CA1188987A - Preparation having excellent absorption property - Google Patents
Preparation having excellent absorption propertyInfo
- Publication number
- CA1188987A CA1188987A CA000397097A CA397097A CA1188987A CA 1188987 A CA1188987 A CA 1188987A CA 000397097 A CA000397097 A CA 000397097A CA 397097 A CA397097 A CA 397097A CA 1188987 A CA1188987 A CA 1188987A
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- water
- acid
- soluble
- absorption
- acyl
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/02—Suppositories; Bougies; Bases therefor; Ovules
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- 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
-
- 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
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Inorganic Chemistry (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
Abstract
PREPARATION HAVING EXCELLENT ABSORPTION PROPERTY
Abstract A preparation containing an absorption promoter selected from N-acyl amino acid derivatives or N-acyl peptide derivatives represented by the formula: R-CO-A (R is an aliphatic hydrocarbon group, an aromatic hydrocarbon group or an aryl-substituted lower hydrocarbon group which may optionally be substituted,and A is an amino acid residue or a peptide residue), preferably in the presense 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.
Abstract A preparation containing an absorption promoter selected from N-acyl amino acid derivatives or N-acyl peptide derivatives represented by the formula: R-CO-A (R is an aliphatic hydrocarbon group, an aromatic hydrocarbon group or an aryl-substituted lower hydrocarbon group which may optionally be substituted,and A is an amino acid residue or a peptide residue), preferably in the presense 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
PREPARATIC)N H~VING 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 ~ the body by a~is~ration of such a medicine simultaneously with a water soluble substance at a concentration exhibiting higher osmotic pressure than isotonic sodium chloride solution and one or more oE an absorp~ion promoter selected from N-acyl aminoacid derivatives or N-acyl peptide derivatives as represented by the ~ormula: R-CO-A (13, (wherein R is an aliphatic hydrocarbon group, an aromatic hydro-carbon group, an aryl-substituted lower hydrocarbon group which may optionally be substituted and A is an amino acid residue or a peptide residue).
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 Dek~er, INC,. p. 31 - 49). Hence, a medicine readily dissociated in the respective organs at absorption sikes or a medicine having poor lipophilicity tends ~o be poorly absorbed. Such difficultly absorptive medicines are administered as injections under the present circumstances. For improvement o~ absorption property of a medicine, there have been made various investigations such as Prodrug, Sofdrug, utilization o~ ion pairs or complex formation. But any of these proposals is ef~ective speci~ically ~or individual medicines, and no universally applicable method is known in the art ("Pharmaceutics" written by Nogami).
The present inventors have made various investigations and consequently found that in the mechanism of membrane absorption through digestive organs or others, which is believed to proceed according to the pH partitions theory as mentioned above, an N-acyl aminoacid derivative or an N-acyl p~ptide deLivative which is represented comprehensively by the above formula ~1) causes some r ,~- .
J.~
'~ - 2 changes in membrane permeability, whereby membrane absorption of a medicine can b~ improved to promote successfully ~he absorption thereof. Further, it has also been found that membrane absorption can be markedly improved by addition of a water-soluble subs-tance at a concentration exhibiting higher osmotic pressure than isotonic sodium chloride solution to make the preparation under conditions of higher tonicity than the osmotic pressure of a body fluid. In addition to these findings, it has further been found that a preparation obtained by use of a vehicle, additives selected as desired and an objective medicine, for example, 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 l.ong time. A very broad range of medicines may be used in the present invention. In ~icularr the so-called water~soluble medicines having aood solubili~y in water, for example, those with partition coefficients of 50 or less in chloroform/water or medicines readily dissociated into ions, are usefuI. Further, medicines applicable only as injections in the prior art are also found to be made excellently absorbable easily as preparations such as suppositories.
; Even a medicine with a high molecular weight such as a polypeptide is also found as the result of this invention to be made efficient-ly absorbable in the form of a preparation such as a suppository.
The present invention has been accomplished based on the ahove findings, and the object of the present invention is to provide a good prepara~ion in which a medicine can be improved to have a markedly enhanced absorption property.
In the accompanying drawings, Figs. 1 and 2 show disappearance curves for various osmotic pressures of Cephalothin Na when using Cephalothin Na as medicine, in which the percentages of Cephalothin disappeared by absorption are plotted at various measurement times;
Fig- 3 is a curve of plasma concentration of Cephalothin when using Cephalothin Na as medicine;
Fig. 4 is a curve of plasma concentration of Tobramycin when using Tobramycin cas medicine;
Fig. 5 is a curve of calcium concentration in serum when using Elcitonin as medicine; and Fig. 6 is a curve of plasma concentration of Elcitonin when using Elcitonin as medicine.
According to the present invention, a preparation is provided which comprises a water-soluble substance at a concent-ration exhibiting an osmotic pressure high than that of i~otonic sodiumchloride solution, at least one absorption promoter selected from the group consisting of N-acyl amino acid derivatives or N-acyl peptide derivatives represented hy the ~ormula~ ~-CO-~ (1) (~hexe R and A are the same as those defined above)~and a therapeu~ically effective amount of a water-soluble medicine having a partition coefficient of 50 or less in chloroform/water.
Also provided by the present invention is a composition for enhancing absorption of norm~lly poorly absorb3ble medicines, comprising a water-soluble substance at a concentration exhibiting h.igher osmotic pressure than isotonic sodium chloxide solution and one or more of N acyl amino acid derivatives or N-acyl peptide derivatives represented b~ the formula: R-CC-A (wherein R is an aliphatic hydrocarbon group, an aromatic hydrocarkon group or an c~yl-substituted lower hydrocarbon group, which may optionally be substituted; and A is an c~mino acid residue or a peptide residue).
To speak first of a water-soluble substance to be used in the present invention at a concentration exhibiting higher osmotic pressure than isotonlc sodium chloride solution, it may be preferably one which is harmless as a whole and can exhibit ;~c high osmotic pressure with as small an amount as possible.
As such a water--soluble substance t there may be included water-soluble salts and water soluble sugars.
- 3a -Particularly among water-soluble salts, sodium chloride is preferred since it is safe and its osmotic pressure is readily controllable and further it is soluble in water rapidly at a high dissolvina rate. Further, mannitol or glucose is pre~erred among water-soluble sugarS~ Generally speaking, water-soluble salts may include, for example, halides,sulfates, phosphates or carbonates of alkali metals such as sodium, potassium or lithium, more specifically 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 chl~ride, etc. q'hese salts may be ad~usted to concent-rations exhibitiny higher tonicity t~an the osmotic pressure of isotonic sodium chloride solution dependin~ on the osmotic characteristlc thereof. For example, in the case of sodium chloride it may generally be adjusted to a concentration of 1 W/~% or higher of the whole content. The upper limit of the concentration is not particularly limited, but preferably the concentration is about 2 to 30 W/W~. As preferable 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 s~lcrose. Such a sugar may be used at a concentration 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 preferably 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 iso~onic sodium chloride solution, but such description with the use of isotonic sodium chloride solution as Control is merely exemplary for comparison between osmotic pressure, and therefore may also be possible with the use of body fluids or other solutions of salts with tolliCity equal to such isotonic sodium chloride solution.
Referring now to the N-acyl aminoacid derivatives or N-acyl peptide derivatives which are represented by the formula R-CO-A (1~ ~R and A are same as those defined above) to ~e used aS an absorption promo~er in ~his invention, they were investi-gated by adding to~ for example, an isotonic preparation for rec-ta]
application containing a medicine for examination of increase or decrease of membrane permeability of the medicine to accomplish ., ~
&7 ~ 5 --the present invention. The mechanism of the promotion effect has not so far been clarified, but it seems ~Xely that the membrane absorption mechanism may be changed through the chelating ~ction and affinity to the membrane possessed by these absorption promoters on the structures of cell membranes or the spaces between the epithelial cells thereby to promote absorption.
Although the mechanism action of the absorption promoter for increase of drug absorption through the rectum or other or~ans may be speculated as mentioned above, such a mechanism action is still no more than mere estimation and it is only sufficient to employ N-acyl aminoacid derivatives or N-acyl peptide derivatives having chelating action capable of bonding to at least calcium ions or magnesium ions.
Further, referring to the N-acyl amino acid derivatives or N~acyl peptide derivatives of the formula 11), these compounds are obtained in this invention by reacting an acid compound of the formula:
R-COOH (2) (wherein R is the same as that defined above) or its reactive derivative of ~he carboxyl group with a compound of formula (3)0 H-A (3) (wherein H~A is an amino acid or a peptide) or its derivative havin~ a protected earboxyl group. Alternatively, the eompound of the formula t1) may also be obtained by condensa-tion of an acyl group of the above acid compound (2) and the amino residue group or the imino residue group of an amino acid or a peptide.
Carboxyl groups ean be activated by agents such as an acid azide, an acid anhydride, an acid imidazolide, an acid halogenide, an acti~e ester or a carbodiimide,an N,N'-carbonyl-diimidazole or an isoxazolium salt such as Woodward's reagent.
~ . .
The preferred condensation reaction in the presentinvention is the carbodiimide, azide, active ester, halogenide or anhydride method.
As an example of a conden5ed reaction, an amino acid or peptide is reacted with reactive derivatives of an acid-ca~und of formula
-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 ~ the body by a~is~ration of such a medicine simultaneously with a water soluble substance at a concentration exhibiting higher osmotic pressure than isotonic sodium chloride solution and one or more oE an absorp~ion promoter selected from N-acyl aminoacid derivatives or N-acyl peptide derivatives as represented by the ~ormula: R-CO-A (13, (wherein R is an aliphatic hydrocarbon group, an aromatic hydro-carbon group, an aryl-substituted lower hydrocarbon group which may optionally be substituted and A is an amino acid residue or a peptide residue).
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 Dek~er, INC,. p. 31 - 49). Hence, a medicine readily dissociated in the respective organs at absorption sikes or a medicine having poor lipophilicity tends ~o be poorly absorbed. Such difficultly absorptive medicines are administered as injections under the present circumstances. For improvement o~ absorption property of a medicine, there have been made various investigations such as Prodrug, Sofdrug, utilization o~ ion pairs or complex formation. But any of these proposals is ef~ective speci~ically ~or individual medicines, and no universally applicable method is known in the art ("Pharmaceutics" written by Nogami).
The present inventors have made various investigations and consequently found that in the mechanism of membrane absorption through digestive organs or others, which is believed to proceed according to the pH partitions theory as mentioned above, an N-acyl aminoacid derivative or an N-acyl p~ptide deLivative which is represented comprehensively by the above formula ~1) causes some r ,~- .
J.~
'~ - 2 changes in membrane permeability, whereby membrane absorption of a medicine can b~ improved to promote successfully ~he absorption thereof. Further, it has also been found that membrane absorption can be markedly improved by addition of a water-soluble subs-tance at a concentration exhibiting higher osmotic pressure than isotonic sodium chloride solution to make the preparation under conditions of higher tonicity than the osmotic pressure of a body fluid. In addition to these findings, it has further been found that a preparation obtained by use of a vehicle, additives selected as desired and an objective medicine, for example, 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 l.ong time. A very broad range of medicines may be used in the present invention. In ~icularr the so-called water~soluble medicines having aood solubili~y in water, for example, those with partition coefficients of 50 or less in chloroform/water or medicines readily dissociated into ions, are usefuI. Further, medicines applicable only as injections in the prior art are also found to be made excellently absorbable easily as preparations such as suppositories.
; Even a medicine with a high molecular weight such as a polypeptide is also found as the result of this invention to be made efficient-ly absorbable in the form of a preparation such as a suppository.
The present invention has been accomplished based on the ahove findings, and the object of the present invention is to provide a good prepara~ion in which a medicine can be improved to have a markedly enhanced absorption property.
In the accompanying drawings, Figs. 1 and 2 show disappearance curves for various osmotic pressures of Cephalothin Na when using Cephalothin Na as medicine, in which the percentages of Cephalothin disappeared by absorption are plotted at various measurement times;
Fig- 3 is a curve of plasma concentration of Cephalothin when using Cephalothin Na as medicine;
Fig. 4 is a curve of plasma concentration of Tobramycin when using Tobramycin cas medicine;
Fig. 5 is a curve of calcium concentration in serum when using Elcitonin as medicine; and Fig. 6 is a curve of plasma concentration of Elcitonin when using Elcitonin as medicine.
According to the present invention, a preparation is provided which comprises a water-soluble substance at a concent-ration exhibiting an osmotic pressure high than that of i~otonic sodiumchloride solution, at least one absorption promoter selected from the group consisting of N-acyl amino acid derivatives or N-acyl peptide derivatives represented hy the ~ormula~ ~-CO-~ (1) (~hexe R and A are the same as those defined above)~and a therapeu~ically effective amount of a water-soluble medicine having a partition coefficient of 50 or less in chloroform/water.
Also provided by the present invention is a composition for enhancing absorption of norm~lly poorly absorb3ble medicines, comprising a water-soluble substance at a concentration exhibiting h.igher osmotic pressure than isotonic sodium chloxide solution and one or more of N acyl amino acid derivatives or N-acyl peptide derivatives represented b~ the formula: R-CC-A (wherein R is an aliphatic hydrocarbon group, an aromatic hydrocarkon group or an c~yl-substituted lower hydrocarbon group, which may optionally be substituted; and A is an c~mino acid residue or a peptide residue).
To speak first of a water-soluble substance to be used in the present invention at a concentration exhibiting higher osmotic pressure than isotonlc sodium chloride solution, it may be preferably one which is harmless as a whole and can exhibit ;~c high osmotic pressure with as small an amount as possible.
As such a water--soluble substance t there may be included water-soluble salts and water soluble sugars.
- 3a -Particularly among water-soluble salts, sodium chloride is preferred since it is safe and its osmotic pressure is readily controllable and further it is soluble in water rapidly at a high dissolvina rate. Further, mannitol or glucose is pre~erred among water-soluble sugarS~ Generally speaking, water-soluble salts may include, for example, halides,sulfates, phosphates or carbonates of alkali metals such as sodium, potassium or lithium, more specifically 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 chl~ride, etc. q'hese salts may be ad~usted to concent-rations exhibitiny higher tonicity t~an the osmotic pressure of isotonic sodium chloride solution dependin~ on the osmotic characteristlc thereof. For example, in the case of sodium chloride it may generally be adjusted to a concentration of 1 W/~% or higher of the whole content. The upper limit of the concentration is not particularly limited, but preferably the concentration is about 2 to 30 W/W~. As preferable 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 s~lcrose. Such a sugar may be used at a concentration 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 preferably 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 iso~onic sodium chloride solution, but such description with the use of isotonic sodium chloride solution as Control is merely exemplary for comparison between osmotic pressure, and therefore may also be possible with the use of body fluids or other solutions of salts with tolliCity equal to such isotonic sodium chloride solution.
Referring now to the N-acyl aminoacid derivatives or N-acyl peptide derivatives which are represented by the formula R-CO-A (1~ ~R and A are same as those defined above) to ~e used aS an absorption promo~er in ~his invention, they were investi-gated by adding to~ for example, an isotonic preparation for rec-ta]
application containing a medicine for examination of increase or decrease of membrane permeability of the medicine to accomplish ., ~
&7 ~ 5 --the present invention. The mechanism of the promotion effect has not so far been clarified, but it seems ~Xely that the membrane absorption mechanism may be changed through the chelating ~ction and affinity to the membrane possessed by these absorption promoters on the structures of cell membranes or the spaces between the epithelial cells thereby to promote absorption.
Although the mechanism action of the absorption promoter for increase of drug absorption through the rectum or other or~ans may be speculated as mentioned above, such a mechanism action is still no more than mere estimation and it is only sufficient to employ N-acyl aminoacid derivatives or N-acyl peptide derivatives having chelating action capable of bonding to at least calcium ions or magnesium ions.
Further, referring to the N-acyl amino acid derivatives or N~acyl peptide derivatives of the formula 11), these compounds are obtained in this invention by reacting an acid compound of the formula:
R-COOH (2) (wherein R is the same as that defined above) or its reactive derivative of ~he carboxyl group with a compound of formula (3)0 H-A (3) (wherein H~A is an amino acid or a peptide) or its derivative havin~ a protected earboxyl group. Alternatively, the eompound of the formula t1) may also be obtained by condensa-tion of an acyl group of the above acid compound (2) and the amino residue group or the imino residue group of an amino acid or a peptide.
Carboxyl groups ean be activated by agents such as an acid azide, an acid anhydride, an acid imidazolide, an acid halogenide, an acti~e ester or a carbodiimide,an N,N'-carbonyl-diimidazole or an isoxazolium salt such as Woodward's reagent.
~ . .
The preferred condensation reaction in the presentinvention is the carbodiimide, azide, active ester, halogenide or anhydride method.
As an example of a conden5ed reaction, an amino acid or peptide is reacted with reactive derivatives of an acid-ca~und of formula
(2) in an inert medium, for example, an organic solvent such as chloroform, methylenechloride, ethylenechloride, ether and hydrophilic solvent or an aqueous hydrophilic solvent such as water, methanol, ethanol, acetone, dimethylacetamide, dimethyl-formamide and dioxane. N-acylation is performed by the usual method, and if necessary, a condensation agent or a base may be added to the above solvent.
In this reaction, ~he reaction temperature is below or at room temperature, and the acid compound of formula (2~ is used about one mole per mole of amino acid or peptide. After the reaction, it may be purified by preferably, a method of gel filtration.
As an acid-compound of the formula (2), there may preferably be used an acid in which R is an aliphatic hydrocarbon group which may be substituted or an aromatic hydrocarbon gro~-which may be substituted or an a~yl-substituted lower aliphatic hydrocarbon group in which the number of car~on atoms of the lower aliphatic group generally is in t}1e range of 1 to 10lpreferably 1 ~o 5,whlch may be substituted.
When R is an aliphatic hydrocarbon group which may be substituted, the hydrocarbon group may have carbon atoms generally in the range of from 1 to 20,preferably ~ to 18. ~s alipha-tic acids having such groups, there may be mentioned, for example, acetic acid, propionic acid, butyric acid, valeric acid, iso~
valeric acid, hexanoic acidtenanthic acid, octanoic acid, pelargonic acid, decanoic acid, undecylic acid, lauric acid, myristic acid~ palmitic acid, stearic acld, acrylic acid, c~otonic acid, vinylacetic acid, 4-pentenoic acid, oleic acid, linoleic acid, linole~ic acid or sorbic acid as the fatty acid and these com~ounds substituted with a lower alkyl group, hydroxyl group, carboxylic a~id group, a]koxy group, phosphoric acid group, amino group, imino group or a halogen.
As acids wherein ~ is an aroma~ic hydrocarbon group which may be substitu~ed, there may be mentioned, f or example, benzoic acid, alkylbenzoic acid, phthalic acid, isophthalic acid, o-, m- or p-aminoben20ic acid, o-, m- or p~hydroxybenzoic acid, o-, m- or p-alkoxyben7oic acid, dihydroxybenzoic acid and these compounds substituted with above functional groups.
Acids wherein R is an aryl-substitu~ed lower aliphatic hydrocarbon group which may be sub~tituted may incl~de, for example, phenylacetic acid, phenylpropionic acid, o~,m- or p-hydroxy phenylacetic acid~
phenylmalonic acid, phenylsuccinic acicl, cinnamic acid, phenyl-pyruvic acid, benzoylacetic acid and ~.hese compounds substituted with the above functional groups.
As an amino acid or a peptide of the formula ~3), natural amino acids or peptides may prefera~ly be used. They can be in either D , L- or DL-form, and the derivatives thereof substituted with hydroxyl, amino, carboxylic acid, lower hydro-carbon, alkoxy, phosphoric acid or a halogen atom as well as ethyl or methyl ester derivatives thereof are also available.
There may be mentioned, for example, various natural amino acids (Chemistxy of Amino Acids, Vol. 1, p. 3~8 etc.) o-, m- or p~hydroxy phenylalanine, o-, m- or p-hydroxy phenylglycine, Q~ or ~-carboxy glutamic acidl glutamic acid Q-methylester, glutamic acid ~-ethylester, aspartic acid ~ ~thylester, ~ or r~amino butyric acid, iminodiacetic acid and o~hers.
As the peptide to be acylated, there may ge~erally be
In this reaction, ~he reaction temperature is below or at room temperature, and the acid compound of formula (2~ is used about one mole per mole of amino acid or peptide. After the reaction, it may be purified by preferably, a method of gel filtration.
As an acid-compound of the formula (2), there may preferably be used an acid in which R is an aliphatic hydrocarbon group which may be substituted or an aromatic hydrocarbon gro~-which may be substituted or an a~yl-substituted lower aliphatic hydrocarbon group in which the number of car~on atoms of the lower aliphatic group generally is in t}1e range of 1 to 10lpreferably 1 ~o 5,whlch may be substituted.
When R is an aliphatic hydrocarbon group which may be substituted, the hydrocarbon group may have carbon atoms generally in the range of from 1 to 20,preferably ~ to 18. ~s alipha-tic acids having such groups, there may be mentioned, for example, acetic acid, propionic acid, butyric acid, valeric acid, iso~
valeric acid, hexanoic acidtenanthic acid, octanoic acid, pelargonic acid, decanoic acid, undecylic acid, lauric acid, myristic acid~ palmitic acid, stearic acld, acrylic acid, c~otonic acid, vinylacetic acid, 4-pentenoic acid, oleic acid, linoleic acid, linole~ic acid or sorbic acid as the fatty acid and these com~ounds substituted with a lower alkyl group, hydroxyl group, carboxylic a~id group, a]koxy group, phosphoric acid group, amino group, imino group or a halogen.
As acids wherein ~ is an aroma~ic hydrocarbon group which may be substitu~ed, there may be mentioned, f or example, benzoic acid, alkylbenzoic acid, phthalic acid, isophthalic acid, o-, m- or p-aminoben20ic acid, o-, m- or p~hydroxybenzoic acid, o-, m- or p-alkoxyben7oic acid, dihydroxybenzoic acid and these compounds substituted with above functional groups.
Acids wherein R is an aryl-substitu~ed lower aliphatic hydrocarbon group which may be sub~tituted may incl~de, for example, phenylacetic acid, phenylpropionic acid, o~,m- or p-hydroxy phenylacetic acid~
phenylmalonic acid, phenylsuccinic acicl, cinnamic acid, phenyl-pyruvic acid, benzoylacetic acid and ~.hese compounds substituted with the above functional groups.
As an amino acid or a peptide of the formula ~3), natural amino acids or peptides may prefera~ly be used. They can be in either D , L- or DL-form, and the derivatives thereof substituted with hydroxyl, amino, carboxylic acid, lower hydro-carbon, alkoxy, phosphoric acid or a halogen atom as well as ethyl or methyl ester derivatives thereof are also available.
There may be mentioned, for example, various natural amino acids (Chemistxy of Amino Acids, Vol. 1, p. 3~8 etc.) o-, m- or p~hydroxy phenylalanine, o-, m- or p-hydroxy phenylglycine, Q~ or ~-carboxy glutamic acidl glutamic acid Q-methylester, glutamic acid ~-ethylester, aspartic acid ~ ~thylester, ~ or r~amino butyric acid, iminodiacetic acid and o~hers.
As the peptide to be acylated, there may ge~erally be
3 .~
used a peptide composed of two or more amino acids, preferably of 2-4 amino acids, which can be obtained by alkali, acid or protease hydrolysis of natural protein such as collagen, keratin, fibroin, albumin, globulin, gelatin and also by conventional synthetic methods. These N-acyl amino acid deriv~tives or N-acyl peptide derivatives preferably possess a chelating activity of about one-thousandth or more of EDTA (ethylenediaminetetraacetic acid).
These N-acyl amino acid derivatives or N-acyl peptide derivatives mentioned above are preferably used in the form of alkali metal salts such as sodium salts, potassium salts or ammonium salts.
An N-acyl amino acid derivative or an N-acyl pepti.de derivative which is represented by the above formula (1) is used in the present invention as the absorption promoter.
These absorption promoters may be employed in amounts 20 of 0.01 W/W~ or more, generally in the range of from 0.1 to 30 W/W%, preferably from 1.0 to 20 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 may suitably be selected one from oily vehicles and water-soluble vehicles conventionally used in the preparation of suppositories or rectal injections, and a surfactant may also be added if desired.
As these oily vehicles or water~soluble vehicles, there may 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 the present invention is not particularly limited, but there may be employed ordinary pharmaceuticals, particularly preferably khe so-called water-solubl~
r ~
medicines which are excellently soluble in water1 such as water-soluble medicines with a partition coefficient of 50 or less in chloroform/water or medicines readily dissociated to ions. For example, there may be included various medicines 5 suc~ as hypnotics, tranquilizers, antiepileptics, antipyretics, analgesics, antidepressants, muscle relaxants, antiinflammatory agents, antiallergic agents, immunosuppressants, an~irheumatics, vasodil~tors, antihemorrhagics~ antihypertensives, antibiotics, antibacterial agents, urinary tract sterilizers, antitumor 10 agents, vitamins, hormones and galenicals. ~ore specifically, typical examples are penicillin type antibiotics such as ampicillin, hetacillin, am~xycillin, cyclacillin, cloxacillin, dicloxacillin~ oxacillin, carindacillin, sulbenicillin, piperacillin, apalcillin, methicillLn etc. or combined drugs 15 of ampicillin or amoxicillin with oxacillin, cloxacillin, floxacillin or dicloxacillin; cephalosporin type antibiotics such as cephalothin, cephaæolin, cephaloridine, cephacetorile, cefoxitin, cefadroxil, cefatridine, cephaloglycin, cephalexin, cephapirin, cephachlor, c~ftexol, cefuroxime, cefsulodin, 20 cefmetazole, etc. and non-toxic salts thereof such as alkali metal salts (e.g. sodium salts or potassium sal~s), ammonium v salts or benzylamine salts. In addition, there may also be mentioned tetracycline type antibiotics such as doxycycline, oxycycline, etc; aminosaccharide type antibiotics such as kanamycin, 25 sisomicin, amikacin, tobramycin, netromycin, ~entamycin, 1-N-~s-3-amino-2-hydroxypropionyl~-gentamicin B, etc.; peptide type antibiotics such as tuberactinomycin N, actinomycin, etc. or non-toxic salts thexeof; further peptide hormones such as insulin, somatostatin, calcitonin, angiotensin, kallikrein, secretin, 30 ~astrisin. parathyroid hor~one~ e~C an~ e~ ~edi~ines such as barbital, ~heophylline, acetylsalicylic acid, mizoribin (bredinine), 5-fluorouracil, methotrexate, L-dopa, etc. The medicine may be employed in an amount, which may suitably be selected and designed.
For example, in case of antibiotics such as ~lactam antibiotics, 2Q to 500 mg activity, generally 100 to 300 mg activity, or in .
, , . , . ... . . , - " ~ . ,, ,, . , - . - , t~ 37 -- ~o --case of peptide hormones such as insulin, 1 to 500 units may b~ contained per gram o~ preparation. In general, the medicin~
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 csnventional methods for production of preparations in general such as rectal suppositories, urethral suppositories or vag ~ 1 ~suppositories,~ 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 o these preparation, there ~ ` may also be added preservatives such as methyl- or propyl-p-: oxybenzoate, colorants, aromas and stabili~ers~
: 20 The present invention is fur~her illustrated in detail by referring to the following Examples, by which the presen~
invention is not limited at all but various medicines, hypertoni-cators and absorp~ion promoters may be selected and combined in addition to those shown in Examples.
The abbreviations employed Ln the Examples are as follows, Gly: Glycine ` Pro: Proline Phe: Phenyl alanine Asp: Aspartic acid Glu~ Glutamic acid Val: Valine Thr: Threonine Ile: Isoleucine Phy: Phenyl glycine " ~
Lys: Lysine ~-Acp: -Aminocaproic acid OEt: Ethyl ester OMe: Methyl ester Boc: t-Butyloxy carbonyl HOBt~ ydroxy benzotriazole TFA: Trifluoroacetic acid DMF: Dimethyl formamide WSC~: N-Ethyl, N-3-dimethylaminopropyl carbodiimide AcO~t: Ethyl acetate NMM: N-Methyl morpholine EtOH: Ethanol HCl: Hydrochloric acid NaOH: Sodium hydroxide TMA: Trimethyl amine Example 1 Absorption effects under conditions with various tonicities were examined. Each sample solution was prepared by adding 0.1 W/V~ cephalothin Na as a medicine together with 0.01 W/V~ N-lauroyl Gly-ONa as an absorption promoter to a phosphate buffer of pH 7.5 conditioned with sodium chloride to a tonicity which was varied from isotonic to twice hypertonic than isotonic (two-fold tonicity), and to four times hypertonic than isotonic (four-fold tonicity).
The experiment was conducted according to the following method. Namely, Wistar-strain male rats, weighing 250 to 300 g, were narcotized (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 from the anus and also another cannulation at a position 5 cm above said irst cannulation. Subsequently, the rectum was internally washed with about 20 ml isotonic sodium chloride solution kept at 38C, ~ ~i and samples each of 10 ml were circulated through the rectum for 5 minutes (2 ml/minute) to make the concentration i.n ~he system constant. Then, 5 ml of each sample was circula~ed at a f low rate of 2 ml/minute, and samples each of 0.05 ml were collected at intervals of 10 minutes from 0 minute. Each sample was diluted to 5 ml with distill~d water and the quantity of medicine disappeared by absorp~ion was ~etermined ~y W - ~pec~ropho~ter.
As the result, the disappearance curve of Cephalothin-Na under the condition of 0.01 W/V~ N-lauroyl Gly-ONa was obtained as shown in Fig. 1, in which D- O shows the result under the l isotonic condition, ~ -~ under two-fold tonicity, ~ - ~ under j four-fold tonicity and ~-~ under no absorp~ion promoter(Control).
'I .
Example 2 Using 0.1 W/V~ cephalothin Na as a medicine and 0.1 W/V% of N-myristoyl Pro-Pro-GlyNa as an absorption promoter under respective osmotic pressure conditions (namely isotonic, two fold tonicity and four fold tonicity with the use of sodium chloride) and following otherwise the same procedure as in Example 1, quantities of Cephalo hin disappeared by absorption were determined. The results are shown in Fig. 2, in which ~- Q
shows the result under the isotonic condition, ~- 0 unaer two-fold tonicity, ~ . ~ under four-tonicity-and -~ - A Control.
Example 3 Quantities of 0.1 W/V% Cephalothin.~a disappeared by absorption under isotonic and two-fold ~onic and four-fold tonic conditions were determined, respectivelyl usincJ N~acyl amino acids and N-acyl peptides where the N-acyl groups are aliphatic hydrocaxbons, similarly as in Example 1. The results axe shown in Table 1.
:
.~
.' i . . .
Table 1 Ivalues after 60 minutes) Two-~old Four-fold Isotonic tonic tonic condition condition condition N-Propionoyl PheONa7.3 % - ~ 19.2 %
N-Hexanoyl PheONa 13.5 20.9 37.6 N-Octanoyl PheONa 22.5 31.7 42.1 N-Octanoyl PheOH 12.5 _ 25.5 N-Hexanoyl ValONa 4.7 - 16.2 10 N-Hexanoyl GlyONa 18.6 25.8 34.8 N-Octanoyl GlyONa 20.5 26.4 34.7 ¦ N-Decanoyl GlyONa 19.5 24.6 36.2 ¦ N-Myri.stoyl GlyONa10.1 - 20.4 N-Hexanoyl AspONa 21.0 15 N-Octanoyl ~spONa 19.5 - 31.0 N-Decanoyl AspONa 16.9 - 26.4 N-Lauroyl AspO~a 21.8 35.8 47.4 N-Myristoyl GlyONa10.3 1S.7 20.7 N-Decanoyl Pro-Pro~GlyONa 7.8 14.0 20.3 20 N-Lauroyl Pro-Pro-GlyONa 12.4 _ 22.4 N-Myristoyl Pro-GlyONa9.5 15.4 20.6 : No adjuvant 2.1 3.3 6.2 Example 4 25 Quantities of 0.l W/V% Cephalothin.Na disappeared by absorption under isotonic,-two-fold tonic and four-fold tonic cond:itions were determined by the high pressure liquid chromatography respectively, using N-acyl amino acids and N-acyl peptide in which the M-acyl ~roups are aromatic hydro-carbons and aryl-substituted low hydrocarbons, similarly as in ~xample 1. The result are shown in Table 2.
Table 2 (values after 60 minutes3 Two~fold Four~fold Isotonic tonic tonic conditioncondition condition N-Benzoyl AlaONa22.6 ~ 30.1 % 39.8 N-Benzoyl ThrONa 23.5 28 7 40.0 N-Benzoyl E-AcpONa20.7 32.3 37O7 I N-Phenacetyl LysONa 7.6 -- 17.8 ¦ N-Phenacetyl IleONa 11.8 - 21.9 p-Aminobenzoyl GlyONa - 16.2 22.5 N-Phthaloyl GluONa24.1 27.3 30.4 N-Phthaloyl Glu ~-methyl ester 22.7 - 32.4 N-Phthaloyl IleONa23.1 30.4 35~1 N-Benzoyl GlyAspONa 12.7 - 25O1 Example 5 CephalothinaNa 1600 mg potency) as a medicine, N-acyl peptides ~100 mg) as an absorption promoter and sodium chloride (200 mg) as a hypertonicator were each pul~eri~ed and dispersed in 1 ml of distilled water. A homogeneous dispersion was prepared by adding the resulting mixtur~ to a base of"Witepsol H-15"previously molten by fusion to a total amount of 10 g. The dispersion was i.ntrarectally administered at a dose of 30 mg/kg to Wister strain rats (male, weighing 200~250 g, our per one group) and blood sampling was performed 5 minutes, 10 minutes, 15 minutes, 20 minutes/~ 30 minutes, 45 minutes and 60 minutes after administration for measurement of Cephalothin concentration in plasma (according to the bioassay using Bacillus subtilis ATCC 6633). As Controls, there was also obtained a preparation without use of the absorption promoter (Control 1). N-Acyl peptides as the absorption promoter used were N-MYri~toyl Pro-Pro-GlyONa, N-Lauroyl Pro~Pro-GlyONa, N-Decanoyl Pro-Pro-GlyONa and N-Myristoyl Pro-Gl~ONa~ The result are shown in FigD 3, wherein 3- ~ indicates plasma concentration * Tradelrlark ..
curve of Cephalothin in the case o~.control, ~- ~ that in the case of N-Myristoyl Pro-Pro-GlvONa as the absorp~ion promoter, ~ that ~ the case of N--Lauroyl Pro-Pro-GlyONa, ~ - ~ that in ~he case of N-Decanoyl Pro-Pro-GlyONa and x - x that in the case of N-Myristoyl Pro-GlyONa, respectively.
Example 6 Tobramycin 1200 mg potency) as a medicine, N-acyl amino acids l10 mg) as a absorption promoter and sodium chloride (200 mg) as a hypertonicator were each pulverized and mixed together. The mixture was mixed with Witepsol H-15 molten by heating to an amount of 1 g. ~he dispersion was intrarectally administered at a dose of 20 mgP/kg and experiment was carried out similarly as in Example 5. As Control, there was also obtained a preparation without use of the absorption promoter.
N-acyl aminoacids as the absorption promoters used were N-Lauroyl PheONa, N-Butyryl ~heONa, N-Lauroyl PhyONa and N-Butyryl PhyNa. The result are shown in ~ig. 4, wherein ~ - o indicates plasma concentration curve of Tobramycin in the case of Control, ~ - ~ that in the case o~ N-Butyryl ~heO~a, o - o that in the case of N-Putyryl PhyONa, ~ ~ ~ that:~ the case of N-Lauroyl PheONa and x - x N-Lauroyl PhyONa, respectively.
Example 7 Elcitonin (Asu1 7-eel calcitonin~ (10 units and 2 units), N-acyl amino acids, N acyl peptide and sodium chloride (50 mg~
were dissolved in 1 ml of 5 ~ gelatin solution. Each solution (0.1 ml) was administered intrarectally to SD-strain male rats ~four weeks of age) and calcium concentrations in serum were 30 measured at 30 minutes, 6Q minutes, ~0 minutes and 120 minutes after Administration by atomic absorption method. As Control, there was used a solution containing no absorp~ion promoter~
( djusted to 10 units of Elcitonin~. N-acyl amino acids and N-acyl peptide as the absorption promoter used were N~Lauroyl GlyONa, N-.~xanoyl PheOH, N-Myristoyl Pro-Pro GlyONa and , ~ . . . .
~8i~8~7 N-Lauroyl AspO~a. The results are shown in Fig. 5, wherein x - x indicates calci~ concentration in serum in ~e case of Control, ~ - b thatin the case ofa solution containing 2 llnits of Elcitonin and N-hexanoyl PheONa, O - O that in the case of 2 units of Elcitonin and N-~auroyl AspONa, ~ - O that in the case of 2 units of Elcitonin and N-Lauroyl GlyONa, o - ~ that in the case of 10 units of E~citonin and N-Myristoyl Pro Pro-GlyONa, o - o ~hat in the case of 10 units of Elcitonin and N
Hexanoyl PheOH and ~ - ~ that in the case Of10 units of Elcitonin with N-Lauroyl GlyONa.
Example 8 Elcitonin (Asu1 7-eel calcitonin) of 200 units, N~acyl amino acids as the absorption promoter (50 mg) and sodium chloride (50 mg) were dissolved in 1 ml of a 5 ~ gelatin solution. Each solution (0.1 ml) was administered intrarectally to Wister-strain rats (200-250 g) and Elcitonin concentration in plasma were determined by enzyme-immunoassay method at 15, 30, 45, 60, 90 and 120 minutes after administration. N-acyl amino acids as the absorption promoter used were N-Octanoyl GlyONa, N-Octanoyl PheONa and N-Lauroyl GlyONa. As Control, there was used a solution containing no absorption promoter. The results are shown in Fiq. S, wherein O - n indicates Elcitonin concentration in plasma in the case of ~-Lauroyl GlyONa , ~ - ~ that in the case of N-OctanoyL
GlyONa, ~ - 0 that in the c~se of N-Octanoyl PheONa and x - x that in the case of the Control. Further, Elcitonin concentration was not detectable in the case of the Control.
Example 9 The collagen was hydrolyzed in 0.1 N-~Cl, then frac-tionation performed using a column of"Sephadex G-2~'and fractions of molecular weight in the region of 900 were collected~ The equimolar quantity of the above peptide was reacted with each acid chloride of hexanoic acid, decanoic acid, lauric acid and stearic acid in DMF containing TMA in an ice-bath, to give * Trademark .~
each hydrolyzed product of N-acyl collagen. These N-acyl peptides were dissolved in equimolar quantities of 1N-NaOH solution, followed by concentration and, freeze-drying ~o obtain sodium salts of these N-acyl peptides, respectively.
1- Using the N~lauroyl derivative of ~he hydrolyzed product of collagen as an a~sorption promoter, each rectal suppository containing 0.1 W/W~, 2.5 W/W%, 5 W/W% and 7.5 WfW~ of the absorption promoter together with ampicillinNa as a medicine and'~itepsol H-15l'as a suppository base. These preparations were intrarectally administered at a dose of 15 mg/kg to male rabbits and ampic,il,lin,concentr,a~ions in plasma were assayed according, to the bioassay method using ATCC 6633.
'l5 As the result, peak plasma concentrations of ampicillin were 1.4 y/ml (no absorption promoter), 2.5 y/ml (addition of 0.1 W/W~, 4.4 y/ml (addition of 2.5 W/W~, 7.0 y/ml (addition of 5.0 W/W%) and 5.8 y/ml (addition of 7.5 W/W~,respectively.
From the result, it can be seen ~hat ~he absorption promoters may preferably be employed in ~he range of from 0.1 W~W~ to 5 W/W~.
2. The rectal suppository containing each 5 W/W~ of N~acyl derivative of hydrolyzed produc~ of collagen together with ampicillin-Na as a medicine and'Wi~epsol~as a base. Then the samples were administered intrc~rectally each at a dose of 15 mg/kg to male rabbits and the concentrations of ampicillin in plasma were assayed. The results are'shown in Table 3.
From the ~esult, it can be seen that the N-stearoyl d rivative of the hydrolyzed product of collagen is preferably effective. Fur~her, using 0.5 W~W% of N-stearoyl derivative of hydrolyzed product of collagen, other ~-lactam an~ibiotics such as cephalothin-Na, cephazolin.Na and cephapirin.Na were examin~d under the same conditions as mentioned above~ ~5 the result, the peak concen-trations of cephalothin was 12.8 r/ml, tha~ of cephazolin 35~8 * Trad~k . .
r/ml and that of cephapLrin l9o0 ~ml, respectively. Qn the other hand, in the case of no absorption promoter, the concen tration was not de~ectable for cephalothin and cephaæolin, or
used a peptide composed of two or more amino acids, preferably of 2-4 amino acids, which can be obtained by alkali, acid or protease hydrolysis of natural protein such as collagen, keratin, fibroin, albumin, globulin, gelatin and also by conventional synthetic methods. These N-acyl amino acid deriv~tives or N-acyl peptide derivatives preferably possess a chelating activity of about one-thousandth or more of EDTA (ethylenediaminetetraacetic acid).
These N-acyl amino acid derivatives or N-acyl peptide derivatives mentioned above are preferably used in the form of alkali metal salts such as sodium salts, potassium salts or ammonium salts.
An N-acyl amino acid derivative or an N-acyl pepti.de derivative which is represented by the above formula (1) is used in the present invention as the absorption promoter.
These absorption promoters may be employed in amounts 20 of 0.01 W/W~ or more, generally in the range of from 0.1 to 30 W/W%, preferably from 1.0 to 20 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 may suitably be selected one from oily vehicles and water-soluble vehicles conventionally used in the preparation of suppositories or rectal injections, and a surfactant may also be added if desired.
As these oily vehicles or water~soluble vehicles, there may 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 the present invention is not particularly limited, but there may be employed ordinary pharmaceuticals, particularly preferably khe so-called water-solubl~
r ~
medicines which are excellently soluble in water1 such as water-soluble medicines with a partition coefficient of 50 or less in chloroform/water or medicines readily dissociated to ions. For example, there may be included various medicines 5 suc~ as hypnotics, tranquilizers, antiepileptics, antipyretics, analgesics, antidepressants, muscle relaxants, antiinflammatory agents, antiallergic agents, immunosuppressants, an~irheumatics, vasodil~tors, antihemorrhagics~ antihypertensives, antibiotics, antibacterial agents, urinary tract sterilizers, antitumor 10 agents, vitamins, hormones and galenicals. ~ore specifically, typical examples are penicillin type antibiotics such as ampicillin, hetacillin, am~xycillin, cyclacillin, cloxacillin, dicloxacillin~ oxacillin, carindacillin, sulbenicillin, piperacillin, apalcillin, methicillLn etc. or combined drugs 15 of ampicillin or amoxicillin with oxacillin, cloxacillin, floxacillin or dicloxacillin; cephalosporin type antibiotics such as cephalothin, cephaæolin, cephaloridine, cephacetorile, cefoxitin, cefadroxil, cefatridine, cephaloglycin, cephalexin, cephapirin, cephachlor, c~ftexol, cefuroxime, cefsulodin, 20 cefmetazole, etc. and non-toxic salts thereof such as alkali metal salts (e.g. sodium salts or potassium sal~s), ammonium v salts or benzylamine salts. In addition, there may also be mentioned tetracycline type antibiotics such as doxycycline, oxycycline, etc; aminosaccharide type antibiotics such as kanamycin, 25 sisomicin, amikacin, tobramycin, netromycin, ~entamycin, 1-N-~s-3-amino-2-hydroxypropionyl~-gentamicin B, etc.; peptide type antibiotics such as tuberactinomycin N, actinomycin, etc. or non-toxic salts thexeof; further peptide hormones such as insulin, somatostatin, calcitonin, angiotensin, kallikrein, secretin, 30 ~astrisin. parathyroid hor~one~ e~C an~ e~ ~edi~ines such as barbital, ~heophylline, acetylsalicylic acid, mizoribin (bredinine), 5-fluorouracil, methotrexate, L-dopa, etc. The medicine may be employed in an amount, which may suitably be selected and designed.
For example, in case of antibiotics such as ~lactam antibiotics, 2Q to 500 mg activity, generally 100 to 300 mg activity, or in .
, , . , . ... . . , - " ~ . ,, ,, . , - . - , t~ 37 -- ~o --case of peptide hormones such as insulin, 1 to 500 units may b~ contained per gram o~ preparation. In general, the medicin~
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 csnventional methods for production of preparations in general such as rectal suppositories, urethral suppositories or vag ~ 1 ~suppositories,~ 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 o these preparation, there ~ ` may also be added preservatives such as methyl- or propyl-p-: oxybenzoate, colorants, aromas and stabili~ers~
: 20 The present invention is fur~her illustrated in detail by referring to the following Examples, by which the presen~
invention is not limited at all but various medicines, hypertoni-cators and absorp~ion promoters may be selected and combined in addition to those shown in Examples.
The abbreviations employed Ln the Examples are as follows, Gly: Glycine ` Pro: Proline Phe: Phenyl alanine Asp: Aspartic acid Glu~ Glutamic acid Val: Valine Thr: Threonine Ile: Isoleucine Phy: Phenyl glycine " ~
Lys: Lysine ~-Acp: -Aminocaproic acid OEt: Ethyl ester OMe: Methyl ester Boc: t-Butyloxy carbonyl HOBt~ ydroxy benzotriazole TFA: Trifluoroacetic acid DMF: Dimethyl formamide WSC~: N-Ethyl, N-3-dimethylaminopropyl carbodiimide AcO~t: Ethyl acetate NMM: N-Methyl morpholine EtOH: Ethanol HCl: Hydrochloric acid NaOH: Sodium hydroxide TMA: Trimethyl amine Example 1 Absorption effects under conditions with various tonicities were examined. Each sample solution was prepared by adding 0.1 W/V~ cephalothin Na as a medicine together with 0.01 W/V~ N-lauroyl Gly-ONa as an absorption promoter to a phosphate buffer of pH 7.5 conditioned with sodium chloride to a tonicity which was varied from isotonic to twice hypertonic than isotonic (two-fold tonicity), and to four times hypertonic than isotonic (four-fold tonicity).
The experiment was conducted according to the following method. Namely, Wistar-strain male rats, weighing 250 to 300 g, were narcotized (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 from the anus and also another cannulation at a position 5 cm above said irst cannulation. Subsequently, the rectum was internally washed with about 20 ml isotonic sodium chloride solution kept at 38C, ~ ~i and samples each of 10 ml were circulated through the rectum for 5 minutes (2 ml/minute) to make the concentration i.n ~he system constant. Then, 5 ml of each sample was circula~ed at a f low rate of 2 ml/minute, and samples each of 0.05 ml were collected at intervals of 10 minutes from 0 minute. Each sample was diluted to 5 ml with distill~d water and the quantity of medicine disappeared by absorp~ion was ~etermined ~y W - ~pec~ropho~ter.
As the result, the disappearance curve of Cephalothin-Na under the condition of 0.01 W/V~ N-lauroyl Gly-ONa was obtained as shown in Fig. 1, in which D- O shows the result under the l isotonic condition, ~ -~ under two-fold tonicity, ~ - ~ under j four-fold tonicity and ~-~ under no absorp~ion promoter(Control).
'I .
Example 2 Using 0.1 W/V~ cephalothin Na as a medicine and 0.1 W/V% of N-myristoyl Pro-Pro-GlyNa as an absorption promoter under respective osmotic pressure conditions (namely isotonic, two fold tonicity and four fold tonicity with the use of sodium chloride) and following otherwise the same procedure as in Example 1, quantities of Cephalo hin disappeared by absorption were determined. The results are shown in Fig. 2, in which ~- Q
shows the result under the isotonic condition, ~- 0 unaer two-fold tonicity, ~ . ~ under four-tonicity-and -~ - A Control.
Example 3 Quantities of 0.1 W/V% Cephalothin.~a disappeared by absorption under isotonic and two-fold ~onic and four-fold tonic conditions were determined, respectivelyl usincJ N~acyl amino acids and N-acyl peptides where the N-acyl groups are aliphatic hydrocaxbons, similarly as in Example 1. The results axe shown in Table 1.
:
.~
.' i . . .
Table 1 Ivalues after 60 minutes) Two-~old Four-fold Isotonic tonic tonic condition condition condition N-Propionoyl PheONa7.3 % - ~ 19.2 %
N-Hexanoyl PheONa 13.5 20.9 37.6 N-Octanoyl PheONa 22.5 31.7 42.1 N-Octanoyl PheOH 12.5 _ 25.5 N-Hexanoyl ValONa 4.7 - 16.2 10 N-Hexanoyl GlyONa 18.6 25.8 34.8 N-Octanoyl GlyONa 20.5 26.4 34.7 ¦ N-Decanoyl GlyONa 19.5 24.6 36.2 ¦ N-Myri.stoyl GlyONa10.1 - 20.4 N-Hexanoyl AspONa 21.0 15 N-Octanoyl ~spONa 19.5 - 31.0 N-Decanoyl AspONa 16.9 - 26.4 N-Lauroyl AspO~a 21.8 35.8 47.4 N-Myristoyl GlyONa10.3 1S.7 20.7 N-Decanoyl Pro-Pro~GlyONa 7.8 14.0 20.3 20 N-Lauroyl Pro-Pro-GlyONa 12.4 _ 22.4 N-Myristoyl Pro-GlyONa9.5 15.4 20.6 : No adjuvant 2.1 3.3 6.2 Example 4 25 Quantities of 0.l W/V% Cephalothin.Na disappeared by absorption under isotonic,-two-fold tonic and four-fold tonic cond:itions were determined by the high pressure liquid chromatography respectively, using N-acyl amino acids and N-acyl peptide in which the M-acyl ~roups are aromatic hydro-carbons and aryl-substituted low hydrocarbons, similarly as in ~xample 1. The result are shown in Table 2.
Table 2 (values after 60 minutes3 Two~fold Four~fold Isotonic tonic tonic conditioncondition condition N-Benzoyl AlaONa22.6 ~ 30.1 % 39.8 N-Benzoyl ThrONa 23.5 28 7 40.0 N-Benzoyl E-AcpONa20.7 32.3 37O7 I N-Phenacetyl LysONa 7.6 -- 17.8 ¦ N-Phenacetyl IleONa 11.8 - 21.9 p-Aminobenzoyl GlyONa - 16.2 22.5 N-Phthaloyl GluONa24.1 27.3 30.4 N-Phthaloyl Glu ~-methyl ester 22.7 - 32.4 N-Phthaloyl IleONa23.1 30.4 35~1 N-Benzoyl GlyAspONa 12.7 - 25O1 Example 5 CephalothinaNa 1600 mg potency) as a medicine, N-acyl peptides ~100 mg) as an absorption promoter and sodium chloride (200 mg) as a hypertonicator were each pul~eri~ed and dispersed in 1 ml of distilled water. A homogeneous dispersion was prepared by adding the resulting mixtur~ to a base of"Witepsol H-15"previously molten by fusion to a total amount of 10 g. The dispersion was i.ntrarectally administered at a dose of 30 mg/kg to Wister strain rats (male, weighing 200~250 g, our per one group) and blood sampling was performed 5 minutes, 10 minutes, 15 minutes, 20 minutes/~ 30 minutes, 45 minutes and 60 minutes after administration for measurement of Cephalothin concentration in plasma (according to the bioassay using Bacillus subtilis ATCC 6633). As Controls, there was also obtained a preparation without use of the absorption promoter (Control 1). N-Acyl peptides as the absorption promoter used were N-MYri~toyl Pro-Pro-GlyONa, N-Lauroyl Pro~Pro-GlyONa, N-Decanoyl Pro-Pro-GlyONa and N-Myristoyl Pro-Gl~ONa~ The result are shown in FigD 3, wherein 3- ~ indicates plasma concentration * Tradelrlark ..
curve of Cephalothin in the case o~.control, ~- ~ that in the case of N-Myristoyl Pro-Pro-GlvONa as the absorp~ion promoter, ~ that ~ the case of N--Lauroyl Pro-Pro-GlyONa, ~ - ~ that in ~he case of N-Decanoyl Pro-Pro-GlyONa and x - x that in the case of N-Myristoyl Pro-GlyONa, respectively.
Example 6 Tobramycin 1200 mg potency) as a medicine, N-acyl amino acids l10 mg) as a absorption promoter and sodium chloride (200 mg) as a hypertonicator were each pulverized and mixed together. The mixture was mixed with Witepsol H-15 molten by heating to an amount of 1 g. ~he dispersion was intrarectally administered at a dose of 20 mgP/kg and experiment was carried out similarly as in Example 5. As Control, there was also obtained a preparation without use of the absorption promoter.
N-acyl aminoacids as the absorption promoters used were N-Lauroyl PheONa, N-Butyryl ~heONa, N-Lauroyl PhyONa and N-Butyryl PhyNa. The result are shown in ~ig. 4, wherein ~ - o indicates plasma concentration curve of Tobramycin in the case of Control, ~ - ~ that in the case o~ N-Butyryl ~heO~a, o - o that in the case of N-Putyryl PhyONa, ~ ~ ~ that:~ the case of N-Lauroyl PheONa and x - x N-Lauroyl PhyONa, respectively.
Example 7 Elcitonin (Asu1 7-eel calcitonin~ (10 units and 2 units), N-acyl amino acids, N acyl peptide and sodium chloride (50 mg~
were dissolved in 1 ml of 5 ~ gelatin solution. Each solution (0.1 ml) was administered intrarectally to SD-strain male rats ~four weeks of age) and calcium concentrations in serum were 30 measured at 30 minutes, 6Q minutes, ~0 minutes and 120 minutes after Administration by atomic absorption method. As Control, there was used a solution containing no absorp~ion promoter~
( djusted to 10 units of Elcitonin~. N-acyl amino acids and N-acyl peptide as the absorption promoter used were N~Lauroyl GlyONa, N-.~xanoyl PheOH, N-Myristoyl Pro-Pro GlyONa and , ~ . . . .
~8i~8~7 N-Lauroyl AspO~a. The results are shown in Fig. 5, wherein x - x indicates calci~ concentration in serum in ~e case of Control, ~ - b thatin the case ofa solution containing 2 llnits of Elcitonin and N-hexanoyl PheONa, O - O that in the case of 2 units of Elcitonin and N-~auroyl AspONa, ~ - O that in the case of 2 units of Elcitonin and N-Lauroyl GlyONa, o - ~ that in the case of 10 units of E~citonin and N-Myristoyl Pro Pro-GlyONa, o - o ~hat in the case of 10 units of Elcitonin and N
Hexanoyl PheOH and ~ - ~ that in the case Of10 units of Elcitonin with N-Lauroyl GlyONa.
Example 8 Elcitonin (Asu1 7-eel calcitonin) of 200 units, N~acyl amino acids as the absorption promoter (50 mg) and sodium chloride (50 mg) were dissolved in 1 ml of a 5 ~ gelatin solution. Each solution (0.1 ml) was administered intrarectally to Wister-strain rats (200-250 g) and Elcitonin concentration in plasma were determined by enzyme-immunoassay method at 15, 30, 45, 60, 90 and 120 minutes after administration. N-acyl amino acids as the absorption promoter used were N-Octanoyl GlyONa, N-Octanoyl PheONa and N-Lauroyl GlyONa. As Control, there was used a solution containing no absorption promoter. The results are shown in Fiq. S, wherein O - n indicates Elcitonin concentration in plasma in the case of ~-Lauroyl GlyONa , ~ - ~ that in the case of N-OctanoyL
GlyONa, ~ - 0 that in the c~se of N-Octanoyl PheONa and x - x that in the case of the Control. Further, Elcitonin concentration was not detectable in the case of the Control.
Example 9 The collagen was hydrolyzed in 0.1 N-~Cl, then frac-tionation performed using a column of"Sephadex G-2~'and fractions of molecular weight in the region of 900 were collected~ The equimolar quantity of the above peptide was reacted with each acid chloride of hexanoic acid, decanoic acid, lauric acid and stearic acid in DMF containing TMA in an ice-bath, to give * Trademark .~
each hydrolyzed product of N-acyl collagen. These N-acyl peptides were dissolved in equimolar quantities of 1N-NaOH solution, followed by concentration and, freeze-drying ~o obtain sodium salts of these N-acyl peptides, respectively.
1- Using the N~lauroyl derivative of ~he hydrolyzed product of collagen as an a~sorption promoter, each rectal suppository containing 0.1 W/W~, 2.5 W/W%, 5 W/W% and 7.5 WfW~ of the absorption promoter together with ampicillinNa as a medicine and'~itepsol H-15l'as a suppository base. These preparations were intrarectally administered at a dose of 15 mg/kg to male rabbits and ampic,il,lin,concentr,a~ions in plasma were assayed according, to the bioassay method using ATCC 6633.
'l5 As the result, peak plasma concentrations of ampicillin were 1.4 y/ml (no absorption promoter), 2.5 y/ml (addition of 0.1 W/W~, 4.4 y/ml (addition of 2.5 W/W~, 7.0 y/ml (addition of 5.0 W/W%) and 5.8 y/ml (addition of 7.5 W/W~,respectively.
From the result, it can be seen ~hat ~he absorption promoters may preferably be employed in ~he range of from 0.1 W~W~ to 5 W/W~.
2. The rectal suppository containing each 5 W/W~ of N~acyl derivative of hydrolyzed produc~ of collagen together with ampicillin-Na as a medicine and'Wi~epsol~as a base. Then the samples were administered intrc~rectally each at a dose of 15 mg/kg to male rabbits and the concentrations of ampicillin in plasma were assayed. The results are'shown in Table 3.
From the ~esult, it can be seen that the N-stearoyl d rivative of the hydrolyzed product of collagen is preferably effective. Fur~her, using 0.5 W~W% of N-stearoyl derivative of hydrolyzed product of collagen, other ~-lactam an~ibiotics such as cephalothin-Na, cephazolin.Na and cephapirin.Na were examin~d under the same conditions as mentioned above~ ~5 the result, the peak concen-trations of cephalothin was 12.8 r/ml, tha~ of cephazolin 35~8 * Trad~k . .
r/ml and that of cephapLrin l9o0 ~ml, respectively. Qn the other hand, in the case of no absorption promoter, the concen tration was not de~ectable for cephalothin and cephaæolin, or
4.5 r/ml for cephapirin.
Table 3 i Chain length Plasma Level (y/ml~
fatty acid Time (min.) 1 o _ _¦ 1 ol 20 ¦ 40 60 ~ 90 C18¦3.0 8.0 10.2 ¦ 5-0 2.9 11.9 __ ~
C125.2 6.8 5.3 3O1 1O8 0.79 C10_ 6~7 ,7.2 4-4 ¦ 1-6 0.63 C84.8 5.1 3.4 7.5 0.61 __ ~ _. _ No addition 1.1 1.2 0.95 d . 68 0.52 3. And the next, absorption effects under ccnditions with various tonicities were examined as follows. Each sample was prepared by adding 5 mg/ml of ampicillin-Na as a medicine ~; together with 5 W/W% or 0.1 W/W~ of N stearoyl derivative of hydrolyzed product of collagen peptides and with 1.7 W/W% oE
NaCl (twice hypertonic condition), 10 W/W~ of glucose (twice hypertonic condition) or 0~85 W/W% of NaCl (isotonic condition).
,~
The experiment was carried out using Recirculating Perfusion Method IWis-tar strain rats~. The plasma concentrations were determined during recirculation of 10 ml each of above solution and the results are shown in Table 4.
. . , , . - . . . . , , . ~ . . .. . . . .. . .
Table 4 . N~acyl dexlvativé Plasma level (y/ml) of hydrolyzed : product of collagen Ti.me (min~
10 ¦ 20 ¦ 40 ¦ 60 90 NaCl 5.0 W/W% 4.5 32.7 59.2¦ 320520.2 .~ 1.7W/W% __ ~__ : 0.1 W/W% 3~728.5 45.0 25.6 14.3 :: _ . .... _ _ Glucose 5.0 W/W% 5.2 33.954.6 34.4 25.1 10 W/W~ 0.1 W/W~ 3.0 25.743.3 30.2 21.5 _~ .. _ _ ~ ~ _ NaCl 5.0 W/W~ 3.9 7.314.9 11~6 10.0 0.85W/W~ 0.1 W/W~ 4.47.6 6.3 4.2 4. The experiment was performed similarly as in Example 9-3 except that N-decanoyl collagen peptide was used as an absorption promoter instead of N-stearoyl collagen peptide~ The results are shown in Table 5.
From the results shown in Tables4 and 5, it may be concluded that the absorption of ampicillin Na can be improved to promote successfully under the hypertonic conditions by addition of NaCl or saccharide. Fu.rther, sim.ilar results were obtained for other ~-lactam an~ibiotics such as cephalothin Na, cephazolin Na arld cephapirin Na.
Table S
Plasma level ~y/ml) Time ~min.) 20 40 _ _ r 1.7 W/W% 3.9 22.7 32.9 16.0 ~ 1 Glucose 3.6 2002 34.2 7705 ¦ l O.Z
. ~ ....
0.85 W/W%_ 2.6 6.6 8.5 7.4 6.9 ~, . . .
':
Example 10 Cephalothin~Na (200 g potency), N-lauroyl ~lyONa (50 g3 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 ml to i provide intrarectal injection preparations.
Example 11 1 10 Gentamycin (100 g po~encyj, N-Decanoyl AspONa l50 g) I and mannitol 1250 g), each being pulverized, were mixed and the mixture was homogeneously dispersed in 5 % yelatin solution to a volume of one liter, which was then filled into injection cylinders in aliquots each of 1 ml to provide intrarectal injection preparations.
Example 12 One thousand units of Elcitonin, 50 g of N-Hexanoyl PheONa and 250 g of mànnitol were each pulverized and mixed together. The resulting mixture was dispersed homogeneously in 5 % gelatin solution to a volume of one liter, which was then filled into injection cylinders in aliquots each of 1 ml I to provide injection preparation5 for va~inal suppositories.
Example 13 One thousand units of Elcitonin, 50 ~ of N Myristoyl Pro-GlyONa and 5 g of sodium chloride were dissolved in 100 ml of distilled water and the solu~.ion was added to"Witepsol H-5"*
containing 1 ~Span 60~produced by Kao-Atlas Co.) to an amount of 500 g, followed further by homogeneous emulsifying. The emulsion was filled in suppository containers in aliquots each of 1 g to provide rectal suppositories.
Example 14 Cefoxitin-Na (200 g potency), ~-phthaloyl ~lyONa ~50 g) * Trademark.
** Trademark for soxbitan monost~a~ate; it is a nonionic s ~ actant.
... . .. ... , . , , . . , ~ . . .. .. . . . .
and soaium chloride (50 g) each being pulverized were mix~d and dispQrsed in'~itepsol H-5"molten by heating to an amount of 1 kg, which was hen illed in suppository containers in aliquots each of 1 g to provide suppositories.
Example 15 Example 14 was repeated except that Cefazolin~Na (200 g potency) was employed in place of Cefoxitin-Na to obtain suppositories.
Example 16 1-N-(s-3-amino-2-hydroxypropionyl) gentamycin B (100 g potency), N-Hexanoyl GlyONa (10 gl and sodium chloride (50 g) were each pulverized and mixed. The mixture was mixed and homogeneously dispersed wi~h"Witepsol H-5"molten by heating to an amount of 1 kg. The dispersion was molded in suppository containers to provide suppositories each of 1 g.
Example 17 Ampicillin Na ~25 g potency), NaCl (3.4 g~ and N-stearoyl derivative of hydrolyzed pxoduct of collagen (5 g), each being pulverized, were mixed and the mixture was homogeneous-ly dispersed in Witepsol H~15 molten by heating at 45C to an amount of 100 g. The emulsion was filled in suppository containers to provide rectal suppositories under cool conditions.
Example 18 Ampicillin Na (20 g potency)l NaCl (205 g) and N-stearoyl derivative of hydrolyzed product of collagen, each being pulverized, were dispersed in peanut oil containing Emulgen 408 ~3.5 g, Kao Atlas Co., Ltd.; polyoxyethylene oleylalcohol ether~ and was made up to an amount of 100 y.
Each 1.5 g o~ dispersion was ~illed in gelatin rectal capsules to provide rectal capsules.
* Trademar~
Example 19 Ampicillin Na (25 g potency), glucose (10 g ) and N-stearoyl d~rivative of hydrolyzed product of collagen ; ~5 g), each being pulverized, were mixed and the mixture was homogeneously dispersed in ~it~psol H-15 molt~n by heating to an~amount of 100 g. Th~ emulsion was filled in suppository containers to provide rectal suppositories~
Example 20 Example 19 was repeated using glucose (10.9 g) and ; N-stearoyl derivative of hydrolyzed product of collagen ~0.1 g3 in place of glucose (10 g) and N-stearoyl derivative of hydrolyzed product of collag2n (5 g) to provide suppositories.
~' Example 21 Example 20 was repeated using NaCl 13.4 g~ in place of glucose to provide suppositories.
Example 22 Exa~ple 19 was repeated using cephalothin~Na as a medicine in place of ampicilline.Na and using NaCl (3.4 y~
instead of glucose to provide suppositories.
Example ~3 ~5 Cephazolin-Na (20 g po~ency), glucose (10 g) and sodium salt o N-stearoyl derivative of hydrolyzed product of collagen (2.5 g) being pulverized were dispersed in peanut oil containing NIKKOL BC-20 TX (4.5 g, Nikko Chemical Co., Ltd.: polyoxyethylene cetylalcohol ether) to an amoun~ of 100 g, which was filled into gelatin rectal capsules in aliquots each of 1.5 ml to provide rectal capsules.
Example 24 Example 23 was r~peated except that sulbenicillin-Na (20 g) was employed in place of cephazolin-Na to provide rectal capsules.
* Trademark -Example 25 Example 23 was repeated ~xcep~ that Enviomycin sulfate (20 g potency) was employed in place of cephazolin-Na to provide rectal capsules.
Example 25 Mannitol (10 g) and N-ste~royl derivative of hydrolyzed product of collagen (2.5 g~, each being pulverized together with 12500 Units of Elcitonin were mixed and the mixture was homo-geneously dispersed in"Witepsol ~-15"molten by heating to an amount of 100 g. Then, the emulsion was filled in suppository containers to provide rectal suppositories.
Example 27 15Example 26 was repeated except that" Witepsol S-55"was used instead of'~itepsol H-15"and homogeneously dispersed. The emulsion was filled in vaginal suppository containers to provide each 2 g of vaginal suppositories.
Exampl~ 28 The pulverized dicloxacillin Na (5 g po~ency) and "Mygriol 812ll(13.8 g with moisture contents of 0.13 %) were mixed and the above mixed solution was added to ampicillin txihydrate (10 g potency), NaCl (3.4 g1 and N-stearoyl derivative of hydrolyzed product of collagen sodium salt (2.5 g), each being pulveriæed, then homogeneously dispersed in Witepsol H-5 molten by heating to an amount of 100 g. The emulsion was filled in-to gelatin rectal capsules to provide 1 g each of rectal suppositories.
Example 29 Pulverized glucose ~10 g) and N-stearoyl derivative of hydrolyzed product of collagen in the form of sodium salt (5 g) and 12500 Units of Elcitonin were added to O.S W/W~ of "Wakogel 103"a~djusted to pH 6.0 (Wako ~ure Chemical Industories Co., Ltd.; carboxy vinyl polymerj to an amount of 100 gO T~en, ,, i- * Trademark ~`J~** Trademark J~7 - 2~ -the mixture was filled into injection cylinders in aliquots each of 1 ml to provide intrarectal injec~ion preparations.
Example 3 0 GlvOEt,HCl (29.31 g), Boc-Pro (43.05 g~, ~OBt (28.37 g~
in DMF ~150 ml) was treated wi~h WSCD 138.43 ml~ in an ice-ba~h, and stirred for ~ hrs. at 0GCs furthex overnight at roo~ t~mpera-ture. The xeaction mixture was ~vaporated in vacuo~ The residue was dissolved in 1 Q of ~cOE~ and washed with 5 ~ aqueous sodium bicarbonate solution, aqueous NaCl solution, 1-N HCl, 1-N NaO~I
and distilled water in this order. The solvent was evaporated in vacuo after dehydration to give a slightly yellowish oily product. ~Boc-Pro-GlyOEt; 70.2 g).
The oily product in methylene chloride (20 ml) was treated with 70 ml of TF~ at 0C and stirred for 30 minutes at room temperature. The solvent was evaporated and resulting oily residue ~as added to NMM for neutralization at 0C.
Myristic acid ~7.54 g) in THF (50 ml) was treated with WSCD
(6.59 ml) at 0C, then stirred for 1 hr. and added to ~bove neutralized ~olution and stirred overnight at room temperature.
This reaction mixture was concentrated and dissolved in chloroform ~300 ml) and washed with 5 ~ sodium bicarbonate, 1N-HCl, IN-NaOH
and distilled water in ~his order. The solution was concentrated after dehydration with sodium s~l~ate and applied to a "Sephadex I,-20"column (4 x 120 cm), and eluted with Benzane~AcOEt (1:1).
The fraction was applied to q'LC on silica gel by the following solvent system (CHCl3:MeOH~AcOH 95:5:3), the part o R=0.30 was collected and extracted with CHCl3.This solution was evaporated in vacuo and an oily product was obtained (N-myristoyl Pro-GlyOEt).
~ield 76. 8~.
The product was dissolved in EtOH ~30 ml) and 1N~NaOH
(33 ml~ was added to the solution at 0C. The resultant solu~ion was stirred for 1 hrs. at room temperature and evaporated in ` 35 vacuo. The concentrated solution was-applied to a column o~
:. .
.
~ * Tra~mark :` . ' `
:~ *
Sephadex L-20"(4 x 120 cm). The UV absorption at 230 nm was determined in each fraction (12.5 ml each). The fraction corresponding to the main peak (tube No. 95-111) were combined and freez,e dried after concentration. Whi-te powders are obtained (N Myristoyl Pro-GlyONa). Yield 56.6 ~, m,p. 145-148~o Rf=0.80 (n-Butanol: Acetic acid: H2O 3:1:1). ~mino acid ratio in a 6-N-HCl hydrolysate: Proline 0.90, Glycine 1.00 Calcd. for: C, 59.70; H, 9.31; N, 6.92 Found: C, 59.61; H, 9.21; N, 7.22 Example 31 Using GlyOMe HC1 (30.2 ~), Boc-Proline (4.3 g), HOBt (28.37 g) and WSCD (38.43 ml~, the process was carried out similarly as in Example 30, whereby, a slightly yellowish oily product was obtained (BOc-Pro-GlyOMe). The product (10.31 g) in dioxane ~5 ml) was added to ~.32 N-HCl in dioxane (30 ml) in an ice bath, then stirred for 30 min. at room temperature. The solution ~7as evaporated and dried in vacuol thereafter dissolved in D~F (30 ml) and neutralized by addition of NMM (0.5 ml). Boc-Proline (6.46 g), HOBt (4.05 g) in DMF
(30 ml) was treated with r~SCD (5.~9 ml) and stirred for 30 min.
in an ice bath. The solution was added to above neutralized solution and stirred for 2 hrs~ at 0C and further overnight at room temperature. The solution was evaporated and dissolved in CHC13(300 ml), then washed with 5 % aqueous sodium bicarbonate solution, 1~-HCl, lN-NaOH in this order. The solution was dehydrated and concentrated to give an oily product (16.84 g~
~Boc-Pro-Pro-GlyOMe). ~f=0.65 lCHCl3: ~tOH: AcOEt 5:2:5) The product was acylated to N-Myristoyl Pro-Pro-GlyOMe (8.50 g) in the same manner as in Example 30O The oily substance dissolved in EtOH ~30 ml) was added to ~-NaOH solution (20.08 ml) and stirred for 30 min., then applied ~ a S~phadex L-~0 column. The main fraction was collected, concentrated and freeze dried to obtain white powders (4.61 g) (N-Myristoyl Pro-Pro-GlyONa).
*Trademark (~ 7 Yield: 54.9~, R=0.66 (n-BuOH:AcOH:H2O 3:1:1) Calcd. for: C, 60.10; H, 8.92; N, 8.09 Found: C, 59.89; H, 9~20; N, 7.~2 Amino acid ratio in a 6N-HCl hydrolysate: Proline 1.90, Glycine 1.00 Example 32 The process was carried out similarly as in Example 31~ using capric acid instead of myristic acid, then N Decanoyl ~ro-Pro-GlyONa (7.22 g) was obtai~ed. Yield: 81.0%, Rf=0.66 (n-BuOH:AcOH:H2O 3:1:1) Amino acid ratio in a 6N-HCl hydrolysate: Proline 1.8, Glycine 1.O
Calcd. for: C, 54.87; H, 8.38; N, 8.73 Found: C, 55~03, H. 8.62; N, 8.39 Example 33 The process was carried out similarly as in Example 31, using lauric acid instead of myristic acid, whereby N-lauroyl Pro-Pro-GlyONa (5.29 g) was obtained. Yield: 73.4 %, Rf-0u66 (n-BuOH:AcOH:H2O 3:1:1) Amino acid ratio in a 6N-~Cl hydrolysate: Proline 1.9, Glycine 1.O
Calcd. for: C, 58.64; H, 8.61; N, 8.55 Found: C, 59.01; H, 8.90; N, 8.20
Table 3 i Chain length Plasma Level (y/ml~
fatty acid Time (min.) 1 o _ _¦ 1 ol 20 ¦ 40 60 ~ 90 C18¦3.0 8.0 10.2 ¦ 5-0 2.9 11.9 __ ~
C125.2 6.8 5.3 3O1 1O8 0.79 C10_ 6~7 ,7.2 4-4 ¦ 1-6 0.63 C84.8 5.1 3.4 7.5 0.61 __ ~ _. _ No addition 1.1 1.2 0.95 d . 68 0.52 3. And the next, absorption effects under ccnditions with various tonicities were examined as follows. Each sample was prepared by adding 5 mg/ml of ampicillin-Na as a medicine ~; together with 5 W/W% or 0.1 W/W~ of N stearoyl derivative of hydrolyzed product of collagen peptides and with 1.7 W/W% oE
NaCl (twice hypertonic condition), 10 W/W~ of glucose (twice hypertonic condition) or 0~85 W/W% of NaCl (isotonic condition).
,~
The experiment was carried out using Recirculating Perfusion Method IWis-tar strain rats~. The plasma concentrations were determined during recirculation of 10 ml each of above solution and the results are shown in Table 4.
. . , , . - . . . . , , . ~ . . .. . . . .. . .
Table 4 . N~acyl dexlvativé Plasma level (y/ml) of hydrolyzed : product of collagen Ti.me (min~
10 ¦ 20 ¦ 40 ¦ 60 90 NaCl 5.0 W/W% 4.5 32.7 59.2¦ 320520.2 .~ 1.7W/W% __ ~__ : 0.1 W/W% 3~728.5 45.0 25.6 14.3 :: _ . .... _ _ Glucose 5.0 W/W% 5.2 33.954.6 34.4 25.1 10 W/W~ 0.1 W/W~ 3.0 25.743.3 30.2 21.5 _~ .. _ _ ~ ~ _ NaCl 5.0 W/W~ 3.9 7.314.9 11~6 10.0 0.85W/W~ 0.1 W/W~ 4.47.6 6.3 4.2 4. The experiment was performed similarly as in Example 9-3 except that N-decanoyl collagen peptide was used as an absorption promoter instead of N-stearoyl collagen peptide~ The results are shown in Table 5.
From the results shown in Tables4 and 5, it may be concluded that the absorption of ampicillin Na can be improved to promote successfully under the hypertonic conditions by addition of NaCl or saccharide. Fu.rther, sim.ilar results were obtained for other ~-lactam an~ibiotics such as cephalothin Na, cephazolin Na arld cephapirin Na.
Table S
Plasma level ~y/ml) Time ~min.) 20 40 _ _ r 1.7 W/W% 3.9 22.7 32.9 16.0 ~ 1 Glucose 3.6 2002 34.2 7705 ¦ l O.Z
. ~ ....
0.85 W/W%_ 2.6 6.6 8.5 7.4 6.9 ~, . . .
':
Example 10 Cephalothin~Na (200 g potency), N-lauroyl ~lyONa (50 g3 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 ml to i provide intrarectal injection preparations.
Example 11 1 10 Gentamycin (100 g po~encyj, N-Decanoyl AspONa l50 g) I and mannitol 1250 g), each being pulverized, were mixed and the mixture was homogeneously dispersed in 5 % yelatin solution to a volume of one liter, which was then filled into injection cylinders in aliquots each of 1 ml to provide intrarectal injection preparations.
Example 12 One thousand units of Elcitonin, 50 g of N-Hexanoyl PheONa and 250 g of mànnitol were each pulverized and mixed together. The resulting mixture was dispersed homogeneously in 5 % gelatin solution to a volume of one liter, which was then filled into injection cylinders in aliquots each of 1 ml I to provide injection preparation5 for va~inal suppositories.
Example 13 One thousand units of Elcitonin, 50 ~ of N Myristoyl Pro-GlyONa and 5 g of sodium chloride were dissolved in 100 ml of distilled water and the solu~.ion was added to"Witepsol H-5"*
containing 1 ~Span 60~produced by Kao-Atlas Co.) to an amount of 500 g, followed further by homogeneous emulsifying. The emulsion was filled in suppository containers in aliquots each of 1 g to provide rectal suppositories.
Example 14 Cefoxitin-Na (200 g potency), ~-phthaloyl ~lyONa ~50 g) * Trademark.
** Trademark for soxbitan monost~a~ate; it is a nonionic s ~ actant.
... . .. ... , . , , . . , ~ . . .. .. . . . .
and soaium chloride (50 g) each being pulverized were mix~d and dispQrsed in'~itepsol H-5"molten by heating to an amount of 1 kg, which was hen illed in suppository containers in aliquots each of 1 g to provide suppositories.
Example 15 Example 14 was repeated except that Cefazolin~Na (200 g potency) was employed in place of Cefoxitin-Na to obtain suppositories.
Example 16 1-N-(s-3-amino-2-hydroxypropionyl) gentamycin B (100 g potency), N-Hexanoyl GlyONa (10 gl and sodium chloride (50 g) were each pulverized and mixed. The mixture was mixed and homogeneously dispersed wi~h"Witepsol H-5"molten by heating to an amount of 1 kg. The dispersion was molded in suppository containers to provide suppositories each of 1 g.
Example 17 Ampicillin Na ~25 g potency), NaCl (3.4 g~ and N-stearoyl derivative of hydrolyzed pxoduct of collagen (5 g), each being pulverized, were mixed and the mixture was homogeneous-ly dispersed in Witepsol H~15 molten by heating at 45C to an amount of 100 g. The emulsion was filled in suppository containers to provide rectal suppositories under cool conditions.
Example 18 Ampicillin Na (20 g potency)l NaCl (205 g) and N-stearoyl derivative of hydrolyzed product of collagen, each being pulverized, were dispersed in peanut oil containing Emulgen 408 ~3.5 g, Kao Atlas Co., Ltd.; polyoxyethylene oleylalcohol ether~ and was made up to an amount of 100 y.
Each 1.5 g o~ dispersion was ~illed in gelatin rectal capsules to provide rectal capsules.
* Trademar~
Example 19 Ampicillin Na (25 g potency), glucose (10 g ) and N-stearoyl d~rivative of hydrolyzed product of collagen ; ~5 g), each being pulverized, were mixed and the mixture was homogeneously dispersed in ~it~psol H-15 molt~n by heating to an~amount of 100 g. Th~ emulsion was filled in suppository containers to provide rectal suppositories~
Example 20 Example 19 was repeated using glucose (10.9 g) and ; N-stearoyl derivative of hydrolyzed product of collagen ~0.1 g3 in place of glucose (10 g) and N-stearoyl derivative of hydrolyzed product of collag2n (5 g) to provide suppositories.
~' Example 21 Example 20 was repeated using NaCl 13.4 g~ in place of glucose to provide suppositories.
Example 22 Exa~ple 19 was repeated using cephalothin~Na as a medicine in place of ampicilline.Na and using NaCl (3.4 y~
instead of glucose to provide suppositories.
Example ~3 ~5 Cephazolin-Na (20 g po~ency), glucose (10 g) and sodium salt o N-stearoyl derivative of hydrolyzed product of collagen (2.5 g) being pulverized were dispersed in peanut oil containing NIKKOL BC-20 TX (4.5 g, Nikko Chemical Co., Ltd.: polyoxyethylene cetylalcohol ether) to an amoun~ of 100 g, which was filled into gelatin rectal capsules in aliquots each of 1.5 ml to provide rectal capsules.
Example 24 Example 23 was r~peated except that sulbenicillin-Na (20 g) was employed in place of cephazolin-Na to provide rectal capsules.
* Trademark -Example 25 Example 23 was repeated ~xcep~ that Enviomycin sulfate (20 g potency) was employed in place of cephazolin-Na to provide rectal capsules.
Example 25 Mannitol (10 g) and N-ste~royl derivative of hydrolyzed product of collagen (2.5 g~, each being pulverized together with 12500 Units of Elcitonin were mixed and the mixture was homo-geneously dispersed in"Witepsol ~-15"molten by heating to an amount of 100 g. Then, the emulsion was filled in suppository containers to provide rectal suppositories.
Example 27 15Example 26 was repeated except that" Witepsol S-55"was used instead of'~itepsol H-15"and homogeneously dispersed. The emulsion was filled in vaginal suppository containers to provide each 2 g of vaginal suppositories.
Exampl~ 28 The pulverized dicloxacillin Na (5 g po~ency) and "Mygriol 812ll(13.8 g with moisture contents of 0.13 %) were mixed and the above mixed solution was added to ampicillin txihydrate (10 g potency), NaCl (3.4 g1 and N-stearoyl derivative of hydrolyzed product of collagen sodium salt (2.5 g), each being pulveriæed, then homogeneously dispersed in Witepsol H-5 molten by heating to an amount of 100 g. The emulsion was filled in-to gelatin rectal capsules to provide 1 g each of rectal suppositories.
Example 29 Pulverized glucose ~10 g) and N-stearoyl derivative of hydrolyzed product of collagen in the form of sodium salt (5 g) and 12500 Units of Elcitonin were added to O.S W/W~ of "Wakogel 103"a~djusted to pH 6.0 (Wako ~ure Chemical Industories Co., Ltd.; carboxy vinyl polymerj to an amount of 100 gO T~en, ,, i- * Trademark ~`J~** Trademark J~7 - 2~ -the mixture was filled into injection cylinders in aliquots each of 1 ml to provide intrarectal injec~ion preparations.
Example 3 0 GlvOEt,HCl (29.31 g), Boc-Pro (43.05 g~, ~OBt (28.37 g~
in DMF ~150 ml) was treated wi~h WSCD 138.43 ml~ in an ice-ba~h, and stirred for ~ hrs. at 0GCs furthex overnight at roo~ t~mpera-ture. The xeaction mixture was ~vaporated in vacuo~ The residue was dissolved in 1 Q of ~cOE~ and washed with 5 ~ aqueous sodium bicarbonate solution, aqueous NaCl solution, 1-N HCl, 1-N NaO~I
and distilled water in this order. The solvent was evaporated in vacuo after dehydration to give a slightly yellowish oily product. ~Boc-Pro-GlyOEt; 70.2 g).
The oily product in methylene chloride (20 ml) was treated with 70 ml of TF~ at 0C and stirred for 30 minutes at room temperature. The solvent was evaporated and resulting oily residue ~as added to NMM for neutralization at 0C.
Myristic acid ~7.54 g) in THF (50 ml) was treated with WSCD
(6.59 ml) at 0C, then stirred for 1 hr. and added to ~bove neutralized ~olution and stirred overnight at room temperature.
This reaction mixture was concentrated and dissolved in chloroform ~300 ml) and washed with 5 ~ sodium bicarbonate, 1N-HCl, IN-NaOH
and distilled water in ~his order. The solution was concentrated after dehydration with sodium s~l~ate and applied to a "Sephadex I,-20"column (4 x 120 cm), and eluted with Benzane~AcOEt (1:1).
The fraction was applied to q'LC on silica gel by the following solvent system (CHCl3:MeOH~AcOH 95:5:3), the part o R=0.30 was collected and extracted with CHCl3.This solution was evaporated in vacuo and an oily product was obtained (N-myristoyl Pro-GlyOEt).
~ield 76. 8~.
The product was dissolved in EtOH ~30 ml) and 1N~NaOH
(33 ml~ was added to the solution at 0C. The resultant solu~ion was stirred for 1 hrs. at room temperature and evaporated in ` 35 vacuo. The concentrated solution was-applied to a column o~
:. .
.
~ * Tra~mark :` . ' `
:~ *
Sephadex L-20"(4 x 120 cm). The UV absorption at 230 nm was determined in each fraction (12.5 ml each). The fraction corresponding to the main peak (tube No. 95-111) were combined and freez,e dried after concentration. Whi-te powders are obtained (N Myristoyl Pro-GlyONa). Yield 56.6 ~, m,p. 145-148~o Rf=0.80 (n-Butanol: Acetic acid: H2O 3:1:1). ~mino acid ratio in a 6-N-HCl hydrolysate: Proline 0.90, Glycine 1.00 Calcd. for: C, 59.70; H, 9.31; N, 6.92 Found: C, 59.61; H, 9.21; N, 7.22 Example 31 Using GlyOMe HC1 (30.2 ~), Boc-Proline (4.3 g), HOBt (28.37 g) and WSCD (38.43 ml~, the process was carried out similarly as in Example 30, whereby, a slightly yellowish oily product was obtained (BOc-Pro-GlyOMe). The product (10.31 g) in dioxane ~5 ml) was added to ~.32 N-HCl in dioxane (30 ml) in an ice bath, then stirred for 30 min. at room temperature. The solution ~7as evaporated and dried in vacuol thereafter dissolved in D~F (30 ml) and neutralized by addition of NMM (0.5 ml). Boc-Proline (6.46 g), HOBt (4.05 g) in DMF
(30 ml) was treated with r~SCD (5.~9 ml) and stirred for 30 min.
in an ice bath. The solution was added to above neutralized solution and stirred for 2 hrs~ at 0C and further overnight at room temperature. The solution was evaporated and dissolved in CHC13(300 ml), then washed with 5 % aqueous sodium bicarbonate solution, 1~-HCl, lN-NaOH in this order. The solution was dehydrated and concentrated to give an oily product (16.84 g~
~Boc-Pro-Pro-GlyOMe). ~f=0.65 lCHCl3: ~tOH: AcOEt 5:2:5) The product was acylated to N-Myristoyl Pro-Pro-GlyOMe (8.50 g) in the same manner as in Example 30O The oily substance dissolved in EtOH ~30 ml) was added to ~-NaOH solution (20.08 ml) and stirred for 30 min., then applied ~ a S~phadex L-~0 column. The main fraction was collected, concentrated and freeze dried to obtain white powders (4.61 g) (N-Myristoyl Pro-Pro-GlyONa).
*Trademark (~ 7 Yield: 54.9~, R=0.66 (n-BuOH:AcOH:H2O 3:1:1) Calcd. for: C, 60.10; H, 8.92; N, 8.09 Found: C, 59.89; H, 9~20; N, 7.~2 Amino acid ratio in a 6N-HCl hydrolysate: Proline 1.90, Glycine 1.00 Example 32 The process was carried out similarly as in Example 31~ using capric acid instead of myristic acid, then N Decanoyl ~ro-Pro-GlyONa (7.22 g) was obtai~ed. Yield: 81.0%, Rf=0.66 (n-BuOH:AcOH:H2O 3:1:1) Amino acid ratio in a 6N-HCl hydrolysate: Proline 1.8, Glycine 1.O
Calcd. for: C, 54.87; H, 8.38; N, 8.73 Found: C, 55~03, H. 8.62; N, 8.39 Example 33 The process was carried out similarly as in Example 31, using lauric acid instead of myristic acid, whereby N-lauroyl Pro-Pro-GlyONa (5.29 g) was obtained. Yield: 73.4 %, Rf-0u66 (n-BuOH:AcOH:H2O 3:1:1) Amino acid ratio in a 6N-~Cl hydrolysate: Proline 1.9, Glycine 1.O
Calcd. for: C, 58.64; H, 8.61; N, 8.55 Found: C, 59.01; H, 8.90; N, 8.20
Claims (6)
1. A preparation having excellent absorption property, comprising a therapeutically effective amount of a water-soluble medicine having a partition coefficient of 50 or less in chloroform/water, a water-soluble substance at a concent-ration exhibiting a higher osmotic pressure than that of isotonic sodium chloride solution, and one or more of N-acyl amino acid derivatives or N-acyl peptide derivatives represented by the formula: R-CO-A (wherein R is an aliphatic hydrocarbon group, an aromatic hydrocarbon group or an aryl-substituted lower aliphatic hydrocarbon group, which may optionally be substituted, and A is an amino acid residue or a peptide residue), as an absorption promoter.
2. 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 of an alkali metal.
3. A preparation according to claim 2, wherein the water-soluble salt of an alkali metal is a halide, a sulfate, a phosphate or a carbonate of sodium, potassium or lithium.
4. A preparation according to claim 1, wherein the water-soluble substance at a concentration exhibiting higher osmotic pressure than isotonic sodium chloride solution is 0.25 M or more of a water-soluble saccharide.
5. A preparation according to claim 4, wherein the water-soluble saccharide is sorbitol, glucose, mannitol, lactose or sucrose.
6. A preparation according to claim 1, wherein the content of the absorption promoter is 0.01 W/W% or higher of the whole content.
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP32705/81 | 1981-03-06 | ||
JP3270581A JPS57146721A (en) | 1981-03-06 | 1981-03-06 | Improver for absorption |
JP57004222A JPS58140026A (en) | 1982-01-14 | 1982-01-14 | Pharmaceutical having improved absorbability |
JP4222/82 | 1982-01-14 |
Publications (1)
Publication Number | Publication Date |
---|---|
CA1188987A true CA1188987A (en) | 1985-06-18 |
Family
ID=26337952
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA000397097A Expired CA1188987A (en) | 1981-03-06 | 1982-02-25 | Preparation having excellent absorption property |
Country Status (4)
Country | Link |
---|---|
CA (1) | CA1188987A (en) |
DE (1) | DE3207480A1 (en) |
FR (1) | FR2509175B1 (en) |
GB (1) | GB2095994B (en) |
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FR2470M (en) * | 1962-03-13 | 1964-04-20 | Mead Johnson & Co | Therapeutic composition. |
GB1294664A (en) * | 1968-12-31 | 1972-11-01 | Unilever Ltd | Modified proteins |
FR2074632B1 (en) * | 1970-01-13 | 1973-01-12 | Roussel Uclaf | |
GB1485694A (en) * | 1975-01-22 | 1977-09-14 | Ajinomoto Kk | Gelling agents |
GB2051574B (en) * | 1979-05-10 | 1984-01-18 | Kyoto Pharma Ind | Adjuvant for promoting absorption of pharmacologically active substances through the rectum |
US4436726A (en) * | 1980-12-15 | 1984-03-13 | Fujisawa Pharmaceutical Co., Ltd. | N-Acylpeptide compound, processes for the preparation thereof and the pharmaceutical compositions |
-
1982
- 1982-02-25 CA CA000397097A patent/CA1188987A/en not_active Expired
- 1982-02-25 FR FR8203123A patent/FR2509175B1/en not_active Expired
- 1982-03-02 DE DE19823207480 patent/DE3207480A1/en active Granted
- 1982-03-05 GB GB8206489A patent/GB2095994B/en not_active Expired
Also Published As
Publication number | Publication date |
---|---|
FR2509175A1 (en) | 1983-01-14 |
DE3207480A1 (en) | 1982-10-07 |
GB2095994A (en) | 1982-10-13 |
GB2095994B (en) | 1985-10-02 |
FR2509175B1 (en) | 1987-01-16 |
DE3207480C2 (en) | 1991-06-06 |
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