DE1467991A1 - Pharmaceuticals and chemical preparations - Google Patents

Description

The invention described in this application relates to the use of certain chemical compounds to potentiate drugs. In particular it concerns the use of various surfactants for this purpose, thereby increasing the physiological Effect of the drug is achieved.

The surfactants which are in the field of The present invention are generally non-toxic in nature and are generally selected from such 3 standard groups, such as quaternary ammonium compounds, Sulfosuccinates, polyoxyethylene of higher alkanols, sulfur

909805/0991

U67991.

Felsäurouonoestern of the designated alkanols, alkylated .thenoxyethanolane and alkylated phenoxy (polyethanol) and the like, the last group named being the most preferred group. The "preferred surfactants The present invention all have the following general structural formula:

\ V_ (üüE ₂ 0H ₂ ) _n 0H

wherein Ii is an allvyl radical of 1 to 13 carbon atoms and η is an integer from 1 to 30 including iat. Typical compounds of these groups include those which have the above ΙΌιμθΙ, wherein IL Konyl or Cctyl and ϊι = 5 or rel. ^ .; eiüe is 9-10.

The medicaments which are applicable for this invention are only restricted in the Jinna that they are otherwise at their iteceptor sites by a lipida barrier (i.e. the absence of the surface-active must be bound by means of) and that they are preferably also medicinal products that can be used parenterally are. Typical examples from the large number of different types of drugs that are under consideration come, sciiliessen stimulants, like adrenaline, nor-adrenaline and digitoxin, blocking drugs such as lidocaine, as well as various forms of curare and Va30-

"~ 3 - 909805/0991

U67991

constrictive agents like serotonin and so on.

In general, the amount of the surfactant which can be used can be broad in view of the selection of the drug for the present purposes
Change area, but it is common in practice
desirable · at least about 0.1 wt.; j of the designated agent with regard to the medicament for
Achievement of effective results, i.e. a substantial degree of potentiated effect, to be used. Optimum results were, however, with the middle of about O, v / o to about 10 percent «$, based on the weight of the drug was obtained. For example, the
Physiological effects of a drug, such as adrenaline, are potentiated as high as $ 100 above normal control levels by the use or practice of this invention. It is therefore in view
on this remarkable degree of drug efficacy improvement thus achieved, smaller amounts of a given drug may be possible for one in particular
set purpose to use and still the same
Effect in quantitative terms, in terms of level of response, to achieve that normally
would be achieved when the drug is used alone, that is, in the absence of the surfactant. For example, the normal doctors

909805/0991

U67991

average doses in the case of representative compounds as mentioned above to such an extent like 907S, reduced to obtain the same appeal, as has normally been achieved with the Aranean agent alone at the higher dosage prescribed is used.

In carrying out the method according to the invention, the surface potentiator can be applied either before or after the parenteral administration of the medicament itself, provided that the time between the two is not too long, i.e. generally not over about 15 minutes. However, in practice it is preferred to use the two constituents together at the same time, that is to say in combination by way of a mixture which comprises the indicated constituents, as will be explained in more detail below. In any case, the surface potentiator must be used "in conjunction" (in the sense of interaction) with the drug.

Solutions can be used purely for the purpose of parenteral use of the drug to be used in sesame or brown oil or in aqueous propylene glycol or B ^ IT-bimethylformamide used, as well as in sterile aqueous solutions of the corresponding water-soluble salt if available or manufacturable. Such watery Lb * -

909805/0991 ~ ⁵ ßAO

U67991

j. -5-

Solutions should be suitably buffered, if necessary, so that the liquid diluent is first absorbed isotonically with sufficient saline or glucose. All of these solutions are particularly valuable for intravenous, intramuscular, and intraperitoneal injections for two purposes. In this context, the sterile aqueous media used are easily obtained using standard techniques known to those skilled in the art. For example, where distilled water is more commonly used as a diluent, the final formulation can be passed through a suitable bacterial filter such as a cleared glass filter or a diatomaceous earth or unglazed porcelain filter. Preferred filters of this type include the Berkefeld, the Chamberland and the Asbestos Disk-Metal SeitJafilter, wherein the liquid is geaaugt through the filter insert in a sterile container with the aid of a suction pump. Eb is actually not necessary to mention that the aseptischen'Bedingungen necessarily during the whole working process, which directly with the production Her advance-designated injectable solutions are connected, must be retained.

This invention is further illustrated by the following examples explains the scope of the invention in none, / eise should restrict. On the contrary, it goes without saying that this should be done on the wrong side. other embodiments,

909806/0391. . ^ mkatio-

BATH ORIGINAL

U67991-

nen and equivalents thereof can be extended which Easily recommend yourself to the IPaohmann without worrying about it of the present invention and / or the scope of the claims.

example 1

A dial-anesthetized dog was equipped with standard procedures for registering ore velocity and breathing and cannulated for rapid injection of various parenteral solutions. Jenn found that the animal had a steady flow, adrenaline in a 0.1 / Sigen solution (in oil) was applied in this way with a 0.2 to 0.6 ml dose level, i.e. a concentration threshold, and then applied Readings with regard to the extent and persistence, or after-effects of the response of the designated animal, also recorded with regard to its recovery over time. After the final recovery, a dose of the same drug was prepared, which was only one-quarter of the concentration of the previously prescribed test dose. This was then mixed with 2 ml of 0.01% Triton-X-100 in Ringer's (salt) solution and the resulting mixture was cannulated into the same animal as before / Triton X-100 is the registered trademark of Rohm & Haas Co. Philadelphia, Pennsylvania for a surfactant of the formula

- 7 909805/0991

BAD OFMGiNAt

), 0-CH ₂ -C (CH _{5) 2} -C ₆ H ₄ (OCH ₂ CH _{2) 9} _ ₁₀ 0Η /. The results thus obtained are such that the dose response achieved in the case of the Triton egg containing solution is at least equal to that caused by the more concentrated epinephrine solution lacking the surfactant. The tests also show that the animal shows no actual response to Triton X-100 when used alone in Ringer's solution at this concentration.

Example 2

The procedure described in Example 1 was carried out with an isolated organ, instead of an intact animal, with the "Substrate" repeated by Jahl. In this particular case a Froechherz was used, which then made it necessary for the Ringer perfusion with a "T" was placed in the line so that the. Secondary pipe entry of the drug, as well as the large-scale (Volume) washing of the system has been facilitated. On the other hand, the experimental procedure or implementation is essentially the same as in Example 1 for the intact animal. In the same way, the Doais-Anspreoh results, which with adrenaline im The present cases, were also essentially the same, i.e. those obtained by the Triton

909805/0991

U67991

surface-active Llittel produced on the drug effect is of essentially the same extent as it was found in Example 1 for the intact animal experiment became.

üexample J>

Adrenaline was injected into the isolated heart following the procedure of Example 2, but the addition of Triton Σ-ICC was omitted at this point. Subject, normal demands and complete ./leather production, subsequent iiohrfaeiieiii pockets, words a small ilenge (2 ml) LJriton X-100 ir! Linger solution with the O, O "J, Jigen! • '.onzeritrntionalu lic in ■ !: .., " do treated Cr ^ an, clme any drug, injiniex't. £ q v / v: .rde observed that ciac Ilerü sufort anaprach ^ it the same reaction which gave the adrenaline in the harvest case, whereby it was indicated that a large unused part of the ia ^% i: neimittelG is still in the isolated, gawasohenen organ

£ 3 bunaen
(without a doubt. ttti ^^ rz ^ iTi + rt; in the Lipid.v.porre) before the Andea oberx'irchenr.iven Hittelc still present v / ar

^: -y :; leit .- .: en .ei.e

ί;

1: 1; ι ierfix'rr '■ - ■.:. r,: i; -; u- uy., - iu deo ν. ■■■

earth.

- 'ioi :: 1 ι -; & ss :: tliehen de .equ? .n -t; ten uund received / enn cat? ^ -. cMun; U-; a special tie -.,.,

9 0 9 β 0 5/0

BAD ORlG'NAt

H67991

Example 4

The procedure described in Example 1 is used on dogs repeatedly, using other compounds instead of adrenaline. For example, the following Connections used on an individual basis: Nor.-iidrenaliii, pipe or bamboo curars, vascular curars and gourd or bottle gourd (gourd or calabash), iidooain, serotonin and digitoxin. In every palle are the results obtained are essentially the same as previously found for adrenaline in Example 1 became.

example 5

The procedure of Example 1 is repeated except that other surfactants were used in place of Triton X-100 and are listed below as follows will:

(OCH ₂ CE ₂ ) _n 0H

E η R η

OH, 1 0 _a H _1Q 1.5

OH ₃ . 30 ^ ig ⁴

iso-O-H «5 ^ 9 ^ 19 ^

-O ₄ H ₉ 18 O ₉ H ₁₉ 9

13 ⁶ ° 9 ^H 19 9-10

909805/0991

- 10 -

H67991

- ίο -

R η 3 η

^ ■ "^ 'ο 2 ~ 5 2 9""1 ^C) ινι — ιι

ι Γ * Τ-Τ ι Γ * - Γ * ΤΤ 'Γ * ΧΤ ι ντ ί * T-I "IR

^ L / ix ^ ^ 3 2 "" ^ ^ ¹ ^ '2 ^ 9 1 ^L '

/ * ^ XJ ^ ΓΙ ΓίΤΧ / * Π ^Τ Τ ^ £ Π ^Τ -Τ O Γι

3 3 ^ ^ 2 i-i'J

(OH ₃ ) ₃ C-CH ₂ - (OH ₃ ) ₂ 7-8 G ₉ H ₁₉ 50

) ₂ 12-15 ° 12 ^H 21 ¹⁵

₃ ο-υΗ ₂ -νθΐι ₅ ; ₂ id U ₁ ^ w ₃₉ y

(GH ₃ ) ₅ G-GH ₂ - (GH ₅ ) ₂ 20 ^C 18 ^E 33 ¹

JJ £ ■ J £ I * ~ s J L ~

In each Pall the results obtained are substantial the same as those in previous example 1 were obtained.

Example 6

The procedure of Example 1 was followed by using / ending other * Animal species, instead of the dog, ..icdarholt. üntar the eggs examined in specific cases in this species -. are cats, Ilaninclien, jVasch and Sitter Eel with result obtained in each case3si, which ixa are essentially comparable to those achieved with the dog.

Example 7
The procedure described in Example 2 was carried out using

909805/0991

BATH

U67991

^ other isolated organs, instead of the Jroschiiersc-iao, repeated. Among the specific of this type cai'tei-jaciiteii ür ^ anexi are the I-ierzen of dogs and eels, just:; ο muscle and icl ITervonpreparationsn, welclie by the each, 3a th drai i'isrspecierj were removed. In every iall oiiid uie erial'ceiieii results essentially with those idcjiitiocii, who received '..' for the heart of the heart.

SC9805 / 0991 - 12 -

Claims (1)

- 12 claims 1. Method for potentiating the physiological Effect of a drug, which by a lipid The barrier layer is bound to the ileceptor site, thereby characterized in that the method includes the step of parenteral administration of a drug of this type in conjunction with a non-toxic surfactant of the formula H - ^ - ^) - (OGH ₂ OH ₂ ) n ^0H where R is an alkyl radical from 1 to 18 carbon atoms and η is an integer from 1 to 30 unified, wherein the surfactant is present to the extent that it is at least about 0.1 6-ew · ^ des drug used. 2. "Method according to claim 1, characterized in that that the surface active agent is applied simultaneously with the drug by mixing with the same. 3. The method according to claim 1, characterized in that that the surfactant is applied separately and subsequently after application of the drug. Λ. Method according to claim 1, characterized in that - 13 909806/0991 H67991 ■ - 13 - that the drug used is a representative selected from the group "consisting of adrenaline, nor-adrenaline, Curare, lidocaine, serotonin and digitoxin, is. 5. The method according to claim 1, characterized in that that R is ITonyl and n = 6. 6. The method according to claim 1, characterized in that R (C5H,), C-CiH ₂ -C (CH ^) ₂ - and n = 9-10. 7. The method according to claim 6, characterized in that that the medicine used is adrenaline. 8. The method according to claim 6, characterized in that the drug used is lidocaine. 9. The method according to claim 6, characterized in that that the drug used is serotonin. 10. The method according to claim 6, characterized in that that the drug used is digitoxin. 11. Preparation suitable for parenteral use daduroh marked that it includes a medicinal product, bound which is asbgsgowöKtft through a lipid barrier layer, 0.1 Gew.jC surface-active agents, the designated Proportion in relation to the amount of drug in the preparation and an isotonic carrier 909805/0991 Η6799Ί - 14 for the surfactant. 12. Eggs described invention with all its new and useful characteristics. BATH ORIGINAL 909805/0991