FR2509175A1 - THERAPEUTIC PREPARATION HAVING EXCELLENT ABSORPTION PROPERTIES - Google Patents

Abstract

THERAPEUTIC PREPARATION WITH EXCELLENT ABSORPTION PROPERTIES. THIS PREPARATION CONTAINS AN ABSORPTION PROMOTING AGENT WHICH IS AN N-ACYL AMINOACID OR AN N-ACYL PEPTIDE, AS WELL AS A SALT IN A CONCENTRATION HAVING A HIGHER OSMOTIC PRESSURE THAN THAT OF ISOTONIC SOLUTION OF MEDICENTIUM CHLORIDE AND SODIUM CHLORIDE. . MEDICINE.

Description

1 2509175

  The present invention relates to a new preparation having excellent absorption properties, which is intended to improve the absorption of a medicament

  poorly able to be absorbed by the rectum or by

  digestive organs of the body, by administering this medication.

  at the same time as a water-soluble substance with a

  centration with osmotic pressure superior to

  the isotonic solution of sodium chloride, and one or more

  sieurs d'absorption agents selected from N-acylated amino acid derivatives or N-acylated peptide derivatives, as represented by the formula: R-CO-A (1), (wherein R is an aliphatic hydrocarbon group, a

  aromatic hydrocarbon group, a lower hydrocarbon group

  aryl substituted, which may be substituted, where appropriate, and A is an amino acid radical or a peptide radical).

  So far, it has been generally considered that

  of a drug through a digestive organ, be it the stomach, small intestine, large intestine, rectum or mouth, is performed according to the sharing theory according to the p H (Modern Pharmaceutics, Marcel Dekker , Inc. pages 31-49) Thus, a drug dissociated easily in the

  respective organs at sites of absorption, or a drug

  These drugs, which are difficult to absorb, are administered in the form of injections at present. In order to improve the absorbability of a drug, various studies have been carried out, such as Prodrug, Sofdrug, the use of ion pairs or

  the formation of complexes But these proposals are effective

  specifically for particular medicines and

  it is not known in the art which methods are

  in a universal way ("Pharmaceutics" written by Nogami). Now, it has now been found that in the mechanism of absorption by a membrane in digestive or other organs, which is thought to be effected according to the theory of

  shares as mentioned above, a derivative of amino-

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  N-acylated acid or an N-acylated peptide derivative which is

  formula (1) above, provokes certain modifications

  the membrane permeability, which can improve the absorption of a drug by the membrane and thus promote the absorption of this drug. It has been found that the absorption can be significantly improved by membrane by adding a water-soluble substance to

  a concentration representing a higher osmotic pressure

  than the isotonic sodium chloride solution of

  to prepare the preparation under conditions of tonicity greater than the osmotic pressure of a fluid of

  In addition, it has been found that a preparation obtains

  by a vehicle, additives chosen as desired and a drug to be administered, for example a suppository for insertion into the rectum or vagina, is a good suppository that can

  to be absorbed in an excellent way through membra-

  and maintain a high concentration of the drug in

  blood for a long time The drugs to be used

  The invention is very diverse. In particular, water-soluble drugs having good solubility in water, for example those having partition coefficients of 50 or less in the chloroform / water system, may be used. or to dissociated drugs

  In addition, it has been found that medicinal products

  applicable only in injections in the prior art.

  can be rendered absorbable in an excellent manner.

  in the form of preparations such as

  Even a drug with a high molecular weight

  such as a polypeptide, can be rendered absorbable

  in an effective manner by the invention in the form of a pre-

paration such as a suppository.

  The invention therefore aims at a preparation which gives

  a drug a significantly increased absorption power.

  In the attached drawings, given solely for the purpose of

For example:

  Figures 1 and 2 show the curves of

  disappearance at various osmotic pressures of the Cephalon

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  thine Na when used as a medicine, the percentages

  doses of cephalothin disappeared by absorption as a function of the duration of measurement; Fig. 3 is a plot of Cephalothin plasma concentration when Cephalothin Na is used as a drug; Figure 4 is a section of the concentration of

  Tobramicine in plasma when using Tobrami-

  as a medicine; Figure 5 is a plot of calcium concentration in serum when using Elcitonin as a drug; and Figure 6 is a curve of the concentration of

  Elcitonin in plasma when using Elcitonin

not as a medicine.

  The invention therefore relates to a preparation which comprises a water-soluble substance in a concentration having an osmotic pressure greater than the isotonic solution

  sodium chloride, at least one agent promoting the ab-

  sorption chosen from N-acylated amino acid derivatives or N-acylated peptide derivatives of formula: R-CO-A (1) (R and A having the meanings indicated above) and a medicament. As regards the water-soluble substance to be used according to the invention at a concentration having an osmotic pressure higher than the isotonic sodium chloride solution, it is preferably a substance which is generally safe and which may have an osmotic pressure. high in an amount as small as

possible.

  These water-soluble substances include

  water-soluble salts and water-soluble sugars.

  Particularly preferred is hydrogen salts.

  sodium chloride, because it is perfectly safe and because it can easily be controlled by its osmotic pressure and, moreover, because it is rapidly soluble in water at a In addition, mannitol or

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  glucose among water-soluble sugars Generally speaking,

  For example, water-soluble salts may include

  halides, sulphates, phosphates or carbonates

  alkali metal compounds, such as sodium, potassium, lithium, more specifically the sodium chloride mentioned above, sodium sulphate, disodium phosphate,

  monosodium phosphate, trisodium phosphate, bicarbonate

  sodium carbonate, sodium carbonate, chloride of

  potassium, potassium sulphate, monopotassium phosphate

  Dipotassium phosphate, potassium carbonate, lithium chloride, etc. These salts can be adjusted to concentrations with higher osmotic pressure than isotonic chloride solution.

  For example, in the case of chlo-

  sodium chloride, it can usually be adjusted to a concentration

  1% in P / P or above this value.

  The higher concentration is not limited in a particular way, but preferably the concentration

  is between 2 and 30% in w / w.

  soluble solvents, one can use monosaccharides or disaccharides often used to adjust the osmotic pressure in the pharmaceutical art and among which include for example glucose, mannitol, sorbitol, xylitol, lactose, maltose and sucrose. use such a sugar at a concentration having a

  osmotic pressure greater than that of the isotonic solution

  sodium chloride, which is usually 0.25

  M or higher than this value.

  water-soluble substances in association with each other to adjust the osmotic pressure which is preferably 1.5 to

  6 times that of the isotonic solution of sodium chloride.

  With regard to the osmotic pressure, it is

  described herein in comparison to a solution

  isotonic sodium chloride, but the use of

  of an isotonic solution of sodium chloride as

  less is simply given as an example for the purpose of

  kill comparisons between osmotic pressures and so it would be possible to also use fluids from

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  organism or other salt solutions with pres-

  osmotic ions equal to this isotdnic solution of

sodium chloride.

  With regard to N-amino acid derivatives

  acylated or N-acylated peptide derivatives, represented by

  the formula R-CO-A (1) (R and A being as defined above

  above) to be used as absorption promoting agents according to the invention, they have been studied by adding by

  example to an isotonic preparation intended for the administration

  rectal administration, containing a drug, in order to

  to study the increase or decrease of permeability

  The mechanism by which absorption is favored has not been elucidated

  hitherto, but it seems likely that the mechanism of

  sorption by the membrane may be modified by

  chelation and affinity to the mem-

  these absorption promoting agents, on cell membrane structures or on the spaces between epithelial cells, which

promotes absorption.

  Although the mechanism of the agent favoring

  sorption to increase the absorption of the drug by the rectum or other organs can be explained as mentioned above, this mechanism remains a simple estimate and it is only necessary to use amino acid derivatives N- acylated, or N-acylated peptide derivatives having a chelating action, capable of binding

  at least calcium ions or magnesium ions.

  With regard to the N-acylated amino acid derivatives or the N-acylated peptide derivatives of formula (1), they can be obtained by reacting an acidic compound of formula

R-COOH (2)

  (R being as defined above)

  or its reactive derivative on the carboxy group on a compound

se of formula (3):

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H-A (3)

  (wherein H-A is an amino acid or a peptide)

  or its derivative having a protected carboxy group

  In addition, the compound of formula (1) can be obtained by condensing an acyl group of the above-mentioned acidic compound (2) and the amino or imino radical of a

amino acid or a peptide.

  The carboxy groups can be activated by agents, such as an acid azide, an acid anhydride, an acid imidazolide, an acid halide, an active ester or a carbodiimide, a N, N'- carbonyldiimidazole or a salt

  isoxazolium such as Woodward's reagent.

  The preferred condensation reaction, according to the

  tion, uses the carbodiimide method, the azide, the active ester, the halide or the anhydride. As examples of the condensation reaction, an amino acid or a peptide is reacted with reactive derivatives of an acidic compound of formula (2) in an inert medium, for example an organic solvent such as chloroform, methylene chloride, ethylene chloride, ether and a hydrophilic solvent or a hydrophilic aqueous solvent

  such as water, methanol, ethanol, acetone, dimethyl

  thylacetamide, dimethylformamide, dioxane

  kill N-acylation by a usual process and, if necessary,

  re, we can add a condensing agent or a base

to the solvent mentioned above.

  In this reaction, the temperature is lower

  at room temperature or is equal to the ambient temperature

  biante and the acidic compound of formula (2) is used in

  about one mole per mole of amino acid or peptide

  Once the reaction is complete, it can be purified preferably by

a gel filtration process.

  As the acidic compound of formula (2), it is possible to use

  preferably an acid in which R is a hydrocarbon group

  aliphatic boné which may be substituted or a hydro-

  aromatic-substituted aromatic carbon or aryl-substituted lower aliphatic acid in which the lower aliphatic acid group carbon atoms are generally from 1 to 10 and, preferably, from the number of

  from 1 to 5, this group may be substituted.

  When R is an aliphatic hydrocarbon group which may be substituted, this hydrocarbon group generally has a

  number of carbon atoms between 1 and 20 and, preferably,

  between 4 and 18 As aliphatic acids with

  such groups, for example, acetic acid may be

  that propionic acid, butyric acid, valence acid,

  that isovaleric acid, hexanoic acid, enzymic acid,

  acid, octanoic acid, pelargonic acid, decanolic acid, undecylic acid, lauric acid, myristic acid, palmitic acid, stearic acid,

  acrylic acid, crotonic acid, vinylacetic acid,

  4-pentenoic acid, oleic acid, linoleic acid, linolenic acid or sorbic acid as acid

  and their compounds substituted by an alkyl group

  a hydroxy group, a carboxylic acid group, a

  alkoxy group, a phosphoric acid group, a

  no, an imino group or a halogen.

  As acids in which R is a hydrocarbon group

  aromatic moiety which may be substituted, there may be mentioned, for example, benzoic acid, an alkylbenzoic acid,

  phthalic acid, isophthalic acid, o-amino acid,

  benzoic acid, m-aminobenzoic acid, p-aminobenzoic acid,

  o-hydroxybenzoic acid, m-hydroxybenzoic acid, phydroxybenzoic acid, o-alkoxybenzoic acid,

  m-alkoxybenzoic acid, a p-alkoxybenzoic acid, the acyl

  dihydroxybenzoic acid and its compounds substituted by

  functional groups mentioned above.

  The acids in which R is a hydrocarbon group

  aryl-substituted lower folate and which may themselves be substituted may include, for example, the acid

  phenylacetic acid, phenylpropionic acid, o-hydro-

  xyphenylacetic acid, m-hydroxyphenylacetic acid, phydroxyphenylacetic acid, phenylmalonic acid, acid

  phenylsuccinic acid, cinnamic acid, phenylpyruvic acid

  that benzoylacetic acid and its compounds substituted by

  functional groups mentioned above.

  As an amino acid or as a peptide of formula (3), an amino acid or a natural peptide may preferably be used. They may be in the D-, L- or DL-form, and their derivatives substituted with a hydroxy, an amino or a carboxylic acid, a lower hydrocarbon, an alkoxy, a phosphoric acid or a halogen atom, as well as their

  Methyl or ethyl ester derivatives are also available.

  For example, various amino acids may be mentioned.

  Turins (Chemistry of Amino Acids, Volume 1, pages 3-8, etc.) ohydroxyphenylalanine, m-hydroxyphenylalanine,

  p-hydroxyphenylalanine, o-hydroxyphenylglycine, m-hy-

  droxyphenylglycine, p-hydroxyphenylglycine, acid a-

  carboxyglutamic acid, e-carboxyglutamic acid, y-acid

  carboxyglutamic acid, the methyl ester ena glutamic acid

  the ethyl ester has glutamic acid,

  ter ethyl ena of aspartic acid, α-amino acid

  butyric acid, e-aminobutyric acid, y-aminobutyric acid

  that, iminodiacetic acid and others.

  As the peptide to be acylated, it is generally possible to use a peptide composed of two or more amino acids, preferably from 2 to 4 amino acids, which can be obtained

  alkaline acid or protease hydrolysis of native protein

  such as collagen, keratin, fibroin, albumin, globulin, gelatin and also by conventional synthetic methods These amino acid derivatives

  N-acyls or these N-acylated peptide derivatives preferably have

  a chelating activity of about one-thousandth

  more than EDTA (ethylenediaminetetraacetic acid).

  acetic). These N-acylated or N-acylated amino acid derivatives mentioned above are preferably used in the form of alkali metal salts such as sodium salts, potassium salts or ammonium salts,

  According to the invention, the preferred

  absorption of an N-acylated amino acid derivative or a derivative

  N-acylated peptide derivative of formula (1) above.

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  These absorption-promoting agents may be used in amounts of 0.01% w / w or more,

  generally from 0.1 to 30% w / w and preferably

  ence; at a rate of 1.0 to 20% w / w As a vehicle to be used

  For the preparation of a suppository containing the abovementioned absorption promoting agent, a medicament and, preferably, a water-soluble salt to be added to increase the tonicity, the oily vehicles can be suitably selected and water-soluble vehicles conventionally used for the preparation of suppositories or rectal injections, and

  can also add, if desired, a surfactant

  active. As oily vehicles or water-soluble vehicles, those described in "The Theory and Practice of Industrial Pharmacy", pages 245-269, may conveniently be used.

(1976).

  The medicament to be used according to the invention is not limited in a particular way and it is possible to use usual medicaments, in particular water-soluble medicaments which have an excellent solubility in water, such as water-soluble drugs having a sharing 50 or less in the chloroform / water system,

  or drugs that dissociate easily into ions.

  For example, it is possible to use di-

  drugs such as hypnotics, tranquil

  to antiepileptics, antipyretics, analgesics, antidepressants, relaxants

  muscles, inflammatory agents, anti-inflammatory agents,

  allergies, immunosuppressants, antirheumatic

  vasodilators, anti-bleeding agents,

  antihypertensives, antibiotics, anti-inflammatory agents,

  bacteria, agents sterilizing the urinary tract, antitumor agents, vitamins, hormones, and galenic products.

  typical examples are penicillin antibiotics

  such as ampicillin, hetacillin, amoxicillin, cyclacillin, cloxacillin, dicloxacillin, and the like.

  oxacillin, carindacillin, sulbenicillin,

  racillin, apalcillin, methicillin, etc., or combination drugs of ampicillin or amoxicillin with oxacillin, cloxacillin, floxacillin or dichloxacillin; to cephalobic antibiotics

  such as cephalothin, cephalozine, cephalothin

  loridine, cephacetoril, cefoxitin, cefadroxil,

  cefatrizine, cephaloglycine, cephalexin, cephalo-

  pirine, cephachlor, ceftezole, cefuroxime,

  cefsulodine, cefmetazole, etc. and their non-toxic salts

  such as their alkali metal salts (especially sodium or potassium salts), or their ammonium salts or their benzylamine salts. In addition, mention may also be made of tetracycline antibiotics such as doxycycline, oxycycline, etc .; aminosaccharide antibiotics such as kanamycin, sisomicin,

  amikacin, tobramycin, netromycin, gentamicin

  ne, etc .; peptidic antibiotics such as tuberactinomycin N, actinomycin, etc. or their non-salts

  toxic; Peptide hormones can also be used.

  such as insulin, somatostatin, calcitonin

  ne, angiotensin, kallikrein, secretin, gastritis,

  sine, parathyroid hormone, etc .; and other medi-

  such as barbital, theophylline, aspirin,

  mizoribine, bredinine, 5-fluorouracil, metho-

  trexate, L-dopa, etc. The drug can be used in the desired amount Thus, for example, in the case of antibiotics such as e-lactam antibiotics an activity of 20 to 500 mg and usually from 100 to 300 mg, or, in the case of peptide hormones such as insulin, from 1 to 500 units may be contained by

  Preparation schedule The drug is preferably used

  in a form finely divided into diameters of

  1 to 50 microns, or in the form of an aqueous solution.

  The training stage of the preparations can be

  carried out by conventional methods of producing pre-

  parations in general such as suppositories for the rectal route, or ointments or creams and suppositories there 2509175 for the vaginal route It is thus, for example, that the agent promoting the absorption that has been chosen, a

  water-soluble substance in an amount having a

  osmotic solution superior to the isotonic chlorine solution

  sodium chloride and a drug are added to a vehicle,

  where appropriate, combined with a surfactant, and these

  are intimately mixed together to form pre-

  repairs. In addition, when producing these preparations,

  can also add preservatives such as p-

  methyl hydroxybenzoate or p-hydroxybenzoate

  pylons, colorants, flavoring agents and stabilizers. The following examples illustrate the invention. These examples do not limit the invention and various drugs, osmotic pressure-giving agents and absorption enhancers may be used in addition to those indicated.

to examples.

  The abbreviations used in the examples are as follows: Gly: Glycine Pro: Proline Phe: Phenylalanine Asp: Aspartic acid Glu: Glutamic acid Val: Thr val: Threonine Ile: Isoleucine Phy: Phenylglycine Lys: Lysine c-Acp: ó-Aminocaproic acid And: Ethyl ester O Me: Methyl ester Boc: t-butyloxycarbonyl HO Bt: 1-hydroxybenzotriazole TFA: Trifluoroacetic acid DMF: Dimethylformamide

12 2509175

  WSCD: N-ethyl, N-3-dimethylaminopropyl carbodiimide Ac O Et: Ethyl acetate NMM: N-methyl morpholine And OH: Ethanol HC 1: Hydrochloric acid Na OH: Sodium hydroxide

TMA: Trimethylamine.

EXAMPLE 1

* The effects of absorption under various

  osmotic pressures which are hereafter called tonicities.

  Each test solution is prepared by adding 0.1% w / v of cephalothin Na as a drug, at the same time

  0.01% w / v N-lauroyl Gly-O Na

  me agent promoting absorption, with a phosphate buffer

  of pH 7.0, conditioned with sodium chloride, at a rate of

  cited, which varies from isotonicity to double hypertonicity of isotonicity (double tonicity), and to equal tonicity

  at four times the isotonicity (quadruple tonicity).

  The experiment is carried out as follows.

  Male rats of Wistar strain, weighing 150 to 300 grams, were treated with pentobarbital (50 mg / kg) for 20 days and then subjected to a hypoabdominal incision for the first cannula, approximately 1.5 cm above the anus and also for the installation of another cannula 5 cm above the first. The rectum is then washed internally with 50 ml about 5% of an isotonic solution of sodium chloride maintained at 38 ° C. and samples of each 10 ml are circulated in the rectum for 5 minutes at a rate of 2 ml / minute to make the concentration in the

  The system then circulates 5 ml of each sample

  at a rate of 2 ml / minute and samples are collected

  lons each 0.05 ml every 10 minutes, starting from

  The instant is diluted each sample with 5 ml of distilled water.

  and the ultraviolet spectrophotometer

  amount of medicine that has disappeared by absorption.

  The result is the disappearance curve

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  dehalothin-Na at a concentration of 0.01% w / v Nlauroyl Gly-O Na as shown in FIG.

  Figure 1, in which a represent the results

  isotonicity, e-e at double tonicity, at quadruple tone and A-A without absorptive

(witness).

EXAMPLE 2

  Using 0.1% w / v cephalothin Na as drug and 0.1% w / v N-myristoyl Pro-Pro-Gly-Na as the absorption enhancer, in

  osmotic pressure conditions which are respectively

  isotonicity, double the isotonicity and the

  druple of the isotonicity, using sodium chloride, and if not following the same operating procedure as in example 1, the quantities of cephalothin are determined

  disappeared by absorption The results obtained are

  born in Figure 2 in which D-O represent the results

  isotonicity, * results in a doubly toned

  at a quadruple tone, while A-A is a

witness.

EXAMPLE 3

  As in Example 1, the amounts of cephalothin Na used in an amount of 0.1% by weight were determined.

  volume disappeared by absorption under

  tonicity, double tonicity and quadruple tonicity, using N-acylated amino acids and N-acylated peptides,

  the N-acyl groups being aliphatic hydrocarbons.

  The results obtained are shown in Table 1.

TABLE 1

  (values after 60 minutes) -%, 9 31.7 Isotonicity Tonicity Tonicity double quadruple N-propionoyl Phe O Na N-hexanoyl Phe O Na N-octanoyl Phe O Na N-octanoyl Phe OH N-hexanoyl Val O Na N-hexanoyl Gly O Na N-octanoyl Gly O Na N-decanoyl Gly O Na N-myristoyl Gly O Na N-hexanoyl Asp O Na Noctanoyl Asp O Na N-decanoyl Asp O Na N-lauroyl Asp O Na N-myristoyl Gly O Na N -decanoyl Pro-Pro-Gly ON N-lauroyl Pro-Pro-Gly O Na N-myristoyl ProGly O Na No adjuvant 7.3% 13.5 22.5 12.5 4.7 18.6, 5 19 , 5, 1 21.0 19, 5 16.9 21.8, 3 7.8 12.4 9.5 2.1, 8 26.4 24.6, 8, 7 14.0, 4 3.319.2 %

  37.6 42.1, 5 16.2 34.8 34.7 36.2, 4 34.0 31.0 26.4 47.4, 7, 3 22.4, 6 6.2

EXAMPLE 4

  As in Example 1, the amounts of cephalothin Na used at a level of 0.1% by weight / volume, disappeared by isotonic absorption, at double tonicity and at fourfold tonicity, are determined by chromatography in phase. under high pressure, while using N-acyl amino acids and N-acyl peptides in which

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  the N-acyl groups are aromatic hydrocarbons,

  and lower hydrocarbons substituted with aryl.

  The results obtained are shown in Table 2.

TABLE 2

EXAMPLE 5

  Spray respectively and disperse in

  1 ml distilled water of cephalothin Na (600 mg of

  As a drug, N-acylated peptides (100 mg) as an absorption enhancer and sodium chloride (200 mg) as a tonicity agent. A homogeneous dispersion is prepared by adding the resulting mixture. to a base of Witepsol H-15 previously melted by

  melting up to a total of 10 grams.

  Rectal dispersion at 30 mg / kg was administered to Wistar strain rats (males, weighing from 200 to 250 grams, four in each group) and a blood sample was taken for 5 minutes, 10 minutes, 15 minutes. minutes, 30 minutes, 45 minutes and 60 minutes after administration to measure the concentration of cephalothin in plasma (according to the biological assay using Bacillus Isoto Tonicity Tonicity double quadruple N-benzoyl Ala O Na 22.6% 30, 1% 39.8% N-benzoyl Thr O Na 23.5 28.7 40.0 N-benzoyl c-Acp O Na 20.7 32.3 37.7 N-phenacetyl Lys O Na 7.6 17.8 N-phenacetyl Ile O Na 11.8 21.9 p-aminobenzoyl Gly O Na 16.2 22.5 N-phthaloyl Glu O Na 24.1 27.3 30.4 N-phthaloyl Glu 227 (L-methyl ester) 3, 4 N-phthaloyl Ile O Na 23.1 30.4 35.1 N-benzoyl Gly Asp O Na 12.7 25.1

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  subtilis ATCC 6633) As controls, a preparation is also obtained which does not use the absorption-promoting agent (control 1). The N-acylated peptides serving

  of the absorption-promoting agent are N-myristoyl Pro-

  Pro-Gly O Na, N-lauroyl Pro-Pro-Gly O Na, N-decanoyl Pro-

  Pro-Glyona and N-myristoyl Pro-Gly O Na The results obtained

  naked are shown in Figure 3 in which e-e indicates

  the concentration curve of cephalothin in the plasma

  ma, in the case of the witness, Q that in the case of N-myris-

  toyl Pro-Pro-glyona as an absorption enhancer,

  o-o that in the case of N-lauroyl Pro-Pro-Gly O Na, A-A

  the in the case of N-decanoyl Pro-Pro-Gly O Na and x-x that

  in the case of N-myristoyl Pro-GlyO Na respectively.

EXAMPLE 6

  Tobramycin (200 mg activity) as drug is respectively sprayed and mixed with N-acylated amino acids (10 mg) as an absorption enhancer, and sodium chloride (200 mg) as the delivery agent. Tonicity The mixture is mixed with Witepsol H-15 melted by heating to obtain an amount of 1 gram. The dispersion is administered rectally at a rate of 20 mg / kg and an experiment is carried out.

  as in example 5 As a witness, we also obtain a pre-

  partion that does not use an agent that promotes ab-

  sorption N-acyl amino acids as a preferred

  the absorption used are N-lauroyl Phe O Na, N-

  butyryl Phe O Na, N-lauroyl Phy O Na and N-butyryl Phy Na.

  The results obtained are shown in FIG. 4 in which ee indicate the concentration curve of tobramycin in the plasma in the case of the control, AA that in the case of N-butyryl Phe O Na, and that in the case of N-butyryl. butyryl Phy O Na, MD that in the case of N-lauroyl

  Phe O Na and x-x that in the case of N-lauroyl Phy O Na, respec-

tively.

EXAMPLE 7

  In 1 ml of a 5% gelatin solution,

  elitin Asu 1.7, elcitonin (Asu '7-eel calcitonin) (10 units and 2 units), N-acylated amino acids, N-acylated peptide

17 2509175

  and sodium chloride (50 mg) Each solution is administered

  0.1 ml rectally to four week old male SD strain rats and serum calcium concentrations were measured at 30 minutes, 60 minutes, 90 minutes and 120 minutes after administration by the method of Atomic absorption As a control a solution containing no absorption promoting agent (adjusted to

  units of Elcitonin) N-acyl amino acids and pep-

  N-acylated acid as an absorption promoting agent

  are N-lauroyl Gly O Na, N-hexanoyl Ph EOH, N-

  myristoyl Pro-Pro-Gly O Na and N-lauroyl Asp O Na The results

  obtained are shown in Figure 5, where x-x indicates the concentration of calcium in the serum in

  the case of the witness, A-A in the case of a solution

  holding 2 units of Elcitonin and N-hexanoyl Phe O Na, G-0

  that in the case of a solution containing 2 units of Elci-

  and in the case of a solution containing 2 units of Elcitonin and N-Lauroyl Gly O Na, and that in the case of a solution containing 10 units of Elcitonin and N-Lauroyl Asp O Na. N-myristoyl Pro-Pro-Gly Ona, oo

  that in the case of a solution containing 10 units of Elcium

  tonine and N-hexanoyl Phe OH and A-A that in the case

  of a solution containing 10 units of Elcitonin and N-

lauroyl Gly O Na.

EXAMPLE 8

  In 1 ml of a 5% gelatin solution,

  200 units of Elcitonin (Asul'7-eel calcitonin), 50

  mg of N-acylated amino acids as an abbreviation

  sorption and 50 mg of sodium chloride.

  solution of 0.1 ml rectally to rats of

  Wister weighing from 200 to 250 grams and the concentration of Elcitonin in the plasma is determined by an enzymatic immunoassay method 15, 30, 45, 60, and 120 minutes after administration The N-acylated amino acids used The absorption promoting agents are N-octanoyl GlyO Na, N-octanoyl PheO Na and N-lauroyl GlyO Na. As a control, a solution containing no absorption-promoting agent is used.

18 2509175

  represented in FIG. 6 in which 1 a indicate the concentration of Elcitonine in the plasma in the case of N-octanoyl Phe O Na, AA that in the case of N-octanoyl Gly O Na, * that in the case of N-lauroyl Gly O Na and xx that in the case of the control In addition, we can not detect

  ter concentration of Elcitonin in the case of the control.

EXAMPLE 9

  The collagen is hydrolyzed in 0.1 N HCl, followed by fractionation using a Sephadex G-25 column and fractions of molecular weight close to 900 are collected.

  equimolar amount of the above peptide with, respectively,

  the chloride of hexanolic acid, decanoate

  In this process, the lauric acid and stearic acid in DMF containing TMA is obtained by operating in an ice bath to obtain each hydrolyzed product of N-acyl collagen. These N-acylated peptides are dissolved in equimolar amounts.

  of 1N NaOH solution, then concentrate and lyophilize

  to obtain sodium salts of these N-peptides

acylated respectively.

  Using the N-lauroyl derivative of the hydrolyzed collagen product as an absorption enhancer, suppositories for the rectal route containing 0.1% w / w, 2.5% w / w, 5% by weight are prepared. weight/

  weight and 7.5% w / w of the ab-

  sorption associated with ampicillin Na as a drug and

  to Witepsol H-15 as a suppository base

  these preparations rectally in a dose of 15 mg /

  kg to male rabbits and the concentration of ampicillin

  in the plasma, according to the biolo-

using ATCC 6633.

  There are peaks of concentration of ampicillin

  in plasma at 1.4 μg / ml (no absorption promoter).

  2.5 y / ml (addition of 0.1% w / w) at 4.4

  y / ml (addition of 2.5% w / w) to 7.0 μ / ml (add

  5.0 w / w%) and 5.8 y / ml (addition of 7.5 w / w%). It is deduced from these results that these absorptive agents can preferably be used.

19 2509175

  from 0.1% w / w to 5% w / w.

  A suppository for the rectal route containing 5% w / w of the N-acylated derivative of the hydrolyzed collagen product was prepared, combined with ampicillin Na as a drug and Witepsol as a base. rectal route, each at a dose of 15 mg / kg to male rabbits and the plasma concentrations of ampicillin are

  Table 3 shows that the N-stearoyl derivative

  of the hydrolyzed collagen product is the most effective

  In addition, using 0.5% w / w of the N-stearoyl derivative of the hydrolysed collagen product, under the same conditions as mentioned above, other ε-lactam antibiotics such as cephalothin Na,

  Cephazolin Na and Cephapilin Na result as a result of

  the peak cephalothin concentration is obtained at 12.8 y / ml, that for cephazolin at 35.8 y / ml and that for cephapilin at 19.0 y / ml. there is no absorption enhancer, no concentration is detected for cephalothin and cephazolin or peak concentration is detected at 4.5 y / ml for cephapilin.

TABLE 3

  Plasma level (y / ml) Chain length Time (minute) of fatty acid (m

10 20 40 60 90

C 18 3.0 8.0 10.2 5.0 2.9 1.9

C 12 5.2 6.8 5.3 3.1 1.8 0.7

Clo 6.7 7.2 4.4 1.6 0.63 -

C 8 4.8 5.1 3.4 1.5 0.61 -

  No addition 1,1 1,2 0,95 0,68 0,52 -

  The effects of absorption under various tonicities are then studied. Each sample is prepared by adding 5 mg / ml ampicillin Na as drug, 5% w / w or 0.1% w / w of the derivative. Nystearoyl of the hydrolysed product of the collagen peptides and 1.7% w / w NaCl (at double the isotonicity), 10% w / w glucose (double the

  isotonicity), or 0.85% w / w NaCl (isotonic)

  cited) The experiment is carried out using a recirculating perfusion method (Wistar strain rats) Concentrations in the plasma are determined during the recirculation of 10 ml of each of the above solutions,

  and the results obtained are shown in Table 4.

TABLE 4

  The experiments of Example 9-3 are repeated except that the N-decanoylated collagen peptide is used as an absorption promoting agent instead of the N-stearolyl collagen peptide. The results obtained are recorded. Derivative N Acylated plasma level (y / ml) of product Hydrolyzed duration (minute) of collagen NaCl 5.0% w / 4.5 32.7 59.2 32.5 20.2 1 , 7% w / w 0.1% w / w 3.7 28.5 45.0 25.6 14.3 wt. Glucose 5.0 wt.% G 1 ucs O wt.% 5.2 33.9 54.6 34.4 25.1% w / w 0.1% w / 3.0 25.7 43.8 30.2 21.5 wt. NaCl 5.0% w / 0.85 5% by weight 3.9 7.3 14.9 11.6 10.0 weight / 0.1% by weight 4 weight 0.1% by weight 1 3.2 4.4 7.6 6.3.4 2 weights

21 2509175

in table 5.

  It is deduced from Tables 4 and 5 that the absorption of ampicillin Na can be improved under hyper-tonicity conditions by addition of NaCl or saccharide. In addition, similar results are obtained for other antibiotics of lactam such as cephalothin Na,

  cephazolin Na and cephapilin Na.

TABLE 5

EXAMPLE 10

  Cephalothin Na (activity of

  grams), N-lauroyl Gly O Na (50 grams) and chlorine

  sodium hydroxide (50 grams), each being sprayed, and the resulting mixture is dissolved in a 1% gelatin solution until a volume of 1 liter is obtained, which is then placed in injection cylinders in aliquots of each 1 ml to obtain preparations to be injected by

rectal route.

EXAMPLE 11

  Gentamycin (a 100 gram activity) is mixed with

  mes), N-decanoyl Asp O Na (50 grams) and mannitol (250 grams), each pulverized, and dispersed

  homogeneously mixed in a gel solution

  5% tine until 1 liter volume is reached, that plasma level (y / ml 'Duration (minute)

20 40 60 90

  Na C 1.7% w / 3.9 22.7 32.9 16.0 8.1 Weight Glucose wt% / 3, 6 20.2 34.2 17.5 10.8 wt. , 85% by weight / 2.6 6.6 8.5 7.4 6.9 weight

22 2509175

  injection cylinders are then placed in

  aliquots of 1 ml each to obtain prepara-

to be injected rectally.

EXAMPLE 12

  1000 units of Elcitonin are sprayed and mixed,

  grams of N-hexanoyl Phe O Na and 250 grams of mannitol.

  The mixture obtained is dispersed homogeneously in a 5% gelatin solution until a volume of 1 m is obtained, which is then placed in injection cylinders in aliquots of 1 ml each.

  to obtain injectable preparations for the purpose of

vaginal site.

EXAMPLE 13

  In 100 ml of distilled water, 1000 units of Elcitonin, 50 grams of N-myristol Pro-Gly Ona and 5 grams of sodium chloride are dissolved, and the solution is added to Witepsol H-5 containing 1% Span. 60 (supplied by Kao-Atlas Co) until a quantity of

  500 grams, followed by a regular emulsification

  The emulsion is placed in suppository molds, in aliquots of 1 gram each, so

  to obtain suppositories for the rectal route.

EXAMPLE 14

  Na cefoxitin (activity 200 gram

  mes), N-phthaloyl Gly O Na (50 grams) and

  sodium (50 grams), each pulverized, and

  Persian in Witepsol H-5 melted while heating until you reach

  a quantity of 1 kg which is then placed in

  suppository molds in aliquots of each

  do 1 gram to get suppositories.

EXAMPLE 15

  Example 14 is repeated, except that we use

  readout of cefazolin Na (activity 200 grams) instead of

  cefoxitin Na to obtain suppositories.

EXAMPLE 16

  1-N- (s-3-amino)

  2-hydroxypropionyl) gentamycin B (activity 100 grams), N-hexanoyl GlyO Na (10 grams) and sodium chloride (50 grams) The mixture is mixed and dispersed homogeneously in Witepsol H-5 melted by heating to a total of 1 kg. The dispersion was molded into suppository molds to obtain suppositories of 1 gram each.

EXAMPLE 17

  Ampicillin Na (activity of 25 grams), NaCl (3.4 grams) and the N-stearoyl derivative of the hydrolyzed collagen product (5 grams) are mixed, each of which is pulverized, and the mixture is dispersed. homogeneously in Witepsol H-15 melted by heating at 45 ° C. until an amount of 100 grams is obtained.

  in suppository molds for suppositions

  for the rectal route to cooling.

EXAMPLE 18

  Ampicillin Na (activity of

  grams), NaCl (2.5 grams) and the N-stearate derivative

  the hydrolysed collagen product, each of which is pul-

  verified, in peanut oil containing Emulgene 408 (3.5 grams, supplied by Kao Atlas Co, Ltd., polyoxyethylenated oleyl ether) and

  that the dispersion represents a quantity of 100 grams.

  The dispersion is each time 1.5 gram in gelatin capsules for the rectal route, in order to obtain capsules for administration by

rectal route.

EXAMPLE 19

  Ampicillin Na (activity of 25

  grams), glucose (10 grams) and the N-stearo derivative

  hydrolysed collagen product (5 grams), each pulverized and the mixture homogeneously dispersed in Witepsol H-15 melted by heating to

  to obtain a quantity of 100 grams We place the emul-

  in suppository molds to obtain suppositories for rectal administration.

24 2509175

EXAMPLE 20

  Example 19 was repeated using 10.9 grams instead of 10 grams of glucose and 0.1 grams instead of grams of the N-stearoyl derivative of the hydrolyzed collagen product to obtain suppositories.

EXAMPLE 21

  Example 20 is repeated using 3.4 grams of

  Na Cl, instead of glucose, to get suppositories.

EXAMPLE 22

  Example 19 is repeated using cepha-

  lothine Na as a drug, instead of ampicillin Na, and using 3.4 grams of Na Cl instead of glucose

to get the suppositories.

EXAMPLE 23

  Cephazolin Na (grams activity), glucose (10 grams), and sodium salt of the N-stearoyl derivative of the hydrolyzed collagen product (2.5 grams) are dispersed, each sprayed in peanut oil. containing NIKKOL BC-20 TX (4.5 grams, supplied by Nikko Chemical Co, Ltd .: ether of polyoxyethylenated cetyl alcohol) to a quantity of grams, which is placed in gelatin capsules for the rectal route in aliquots of each

  1.5 ml to obtain capsules for the rectal route.

EXAMPLE 24

  Example 23 is repeated, except that we use

  read 20 grams of sulbenicillin Na instead of cephalosporin

  line D to obtain capsules for the rectal route.

EXAMPLE 25

  Example 23 is repeated, except that enviomycin sulfate (activity of 20 grams) is used instead of cephazoline Na to obtain capsules for

rectal route.

EXAMPLE 26

  10 grams of mannitol and 2.5 grams of the N-stearoyl derivative of the hydrolyzed collagen product, each sprayed at 12500 units of elcitonin, are mixed and homogeneously dispersed in Witepsol H-15.

2509175

  by heating until a quantity of 100 gram

  The emulsion is then placed in molds

  to obtain suppositories for the rectal route.

EXAMPLE 27

  Example 26 is repeated except that Witepsol S-55 is used instead of Witepsol H-15 and is dispersed in a homogeneous manner. The emulsion is placed in molds. to suppositories for the vaginal route in order to obtain

  suppositories for the vaginal route of 2 grams each.

EXAMPLE 28

  The pulverized dicloxacillin Na (activated

  5 grams) and Mygriol 812 (13.8 grams with a moisture content of 0.13%) and the above mixed solution is added to ampicillin trihydrate (

  10 grams) to NaCl (3.4 grams) and the N-stearoyl derivative

* the hydrolysed product of sodium salt of collagen (2.5

  grams), each in the form of a powder, and then

  homogeneously in Witepsol H-5 melted by

  heating until a quantity of 100 grams.

  The emulsion is placed in gelatin capsules for the rectal route to obtain suppositories for the route.

rectal 1 gram each.

EXAMPLE 29

  Powdered glucose (10 grams) and the N-stearoyl derivative of the collagen hydrolyzed product are added.

  the form of sodium salt (5 grams) and 12500 units of elcium

  0.5% w / w% Wakogel 103 adjusted to pH 6.0, supplied by Wako Pure Chemical Industories Co Ltd; carboxyvinyl polymer) until an amount of 100 grams is obtained. The mixture is then put into injection molding molds in aliquots of 1 ml each to obtain preparations.

inject intra-rectally.

EXAMPLE 30

  29.31 grams of Gly O and HCl, 43.05 gram

  of Boc-Pro, 28.37 grams of HO Bt in 150 ml of

  thylformamide with 38.43 ml of WSCD in an ice bath and stirred for 2 hours at 0 ° C. overnight at room temperature.

26 2509175

  The reaction mixture is evaporated in vacuo. The residue is dissolved in 1 liter of AcO Et and washed with a 5% aqueous sodium bicarbonate solution, with an aqueous NaCl solution and with HCl 1. -N, with NaOH 1-N and with distilled water in this order.

  solvent under vacuum after dehydration to obtain a

  slightly yellowish oily dough (Boc-Pro-Gly O and 70.2 grams). The oily product is treated in 20 ml of methylene chloride, with 70 ml of TFA operating at 00 ° C. and stirred for 30 minutes at room temperature. The solvent is evaporated off and the resulting oily residue is added to NMM to neutralize. operating at OC On

  treats 7.54 grams of myristic acid in 50 ml of tetra-

  hydrofuran, by 6.59 ml of WSCD operating at 0 ° C., then it is added to the neutralized solution above and stirred overnight at room temperature.

  reaction mixture and dissolved in 300 ml of chlorine

  form, then washed with 5% sodium bicarbonate,

  HCl-1N, NaOH-1N and distilled water in that order.

  The solution is concentrated after dehydration on sulfa

  of sodium and is sent to a Sephadex column

  L-20 (4 x 120 cm) and eluted with benzene-Ac O- (1: 1).

  The fraction is subjected to thin-layer chromatography on silica gel using the following solvent system (CHCl 3: MeOH: AcOH 95: 5: 3), the part having a Rf of 0.30 is collected and treated. extracted with CHC 13 This solution is evaporated

  under vacuum and an oily product (N-myristoyl Pro-

Gly O And) Yield 76.8%.

  The product is dissolved in 30 ml of EtOH and 33 ml of 1N NaOH is added to the solution at 0 ° C. The resulting solution is stirred for 1 hour at room temperature and evaporated in vacuo. Sephadex L-20 column (4 × 120 cm) The UV absorption at 230 n of each fraction (12.5 ml each) was determined. The fractions corresponding to the main peak (tubes No. 95 to 111) were pooled and lyophilized after concentration A white powder is obtained (Nmyristoyl Pro-GlyO Na) Yield 56.6%, mp 145 to 148 ° C. Rf = 0.80% (n-butanol: acetic acid: H 3: 1: 1) Amino acid ratio in a hydrolyzate with HCl-6-N: proline 0.90,

glycine 1.0.

  Calculated: C, 59.70; H, 9.31; N, 6.92

  found: C, 59.61; H, 9.21; N, 7.22.

EXAMPLE 31

  Using 30.2 grams of Gly O Me E Cl, 4.3 gram

  of Boc-Proline, 28.37 grams of HO Bt and 38.43 ml of WSCD, the procedure is carried out as in Example 30,

  obtaining an oily product slightly yellowish (Boc-Pro-

  Gly O Me) 10.31 grams of the product in 5 ml of dioxane are added to HCl-4.32 N in 30 ml of dioxane in an ice-bath, then the mixture is stirred for 30 minutes at room temperature. The solution is evaporated and it is dried under vacuum and then dissolved in 30 ml of dimethylformamide and neutralized by the addition of 0.5 ml of NM-treated with 6.46 grams of BocProline and 4.05 grams of Bt EO in ml of dimethylformamide, 5.49 ml of WSCD and stirred for 30 minutes in an ice bath. The solution is added to the above neutralized solution and stirred for 2 hours at 0 ° C., then for a further overnight at room temperature. The solution is evaporated and we have it

  taken up in 300 ml of CHC 13, then washed with a

  5% aqueous solution of sodium bicarbonate, with HCl-1n and with 1N NaOH in this order. The solution is dehydrated and concentrated to obtain 16.84 grams of an oily product (Boc-Pro). -Pro-Gly O Me} E Rf = 0.65

(CH C 13: And OH: Ac O and 5: 2: 5).

  The product is acylated to obtain 8.50 grams of

  N-myristoyl Pro-Pro-Gly O Me in the same way as in the example

  The oily substance dissolved in 30 ml of EtOH is added to 20.08 g of a 1 N NaOH solution and stirred for 30 minutes, then it is sent to a column of Sephadex L-20 collected. the main fraction, concentrated and lyophilized to obtain 4.61 grams of

  white powder (N-myristoyl Pro-Pro-Gly O Na)).

  Yield: 54.9%, Rf = 0.66 (n-Bu OH: OH: H 3: 1: 1) * Calculated: C, 60, 10; H, 8.92; N, 8.09 found: C, 59.89; H, 9.20; N, 7.82

  Ratio of amino acids in a hydrolyzate by HCl

N: proline 1.90, glycine 1.00.

EXAMPLE 32

  The procedure of Example 31 is repeated using

  of capric acid instead of myristic acid and

  7.22 grams of N-decanoyl Pro-Pro are then obtained.

  Gly O Na Yield: 81.0%, Rf = 0.66 (n-Bu OH: Ac OH: H 20

3: 1: 1).

  Ratio of amino acids in a hydrolyzate by HCl

6 N: proline'1.8, glycine 1.0.

  Calculated: C, 54.87; H, 8.38; N, 8.73

  found: C, 55.03; H, 8.62; N, 8.39.

EXAMPLE 33

  The procedure of Example 31 is repeated using

  lauric acid instead of inyristic acid

  obtaining 5.29 grams of N-lauroyl Pro-Pro-Gly O Na Rende-

  73.4%, R f = 0.66 (n-Bu OH: Ac OH: H 3: 1: 1)

  Ratio of amino acids in a hydrolyzate by HCl

6 N: proline 1.9, glycine 1.0 -

  Calculated: C, 58.64; H, 8; 61 "N, 8.55

  found: C, 59.01; H, 8.90; N, 8.20.

29 2509175

Claims (9)

  Preparation having excellent properties of   sorption comprising a medicament and a hydro-   soluble in a concentration having osmotic pressure   than that of the isotonic chlorine solution   sodium salt, characterized in that it comprises one or more   n-acylated amino acid derivatives or N-acylated peptide derivatives of formula R-CO-A, wherein R is an aliphatic hydrocarbon group, an aromatic hydrocarbon group, or an aryl-substituted lower hydrocarbon group, which may be the case substituted and A is an amino acid radical or a peptide radical, acting as an promoting absorption.   Preparation according to claim 1, characterized   in that the water-soluble substance in a concentration   osmotic pressure greater than that of the isotonic sodium chloride solution is a   solution at 1% w / w or more of a hydro salt solble of an alkaline metal.   Preparation according to claim 2, characterized   in that the water-soluble alkali metal salt is a halide, a sulfate, a phosphate or a carbonate of sodium, potassium or lithium.   Preparation according to claim 1, characterized   in that the water-soluble substance at a concentration   A higher osmotic pressure than the isotonic sodium chloride solution is a 0.25 M solution or greater than 0.25 M of a water-soluble saccharide.   Preparation according to claim 4, characterized   in that the water-soluble saccharide is sorbitol,   glucose, mannitol, lactose, or sucrose.   6 Preparation according to one of the claims   preceding, characterized in that the content of the agent promoting the absorption represents 0.01% of the total weight of the preparation or represents a weight greater than this value.   7 Preparation according to one of the claims 2509175   previous, characterized in that the drug is a water-soluble drug having good solubility in water.   8 Preparation according to claim 7, characterized   in that the water-soluble drug has a coefficient   of 50 or less than 50 in the chloro   form / water. An absorption promoting agent comprising a water-soluble substance in a concentration having a   osmotic pressure greater than that of the isotonic solution   sodium chloride, characterized in that   takes one or more N-acylated amino acid derivatives or   N-acylated peptide derivatives of formula R-CO-A, in the   which R is an aliphatic hydrocarbon group, an aromatic hydrocarbon group or an aryl-substituted lower hydrocarbon group, which may be optionally substituted, and A is an amino acid radical or a peptide radical.