonate, dibutyl ethoxymethylmalonate, etc.). In addition, the above diketo co~pounds per se can also be employed as absorption promoters. These absorption promoters are generally used in the form of alkali metal salts such as sodium salts or potassium salts, or ammonium salts, but they may also be esterified to the extent such that water solubility is not impaired. In some of absorption promoters, for example, polyacid compounds such as ethylenediamine-tetraacetic acid ~EDTA) or ethyleneglycol-bis(~-aminoethyl ether)-N,N'-tetraacetic acid (EGTA), a part of the acid groups may be protected by esterification, etc. to be converted to derivatives. In particular, in the case of EDTA, one of the carboxylic groups may be converted to the ethyl ester to obtain a derivative having a better effect of promoting absorption o~ a medicine.
Further, as water-soluble macromolecular compounds having chelating action capable of bonding to at least calcium ions or magnesium ions, any water-soluble macro-molecular comp~ound having tw~ or re chelating ligands may be 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 water-soluble derivatives thereof having two or more chelating ligands.
These compounds may also be esterified to the extent such that chelating activity is not lost. These compounds may contain at least two of one or more kinds of chelating ligands selected from carboxylic acid groups, sulfonic acid groups, phosphoric acid groups, phenolic hydroxyl groups, hydroxyl groups, imino groups, carbcnyl groups and amino groups, and they may be either natural, semi-synthetic or synthetic products. Examples of these natural, semi-synthetic or synthetic water-soluble macromolecular com-pounds having chelating activity are enumerated below, butthe present invention is not limited thereto.
Water-soluble polysaccarides containing uronic acid: alginic acid, pectinic acid, chondroitin sulfate, hyaluronic acid, arabic acid, Water-soluble cellulose related compounds : carboxymethyl cellulose, carboxyethyl cellulose, carbo-xypropyl cellulose, cellulose acetate phthalate;
Water-soluble starch related compounds : carboxymethyl starch, carboxy-ethyl starch;
Dextran related compounds : carboxymethyl dextran, dextran sulfate;
Polypeptide compounds : polyglutamic acid, poly-~-carboxyglutamic acid, poly-. aspartic acid, polylysine, polyarginine and copolymers of these amino acids;
Water-soluble synthetic polymer compounds : polyacrylic acid, polymeth-acrylic acid, methacrylic acid-acrylic acid copolymer, acryl-amide-acrylic acid copolymer, polyphosphoric acid Further, these compounds or water-soluble base polymers exhibiting no detectable chelating activity may be bound wit~ a chelatiny agent of low molecular weight having chelating activity to be converted to water-soluble macro-molecular compounds having chelating activity as a whole.
In this case, the base polymer may be any one having water-solubility and may be exemplified by synthetic polymers such as polyvinyl alcohol, polyethylene oxide, etc~
or various natural polymers. Preferably, a polymer harmless to living bodies is employed and such a polymer may have side chain functional groups for introduction of a chelater such as hydroxyl group~, carboxyl groups, amino groups or imino groups.
The polymer have a molecular weight which is not particularly limited, so long as it is soluble in water or capable of forming hydrogels, but generally in the range of from 1000 to 1,000,000.
Typical examples of such a water-soluble base polymer are set forth below, to which the present invention is not limited.
Typical examples of water-soluble base polymers _ Polysaccharides containing 25 uronic acid : chondroitin sulfate, heparin, arabic acid, pectin, gum tragacanth, tragacanthic acid, pectinic acid;
Other polysaccharides : carrageenan, ~--glucan, galacto-mannan, konjakamannan, galactan, fucan, inulin, levan;
Cellulose related compounds : hydroxyethyl cellulose, hydroxy-propyl cellulose, cellulose, methyl cellulose, ethyl cellulose, hydroxypropylmethyl cellulose, agarose;
Starch related compounds : soluble starch, phosphoric acid starch, acetyl starch, hydroxy-ethyl starch, dextrin, amylose, amylopectin;
Dextran related compounds: dextran, diethylaminoethyl dextran, aminoethyl dextran;
Polypeptides: gelatin, casein, albumin, globulin;
Synthetic polymers: polyethylene glycol, polyvinyl alcohol, polyethylene oxide, vinyl acetate-mal0ic acid copolymer, vinyl acetate-crotonic acid copolymer,vinyl acetate-acrylic acid copolymer, polyvinyl alcohol-maleic acid copolymer, polyacrylamide, poly-vinylacetal diethylaminoacetate, 2-methyl-5-vinylpyridine/methyl acrylate/
methacrylic acid copolymer.
As ~he chelating agent to be incorporated into these water-soluble base polymers, there may be used a compound ~ capable of forming a chelate with calcium ions or magnesium ions which can be introduced into the polymer side chain and has still chelate forming activity after introduction.
There may be employed a chelating agent which has 2S an atomic group capable of forming a ring containing ligands between central metallic ions, can be introduced into the polymer side chain and coordinated with two or more mole-cules per metal ion. More preferably, the chelating agent may be one containing three kinds of ligand or functional group, namely a ligand (I) containing a proton as the chelate forming functional group to be substituted by said metal ion (e.g. hydroxyl group, carboxyl group, imino group, etc.), a ligand (II) capable of coordination bonding to the metal ion (e.g. carbonyl group, amino group, etc.) and a functional group (III) for bondin~ the chelater to the polymer sïde chain through formation of bondings such as amide bonding, ester .~
, . .
bonding or ether bonding by reaction with side chains of the above polymer ~e.g. amino group, carboxyl group, hydroxyl group, halogen, etc.) and having a structure such that the chelate forming ligands ~I~ and (II) are separated by a link having l to 2 carbon atoms or that (I) and (II) are separated from (III), which is the link with a polymer, by an organic group having l to lO carbon atoms such as an aliphatic group or an aromatic group.
Typical examples of such compounds are enumerated below, but the present invention is not limited thereto.
Aliphatic polycarboxylic acid compounds: oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, aconitic acid, pimellic acid, sebacic acid, allylmalonic acid, ethylmalonic acid;
Aliphatic oxycarboxylic acid compounds: citric acid, malic acid, glyceric acid,tartaric acid, mevaloic acid, oxyglutaric acid;
Aliphatic keto-poly-carboxylic acid compounds: oxaloacetic acid, ~-Xeto-glutaric acid, ~~ketoglutaric acid, ~-ketomalonic acid, Uronic acid compounds: glucuronic acid, galacturonic acid, mannuronic acid;
~mino acid compounds: aspartic acid, glutamic acid, glycine, alanine, lysine, histidine, arginine, cysteine, -aminocaproic acid/ phenyl-alanine, phenylglycine, p-hydroxyphenylglycine, p-amino-phenylalanine, y~-carboxyglutamic acid Aminopolycarboxyl.ic acid compounds: iminodiacetic acid, hydroxy~
ethyliminodiacetic acid, ethylenediaminediacetic acid, ethylenediaminetetraacetic acid, trans-cyclohexanediaminetetra-acetic acid, diethylenediamine-pentaacetic acid, ~-alanine-diacetic acid, diaminopimellic acid;
Aromatic carboxylic acid compounds: phthalic acid, terephthalic acid, homophthalic acid, phenylsuccinic acid, phenylmalonic acid, oxanylic acid-o-carboxylic acid, anthrany-linoacetic acid, 2,4-dihydroxy-benzoic acid, p-aminosalicylic acid, phthalylglutamic acid, kynurenine, ~liphatic and aromatic sulfonic acid compounds: 1,2-hydroxybenzene-3,5-disulfo-nic 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-diphosphoric acid.
For incorporation of such a chelating agent into a water-soluble base polymer, the chelatiny agent and the incorporation method to be employed are suitably selected depending on the side chains of the water-soluble base polymer employed, and the bonding formed as the result of the reactlon is also determined by their combination, as described ir, detail in Japanese Patent Publication No.
16979/1979 (USP 4024073)~
- 15 ~
The effect of promoting absorption of a medicine by the water-soluble macromolecular compound having chelat-ing activity obtained according to the present invention was examined by use of, for example, an Elcitonin preparation containing the lysine-dextran T-lS0 prepared according to Example 1 disclosed in Japanese Patent Publication No.
16979/1979 (USP 4024073) by .intrarectal in~ection in viv~
into rats and measuring the decrease in calcium concentration in se'rum, whereby it was found that said preparation exhibited a significant absorption promoting effect as compared with Control using no lysine-dextran T-150. These macromolecular adsorption are generally used in the formed alkali metal salts such as sodium sal~s or potassium salts, or ammonium salts.
The water soluble low molecular compound and the macromolecular compound having chelating action or the water-soluble polymer having incorporated a chelating agent in the present invention is used as a membrane absorption promoter.
These absorption promoters may be employed in amounts of 0.05 W~W % or more, generally in the range of from 0.1 to 50 W/W %, preferably from lo O to 30 W/W ~. As the vehicle to be employed for preparation of a suppository containing the above absorption promoter, a medicine and preferably a water-soluble salt to be added for increase of tonicity, there maysuitably be selected one from oily vehicles and water-soluble vehicles conventionally used in preparation of suppositories or rectal injections, and a surfactant may also be added if desired. of course, two or more promoters may be used together.
As these oily vehicles or water-soluble vehicles, there ma~ conveniently be used those as described in "The Theory and Practice of Industrial Pharmacy", p. 245 to 269 (1976).
The medicine to be used in th~ present invention is not particularly limited, but there may be employed ordinary pharmaceuticals, particularly pref~rably the so called water-soluble medicines ~hich are excellently soluble in water, such as water-soluble medicines with a partition coefficient of 50 or less in chloroform/water or medicines readily dissociated to ionsO For example, there may be included ~arious medicines such as hypnotics, tranquilizers, antiepileptics, antipyretics ! analgesics, antidepressants, muscle relaxants, antiin~lammatory agents, antiallergic agents, immunosuppressan~s, antirheumatics, vasodilators, antihemorrhagics antihypertensives, antibiotics, antibacterial agents, urinary tract sterilizers, antitumor agents, vitamins, hormones and galenicals. More specifically, typical examples are penicillin type antibiotics such as ampicillin, heta-cillin, amoxicillin, cyclacillin, cloxacillin, dicloxacillin, oxacillin, carindacillin, sulbenicillin, piperacillin, apal-cillin, methicillin, etc. or combined drugs of ampicillin or amoxicillin with oxacillin, cloxacillin, flo~acillin or dichloxacillin; cephalosporin type antibiotics such as cephalo-thine, cephazoline, cephaloridine, cephacetorile, cefoxitin, cefadroxil, cefatrizine, cephaloglycin, cephalexin, cephapirin, cephaclor, ceftezol, cefuroxime, cefsulodin, cefmetazole, etc.
and non-toxic salts thereof such as alkali metal salts (e.g.
sodium salts or potassium salts), ammonium salts or benzyl-amine salts. In addition, there may also be mentioned tetracycline type antibiotics such as doxycycline, oxycycline, etc.; aminosaccharide type antibiotics such as kanamycin, sisomicin, amikacin, tobramycin, netromycin, gentamycin, etc.;
peptide type antibiotics such as tuberactinomycin N, actino-mycin, etc. or non-toxic salts thereof; further peptide hormones such as insulin, somatostatin, calcitonin, angio-tensin,kallikrein, secretin, gastrisin, parathyroid hormone, etc.; and other medicines such as barbital, theophylline, "Aspirin"~mizoribine, bredinin, 5-fluorouracil, methotrexate, L-dopa, etc. The medicine may be employed in an amount, * Trademark for acetylsalicylic acid.
which may suitably be selected and designed. For example, in case of antibiotics such as ~-lactam antibiotics, 20 to 500 mg activity, generally 100 to 300 mg activity, or in case of peptide hormones such as insulin, 1 to 500 units may be contained per gram of preparation. In general the medicine may preferably be used in finely divided forms with 1 to 50 ~ diameters or as an aqueous solution.
The step of forming preparations may be performed according to conventional methods for production of prepa-rations in general such as rectal suppository, urethral suppository or vaginal suppository ointments or creams.
For example~ the absorption promoter selected, a water-soluble substance in an amount exhibiting higher osmotic pressure than isotonic sodium chloride solution and a medicine are added to a vehicle, optionally in combination with a surfactant, and these components are thoroughly mixed to provide preparations.
Further, in production of these preparation, there may also he added preservatives such as methyl- or propyl-p-oxybenzoate, colorants, aromas and stabilizers.
The present invention is further illustrated in detail by referring to the following Examples, by which the present invention is not limited at all but various medi-cines, hypertonicators and absorption promoters may be selected and combined in addition to those shown in Examples.
Example 1 Absorption effects under conditions with various tonicities were examined. Each sample solution was prepared by adding 0.1 W/W ~ CefmetazoleNa as medicine together with sodium oxalate or sodium glyoxylate as absorption promoter to a phosphate buffer of pH 7.0 conditioned with sodium chloride to a tonicity which is varied from isotonic to ,' .~. j twice hypertonic than isotonicttwo-fold tonicity), three times hypertonic than isotonic(three-fold tonicity), 5 times hypertonic than isotonic(five fold tonicity), 6 times higher than isotonic(six-fold tonicity) and 7 times hypertonic than isotonic~seven-fold tonicity).
The experiment was conducted in the following manner. Namely, Sprague Dawleg rats(male), weighing 200 to 300 g, were narco-tized (after fast for 20 hours) with pentobarbital(50 mg/kg) and thereafter subjected to hypoabdominal incision for a first cannulation at a position about 1.5 cm frcm the anus andalso another cannul-ation at a position 5 cm above said first cannulation.
Subsequently, the rectum was internally washed with about 50 mQ
of isotonic sodium chloride solution kept at 38C, and samples each of 10 mQ were circulated through the rectum for 5 minutes (2 mQ/minute) to make the concentration in the system constant. Then, 5 mQ of each sample was circulated at a flow rate of 2 mQ/minute, and samples each of 0.05 mQ
were collected at intervals of 10 minutes from 0 minute.
Each sample was diluted to 5 mQ with distilled water and the quantity of medicine disappeared by absorption was determined by W -SPeCtrophotometer.
As the result, the disappearance curve of Cefmetazole Wa under the condition of 0.1 W/W ~ sodium oxalate was obtained as shown in Fig. 1, in which x - x shows the result under the isotonic condition, a - a under two-fold tonicity, ~ - ~ under three-fold tonicity, o - o under five-fold tonicity, o - o under six-fold tonicity and ~ - ~ under seven-fold tonicity.
Fig. 2 also shows the absorption curve of Cefmetazole-Na under the above condition of 0.1 W/W
sodium oxalate at respective osmotic pressures.
., ,.~.. .
Fig. 3 shows the absorption curve of Cefmetazole~Na under the condition of 0.2 W/W % sodium oxalate at respective osmotic pressures.
Further, Fig. 4 shows the absorption curve of Cefmetazole Na under the condition of 0.5 W/W % sodium glyoxalate at respective osmotic pressures.
Example 2 Using 0.1 W/W % Cefoxitin-Na as medicine and 0.5 W/W % of sodium glyoxylate as absorption promoter under respective osmotic pressure conditions (namely two-fold, four-fold and six-fold tonicities with the use of sodium chloride) and following otherwise the same procedure as in Example 1, quantities of Cefoxitin disappeared by absorption were determined by UV-spectrophotometer similarly as in Example 1.
The results are shown in Fig~ 5, in which x---x is the disappearance curve by absorption only of Cefoxitin under isotonic condition without the use of sodium glyoxylate, x - x the disappearance curve of Cefoxitin with the use of sodium ~lYXYlate under isotonic condition, ~ - Q that under two-fold toni~ condition, o - o that under four-fold tonic condition, and ~ that under six-fold tonic condition, respectively.
Example 3 Quantities of 0.5 W/W ~ Cefmetazole-Na disappeared by absorption under isotonic and three-fold tonic conditions were determined, respectively, using sodium malate, sodium pyruvate, sodium phosphenolpyruvate, sodium ~-hydroxybutyrate, sodium ~-hydroxy glutarate, and sodium 2~phospho-D-glycerate.
The results ~re shown in Table 1.
~4~
This invention relates to a novel preparation having excellent absorption property which is intended for improvement of absorption of a medicine poor in absorption property through the rectum or other digestive organs in a body by administration of such a medicine into the rectum or others simultaneously with a water-soluble substance exhibiting higher osmotic pressure than isotonic sodium chloride solution and a water-soluble compound having chelating action. Further, it also pertains to a prepa-ration having good absorption property comprising a water-soluble macromoleeular compound having chelating activity and a medicine, which can improve absorption property to a great e~tent of a medicine, which is itself poor in absorp-tion property, and also maintain a high concentration thereof in blood for a long time.
Absorption of a medicine through a digestive organ, irrespective of whether it may be the stomach, small intestine, large intestine, rectum or mouth, has heretofore been generally believed to proceed according to pH Partition theory (Modern Pharmaceutics, Marcel Dekker, INC., p. 31 ~
49). Hence, a medicine readily dissociated in respective organs at absorption sites or a medicine having poor lipophilicity tends to be poorly absorbed. Such difficultly absorptive medicines are administered as injections under the present circumstances. For improvement of absorption property of a medicine, there have been made various investigations such as Prodrug, Sofdrug, utilization of ion pairs or complex formation. But any of these proposals is effective specifically for individual medicines, and no universally applicable method is known in the art ("Pharma-ceutics" wr-.tten by Nogami).
The present inventors have made various ~`
r ~
~ ., investigations and consequently found that in the mechanlsm of membrane absorption through digestive organs or others, which is believed to proceed according to the pH Partition theory as mentioned above, a compound having a chelating action capable of bonding at least calcium ions or magne-sium ions causes a change in membrane permeability, whereby membrane absorption of a medicine can be improved to promote successfully absorption thereof. It has also been found that a water-soluble macromolecular compound having a chelating action capable of bonding at least calcium ions or magnesium ions is also useful as a compound having such an absorption promoting action. Further, it has also been found that membrane absorption can be markedly improved by addition of a water-soluble substance at a concentration exhibiting higher osmotic pressure than isotonic sodium chloride solution to make the preparation under condition of higher tonicity than the osmotic pressure of a body fluid. In addition to these findings, it has further been found that a preparation obtain~d by use of a vehicle, addi-tives selected as desired and an objective medicine, forexample, a suppository to be inserted into the rectum or vagina is a good suppository which can excellently be absorbed through membranes and maintain a high concentration of the medicine in blood for a long time. A very broad range of medicines may be used in the present invention. In parti-cular, the so called water-soluble medicines having good solubility in water, for example, those with partition coefficients of 50 or less in chloroform/water or medicines readily dissociated into ions, are us~ful. Further, medi-cines applicable only as injections in the prior art arealso found to be made excellently absorbable easily as preparations such as suppositories. Even a medicine with a high molecular weight such as polypeptide hormones is also found as the result of this invention to be made efficiently absorbable in the form of a preparation such as a suppository.
The present invention has been accomplished based on the above ~indings, and the object of the present inven-tion is to provide a good preparation in which a medicine can be improved to have a markedly enhanced absorption property.
In the accompanying drawings, Fig. 1 shows disappearance curves for various osmotic pressures of Cefmetazole when using Cefmetazole Na as medicine, in which the percentages of Cefmetazole disappeared by absorption are plotted versus measuremen~
time;
.
Figs. 2,3, and 4 are variation curves of percentages of disappearance of Cefmetazole-Na versus osmotic pressure, respectively;
Fig. 5 is a disappearance curve of Cefoxitin-Na versus osrnotic pressure;
Fig. 6 shows disappearance curves of respective samples (A,B,C,D and E) in Example 4;
Fig. 7 shows disappearance curves of respective samples [A,B,C,D,E,F and G) in Example 7;
Fig, 8 is a curve of calcium concentration in serum when using Elcitonin as medicine;
Fig. g is a disappearance curve of Cephalothin-Na ~ersus osmotic pressure; and Fig. 10 is a curve of calcium concentration in serum when using Elcitonin as medicine.
According to the present invention, a preparation is provided which comprises a water-soluble substance at a concentration exhibiting an osmotic pressure higher than iso-tonic sodium chloride solution, a water-soluble compound having chelating ac-tivity and a medicine.
According to the present invention, there is also provided a preparation, which comprises a water~soluble macromolecular cornpound having chelating activity and a medicine.
To speak first of a water-soluble substance to be used in the present invention at a concentration exhibiting higher osmotic pressure than isotonic sodium chloride solu-tion, it may preferably be one which is harmless as a whole and can exhibit high osmotic pressure with an amount as small as possible.
As such a water-soluble substance, there may be included water-soluble salts and water-soluble sugars.
Particularly among water-soluble salts, sodium chloride is preferred since it is safe and readily control-lable of its osmotic pressure, and further soluble in water rapidly at a high dissolving rate. Further, mannitol or glucose is preferred among water-soluble sugars. Generally speaking, wa-ter-soluble salts may include, for example, halides, sulfates, phosphates or carbonates of alkali metals such as sodium, potassium or lithium, more specifi-cally the aforesaid sodium chloride, sodium sulfate, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium phosphate, sodium hydrogen carbonate, sodium carbonate, potassium chloride, potassium sulfate, potassium hydrogen phosphate, potassium carbonate, lithium chloride, etc. These salts may be adjusted to concentrations exhibit-3S ing higher tonicity than osmotic pressure of isotonic sodiumchloride solution depending on the osmotic characteristic thereof. For example, in the case of sodium chloride, it may generally be adjusted to a concen~ration of 1 W/W % or higher for whole content~ The upper limit of the concen-tration is not particularly limited, but preferably the concentration is about 2 to 30 W~W %. As preferred water-soluble sugars, there may be employed monosaccharides or disaccharides frequently used for adjustment of osmotic pressure in pharmaceutical technology, including, for example, glucose, mannitol, sorbitol, xylitol, lactose, maltose and sucrose. Such a sugar may be used at a concen-tration with higher tonicity than isotonic sodium chloride solution, which is generally 0.25 M or higher. These water soluble substances may be used in combination of two or more kinds for adjustment of osmotic pressure, which is preerably 1.5 to 6-fold of-the osmotic pressure exhibited by isotonic sodium chloride solution.
In connection with osmotic pressure, description is herein made by comparison with isotonic sodium chloride solution, but such a description with the use of isotonic sodium chloride solution as Control is merely exemplary for comparison between osmotic pressures, and therefore may also be possible with the use of body fluids or other solutions of sal~s with tonicity equal to such isotonic sodium chloride solution.
Referring now to the compounds having chelating action to be used as absorption promoters in this invention, they were investigated by adding to, for example, isotonic preparations for rectal application containing a medicine for examination o increase or decrease of membrane absorption o the medicine to accomplish the present invention. The mechanism of promotion effect has not so far been clarified, but it seems likely that the membrane absorption mechanism may be changed through the chelating action and affinity to the membrane possessed by~these %
absorption promoters on the structures of cell membranes or the spaces between the epithelial cells ~hereby to promote absorption. Although the mechanism o action of the absorption promoter for increase of membrane absorption through the rectum or other organs may be speculated as men-tioned above, such a mechanism action is still no more than mere estimation and it is only sufficient to employ a com-pound having chelating action capable of bonding to at least calcium ions or magnesium ions. More specifically, as the chelating ligands for effective chelating action, there may be mentioned, for example, acid groups such as a carboxylic acid group, sulfonic acid group, phosphoric acid group, phenolic hydroxyl group, etc., hydroxyl group, imino group, carbonyl group, amino group, etc. Further, as the compounds having chelating action with these chelating ligands, there may be included organic compounds having at least one acid group , as exemplified by organic compounds having acid groups such as carboxylic acid groups, thiocarboxylic acid groups, sulfonic acid groups or phosphoric acid groups, organic acid compounds having acid groups having phenolic hydroxyl groups or organic compouncls having at least 2 carbonyl groups. As the organic compourlds having at least one carboxylic acid group, sulfonic acid group or phosphoric acid group, there may be included various compounds having carboxylic acid groups, sulfonic acid groups or phosphoric acid groups such ~s monocarboxylic-, sulfonic- phosphoric-compounds or keto-carboxylic-, sulfonic-, phosphoric-compounds having carbonyl groups, hydroxy- or amino-carboxylic~, imino-carboxylic-, sulfonic-, phosphoric-compounds having hydroxyl groups or amino groups and polyacid compounds having two or more carboxylic acid groups, sulfonic acid groups or phosphoric acid groups. These compounds may also be classified into respective groups of aliphatic compounds, alicyclic com-pounds, aromatic compounds and heterocyclic compounds.
Further, keto-enol type tautomeric isomers may be classi-fied either as compounds having carbonyl groups or as 1~ , compounds having hydroxyl groups. Further, compounds having plural kinds of groups such as a carboxyl group, hydroxyl group, amino group and imino group are not necessarily clearly selected for each grouping. To set forth examples of these groups, polyaci~ compounds may 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, acridinic acid, allylmalonic acid, mesaconic acid, brassylic acid, dodecanoic acid, methylmalonic acid, ethylmalonic acid, phthalic acid, terephthalic acid, homophthalic acid, phenylsuccinic acid, phenylmalonic acid, phenylenediacetic acid, 1,3-naphthalenedicarboxylic acid, iminodiacetic acid, ~-alaninediacetic acid, hydrochelidonic acid, 1,2-cyclo-hexanedicarboxylic acid, anthranylinoac~tic acid, oxanylicacid-o-carboxylic acid, tricarballylic acid, 1,3-diamino-propanetetraacetic acid, hydroxyethyliminodiacetic acid, ethylenediaminediacetic acid, ethylenediaminedipropionic acid, hydroxyethylethylenediaminetriacetic acid, ethylene-diaminetetraacetic acid, ethyleneglycol-bis(~ aminoethyl ether)N,N'~tetraacetic acid, trans-cyclohexanediamine-tetraacetic acid, diaminopropanoltetraacetic acid, diethylenetriaminepentaacetic acid, ethylenediamine-di-o-hydroxyphenylacetic acid, triethylenetetraminehexaacetic acid, nitrilotriacetic acid, nitrilotripropionic acid and the like. Examples of hydroxy-acid compounds or phenolic hydroxyl group-acid compounds are lactic acid, citric acid, isocitric acid, malic acid, glyceric acid, tartaric acid, oxyacetic acid, dihydroxylethylglycinepanthotenic acid, pantoic acid, mevalonic acid, iduronic acid, saccharic acid, phosphenolpyruvic acid, 2-phosphoglyceric acid, 3-phosphoglyceric acid, glycero-3-phosphoric acid, gl.ucose-1,6-diphosp~oric acid, fructose-1,6-diphosphoric acid, ~-oxybutyric acid, ~oxybutyric acid, gluconic acid, ~-oxyisobutyric acid, glucuronic acid, galacturonic acid,leusinic acid, oxyglutamic acid, diethooxalic acid, ~.`
atrolactinic acid, phenyllactic acid, naphthylglycolic acid, phenylhydroacrylic acid, benzylic acid, mandelic acid, salicylic acid, 2,5-dihydroxybenzoic acid, 2,3-dihydroxybenzoic acid, 2,6-dihyd~oxybenzoic acid, tetra-oxyhexahydrobenzoic acid, shikimic acid, melilotic acid,hexahydrosalicylic acid, o-, m-, p-phenolsulfonic acid, 1,2-hydroxybenzene-3,5-disulfonic acid, 1-naphthol-2-sulfonic acid, l-naphthol-3,6-disulfonic acid, 4-amino-phenol-2-sulfonic acid, and the like. Exemplary carbonyl-acid compounds are glyoxylic acid, glyoxylylacetic acid,acetoacetic acid, oxaloacetic acid, ~-ketobutyric acid, acetopyruvic acid, pyruvic acid~ ~-ketoglutaric acid, ~-ketoglutaric acid, ~-ketomalonic acid, ~-ketovaleric acid, ~-ketovaleric acid, benzoylformic acid, benzoylglycolic acid, benzoylpropionic acid, benzoylbutyric acid, levulinic acid, ~ ketocapric acid, phenylpyruvic acid, oxanylic 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, eicosanic acid, arachidonic acid, linoleic acid, linolenic acid, phenylthioacetic acid, phenylpropionic acid, ~-phenylbutyric acid, acetylsalicyllc acid, anisic acid, phenylphosphoric acid and the like. A
compound containing phenolic hydroxyl groups may be, for example, salicylic acid as mentioned above. Amino-acid compounds may include amino acids such as quinaldic acid, kynurenic acid, glycine, alanine, proline, hydroxyproline, phenylalanine, phenylglycine, thyrosine, cystine, cysteic acid, -aminocaproic acid, aspartic acid, glutamine, glutamic acid, leucine, isoleucine, serine, valine, threo-nine, methionine, p-hydroxyphenylglycine, arginine, tryptophan, histidine~ ly~ine, y-carbo~yglutamic acid, kynurenine and the like. Further, as the organic compounds having at least two carbonyl groups, there may be prefer-ably employed enamine derivatives between amino acids(e.g. glycine, lysine, leucine, serine, phenylalanine, z _ 9 _ glutamic acid, thyrosine, phenylglycine, p-hydroxyphenyl-glycine, proline, hydroxyproline) and diketo compou~ds ~e.g. acetylacetone, propionylacetone, butyroylacetone, 3-phenylacetylacetone, methylacetoacetate, ethylacetoacetate, ethyldiacetoacetate, propylacetoacetate, methoxyethylaceto-acetate, ethoxyethylacetoacetate, diethyl ethoxymethylene~
malonate, dibutyl ethoxymethylmalonate, etc.). In addition, the above diketo co~pounds per se can also be employed as absorption promoters. These absorption promoters are generally used in the form of alkali metal salts such as sodium salts or potassium salts, or ammonium salts, but they may also be esterified to the extent such that water solubility is not impaired. In some of absorption promoters, for example, polyacid compounds such as ethylenediamine-tetraacetic acid ~EDTA) or ethyleneglycol-bis(~-aminoethyl ether)-N,N'-tetraacetic acid (EGTA), a part of the acid groups may be protected by esterification, etc. to be converted to derivatives. In particular, in the case of EDTA, one of the carboxylic groups may be converted to the ethyl ester to obtain a derivative having a better effect of promoting absorption o~ a medicine.
Further, as water-soluble macromolecular compounds having chelating action capable of bonding to at least calcium ions or magnesium ions, any water-soluble macro-molecular comp~ound having tw~ or re chelating ligands may be 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 water-soluble derivatives thereof having two or more chelating ligands.
These compounds may also be esterified to the extent such that chelating activity is not lost. These compounds may contain at least two of one or more kinds of chelating ligands selected from carboxylic acid groups, sulfonic acid groups, phosphoric acid groups, phenolic hydroxyl groups, hydroxyl groups, imino groups, carbcnyl groups and amino groups, and they may be either natural, semi-synthetic or synthetic products. Examples of these natural, semi-synthetic or synthetic water-soluble macromolecular com-pounds having chelating activity are enumerated below, butthe present invention is not limited thereto.
Water-soluble polysaccarides containing uronic acid: alginic acid, pectinic acid, chondroitin sulfate, hyaluronic acid, arabic acid, Water-soluble cellulose related compounds : carboxymethyl cellulose, carboxyethyl cellulose, carbo-xypropyl cellulose, cellulose acetate phthalate;
Water-soluble starch related compounds : carboxymethyl starch, carboxy-ethyl starch;
Dextran related compounds : carboxymethyl dextran, dextran sulfate;
Polypeptide compounds : polyglutamic acid, poly-~-carboxyglutamic acid, poly-. aspartic acid, polylysine, polyarginine and copolymers of these amino acids;
Water-soluble synthetic polymer compounds : polyacrylic acid, polymeth-acrylic acid, methacrylic acid-acrylic acid copolymer, acryl-amide-acrylic acid copolymer, polyphosphoric acid Further, these compounds or water-soluble base polymers exhibiting no detectable chelating activity may be bound wit~ a chelatiny agent of low molecular weight having chelating activity to be converted to water-soluble macro-molecular compounds having chelating activity as a whole.
In this case, the base polymer may be any one having water-solubility and may be exemplified by synthetic polymers such as polyvinyl alcohol, polyethylene oxide, etc~
or various natural polymers. Preferably, a polymer harmless to living bodies is employed and such a polymer may have side chain functional groups for introduction of a chelater such as hydroxyl group~, carboxyl groups, amino groups or imino groups.
The polymer have a molecular weight which is not particularly limited, so long as it is soluble in water or capable of forming hydrogels, but generally in the range of from 1000 to 1,000,000.
Typical examples of such a water-soluble base polymer are set forth below, to which the present invention is not limited.
Typical examples of water-soluble base polymers _ Polysaccharides containing 25 uronic acid : chondroitin sulfate, heparin, arabic acid, pectin, gum tragacanth, tragacanthic acid, pectinic acid;
Other polysaccharides : carrageenan, ~--glucan, galacto-mannan, konjakamannan, galactan, fucan, inulin, levan;
Cellulose related compounds : hydroxyethyl cellulose, hydroxy-propyl cellulose, cellulose, methyl cellulose, ethyl cellulose, hydroxypropylmethyl cellulose, agarose;
Starch related compounds : soluble starch, phosphoric acid starch, acetyl starch, hydroxy-ethyl starch, dextrin, amylose, amylopectin;
Dextran related compounds: dextran, diethylaminoethyl dextran, aminoethyl dextran;
Polypeptides: gelatin, casein, albumin, globulin;
Synthetic polymers: polyethylene glycol, polyvinyl alcohol, polyethylene oxide, vinyl acetate-mal0ic acid copolymer, vinyl acetate-crotonic acid copolymer,vinyl acetate-acrylic acid copolymer, polyvinyl alcohol-maleic acid copolymer, polyacrylamide, poly-vinylacetal diethylaminoacetate, 2-methyl-5-vinylpyridine/methyl acrylate/
methacrylic acid copolymer.
As ~he chelating agent to be incorporated into these water-soluble base polymers, there may be used a compound ~ capable of forming a chelate with calcium ions or magnesium ions which can be introduced into the polymer side chain and has still chelate forming activity after introduction.
There may be employed a chelating agent which has 2S an atomic group capable of forming a ring containing ligands between central metallic ions, can be introduced into the polymer side chain and coordinated with two or more mole-cules per metal ion. More preferably, the chelating agent may be one containing three kinds of ligand or functional group, namely a ligand (I) containing a proton as the chelate forming functional group to be substituted by said metal ion (e.g. hydroxyl group, carboxyl group, imino group, etc.), a ligand (II) capable of coordination bonding to the metal ion (e.g. carbonyl group, amino group, etc.) and a functional group (III) for bondin~ the chelater to the polymer sïde chain through formation of bondings such as amide bonding, ester .~
, . .
bonding or ether bonding by reaction with side chains of the above polymer ~e.g. amino group, carboxyl group, hydroxyl group, halogen, etc.) and having a structure such that the chelate forming ligands ~I~ and (II) are separated by a link having l to 2 carbon atoms or that (I) and (II) are separated from (III), which is the link with a polymer, by an organic group having l to lO carbon atoms such as an aliphatic group or an aromatic group.
Typical examples of such compounds are enumerated below, but the present invention is not limited thereto.
Aliphatic polycarboxylic acid compounds: oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, aconitic acid, pimellic acid, sebacic acid, allylmalonic acid, ethylmalonic acid;
Aliphatic oxycarboxylic acid compounds: citric acid, malic acid, glyceric acid,tartaric acid, mevaloic acid, oxyglutaric acid;
Aliphatic keto-poly-carboxylic acid compounds: oxaloacetic acid, ~-Xeto-glutaric acid, ~~ketoglutaric acid, ~-ketomalonic acid, Uronic acid compounds: glucuronic acid, galacturonic acid, mannuronic acid;
~mino acid compounds: aspartic acid, glutamic acid, glycine, alanine, lysine, histidine, arginine, cysteine, -aminocaproic acid/ phenyl-alanine, phenylglycine, p-hydroxyphenylglycine, p-amino-phenylalanine, y~-carboxyglutamic acid Aminopolycarboxyl.ic acid compounds: iminodiacetic acid, hydroxy~
ethyliminodiacetic acid, ethylenediaminediacetic acid, ethylenediaminetetraacetic acid, trans-cyclohexanediaminetetra-acetic acid, diethylenediamine-pentaacetic acid, ~-alanine-diacetic acid, diaminopimellic acid;
Aromatic carboxylic acid compounds: phthalic acid, terephthalic acid, homophthalic acid, phenylsuccinic acid, phenylmalonic acid, oxanylic acid-o-carboxylic acid, anthrany-linoacetic acid, 2,4-dihydroxy-benzoic acid, p-aminosalicylic acid, phthalylglutamic acid, kynurenine, ~liphatic and aromatic sulfonic acid compounds: 1,2-hydroxybenzene-3,5-disulfo-nic 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-diphosphoric acid.
For incorporation of such a chelating agent into a water-soluble base polymer, the chelatiny agent and the incorporation method to be employed are suitably selected depending on the side chains of the water-soluble base polymer employed, and the bonding formed as the result of the reactlon is also determined by their combination, as described ir, detail in Japanese Patent Publication No.
16979/1979 (USP 4024073)~
- 15 ~
The effect of promoting absorption of a medicine by the water-soluble macromolecular compound having chelat-ing activity obtained according to the present invention was examined by use of, for example, an Elcitonin preparation containing the lysine-dextran T-lS0 prepared according to Example 1 disclosed in Japanese Patent Publication No.
16979/1979 (USP 4024073) by .intrarectal in~ection in viv~
into rats and measuring the decrease in calcium concentration in se'rum, whereby it was found that said preparation exhibited a significant absorption promoting effect as compared with Control using no lysine-dextran T-150. These macromolecular adsorption are generally used in the formed alkali metal salts such as sodium sal~s or potassium salts, or ammonium salts.
The water soluble low molecular compound and the macromolecular compound having chelating action or the water-soluble polymer having incorporated a chelating agent in the present invention is used as a membrane absorption promoter.
These absorption promoters may be employed in amounts of 0.05 W~W % or more, generally in the range of from 0.1 to 50 W/W %, preferably from lo O to 30 W/W ~. As the vehicle to be employed for preparation of a suppository containing the above absorption promoter, a medicine and preferably a water-soluble salt to be added for increase of tonicity, there maysuitably be selected one from oily vehicles and water-soluble vehicles conventionally used in preparation of suppositories or rectal injections, and a surfactant may also be added if desired. of course, two or more promoters may be used together.
As these oily vehicles or water-soluble vehicles, there ma~ conveniently be used those as described in "The Theory and Practice of Industrial Pharmacy", p. 245 to 269 (1976).
The medicine to be used in th~ present invention is not particularly limited, but there may be employed ordinary pharmaceuticals, particularly pref~rably the so called water-soluble medicines ~hich are excellently soluble in water, such as water-soluble medicines with a partition coefficient of 50 or less in chloroform/water or medicines readily dissociated to ionsO For example, there may be included ~arious medicines such as hypnotics, tranquilizers, antiepileptics, antipyretics ! analgesics, antidepressants, muscle relaxants, antiin~lammatory agents, antiallergic agents, immunosuppressan~s, antirheumatics, vasodilators, antihemorrhagics antihypertensives, antibiotics, antibacterial agents, urinary tract sterilizers, antitumor agents, vitamins, hormones and galenicals. More specifically, typical examples are penicillin type antibiotics such as ampicillin, heta-cillin, amoxicillin, cyclacillin, cloxacillin, dicloxacillin, oxacillin, carindacillin, sulbenicillin, piperacillin, apal-cillin, methicillin, etc. or combined drugs of ampicillin or amoxicillin with oxacillin, cloxacillin, flo~acillin or dichloxacillin; cephalosporin type antibiotics such as cephalo-thine, cephazoline, cephaloridine, cephacetorile, cefoxitin, cefadroxil, cefatrizine, cephaloglycin, cephalexin, cephapirin, cephaclor, ceftezol, cefuroxime, cefsulodin, cefmetazole, etc.
and non-toxic salts thereof such as alkali metal salts (e.g.
sodium salts or potassium salts), ammonium salts or benzyl-amine salts. In addition, there may also be mentioned tetracycline type antibiotics such as doxycycline, oxycycline, etc.; aminosaccharide type antibiotics such as kanamycin, sisomicin, amikacin, tobramycin, netromycin, gentamycin, etc.;
peptide type antibiotics such as tuberactinomycin N, actino-mycin, etc. or non-toxic salts thereof; further peptide hormones such as insulin, somatostatin, calcitonin, angio-tensin,kallikrein, secretin, gastrisin, parathyroid hormone, etc.; and other medicines such as barbital, theophylline, "Aspirin"~mizoribine, bredinin, 5-fluorouracil, methotrexate, L-dopa, etc. The medicine may be employed in an amount, * Trademark for acetylsalicylic acid.
which may suitably be selected and designed. For example, in case of antibiotics such as ~-lactam antibiotics, 20 to 500 mg activity, generally 100 to 300 mg activity, or in case of peptide hormones such as insulin, 1 to 500 units may be contained per gram of preparation. In general the medicine may preferably be used in finely divided forms with 1 to 50 ~ diameters or as an aqueous solution.
The step of forming preparations may be performed according to conventional methods for production of prepa-rations in general such as rectal suppository, urethral suppository or vaginal suppository ointments or creams.
For example~ the absorption promoter selected, a water-soluble substance in an amount exhibiting higher osmotic pressure than isotonic sodium chloride solution and a medicine are added to a vehicle, optionally in combination with a surfactant, and these components are thoroughly mixed to provide preparations.
Further, in production of these preparation, there may also he added preservatives such as methyl- or propyl-p-oxybenzoate, colorants, aromas and stabilizers.
The present invention is further illustrated in detail by referring to the following Examples, by which the present invention is not limited at all but various medi-cines, hypertonicators and absorption promoters may be selected and combined in addition to those shown in Examples.
Example 1 Absorption effects under conditions with various tonicities were examined. Each sample solution was prepared by adding 0.1 W/W ~ CefmetazoleNa as medicine together with sodium oxalate or sodium glyoxylate as absorption promoter to a phosphate buffer of pH 7.0 conditioned with sodium chloride to a tonicity which is varied from isotonic to ,' .~. j twice hypertonic than isotonicttwo-fold tonicity), three times hypertonic than isotonic(three-fold tonicity), 5 times hypertonic than isotonic(five fold tonicity), 6 times higher than isotonic(six-fold tonicity) and 7 times hypertonic than isotonic~seven-fold tonicity).
The experiment was conducted in the following manner. Namely, Sprague Dawleg rats(male), weighing 200 to 300 g, were narco-tized (after fast for 20 hours) with pentobarbital(50 mg/kg) and thereafter subjected to hypoabdominal incision for a first cannulation at a position about 1.5 cm frcm the anus andalso another cannul-ation at a position 5 cm above said first cannulation.
Subsequently, the rectum was internally washed with about 50 mQ
of isotonic sodium chloride solution kept at 38C, and samples each of 10 mQ were circulated through the rectum for 5 minutes (2 mQ/minute) to make the concentration in the system constant. Then, 5 mQ of each sample was circulated at a flow rate of 2 mQ/minute, and samples each of 0.05 mQ
were collected at intervals of 10 minutes from 0 minute.
Each sample was diluted to 5 mQ with distilled water and the quantity of medicine disappeared by absorption was determined by W -SPeCtrophotometer.
As the result, the disappearance curve of Cefmetazole Wa under the condition of 0.1 W/W ~ sodium oxalate was obtained as shown in Fig. 1, in which x - x shows the result under the isotonic condition, a - a under two-fold tonicity, ~ - ~ under three-fold tonicity, o - o under five-fold tonicity, o - o under six-fold tonicity and ~ - ~ under seven-fold tonicity.
Fig. 2 also shows the absorption curve of Cefmetazole-Na under the above condition of 0.1 W/W
sodium oxalate at respective osmotic pressures.
., ,.~.. .
Fig. 3 shows the absorption curve of Cefmetazole~Na under the condition of 0.2 W/W % sodium oxalate at respective osmotic pressures.
Further, Fig. 4 shows the absorption curve of Cefmetazole Na under the condition of 0.5 W/W % sodium glyoxalate at respective osmotic pressures.
Example 2 Using 0.1 W/W % Cefoxitin-Na as medicine and 0.5 W/W % of sodium glyoxylate as absorption promoter under respective osmotic pressure conditions (namely two-fold, four-fold and six-fold tonicities with the use of sodium chloride) and following otherwise the same procedure as in Example 1, quantities of Cefoxitin disappeared by absorption were determined by UV-spectrophotometer similarly as in Example 1.
The results are shown in Fig~ 5, in which x---x is the disappearance curve by absorption only of Cefoxitin under isotonic condition without the use of sodium glyoxylate, x - x the disappearance curve of Cefoxitin with the use of sodium ~lYXYlate under isotonic condition, ~ - Q that under two-fold toni~ condition, o - o that under four-fold tonic condition, and ~ that under six-fold tonic condition, respectively.
Example 3 Quantities of 0.5 W/W ~ Cefmetazole-Na disappeared by absorption under isotonic and three-fold tonic conditions were determined, respectively, using sodium malate, sodium pyruvate, sodium phosphenolpyruvate, sodium ~-hydroxybutyrate, sodium ~-hydroxy glutarate, and sodium 2~phospho-D-glycerate.
The results ~re shown in Table 1.
~4~
- 2~ -Table 1 (values after 60 minutes) Isotonic Three-fold condition tonic condition Sodium malate 4.9% 10.2~
Sodium pyruvate 5.2% 10.9%
Sodium phosphenolpyruvate 7.3% 16.6%
Sodium ~-oxybutyrate 6.6% 14.0%
Sodium ~-oxyglutara~e 7.8% 16.5%
Sodium 2-phospho-D-glycerate 5.4% 13.8%
When no absorption promoter was employed, the quantity of 0.1 W/W % Cefmetazole-Na disappeared by absorption under isotonic condition was substantially negligible.
Example 4 Using a 0.01 % solution of Tuberactinomycin, rectum circulation experiments were conducted in the same manner as in Example 1, and the Tuberactinomycin concentrations in the Perfusates were determined by measurement of antimicrobial activities (according to Japanese antimicrobial standards) with lapse of time. As the result, absorptions through the rectum were found to be increased by the presence of EDTA-2Na and sodium chloride, as shown in Fig. 6.
Sample A (Control): 0.01% Tuberactinomycin 0.9~ sodium chloride Sample B (Control): 0.01% Tuberactinomycin 5% sodium chloride Sample C (Present invention): 0.01% Tuberactinomycin 5~ sodium chloride 0.05% EDTA disodium salt Sample D (Present invention): 0.01% Tuberactinomycin 5% sodium chloride 0.1% EDTA disodium salt o ~''` 1 Sample E (Present invention): 0.01~ Tuberactinomycin 5% sodium chloride 1~ EDTA disodium salt (Each samplP was dissolved in 0.1 M Tris-HCQ buffer and adjusted to pH 7~5.) Example 5 Using 1% solution of Tubexactinomycin (in 0.1 M
Tris-HCQ buffer, pH 7.5) as Control, an injection agent was prepared by adding 5% sodium chloride and 1.0% EDTA disodium salt to said solution. Each 0.5 mQ of these samples was injected into a rat through the anus and the concentration of Tuberactinomycin in the blood was measured to find that it appeared in the blood at concentrations shown below.
1~
Concentration ln blood (y/mQ) 10 min. 20 mln. 30 min. 45 min. 60 min. 90 min.
Control~ lower than measureable limit of anti-microbial activity Present invention: 5y 10~ lly 8~ 7~ 2y Example 6 Using 2% solution of Cephalotin-Na (in 0.1 M Tris~
HCQ buffer, pH 800) as Control, and injection agent was prepared by adding 6% sodium chloride and 1.0~ disodium EDTA mono-ethylate to said solùtion. Each 0.5 m~ of these samples was injected into a rat through the anus, and concentra-tions of Cephalothin in the blood were determined by measurement of antimicrobial activities (according to Japanese anti-microbial standards) to find the concentrations in blood were signifi~antly increased.
- 22 ~
Concentration in blood (y/mQ) 10 min~ 20 min. 30 min. 45 min~ 60 min. 90 min.
Control: - + <ly <ly 5 Present inv~ntion: 8y 12y 14y 5y 3~ -Example 7 Using a 0-04% solution of Theophylline (in 0.1 M
Tris-HCQ buffer, pH 8.0), concentrations of circulated fluids were measured by W absorption (~ma~=270 nm) with lapse of time similarly as in Example 1, whereby absorption by rectum was found to be increased by the presence of EDTA-2Na and sodium chloride as shown in Fig. 7.
A ~Control): 0.04% Theophylline, 0.9% sodium chloride B (Control); 0.04% Theophylline, 0.1% EDTA disodium salt, 0.8% sodium chloride, C (Present invention): 0~04% Theophylline, 0.1% EDTA
disodium salt, 2% sodium chloriae D (Present invention~: 0.04% Theophylline, 0.1% EDTA
disodium salt, 4% sodium chloride E (Present invention): 0.04% Theophylline, 0.1% EDTA
disodium salt, 8~ sodium chloride F (Present invention): 0.04% Theophylline, 1.0~ EDTA
disodium salt, 4% sodium chloride G (Present invention): 0.04% Theophylline, 4.0% ÉDTA
disodium salt, 4% sodium chloride (Every sample was dissolved in 0.1 M Tris-HCQ buffer and pH was adjusted all to 8Ø) Example 8 An intrarectal injection preparation was obtained by adding calcitonin (CT: 625 mu/mQ)based one the total amount; 25 ng/0.2 mQ), sodium oxalate (0.2 W/W % based on the total amount) and glucose (isotonic; 0.25 M/ three-fold tonic; 0.75 M, six-fold tonic; 1.5 M) to a base of ''```
iA'. ' ' " " ~
carboxyvinyl polymer (CVP: Wako Gel 105, produced by Wako Junyaku Co., Ltd~ and 0.2 mQ of this preparation was injected into rats (SD rats, four weeks of age). Calcium concentration after one hour was measured, and the relative efects were evaluated as compared with calcium concentra-tion by CVP and CT which was set at standard value of 1.
The results are shown in Table 2.
Table 2 MedicineIsotonic 3-fold tonic 6-fold tonic CT 1 1.05 1.67 CT ~ sodium oxalate 5.4 6.9 10.9 Example 9 Suppositories having the following compositions were inserted through the anus into six male beagle dogs, weigh-ing 9.5 to 10.5 kg, and concentrations in the blood were measured 15 minutes, 30 minutes, 60 minutes, 120 minutes and 180 minutes after administration to obtain the results as shown in Table 3.
Control: Suppository comprising 100 mg activity of TuberactinomyCin N-sulfate pulverized to 50 microns or less and 400 mg o~ cacao butter Present invention: Suppository comprising 100 mg activity of Tuberactinomycin N sulfate, 50 mg of sodium chloride, 10 mg of EDTA-2Na and 180 mg of cacao butter * Trademark Table 3 Beagle~og No. Concentration in blood (y/mQ) 15 min.30 min.60 min.120 min.180 min.
1 - 0.8 0 - -2 1.0 2.3 1.3 - -Control 3 1.5 4 - 0.9 0.7 - - _ _ _ 6 - _ _ _ 1 3.9 12.0 7.6 4.2 2.2 2 9.7 11.7 5.4 3.5 2.7 Present 3 9.2 10.0 8.1 4.8 3.0 invention 4 5.6 7.7 7.4 3.2 1.9 5 10.8 9.2 7.3 6.0 2.0 ~5 6 6.9 11.4 9.3 7.7 4.4 Example 10 As the group of polycarboxylic acid compounds (aliphatic compounds, there were employed sodium oxalate, malonic acidt maleic acid, fumaric acid, adipic acid, glutaric acid, pimellic acid, EDTA-2Na, trans-cyclohexane-diaminetetraacetic acid (CyDTA), iminodiacetic acid, nitrilotriacetic acid, ethylmalonic acid~ trans-aconitic acid, diaminopropanoltetraacetic acid (DTPA-OH), eac~ at a concentration of 0~1% W/V, and the quantities of Cephalothin disappeared by absorption were determined one hour after administration of 0.1% W/V Cephalothin-Na under isotonic (X 1), two-fold tonic (X 2) and four-fold tonic conditions (X 4), respectively. The experiments were conducted similarly as in Example 1~ That is, Wistar-strain male rats, weighing 250 to 300 g, were narcotized with pentobarbital (50 mg/kg) and thereafter subjected to hypoabdominal incision for a first cannulation at a posi-tion about 1.5 cm from the anus and also another cannulation at a position 5 cm ~x~e said first cannulation.
Subse~uently, ~e rectum was internally washed with about 20 mQ of isotonic sodium chlorid~ solution kept at 38C, and each sample was circulated at a flow rate of 2 ~Q/minute for 5 minutes to make the concentration in the system constant. Then, 5 mQ of each sample was circulated at a flow rate of 2 mQ/minute, and samples each of 0.05 mQ were collected at intervals of 10 minutes. Each sample was diluted and the qua~tity of Cephalothin diappeared was determined by UV- Spectrophotometer or high-speed liquid chromatography.
The results of Cephalothin disappeared when collecting respective samples after one hour are shown below in Table 4.
Table 4 15 Group of polycarboxylic Osmotic pressure acids_~aliphatic compounds) No additlOn 1.2% 1.6% 3.1%
Sodium oxalate 6.6% 11.1% 18.3%
Malonic acid 4.5% - 13O0%
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-acGnitic acid 10.5% 18.6% 27.8%
Ethylmalonic acid 12.3% 24.2% 36.9%
Example 11 As the group of aliphatic keto-carboxylic acid 4~2 - 2~ ~
compounds, there were employed sodium glyoxylate~ sodium pyruvate, sodium ketomalonate, sodium ~-ketoglutarate, sodium oxaloacetate, ~-ketobutyric acid, ~-ketovaleric acid and levulinic acid each at a concentration of 0.1 W/V ~ and the quantities of Cephalothin disappeared by absorption were determined one hour after administration of 0.1 W/V ~ Cephalothin-Na under isotonic (X 1), two-fold tonic (X 2) and four-fold tonic conditions, respectively.
The results are shown in Table 5. ~The experimental method was the same as in Example 10, and units in Table are percents.) Table 5 Group of aliphatic keto- Osmotic pressure carboxylic acids __X 1 X 2 X 4 Sodium glyoxylate ~.9 _ 13.1 Sodium pyruvate 7.0 11.~ 23.1 Sodium ketomalonate 8.4 12.7 19.6 ~-ketoglutaric acid 7.1 - 25.6 Sodium oxaloacetate 13.8 17.5 22.2 ~-ketobutyric acid 11.2 18.3 30.9 ~-ketovaleric acid 9.8 14.7 23.2 Levulinic acid 11.9 21.1 34.3 No addition 1.2 1.6 3.1 Example 12 Using citric acid, malic acid, lactic acid, glucuronic acid and galacturonic acid as the group of aliphatic hydroxy-carboxylic acid compounds each at a concentration of 0.1 W/V %, quantities of Cephalothin disappeared by absorption were determined one hour after administration of 0.1 W/V % Cephalothin-Na under isotonic (X 1), two-~old tonic (X 2) and four~fold tonic (X 4) conditions, respectively. The results are shown in Table 3S 6. (The experiment method was the same as in Example 10, and units in the Table are percents.) Table 6 Group of aliphatic hydroxy- Osmotie pressure carboxylic aeid c_mpounds X 1 X 2 X 4 Citrle acid 4.5 - 11.3 Malie aeid 7.2 12.3 18.8 Lactic acid 4.3 - 13.5 Glucuronic acid 5.5 11.1 16.4 Galacturonic acid5.8 10.5 16.1 No addition 1.2 1.6 3.1 Example 13 Using as the group of aromatic earboxylie acids, sodium salicylate, sodium sulfosalicylate, sodium phthalate and 2,6-dihydrox~benzoic acid, each at a eoncentration of 0.5 W/V %, quantities of Cephalothin disappeared by absorp-tion were determined one hour after administration of 0.1 W/V % Cephalothin-Na under isotonic (X 1), two-fold tonie (X 2) and 4-fold tonie (X 4) eonditions, respectively.
The results are shown in Table 7. (The experiment method was the same as in Example 10, and the units in the Table are percents.) Table 7 Group of aromatie earboxylic _ Osmotic pressure 25 aeid eompounds X 1 _X 2 X 4 Sodium salieylate 8.9 16.5 29.8 Sodium sulfosalieylate 10.4 - 19.7 Sodium phthalate 7.1 - 18.9 30 2,6-dihydroxybenzoie aeid 9.5 15.3 22.9 Example 14 As the group of aromatie sulfonie aeid eompounds, 1,2-dihydroxybenzene-3,5-disulfonie aeid (DHBDS) and 1-naphthol-3,6-disulfonie aeid (NDS) were employed, eaeh at a eoneentration of 0.1 W/V %, and the experiments were ~L~8~
performed similarly as i.n Example 10. The results are shown in Table 8, wherein the units are percents.
Table 8 5 Group of aromatic sulfonic Osmotic pressure acid compounds X 1 X ~ X 4 DHBDS 9.8 - 22.0 NDS 12~6 19.8 31.6 Example 15 Example 1 was repeated except that butyric acid, isovaleric acid, sodium caproate, sodium caprylate, sodium caprate and sodium laurate were employed as aliphatic carboxylie aeid compounds, each at a concentration of 0.1 W/V %, to obtaln the results as shown in Table 9.
(The units in the Table are percents.) Table_9 Fat-ty acids Osmotic pressure Butyrie acid 9.9 17.1 21.0 Isovaleric acid 7.7 - 14.4 Sodium caproate10.4 14.7 17.2 Sodium caprylate5.8 _ 13.0 Sodium caprate 5.2 - 8.6 Sodium laurate 3.9 - 6.5 Example 16 Example 10 repeated except that the aliphatic earboxylic eompounds were replaced with ethylacetoacetate and 3-phenylacetyl acetone as diketo-compounds to obtain the results as shown in Table 10, wherein the units are pereents.
T _ e 10_ Group of diketo-compounds Osrnotic pressure Ethylacetoacetate14.6 20.2 26.7
Sodium pyruvate 5.2% 10.9%
Sodium phosphenolpyruvate 7.3% 16.6%
Sodium ~-oxybutyrate 6.6% 14.0%
Sodium ~-oxyglutara~e 7.8% 16.5%
Sodium 2-phospho-D-glycerate 5.4% 13.8%
When no absorption promoter was employed, the quantity of 0.1 W/W % Cefmetazole-Na disappeared by absorption under isotonic condition was substantially negligible.
Example 4 Using a 0.01 % solution of Tuberactinomycin, rectum circulation experiments were conducted in the same manner as in Example 1, and the Tuberactinomycin concentrations in the Perfusates were determined by measurement of antimicrobial activities (according to Japanese antimicrobial standards) with lapse of time. As the result, absorptions through the rectum were found to be increased by the presence of EDTA-2Na and sodium chloride, as shown in Fig. 6.
Sample A (Control): 0.01% Tuberactinomycin 0.9~ sodium chloride Sample B (Control): 0.01% Tuberactinomycin 5% sodium chloride Sample C (Present invention): 0.01% Tuberactinomycin 5~ sodium chloride 0.05% EDTA disodium salt Sample D (Present invention): 0.01% Tuberactinomycin 5% sodium chloride 0.1% EDTA disodium salt o ~''` 1 Sample E (Present invention): 0.01~ Tuberactinomycin 5% sodium chloride 1~ EDTA disodium salt (Each samplP was dissolved in 0.1 M Tris-HCQ buffer and adjusted to pH 7~5.) Example 5 Using 1% solution of Tubexactinomycin (in 0.1 M
Tris-HCQ buffer, pH 7.5) as Control, an injection agent was prepared by adding 5% sodium chloride and 1.0% EDTA disodium salt to said solution. Each 0.5 mQ of these samples was injected into a rat through the anus and the concentration of Tuberactinomycin in the blood was measured to find that it appeared in the blood at concentrations shown below.
1~
Concentration ln blood (y/mQ) 10 min. 20 mln. 30 min. 45 min. 60 min. 90 min.
Control~ lower than measureable limit of anti-microbial activity Present invention: 5y 10~ lly 8~ 7~ 2y Example 6 Using 2% solution of Cephalotin-Na (in 0.1 M Tris~
HCQ buffer, pH 800) as Control, and injection agent was prepared by adding 6% sodium chloride and 1.0~ disodium EDTA mono-ethylate to said solùtion. Each 0.5 m~ of these samples was injected into a rat through the anus, and concentra-tions of Cephalothin in the blood were determined by measurement of antimicrobial activities (according to Japanese anti-microbial standards) to find the concentrations in blood were signifi~antly increased.
- 22 ~
Concentration in blood (y/mQ) 10 min~ 20 min. 30 min. 45 min~ 60 min. 90 min.
Control: - + <ly <ly 5 Present inv~ntion: 8y 12y 14y 5y 3~ -Example 7 Using a 0-04% solution of Theophylline (in 0.1 M
Tris-HCQ buffer, pH 8.0), concentrations of circulated fluids were measured by W absorption (~ma~=270 nm) with lapse of time similarly as in Example 1, whereby absorption by rectum was found to be increased by the presence of EDTA-2Na and sodium chloride as shown in Fig. 7.
A ~Control): 0.04% Theophylline, 0.9% sodium chloride B (Control); 0.04% Theophylline, 0.1% EDTA disodium salt, 0.8% sodium chloride, C (Present invention): 0~04% Theophylline, 0.1% EDTA
disodium salt, 2% sodium chloriae D (Present invention~: 0.04% Theophylline, 0.1% EDTA
disodium salt, 4% sodium chloride E (Present invention): 0.04% Theophylline, 0.1% EDTA
disodium salt, 8~ sodium chloride F (Present invention): 0.04% Theophylline, 1.0~ EDTA
disodium salt, 4% sodium chloride G (Present invention): 0.04% Theophylline, 4.0% ÉDTA
disodium salt, 4% sodium chloride (Every sample was dissolved in 0.1 M Tris-HCQ buffer and pH was adjusted all to 8Ø) Example 8 An intrarectal injection preparation was obtained by adding calcitonin (CT: 625 mu/mQ)based one the total amount; 25 ng/0.2 mQ), sodium oxalate (0.2 W/W % based on the total amount) and glucose (isotonic; 0.25 M/ three-fold tonic; 0.75 M, six-fold tonic; 1.5 M) to a base of ''```
iA'. ' ' " " ~
carboxyvinyl polymer (CVP: Wako Gel 105, produced by Wako Junyaku Co., Ltd~ and 0.2 mQ of this preparation was injected into rats (SD rats, four weeks of age). Calcium concentration after one hour was measured, and the relative efects were evaluated as compared with calcium concentra-tion by CVP and CT which was set at standard value of 1.
The results are shown in Table 2.
Table 2 MedicineIsotonic 3-fold tonic 6-fold tonic CT 1 1.05 1.67 CT ~ sodium oxalate 5.4 6.9 10.9 Example 9 Suppositories having the following compositions were inserted through the anus into six male beagle dogs, weigh-ing 9.5 to 10.5 kg, and concentrations in the blood were measured 15 minutes, 30 minutes, 60 minutes, 120 minutes and 180 minutes after administration to obtain the results as shown in Table 3.
Control: Suppository comprising 100 mg activity of TuberactinomyCin N-sulfate pulverized to 50 microns or less and 400 mg o~ cacao butter Present invention: Suppository comprising 100 mg activity of Tuberactinomycin N sulfate, 50 mg of sodium chloride, 10 mg of EDTA-2Na and 180 mg of cacao butter * Trademark Table 3 Beagle~og No. Concentration in blood (y/mQ) 15 min.30 min.60 min.120 min.180 min.
1 - 0.8 0 - -2 1.0 2.3 1.3 - -Control 3 1.5 4 - 0.9 0.7 - - _ _ _ 6 - _ _ _ 1 3.9 12.0 7.6 4.2 2.2 2 9.7 11.7 5.4 3.5 2.7 Present 3 9.2 10.0 8.1 4.8 3.0 invention 4 5.6 7.7 7.4 3.2 1.9 5 10.8 9.2 7.3 6.0 2.0 ~5 6 6.9 11.4 9.3 7.7 4.4 Example 10 As the group of polycarboxylic acid compounds (aliphatic compounds, there were employed sodium oxalate, malonic acidt maleic acid, fumaric acid, adipic acid, glutaric acid, pimellic acid, EDTA-2Na, trans-cyclohexane-diaminetetraacetic acid (CyDTA), iminodiacetic acid, nitrilotriacetic acid, ethylmalonic acid~ trans-aconitic acid, diaminopropanoltetraacetic acid (DTPA-OH), eac~ at a concentration of 0~1% W/V, and the quantities of Cephalothin disappeared by absorption were determined one hour after administration of 0.1% W/V Cephalothin-Na under isotonic (X 1), two-fold tonic (X 2) and four-fold tonic conditions (X 4), respectively. The experiments were conducted similarly as in Example 1~ That is, Wistar-strain male rats, weighing 250 to 300 g, were narcotized with pentobarbital (50 mg/kg) and thereafter subjected to hypoabdominal incision for a first cannulation at a posi-tion about 1.5 cm from the anus and also another cannulation at a position 5 cm ~x~e said first cannulation.
Subse~uently, ~e rectum was internally washed with about 20 mQ of isotonic sodium chlorid~ solution kept at 38C, and each sample was circulated at a flow rate of 2 ~Q/minute for 5 minutes to make the concentration in the system constant. Then, 5 mQ of each sample was circulated at a flow rate of 2 mQ/minute, and samples each of 0.05 mQ were collected at intervals of 10 minutes. Each sample was diluted and the qua~tity of Cephalothin diappeared was determined by UV- Spectrophotometer or high-speed liquid chromatography.
The results of Cephalothin disappeared when collecting respective samples after one hour are shown below in Table 4.
Table 4 15 Group of polycarboxylic Osmotic pressure acids_~aliphatic compounds) No additlOn 1.2% 1.6% 3.1%
Sodium oxalate 6.6% 11.1% 18.3%
Malonic acid 4.5% - 13O0%
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-acGnitic acid 10.5% 18.6% 27.8%
Ethylmalonic acid 12.3% 24.2% 36.9%
Example 11 As the group of aliphatic keto-carboxylic acid 4~2 - 2~ ~
compounds, there were employed sodium glyoxylate~ sodium pyruvate, sodium ketomalonate, sodium ~-ketoglutarate, sodium oxaloacetate, ~-ketobutyric acid, ~-ketovaleric acid and levulinic acid each at a concentration of 0.1 W/V ~ and the quantities of Cephalothin disappeared by absorption were determined one hour after administration of 0.1 W/V ~ Cephalothin-Na under isotonic (X 1), two-fold tonic (X 2) and four-fold tonic conditions, respectively.
The results are shown in Table 5. ~The experimental method was the same as in Example 10, and units in Table are percents.) Table 5 Group of aliphatic keto- Osmotic pressure carboxylic acids __X 1 X 2 X 4 Sodium glyoxylate ~.9 _ 13.1 Sodium pyruvate 7.0 11.~ 23.1 Sodium ketomalonate 8.4 12.7 19.6 ~-ketoglutaric acid 7.1 - 25.6 Sodium oxaloacetate 13.8 17.5 22.2 ~-ketobutyric acid 11.2 18.3 30.9 ~-ketovaleric acid 9.8 14.7 23.2 Levulinic acid 11.9 21.1 34.3 No addition 1.2 1.6 3.1 Example 12 Using citric acid, malic acid, lactic acid, glucuronic acid and galacturonic acid as the group of aliphatic hydroxy-carboxylic acid compounds each at a concentration of 0.1 W/V %, quantities of Cephalothin disappeared by absorption were determined one hour after administration of 0.1 W/V % Cephalothin-Na under isotonic (X 1), two-~old tonic (X 2) and four~fold tonic (X 4) conditions, respectively. The results are shown in Table 3S 6. (The experiment method was the same as in Example 10, and units in the Table are percents.) Table 6 Group of aliphatic hydroxy- Osmotie pressure carboxylic aeid c_mpounds X 1 X 2 X 4 Citrle acid 4.5 - 11.3 Malie aeid 7.2 12.3 18.8 Lactic acid 4.3 - 13.5 Glucuronic acid 5.5 11.1 16.4 Galacturonic acid5.8 10.5 16.1 No addition 1.2 1.6 3.1 Example 13 Using as the group of aromatic earboxylie acids, sodium salicylate, sodium sulfosalicylate, sodium phthalate and 2,6-dihydrox~benzoic acid, each at a eoncentration of 0.5 W/V %, quantities of Cephalothin disappeared by absorp-tion were determined one hour after administration of 0.1 W/V % Cephalothin-Na under isotonic (X 1), two-fold tonie (X 2) and 4-fold tonie (X 4) eonditions, respectively.
The results are shown in Table 7. (The experiment method was the same as in Example 10, and the units in the Table are percents.) Table 7 Group of aromatie earboxylic _ Osmotic pressure 25 aeid eompounds X 1 _X 2 X 4 Sodium salieylate 8.9 16.5 29.8 Sodium sulfosalieylate 10.4 - 19.7 Sodium phthalate 7.1 - 18.9 30 2,6-dihydroxybenzoie aeid 9.5 15.3 22.9 Example 14 As the group of aromatie sulfonie aeid eompounds, 1,2-dihydroxybenzene-3,5-disulfonie aeid (DHBDS) and 1-naphthol-3,6-disulfonie aeid (NDS) were employed, eaeh at a eoneentration of 0.1 W/V %, and the experiments were ~L~8~
performed similarly as i.n Example 10. The results are shown in Table 8, wherein the units are percents.
Table 8 5 Group of aromatic sulfonic Osmotic pressure acid compounds X 1 X ~ X 4 DHBDS 9.8 - 22.0 NDS 12~6 19.8 31.6 Example 15 Example 1 was repeated except that butyric acid, isovaleric acid, sodium caproate, sodium caprylate, sodium caprate and sodium laurate were employed as aliphatic carboxylie aeid compounds, each at a concentration of 0.1 W/V %, to obtaln the results as shown in Table 9.
(The units in the Table are percents.) Table_9 Fat-ty acids Osmotic pressure Butyrie acid 9.9 17.1 21.0 Isovaleric acid 7.7 - 14.4 Sodium caproate10.4 14.7 17.2 Sodium caprylate5.8 _ 13.0 Sodium caprate 5.2 - 8.6 Sodium laurate 3.9 - 6.5 Example 16 Example 10 repeated except that the aliphatic earboxylic eompounds were replaced with ethylacetoacetate and 3-phenylacetyl acetone as diketo-compounds to obtain the results as shown in Table 10, wherein the units are pereents.
T _ e 10_ Group of diketo-compounds Osrnotic pressure Ethylacetoacetate14.6 20.2 26.7
3-Phenylacetyl acetone9.1 16.3 22.2 Example 17 Example 10 was .repeated except that the aliphatic carboxylic acid compounds were replaced with the group of amino-carboxylic acid compounds and imino-carboxylic acid compounds of DL-glycine, DL-hydroxyproline (each at 0.5 W/V ~), DL-phenylalanine, DL~phenylglycine, N-phenylglycine, DL-aspartic acid, DL-glutamic acid, ~-methyl DL-glutamate, DL-cysteic acid, ~-aminocaproic acid, N-dimethylphenyl-alanine, y-carboxyglutamic acid, glycyl-DL-aminobutyric acid, glycyl-DL aspartic acid (each at 0.1 W/V %). The results are shown in Table ll,wherein the units are percents.
Table 11 Group of amino-carboxylic _ Osmotic pressure acid and iminocarboxylic acid compounds 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 ~-methyl DL-glutamate11.9 - 21.4 DL-cysteic acid 5.3 9.0 14.6 -aminoCaproiC acid7.1 11.8 17.0 N-dimethylphenylalanine 10.9 - 25.5 3S y-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 was repeated except that as other acid compounds glyceLo-3-phosphoric acid, fructose-1,6-diphos-phoric acid and ethylenediaminetetrakis5methylenephosphonic acid)(EDTPO) were used each at 0.1 W/V % in place of the aliphatic carhoxylic acid compounds. The results are shown in Table 12, wherein the units are percents.
Table 12 Acid compounds Osmotic pressure X 1 X 2_ X
Glycero-3-phosphoric acid 4.0 - 11.5 Fructose~1,6-diphosphoric acid4.1 7.5 13.3 EDTPO 7.6 - 20.0 Example 19 Cephalothin-Na ~1 g activity) as medicine, ~-ke'ro-glutaric acid-Na (1 g) as absorption promoter and sodium chloride (500 mg) as hypertonicator were each pulverized and-mixed together. A homogeneous dispersion was prepared by adding to the resulting mixture a base of~Witepsol H-15~*
previously molten by fusion to a total amount of 10 g.
The dispersion was intrarectally administered at a dose of 50 mg/kg to Wistar-strain rats (male, weighing 250 to 300 g four per one group) and blood sampling was performed 15 minutes, 30 minutes, 60 minutes and 120 minutes after administration for measurement of Cephalothin concentration in serum (according to the bioassay using Bacillus subtilis ATCC 6633). As Controls, there were also obtained a preparation containing sodium chloride without use of the absorption promoter (Control 1) and a preparation containing the absorption promoter without use of sodium chloride (Control 2). Further, another preparation of this invention was also prepared by use of 1 g of a-ketobutyric acid in * Trademark for a suppository base consisting of ~C12-C~ ) saturated fatty acid trigIycerides with varying propor~ions of partial glycerides.
place of the above absorption promoter, following otherwise the same procedure as described above.
As the result, Cephalothin concentrations Eor respective preparations were found as listed in Table 13.
_able 13 Preparation Concentration in blood (~/mQ) -15 min. 30 min. 60 min. 120 min.
Control 1 (sodium chloride) 0.20.5 Control 2 (~-ketoglutaric acid-Na) 2.1 5.3 1.2 0.3 Present invention (~-ketoglutaric acid-Na/ 5.9 11.4 3.1 1.2 sodium chloride) Present invention (~-ketobutyric ~cid/ 7.913.0 4~5 1.4 sodium chloride) Example 20 Tuberactinomycin N-sulfate (1 g activity) as medicine, D-phenylglycine as absorption promoter (1 g) and sodium chloride as hypertonicator (500 mg) were each pulverized and thoroughly mixed. To the resulting mixture, there was added Witepsol H-15 previously molten by heating, followed by homogeneous dispersion, to provide a suppository for intrarectal administration. Example 19 was also repeated except that L-aspartic acid (1 g) was used in place of D-phenylglycine to obtain a suppository for intrarectal administration.
As Control, a preparation with the same composi-tion as the above preparation except for containing no absorption promoter was also prepared. Each of these prepa-rations was administered to rats and concentrations in blood were measured in the same manner as in Example 19 to obtain the results as shown in Table 1~.
- 3~ -Table 14 Preparation Concentrations in blood (~/mQ) 15 min.30 min. 60 min.120 minO
5Control (sodium chloride) 0.9 1.8 0.3 Present inven-tion ~D-phenylglycine/ 13.1 10.7 3.5 1.3 sodium chloride) Present invention 10(L-aspartic acid/ 8.4 10.3 2.8 0.9 sodium chloride) Example 21 Ten units of Elcitonin[Asu. (1.7) eel calcitonin]
as meaicine, pulverized EDTA-2Na (20 mg) as absorption promoter and pulverized sodium chloride as hypertonicator (50 mg) were dissolved in 5~ gelatin solution to an amount of 1 g, which was then administered intrarectally to S.D.
rats of four weeks of age each in an amount of 0.1 mQ.
Calcium concentrations in serum were measured 15 minites, 30 minutes, 60 minutes and 90 minites after administration according to the atomlc absorption method. The same experi-ment was repeated except that 20 mg of CyDTA was employed in place of EDTA-2Na. Further, as Control, a preparation was prepared without use of the absorption promoter, followed by similar procedure. The results are shown in Fig. 8, in which o - o indicate calcium concentrations in serum in case of the preparation containing EDTA-2Na as absorption promoter of this invention, ~ - ~ indicating calcium concen-trations in serum in the case of the preparation containing CyDTA of this invention and further o - o indicatiny calcium concentration in serum in the case of the preparation as Control containing no absorption promoter.
Example 22 To a 0.1 W/W ~ Cephalothin-Na solution, there was added 0.1 W/W ~ pectinic acid and further mannitol was added at various levels to prepare isotonic solution, two-fold tonic solution and four-fold tonic solution, respectively.
As the Control,an isotonic solution without use of pectinic acid was also prepared. Subsequently, these samples were administered to Wistar-strain rats similarly as in E~ample 10 and quantities of Cephalothin disappeared by absorption were measured.
The results are shown in Fig. ~, wherein ~ - ~
indicates the disappearance curve of Cephalothin in the case of the Control using no pectinic acid, ~ -O disappearance curve in the case of an isotonic solution using pectinic acid, o - o that of two-fold tonic solution using pectinic acid and ~
that of f~ur-fold tonic solution using pectinic acid.
As apparently seen from Fig. 9, the use of pectinic acid improves remarkably the absorption of Cephalothin and further improvement is brought about by using in combination pectinic acid under hypertonic conditions.
Example 23 In place of pectinic acid in the above Example 22, there were employed sodium alginate, sodium carboxymethyl cellulose, sodium polyacrylate, chondroitin sulfate, sodium polyaspartate and sodium polyglutamate each at a concentra-tion of 0.1 W/W ~, and each solution was ad~usted with sodium chloride to various tonicities, namely isotonic (X 1), two-fold tonic (X 2) and four fold tonic (X 4) solutions.
As the result, the quantities of Cephalothin disappeared at the time of sampling 60 minutes after circulat:ion were found as shown in Table 15.
Table 15 Absorption promoter ___ Osmotic pressure Sodium alginate 6.3%10.2~ 22.4%
Sodium carboxymethyl cellulose 7.1%10.2% 18.7%
Sodium polyacrylate 6.7% - 14.6%
Chondroitin sulfate4~0% 6.7% 11.5%
Sodium polyaspartate8.4%11.5% ~0.4%
Sodium polyglutamate7.9%15.0% 33.6%
No addition 1.2%1.6% 3.1 Example 24 Using absorption promoters, prepared as described hereinafter in Reference examples, of aspartic acid-carboxy-methyl cellulose, iminodiacetic acid-alginic acid, imino-diacetic acid-carboxymethyl starch, glycine-starch, glycine-polyacrylic acid, ethylenediaminetetraacetic acid-dextran and hydrochelidonic acid-albumin, various samples of preparations were obtained with adjustment of tonicity to isotonic (X 1), two-fold tonic (X 2) and four-fold tonic (X 4). For each sample, the quantity of Cephalothin disappeared was determined similarly as in Example 10. As the result, the quantities of Cephalothin disappeared at the time of sampling 60 minutes after circulation were found as shown in Table 16.
Table 16 Absorption promoter _ Osmotic pressure X 1 X 2_ X 4 S Aspartic acid-carboxymethyl7.0% 10.4% 22.6%
cellulose Iminodiacetic acid-alginic acid 7.2%10.5% 24.6%
Iminodiacetic acid-carboxy-methyl starch 5.2~9.8~ 18.8 10 Glycine-starch 5.1%8.8~ 11.9~
Glycine polyacrylic acid 6.9% 10.1~ 17.0%
Ethylenediaminetetraacetic acid-dextran 5.8%9.2~ 16.7%
Hydrochelidonic acid-albumin4.2% - 9.5 Example 25 Elcitonin[Asu -eel calcitonin] (100 units and 10 units), sodium alginate (50 mg~ and sodlum chloride (50 mg) were dissolved in 1 mQ of distilled water. Each solution (0.1 mQ) was administered intrarectally to SD-strain male rats tfour weeks of age) and calcium concen-trations in serum were measured 30 minutes, 60 minutes and 90 minutes after administration by the atomic absorption method. As Control, there was used a solution containing no sodium alginate (adjusted to 100 units of Elcitonin).
Further, a s~lar test was conducted by use of 50 mg of pectinic acid in place of sodium alginate.
The results are shown in Fig. 10, wherein x-~--x indicates calcium concentrations in serum in the case of the Control, o - o those in the case of a solution containing sodium alginate and sodium chloride adjusted to 100 units of Elcitonin, ~ - ~ those in the case of a solution containing pectinic acid and sodium chloride at 100 units of Elcitonin, ~ ~ those in the case of a solution containing sodium alginate and sodium chloride at 10 units of Elcitonin, A - ~ those in the case of a solution containing pectinic acid and sodium chloride at 10 units of Elcitonin, respectively.
Example 26 Using ampicillin-Na (20 g potency) as medicine, sodium oxalate as absorption promoter (0.5 g) and sodium chloride (4 g) as water-soluble solution for higher tonic conditions, which are each pulverized, a homogeneous dis-persion was prepared by adding these components to a base of 50 g of peanut oil, followed further by dilution with peanut oil to a total amount of 100 g. The preparation was then filled in aliquots each of 1 g in gelatin soft capsules.
Example 27 Tuberactinomycin N sulfate (20 g), sodium chloride (3 g) as water-soluble substance for hypertonic conditions and sodium oxalate as absorption promoter (0.2 g), which were each pulverized, were added to an oily base of peanut oil to a total amount of 100 g to obtain rectal capsules.
Example 28 Cefazolin Na (200 g activity), D-phenylglycine (50 g) and sodium chloride (50 g) were each pulveri~ed and mixed together To the resulting mixture, there was added "Witepsol W 35"molten by heating to 1 kg, followed by homo geneous dispersion. The dispersion was then molded in a suppository containing to provide suppositories each of 1 g.
Example 29 Ampicillin-Na (250 g activity), D-phenylglycine (200 g) and sodium chloride (50 g), each being pulverized, were mixed and the resulting mixture was mixed with l'Witepsol H-15"molten by heating to an amount of 1 kg, which was further homogeneously dispersed. The dispersion was molded in suppository containers to provide suppositories * Trademark each of 1 g.
Example 30 Finely pulverized ampicillin3H2O (250 g activity), ~-ketobutyric acid (100 g) and finely pulverized sodium chloride (50 g) were mixed together. The resultlng mixture was mixed with Witepsol W-35 molt~n by hea-ting to an amoun-t of 1 kg, followed by homogeneous dispersion. Suppositories each of 1 g were molded in suppository con-tainers.
Example 31 Einely pulverized Cephalothin-Na (250 g Potency), ethyl acetate ~100 g) and finely divided sodium chloride (50 g) were mixed with sesame oil to an amount of 1 kg to form a homogeneous dispersion. The dispersion was filled in aliquots each of 2 g into plastic injection cylinders to obtain intrarectal injection preparations.
Example 32 Tuberactinomycin N sulfate (500 g Potency), oxalo-acetic acid (100 g) and sodium chloride (50 g) were each pulverized and mixed. The mixture was mixed and homogeneously dispersed with Witepsol ~-5 molten by heating -to an amount of 1 kg. The dispersion was molded in suppository containers to provide suppositories (each 2.5 g).
Example 33 One hundred thousand units of E,lcitonin, 20 g of finely pulverized CyDTA and 50 g of finely pulverized sodium chloride were added to Witepsol ~1-15 molten by heating to an amount of 1 kg, and the resultiny mixture was molded in aliquots each of 1 g in suppository containers to provide suppositories (1 g).
Example 34 One hundred thousand units of Elcitonin, 30 g of finely pulveri2ed sodium phenylpyruvate and 250 g of finely pulverized mannitol were dispersed by dissolution in 0.1%
carboxyvinyl polymer solution"(Wako Gel', trademaxk , produced by Wako Junyaku Co., Ltd.) to an amount of 1 kg, which was then injected into plastic applicators in aliquots each of 1 g to provide intrarectal injection preparations.
Example 35 Gentamycin (200 g Potency), sodium caproate (50 g) and sodium chlorid~ (50 g) were each finely pulverized and mixed together. The mixture was mixed with ~itepsol W-35 molten by heating to an amount of 1 kg, and the resulting mixture was molded in suppository containers to provide 1 g suppositories.
Example 36 Amicacin sulfate (200 g Potency), y-ketoglutamic acid (50 g) and sodium chloride (50 g) were each finely divided and mixed together, and Witepsol H 15 molten by ~0 mixing was added to the mixture to an amount of 1 kg.
Further, the resulting mixture was molded in suppository containers to provide 1 g suppositories.
Example 37 Cephalothin-Na (200 g Potency), sodium alginate (50 g) and sodium chloride (50 g), each being pulverized, were mixed and the resulting mixture was dissolved in 2%
gelatin solution to a volume of one liter, which was then filled into injection cylinders in aliquots each of 1 mQ
to provide intrarectal injection preparations.
Example 38 Gentamycin (100 g Potency), sodium pectinate (50 g) and mannitol (250 g), each being pulverized, were mixed and the mixture was homogeneously dispersed in 5~
gelatin solution to a volume of one liter, which was then filled into injection Cylinder5 in aliquots each of 1 mQ
to provide intrarectal injection preparations.
Example 39 One thousand units of Elcitonin , 50 g of sodium pectinate and 250 g of mannitol were each pulverized and mixed together. The resulting mixture was dispersed homo-geneously in 5~ gelatin solution to a volume of one liter, which was then filled into injection cylinders in aliquots each of 1 mQ to provide injection preparations for vaginal suppositories.
Example 40 One thousand units of Elcitonin, 50 g of sodium pectinate and 250 g of mannitol were dispersed homogeneously in Witepsol H-15 molten by heating to an amount of 1 kg, which was then filled in suppository containers in ali~uots each of 1 g to provide rectal suppositories.
Example 41 One thousand units of Elcitonin, 50 g of sodium alginate and 5 g of sodium chloride were dissolved in 100 mQ
of distilled water and the solution was added to'~itepsol H-5~containing l~Span 60~produced by Kao-Atlas Co.) to an amount of 500 g, followed further by homogeneous emulsi-fying. The emulsion was filled in suppository containers in aliquots each of 1 g to provide rectal suppositories.
Example 42 Cefoxitin-Na (200 g Potency), sodium alginate (50 g) and sodium chloride (50 g) each being pul~erized were mixed and dispersed in Witepsol H-5 molten by heating to an amount of 1 kg, which was then filled in suppository c~ntainers in aliquots each Of 1 g to provide 5UPPSitories.
* Trademark for sorbitan monostearate; it is a nonionic surfactant and emulsifier.
Example 43 Example 42 was repeated except that Cephazolin-Na (200 g Potency) was employed in place of Cefoxitin Na to obtain suppositories.
Reference example 1 Ten grams of commercially available carboxymethyl cellulose-Na were dissolved in 400 mQ of 17.5~ sodium hydroxide solution and subjected to mercerization at 3 to 5C under a nitrogen atmosphere. The product was diluted to 2 liters with deionized water and then adjusted to pH 11 with hydrochloric acid. Then, 100 mQ of an aqueous solution containing 5 g of bromocyan was added to the solution and the reaction was carried out at room tempera~ure for 5 minutes. After the reaction was over, pieces of ice were added to cool the mixture to lower than 5C, whereupon an aqueous solution of pH 10 containing 150 mmol of aspartic acid and 1 mmol of ethylenediaminetetraacetic acid was added and the reaction was carried out at SC overnight.
After the reaction, the reaction mixture was neutralized with 6N-hydrochloric acid, concentrated under reduced pressure, and further adjusted to pH 10.5 with 5 N-sodium hydroxide solution to dissolve insolubles formed during concentration. Then, the mixture was dialyzed against water and further ayainst 0.01 N hydrochloric acid, followed by lyophilization to obtain 8.5 g of aspartic acid-carboxy-methyl cellulose.
Reference example 2 Sodium alginate (1.5 g) was dissolved in 100 mQ
of distilled water, adjusted to pH 8.0 and 10 mmol of hydroxysuccinimide was added thereto, and the reaction was carried at 5~C for 60 minutes to obtain an activated ester. After the reaction, 10 mmol of aminodiacetic acid was added to effect the reaction~ Then, the reaction mixture was charged to"Sephadex G-20~0"and eluted with 10 mM
* Trademark for a hydrophilic, insoluble molecular-sieve e ~ chromatographic medium, made by cross-linking dextran.
phosphate buEfer (pH 6.S). The eluted fractions were recovered and lyophilized to obtain 1.0 g of iminodiacetic acid-alginic acid~
5 Reference example 3 Reference example 2 was repeated except that 1.5 g of carboxymethyl starch Na was employed in place of sodium alginate to obtain 0.8 g of iminodiacetic acid-carboxymethyl starch.
Reference example 4 Using a commercially available soluble starch, aftex activation similarly as in Reference example 1, it was reacted with glycine to obtain 7.6 g of glycine-starch.
Reference example 5 After a commercially available sodium polyacrylate was subjected to activated esterification similarly as in Reference example 2, the reaction product was allowed to react with glycine to obtain 8.2 y of glycine-polyacrylic acid.
Reference example 6 A mixture of ethylenediaminetetraacetic acid, acetic acid, anhydride and pyridine was subjected to the reaction at 65C for 24 hours to obtain the dihydride of ethylenediamine-tetraacetic acid. The pxoduct was then added into dimethyl-formamide and further dextran was added to carry out the reaction. Distilled water was added to the reaction mixture, and then e~hylenediamine-dextran was obtained by filtration.
Reference example 7 After hydrochelidonic acid was converted to an active ester similarly as in Reference example 6, the ester was reacted with albumin to obtain hydrochelidonic acid-albumin.
'~' ' ` 'l!
Table 11 Group of amino-carboxylic _ Osmotic pressure acid and iminocarboxylic acid compounds 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 ~-methyl DL-glutamate11.9 - 21.4 DL-cysteic acid 5.3 9.0 14.6 -aminoCaproiC acid7.1 11.8 17.0 N-dimethylphenylalanine 10.9 - 25.5 3S y-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 was repeated except that as other acid compounds glyceLo-3-phosphoric acid, fructose-1,6-diphos-phoric acid and ethylenediaminetetrakis5methylenephosphonic acid)(EDTPO) were used each at 0.1 W/V % in place of the aliphatic carhoxylic acid compounds. The results are shown in Table 12, wherein the units are percents.
Table 12 Acid compounds Osmotic pressure X 1 X 2_ X
Glycero-3-phosphoric acid 4.0 - 11.5 Fructose~1,6-diphosphoric acid4.1 7.5 13.3 EDTPO 7.6 - 20.0 Example 19 Cephalothin-Na ~1 g activity) as medicine, ~-ke'ro-glutaric acid-Na (1 g) as absorption promoter and sodium chloride (500 mg) as hypertonicator were each pulverized and-mixed together. A homogeneous dispersion was prepared by adding to the resulting mixture a base of~Witepsol H-15~*
previously molten by fusion to a total amount of 10 g.
The dispersion was intrarectally administered at a dose of 50 mg/kg to Wistar-strain rats (male, weighing 250 to 300 g four per one group) and blood sampling was performed 15 minutes, 30 minutes, 60 minutes and 120 minutes after administration for measurement of Cephalothin concentration in serum (according to the bioassay using Bacillus subtilis ATCC 6633). As Controls, there were also obtained a preparation containing sodium chloride without use of the absorption promoter (Control 1) and a preparation containing the absorption promoter without use of sodium chloride (Control 2). Further, another preparation of this invention was also prepared by use of 1 g of a-ketobutyric acid in * Trademark for a suppository base consisting of ~C12-C~ ) saturated fatty acid trigIycerides with varying propor~ions of partial glycerides.
place of the above absorption promoter, following otherwise the same procedure as described above.
As the result, Cephalothin concentrations Eor respective preparations were found as listed in Table 13.
_able 13 Preparation Concentration in blood (~/mQ) -15 min. 30 min. 60 min. 120 min.
Control 1 (sodium chloride) 0.20.5 Control 2 (~-ketoglutaric acid-Na) 2.1 5.3 1.2 0.3 Present invention (~-ketoglutaric acid-Na/ 5.9 11.4 3.1 1.2 sodium chloride) Present invention (~-ketobutyric ~cid/ 7.913.0 4~5 1.4 sodium chloride) Example 20 Tuberactinomycin N-sulfate (1 g activity) as medicine, D-phenylglycine as absorption promoter (1 g) and sodium chloride as hypertonicator (500 mg) were each pulverized and thoroughly mixed. To the resulting mixture, there was added Witepsol H-15 previously molten by heating, followed by homogeneous dispersion, to provide a suppository for intrarectal administration. Example 19 was also repeated except that L-aspartic acid (1 g) was used in place of D-phenylglycine to obtain a suppository for intrarectal administration.
As Control, a preparation with the same composi-tion as the above preparation except for containing no absorption promoter was also prepared. Each of these prepa-rations was administered to rats and concentrations in blood were measured in the same manner as in Example 19 to obtain the results as shown in Table 1~.
- 3~ -Table 14 Preparation Concentrations in blood (~/mQ) 15 min.30 min. 60 min.120 minO
5Control (sodium chloride) 0.9 1.8 0.3 Present inven-tion ~D-phenylglycine/ 13.1 10.7 3.5 1.3 sodium chloride) Present invention 10(L-aspartic acid/ 8.4 10.3 2.8 0.9 sodium chloride) Example 21 Ten units of Elcitonin[Asu. (1.7) eel calcitonin]
as meaicine, pulverized EDTA-2Na (20 mg) as absorption promoter and pulverized sodium chloride as hypertonicator (50 mg) were dissolved in 5~ gelatin solution to an amount of 1 g, which was then administered intrarectally to S.D.
rats of four weeks of age each in an amount of 0.1 mQ.
Calcium concentrations in serum were measured 15 minites, 30 minutes, 60 minutes and 90 minites after administration according to the atomlc absorption method. The same experi-ment was repeated except that 20 mg of CyDTA was employed in place of EDTA-2Na. Further, as Control, a preparation was prepared without use of the absorption promoter, followed by similar procedure. The results are shown in Fig. 8, in which o - o indicate calcium concentrations in serum in case of the preparation containing EDTA-2Na as absorption promoter of this invention, ~ - ~ indicating calcium concen-trations in serum in the case of the preparation containing CyDTA of this invention and further o - o indicatiny calcium concentration in serum in the case of the preparation as Control containing no absorption promoter.
Example 22 To a 0.1 W/W ~ Cephalothin-Na solution, there was added 0.1 W/W ~ pectinic acid and further mannitol was added at various levels to prepare isotonic solution, two-fold tonic solution and four-fold tonic solution, respectively.
As the Control,an isotonic solution without use of pectinic acid was also prepared. Subsequently, these samples were administered to Wistar-strain rats similarly as in E~ample 10 and quantities of Cephalothin disappeared by absorption were measured.
The results are shown in Fig. ~, wherein ~ - ~
indicates the disappearance curve of Cephalothin in the case of the Control using no pectinic acid, ~ -O disappearance curve in the case of an isotonic solution using pectinic acid, o - o that of two-fold tonic solution using pectinic acid and ~
that of f~ur-fold tonic solution using pectinic acid.
As apparently seen from Fig. 9, the use of pectinic acid improves remarkably the absorption of Cephalothin and further improvement is brought about by using in combination pectinic acid under hypertonic conditions.
Example 23 In place of pectinic acid in the above Example 22, there were employed sodium alginate, sodium carboxymethyl cellulose, sodium polyacrylate, chondroitin sulfate, sodium polyaspartate and sodium polyglutamate each at a concentra-tion of 0.1 W/W ~, and each solution was ad~usted with sodium chloride to various tonicities, namely isotonic (X 1), two-fold tonic (X 2) and four fold tonic (X 4) solutions.
As the result, the quantities of Cephalothin disappeared at the time of sampling 60 minutes after circulat:ion were found as shown in Table 15.
Table 15 Absorption promoter ___ Osmotic pressure Sodium alginate 6.3%10.2~ 22.4%
Sodium carboxymethyl cellulose 7.1%10.2% 18.7%
Sodium polyacrylate 6.7% - 14.6%
Chondroitin sulfate4~0% 6.7% 11.5%
Sodium polyaspartate8.4%11.5% ~0.4%
Sodium polyglutamate7.9%15.0% 33.6%
No addition 1.2%1.6% 3.1 Example 24 Using absorption promoters, prepared as described hereinafter in Reference examples, of aspartic acid-carboxy-methyl cellulose, iminodiacetic acid-alginic acid, imino-diacetic acid-carboxymethyl starch, glycine-starch, glycine-polyacrylic acid, ethylenediaminetetraacetic acid-dextran and hydrochelidonic acid-albumin, various samples of preparations were obtained with adjustment of tonicity to isotonic (X 1), two-fold tonic (X 2) and four-fold tonic (X 4). For each sample, the quantity of Cephalothin disappeared was determined similarly as in Example 10. As the result, the quantities of Cephalothin disappeared at the time of sampling 60 minutes after circulation were found as shown in Table 16.
Table 16 Absorption promoter _ Osmotic pressure X 1 X 2_ X 4 S Aspartic acid-carboxymethyl7.0% 10.4% 22.6%
cellulose Iminodiacetic acid-alginic acid 7.2%10.5% 24.6%
Iminodiacetic acid-carboxy-methyl starch 5.2~9.8~ 18.8 10 Glycine-starch 5.1%8.8~ 11.9~
Glycine polyacrylic acid 6.9% 10.1~ 17.0%
Ethylenediaminetetraacetic acid-dextran 5.8%9.2~ 16.7%
Hydrochelidonic acid-albumin4.2% - 9.5 Example 25 Elcitonin[Asu -eel calcitonin] (100 units and 10 units), sodium alginate (50 mg~ and sodlum chloride (50 mg) were dissolved in 1 mQ of distilled water. Each solution (0.1 mQ) was administered intrarectally to SD-strain male rats tfour weeks of age) and calcium concen-trations in serum were measured 30 minutes, 60 minutes and 90 minutes after administration by the atomic absorption method. As Control, there was used a solution containing no sodium alginate (adjusted to 100 units of Elcitonin).
Further, a s~lar test was conducted by use of 50 mg of pectinic acid in place of sodium alginate.
The results are shown in Fig. 10, wherein x-~--x indicates calcium concentrations in serum in the case of the Control, o - o those in the case of a solution containing sodium alginate and sodium chloride adjusted to 100 units of Elcitonin, ~ - ~ those in the case of a solution containing pectinic acid and sodium chloride at 100 units of Elcitonin, ~ ~ those in the case of a solution containing sodium alginate and sodium chloride at 10 units of Elcitonin, A - ~ those in the case of a solution containing pectinic acid and sodium chloride at 10 units of Elcitonin, respectively.
Example 26 Using ampicillin-Na (20 g potency) as medicine, sodium oxalate as absorption promoter (0.5 g) and sodium chloride (4 g) as water-soluble solution for higher tonic conditions, which are each pulverized, a homogeneous dis-persion was prepared by adding these components to a base of 50 g of peanut oil, followed further by dilution with peanut oil to a total amount of 100 g. The preparation was then filled in aliquots each of 1 g in gelatin soft capsules.
Example 27 Tuberactinomycin N sulfate (20 g), sodium chloride (3 g) as water-soluble substance for hypertonic conditions and sodium oxalate as absorption promoter (0.2 g), which were each pulverized, were added to an oily base of peanut oil to a total amount of 100 g to obtain rectal capsules.
Example 28 Cefazolin Na (200 g activity), D-phenylglycine (50 g) and sodium chloride (50 g) were each pulveri~ed and mixed together To the resulting mixture, there was added "Witepsol W 35"molten by heating to 1 kg, followed by homo geneous dispersion. The dispersion was then molded in a suppository containing to provide suppositories each of 1 g.
Example 29 Ampicillin-Na (250 g activity), D-phenylglycine (200 g) and sodium chloride (50 g), each being pulverized, were mixed and the resulting mixture was mixed with l'Witepsol H-15"molten by heating to an amount of 1 kg, which was further homogeneously dispersed. The dispersion was molded in suppository containers to provide suppositories * Trademark each of 1 g.
Example 30 Finely pulverized ampicillin3H2O (250 g activity), ~-ketobutyric acid (100 g) and finely pulverized sodium chloride (50 g) were mixed together. The resultlng mixture was mixed with Witepsol W-35 molt~n by hea-ting to an amoun-t of 1 kg, followed by homogeneous dispersion. Suppositories each of 1 g were molded in suppository con-tainers.
Example 31 Einely pulverized Cephalothin-Na (250 g Potency), ethyl acetate ~100 g) and finely divided sodium chloride (50 g) were mixed with sesame oil to an amount of 1 kg to form a homogeneous dispersion. The dispersion was filled in aliquots each of 2 g into plastic injection cylinders to obtain intrarectal injection preparations.
Example 32 Tuberactinomycin N sulfate (500 g Potency), oxalo-acetic acid (100 g) and sodium chloride (50 g) were each pulverized and mixed. The mixture was mixed and homogeneously dispersed with Witepsol ~-5 molten by heating -to an amount of 1 kg. The dispersion was molded in suppository containers to provide suppositories (each 2.5 g).
Example 33 One hundred thousand units of E,lcitonin, 20 g of finely pulverized CyDTA and 50 g of finely pulverized sodium chloride were added to Witepsol ~1-15 molten by heating to an amount of 1 kg, and the resultiny mixture was molded in aliquots each of 1 g in suppository containers to provide suppositories (1 g).
Example 34 One hundred thousand units of Elcitonin, 30 g of finely pulveri2ed sodium phenylpyruvate and 250 g of finely pulverized mannitol were dispersed by dissolution in 0.1%
carboxyvinyl polymer solution"(Wako Gel', trademaxk , produced by Wako Junyaku Co., Ltd.) to an amount of 1 kg, which was then injected into plastic applicators in aliquots each of 1 g to provide intrarectal injection preparations.
Example 35 Gentamycin (200 g Potency), sodium caproate (50 g) and sodium chlorid~ (50 g) were each finely pulverized and mixed together. The mixture was mixed with ~itepsol W-35 molten by heating to an amount of 1 kg, and the resulting mixture was molded in suppository containers to provide 1 g suppositories.
Example 36 Amicacin sulfate (200 g Potency), y-ketoglutamic acid (50 g) and sodium chloride (50 g) were each finely divided and mixed together, and Witepsol H 15 molten by ~0 mixing was added to the mixture to an amount of 1 kg.
Further, the resulting mixture was molded in suppository containers to provide 1 g suppositories.
Example 37 Cephalothin-Na (200 g Potency), sodium alginate (50 g) and sodium chloride (50 g), each being pulverized, were mixed and the resulting mixture was dissolved in 2%
gelatin solution to a volume of one liter, which was then filled into injection cylinders in aliquots each of 1 mQ
to provide intrarectal injection preparations.
Example 38 Gentamycin (100 g Potency), sodium pectinate (50 g) and mannitol (250 g), each being pulverized, were mixed and the mixture was homogeneously dispersed in 5~
gelatin solution to a volume of one liter, which was then filled into injection Cylinder5 in aliquots each of 1 mQ
to provide intrarectal injection preparations.
Example 39 One thousand units of Elcitonin , 50 g of sodium pectinate and 250 g of mannitol were each pulverized and mixed together. The resulting mixture was dispersed homo-geneously in 5~ gelatin solution to a volume of one liter, which was then filled into injection cylinders in aliquots each of 1 mQ to provide injection preparations for vaginal suppositories.
Example 40 One thousand units of Elcitonin, 50 g of sodium pectinate and 250 g of mannitol were dispersed homogeneously in Witepsol H-15 molten by heating to an amount of 1 kg, which was then filled in suppository containers in ali~uots each of 1 g to provide rectal suppositories.
Example 41 One thousand units of Elcitonin, 50 g of sodium alginate and 5 g of sodium chloride were dissolved in 100 mQ
of distilled water and the solution was added to'~itepsol H-5~containing l~Span 60~produced by Kao-Atlas Co.) to an amount of 500 g, followed further by homogeneous emulsi-fying. The emulsion was filled in suppository containers in aliquots each of 1 g to provide rectal suppositories.
Example 42 Cefoxitin-Na (200 g Potency), sodium alginate (50 g) and sodium chloride (50 g) each being pul~erized were mixed and dispersed in Witepsol H-5 molten by heating to an amount of 1 kg, which was then filled in suppository c~ntainers in aliquots each Of 1 g to provide 5UPPSitories.
* Trademark for sorbitan monostearate; it is a nonionic surfactant and emulsifier.
Example 43 Example 42 was repeated except that Cephazolin-Na (200 g Potency) was employed in place of Cefoxitin Na to obtain suppositories.
Reference example 1 Ten grams of commercially available carboxymethyl cellulose-Na were dissolved in 400 mQ of 17.5~ sodium hydroxide solution and subjected to mercerization at 3 to 5C under a nitrogen atmosphere. The product was diluted to 2 liters with deionized water and then adjusted to pH 11 with hydrochloric acid. Then, 100 mQ of an aqueous solution containing 5 g of bromocyan was added to the solution and the reaction was carried out at room tempera~ure for 5 minutes. After the reaction was over, pieces of ice were added to cool the mixture to lower than 5C, whereupon an aqueous solution of pH 10 containing 150 mmol of aspartic acid and 1 mmol of ethylenediaminetetraacetic acid was added and the reaction was carried out at SC overnight.
After the reaction, the reaction mixture was neutralized with 6N-hydrochloric acid, concentrated under reduced pressure, and further adjusted to pH 10.5 with 5 N-sodium hydroxide solution to dissolve insolubles formed during concentration. Then, the mixture was dialyzed against water and further ayainst 0.01 N hydrochloric acid, followed by lyophilization to obtain 8.5 g of aspartic acid-carboxy-methyl cellulose.
Reference example 2 Sodium alginate (1.5 g) was dissolved in 100 mQ
of distilled water, adjusted to pH 8.0 and 10 mmol of hydroxysuccinimide was added thereto, and the reaction was carried at 5~C for 60 minutes to obtain an activated ester. After the reaction, 10 mmol of aminodiacetic acid was added to effect the reaction~ Then, the reaction mixture was charged to"Sephadex G-20~0"and eluted with 10 mM
* Trademark for a hydrophilic, insoluble molecular-sieve e ~ chromatographic medium, made by cross-linking dextran.
phosphate buEfer (pH 6.S). The eluted fractions were recovered and lyophilized to obtain 1.0 g of iminodiacetic acid-alginic acid~
5 Reference example 3 Reference example 2 was repeated except that 1.5 g of carboxymethyl starch Na was employed in place of sodium alginate to obtain 0.8 g of iminodiacetic acid-carboxymethyl starch.
Reference example 4 Using a commercially available soluble starch, aftex activation similarly as in Reference example 1, it was reacted with glycine to obtain 7.6 g of glycine-starch.
Reference example 5 After a commercially available sodium polyacrylate was subjected to activated esterification similarly as in Reference example 2, the reaction product was allowed to react with glycine to obtain 8.2 y of glycine-polyacrylic acid.
Reference example 6 A mixture of ethylenediaminetetraacetic acid, acetic acid, anhydride and pyridine was subjected to the reaction at 65C for 24 hours to obtain the dihydride of ethylenediamine-tetraacetic acid. The pxoduct was then added into dimethyl-formamide and further dextran was added to carry out the reaction. Distilled water was added to the reaction mixture, and then e~hylenediamine-dextran was obtained by filtration.
Reference example 7 After hydrochelidonic acid was converted to an active ester similarly as in Reference example 6, the ester was reacted with albumin to obtain hydrochelidonic acid-albumin.
'~' ' ` 'l!
Claims (32)
1. A preparation having excellent absorption property, comprising a water-soluble substance at a concentration exhibiting higher osmotic pressure than isotonic sodium chloride solution a water-soluble compound having chelat-ing activity and medicine.
2. A preparation according to claim 1 wherein the water-soluble compound having chelating activity is a water-soluble low molecular weight compound having at least one chelating ligand.
3. A preparation according to claim 1 wherein the water-soluble compound having chelating activity is a water-soluble macromolecular compound having two or more chelating ligands.
4. A preparation according to claim 2 wherein the chelating ligand is selected from a carboxylic acid group, sulfonic acid group, phosphoric acid group, phenolic hydroxyl group, hydroxyl group, carbonyl group, amino group, or imino group or combinations thereof.
5. A preparation according to claim 3 wherein the water-soluble macromolecular compound having two or more chelating ligands is selected from water-soluble polysaccharide com-pounds, water-soluble cellulose derivatives, water-soluble starch derivatives, dextran derivatives and water-soluble polypeptide compounds and water-soluble synthetic polymer compounds having two or more chelating ligands.
6. A preparation according to claim 3 wherein the water-soluble macromolecular compound is a compound having chelate functional groups incorporated into a water-soluble base polymer.
7. A preparation according to claim 2 wherein the water-soluble low molecular weight compound having at least one chelating ligand is a polycarboxylic acid compound, a hydroxycarboxy-lic acid compound, a keto-carboxylic acid compound or a monocarboxylic acid compound.
8. A preparation according to claim 2 wherein the water-soluble low molecular weight compound is an aminocarboxylic acid compound, an iminocarboxylic acid compound, an amino-polycarboxylic acid compound, or an iminopolycarboxylic acid compound.
9. A preparation according to claim 2 wherein the water-soluble low molecular weight compound having at least one chelating ligand is a sulfonic acid compound or a phosphoric acid compound.
10. A preparation according to claim 6 wherein the water-soluble base polymer is selected from water-soluble poly-saccharides, water-soluble cellulose derivatives, water-soluble starch derivatives, dextran derivatives, water-soluble polypeptides and water-soluble synthetic polymers.
11. A preparation according to claim 6 wherein the compound having chelate functional groups to be incorporated into the water-soluble base polymer has one or more bonding functional groups and two or more chelating ligands.
12. A preparation according to claim 11 wherein the compound having chelate functional groups to be incorporated into the water-soluble base polymer is 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 phosphoglyceric acid, a glycerophosphoric acid or a phosphoric acid ester of a saccharide.
13. A preparation according to claim 2 wherein the water-soluble low molecular weight compound having at least one chelating ligand is one selected from the group consisting of succi-nic acid, ethylmalonic acid, adipic acid, aconitic acid, pyruvic acid, .alpha.-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-phenyl-glycine, .gamma.-carboxyglutamic acid, N-phenylglycine ethyl ester, glycyl-DL-aminobutyric acid, N-dimethylphenylalanine, ethylenediaminetetraacetic acid, trans-cyclohexanediamine-tetraacetic acid, diethyltriaminepentaacetic acid, ethylene-diaminetetrakis(methylphosphonic acid), l-naphthol-3,6-sulfonic acid, chromotropic acid, 1,2-dihydroxybenzene-3,5-disulfonic acid ethyl acetoacetate, or their salts.
14. A preparation according to claim 3, wherein the water-soluble macromolecular compound having two or more chelating ligands is selected from the group consisting of alginic acid, pectinic acid,polyacrylic acid, polyaspartic acid and polyglutamic acid, or their salts.
15. A preparation according to claim 1 wherein the water-soluble substance at a concentration exhibiting higher osmotic pressure than isotonic sodium chloride solution is 1 W/W % or more of a water-soluble salt.
16. A preparation according to claim is, wherein the water-soluble salt is a water-soluble salt of an alkali metal.
17. A preparation according to claim 16 wherein the water-soluble salt of an alkali metal is a halide, a sulfate, a phosphate or a carbonate of sodium, potassium or lithium.
18. A preparation according to claim 1 wherein the water-soluble substance at a concentration exhibiting higher osmotic pressure than isotonic sodium chloride solution is a 0.25 M or more of a water-soluble saccharide.
19. A preparation according to claim 18 wherein the water-soluble saccharide is sorbitol, glucose, mannitol, maltose, lactose or sucrose.
20. A preparation according to claim 1 wherein the principal ingredient medicine is a water-soluble medicine having good water-solubility.
21. A preparation according to claim 20 wherein the water-soluble medicine has a partition coefficient of 50 or less in chloroform/water.
22. A preparation having excellent absorption property, comprising a water-soluble macromolecular compound having chelating activity and a medicine.
23. A preparation according to claim 22 wherein the water-soluble compound having chelating activity is a water-soluble macromolecular compound having two or more chelating ligands.
24. A preparation according to claim 23 wherein the chelat-ing ligand is selected from carboxylic acid group, sulfonic acid group, phosphoric acid group, phenolic hydroxyl group, hydroxyl group, carbonyl group, amino group, imino group or combinations thereof.
25. A preparation according to claim 23 wherein the water-soluble macromolecular compound having two or more chelat-ing ligands is selected from water-soluble polysaccharide compounds, water-soluble cellulose derivatives, water-soluble starch derivatives, dextran derivatives and water soluble polypeptide compounds and water-soluble synthetic polymer compounds having two or more chelating ligands.
26. A preparation according to claim 23 wherein the water soluble macromolecular compound having two or more chelating ligands is a compound having chelate functional groups incorporated into a water-soluble base polymer.
27. A preparation according to claim 26 wherein the water-soluble base polymer is selected from water-soluble polysaccharides, water-soluble cellulose derivatives, water-soluble starch derivatives, dextran derivatives, water soluble polypeptides and water-soluble synthetic polymers.
28. A preparation according to claim 26 wherein the com-pound having chelate functional groups to be incorporated into the water-soluble base polymer has one or more bonding functional group and two or more chelating ligands.
29. A preparation according to claim 28 wherein the com-pound having chelate functional groups to be incorporated into the water-soluble base polymer is an aliphatic poly-carboxylic 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 phosphoglyceric acid, a glycerophosphoric acid or a phosphoric acid ester of a saccharide.
30. A preparation according to claim 23, wherein the water-soluble macromolecular compound having two or more chelating ligands is selected from the group consisting of alginic acid, pectinic acid, polyacrylic acid, polyaspartic acid and poly-glutamic acid, or their salts.
31. A preparation according to claim 22 wherein the medicine is a water-soluble medicine having good water-solubility.
32. A preparation according to claim 31 wherein the water-soluble medicine has a partition coefficient of 50 or less in chloroform/water.
Applications Claiming Priority (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP003263/81 | 1981-01-14 | ||
| JP56003263A JPS57118509A (en) | 1981-01-14 | 1981-01-14 | Novel preparation of high absorbability |
| JP56032951A JPS57146722A (en) | 1981-03-06 | 1981-03-06 | Pharmaceutical preparation having improved absorption |
| JP032951/81 | 1981-03-06 | ||
| JP18150881A JPS57146723A (en) | 1981-03-06 | 1981-11-11 | Pharmaceutical preparation having improved absorption |
| JP181508/81 | 1981-11-11 | ||
| JP56184861A JPS5885813A (en) | 1981-11-17 | 1981-11-17 | Drug preparation having high absorbability |
| JP184861/81 | 1981-11-17 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1184492A true CA1184492A (en) | 1985-03-26 |
Family
ID=27453826
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000394029A Expired CA1184492A (en) | 1981-01-14 | 1982-01-13 | Preparation having excellent absorption property |
Country Status (2)
| Country | Link |
|---|---|
| CA (1) | CA1184492A (en) |
| DE (2) | DE3250023T (en) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2542616B1 (en) * | 1983-03-17 | 1987-07-31 | Unilever Nv | COMPOSITION FOR THE TREATMENT OF MUCOSA BASED ON AN ANTIBIOTIC AND A GEL-FORMING HYDROCOLLOID |
| JPS61189230A (en) * | 1985-02-19 | 1986-08-22 | Nippon Kayaku Co Ltd | Etoposide preparation |
| US5554386A (en) * | 1986-07-03 | 1996-09-10 | Advanced Magnetics, Inc. | Delivery of therapeutic agents to receptors using polysaccharides |
| AU618517B2 (en) * | 1986-12-23 | 1992-01-02 | Eugene J. Van Scott | Additives enhancing topical actions of therapeutic agents |
| EP0326151B1 (en) * | 1988-01-29 | 1993-06-16 | Sumitomo Pharmaceuticals Company, Limited | Improved controlled release formulation |
| US5554388A (en) * | 1989-02-25 | 1996-09-10 | Danbiosyst Uk Limited | Systemic drug delivery compositions comprising a polycationi substance |
| GB8904370D0 (en) * | 1989-02-25 | 1989-04-12 | Cosmas Damian Ltd | Liquid delivery compositions |
| FR2650502B1 (en) * | 1989-08-07 | 1994-05-27 | Delagrange Laboratoires | NEW ORAL GALENIC FORM IMPROVING BIOAVAILABILITY |
| EP0646018A1 (en) * | 1992-06-17 | 1995-04-05 | Advanced Magnetics Incorporated | Arabinogalactan derivatives and uses thereof |
| AU2002234506A1 (en) * | 2001-01-20 | 2002-07-30 | Klaus-Dieter Kunze | Method for reducing the side effects of medicaments |
| US20030017181A1 (en) | 2001-05-31 | 2003-01-23 | Rood Gloria A. | Dermatological compositions and methods |
| DE102010015350A1 (en) | 2010-04-16 | 2011-10-20 | Michael Zimmermann | vaginal applicator |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB761809A (en) * | 1953-09-02 | 1956-11-21 | Merck & Co Inc | Solid pharmaceutical preparation containing streptomycin and/or dihydrostreptomycin |
| GB1061426A (en) * | 1964-05-22 | 1967-03-15 | Olin Mathieson | Water-soluble penicillin composition |
| US4024073A (en) * | 1972-01-08 | 1977-05-17 | Toray Industries, Inc. | Hydrogel and production thereof |
| GB2051574B (en) * | 1979-05-10 | 1984-01-18 | Kyoto Pharma Ind | Adjuvant for promoting absorption of pharmacologically active substances through the rectum |
| AU541247B2 (en) * | 1979-12-20 | 1985-01-03 | R.P. Scherer Corporation | Adjuvants for rectal delivery of drug substances |
-
1982
- 1982-01-13 CA CA000394029A patent/CA1184492A/en not_active Expired
- 1982-01-13 DE DE19823250023 patent/DE3250023T/de active Pending
- 1982-01-13 DE DE19823200766 patent/DE3200766A1/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| DE3200766A1 (en) | 1982-09-16 |
| DE3250023T (en) | 1990-03-29 |
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