US3440318A - Methods for enhancing the effectiveness of drugs,which employ an alkylated phenoxy (polyethanol) - Google Patents

Description

United States Patent METHODS FOR ENHANCING THE EFFECTIVE- NESS OF DRUGS, WHICH EMPLOY AN ALKYL- ATED PHENOXY (POLYETHANOL) Herbert S. Polin, Veyrier pres Geneve, Geneva, Switzerland N0 Drawing. Filed Feb. 12, 1964, Ser. N0. 344,223 lint. Cl. A61k 27/00, 9/00 US. Cl. 424182 Claims ABSTRACT OF THE DISCLOSURE Methods and compositions are disclosed for parenteral administration, which include the administration of a drug, such as a stimulant, blocking agent or vasoconstrictor, in conjunction with a surface active agent, such as an alkylated phenoxy (polyethanol), for enhancing the effectiveness of the drug.

The invention described in this application relates to the use of certain chemical compoundsfor potentiating drugs. More particularly, it is concerned with the use of various surface-active agents for this purpose whereby an enhancement of the physiological effect of the drug is thus achieved.

The surface-active agents which come within the purview of the present invention are all non-toxic in nature and, in general, are selected from such standard groupings as quaternary ammonium compounds, sulfosuccinates, polyoxyethylene' higher alkanols, sulfuric acid monoesters of said alkanols, alkylated phenoxyethanols and alkylated phenoxy (polyethanols), and the like, with the last named grouping being the most preferred. The preferred surface-active agents of this invention all possess the following general structural formula:

RQm 0132011.)..011

wherein R is an alkyl radical of from one to eighteen carbon atoms and n is an interger of from one to thirty, inclusive. Typical member compounds of this group include those which have the above formula wherein R is nonyl or octyl and n=6 or 9-l0', respectively.

The drugs which are applicable to this invention are only limited in the sense that they must otherwise be bound at their receptor sites by a lipid barrier layer (i.e., in the absence of the surface-active agent), and preferably, they are also drugs which are parenterally-administrable. Typical examples of the wide variety of different type drugs concerned here include stimulants such as adrenaline, nor-adrenaline and digitoxin, blocking agents such as lidocaine as well as various forms of curare, and vasoconstrictors like serotonin and so forth.

In general, the amount of surface-active agent to be employed with respect to the drug of choice for the purposes at hand may vary over a wide range, but it is usually desirable in practice to use at least about 0.1% by weight of said agent with respect to the drug in order to achieve effective results, i.e., a substantial degree of potentiation. Optimum results, however, have been obtained with from about 0.1% to about 10% by weight of the agent with respect to the weight of the drug. For instance, the physiological effects of a drug such as adrenaline have been potentiated by as much as 100% over the normal control value by the use of or practice of this invention. Hence, in view of this remarkable degree of drug-activity enhancement thus achieved, it is possible to use lesser amounts of a given drug for a particular stated purpose and still achieve the same effect quantitatively as regards order of magnitude of response that "ice would normally be achieved when the drug is used alone, i.e., in the absence of surfactant. For example, normal drug doses in the case of the representative compounds previously mentioned have been reduced by as much as to gain the same response normally achieved when the drug is used alone at the aforementioned higher level.

In carrying out the process of this invention, the surfactant potentiator can be administered either before or after the parenteral administration of the drug itself provided that the interval between the two is not too great, i.e., not generally in excess of about fifteen minutes. However, it is preferred in practice to administer the two components together simultaneously, i.e., in combination via an admixture comprising said components as will be hereinafter discussed in more detail. In either case, the surfactant potentiator is said to be administered in conjunction with the drug.

For purposes of parenteral administration, solutions of the drug to be administered in sesame or peanut oil or in aqueous-propylene glycol or N,N-dimethylformamide may be employed, as well as sterile aqueous solu tions of the corresponding water-soluble salts if available or preparable. Such aqueous solutions should be suitably buffered if necessary, wherein the liquid diluent is first rendered isotonic with sufficient saline or glucose. All these solutions are particularly valuable for intravenous, intramuscular and intraperitioneal injection purposes. In this connection, the sterile aqueous media employed are readily obtained by standard techniques well-known to those in the art. For instance, when distilled water is ordinarily used as the liquid diluent, the final preparation can be passed through a suitable bacterial filter, such as a sintered glass filter or a diatomaceous earth or unglazed poreclain filter. Preferred filters of this type include the Berkefeld, the Chamberland and the asbestos disc-metal Seitz filter, wherein the fluid is sucked through the filter candle into a sterile container with the aid of a suction pump. Needless to say, aseptic conditions must necessarily be maintained throughout all these operations which are directely connected with the preparation of the aforesaid injectable solutions.

This invention is further illustrated by the following examples, which are not to be construed in any way or manner as imposing limitations upon the scope thereof. On the contrary, it is to be clearly understood that resort may be had to various other embodiments, modifications and equivalents thereof which readily suggest themselves to those skilled in the art without departing from the spirit of the present invention and/or the scope of the appended claims.

EXAMPLE I A dial-aenesthetized dog was rigged for registration of heart-rate and respiration in the standard way and canulated for ready injection of various parenteral solutions. When the animal registered a steady state, adrenaline in a 0.1% solution (in oil) was administered via this route at the 0.2-0.6 ml. dose level, i.e., a threshold concentration, and readings were thereafter taken with respect to the amplitude and persistance of response of said animal, as well as to its recovery with time. After final recovery, a dose of the same drug was prepared having only one-tenth the concentration of the aforesaid test dose. This was then mixed with 2 ml. of 0.01% Trition X-l00 in Ringer (saline) solution, and the resulting mixture was injected into the same animal as before via the canula [Trition X400 is the registered trademark name of the Rohn & Haas Co. of Philadelphia, Pa. for a surface-active agent of the formula The results obtained in this manner are such that the dose-response effect which is produced in the case of the Triton-containing solution at least equals that which is caused by the more concentrated adrenaline solution lacking the surfactant agent. The tests also established that the animal shows no real response to the Triton X-lOO when employed at this concentration alone in Ringer solution.

Example II The procedure described in Example I was repeated with an isolated organ rather than an intact animal as the substrate of choice. In this particular case, a frog heart was used which, in turn, required that it be mounted for Ringer perfusion with a T in the line so as to facilitate side-tube introduction of the drug as well as large-scale (volume) washing of the system. Otherwise, the experimental routine or test procedure is essentially the same as in Example I for the intact animal. In like manner, the dose-response results obtained with adrenaline in the present case are also substantially the same, i.e., the effect produced by the Triton surfactant on the drug is of substantially the same order of magnitude as that reported in Example I for the intact animal experiment.

Example III Adrenaline was injected into the isolated heart as in accordance with the procedure of Example II, but lacking the added Triton X-lOO at this point. After normal response and full recovery, followed by a multiple-washing, a small quantity (2 ml.) of Triton X100 in Ringer solution at the 0.01% concentration level was injected into the so-treated organ without any drug. It was observed that the heart immediately responded with the same reaction that the adrenaline gave in the first instance, thereby indicating that a large unused portion of the drug had still been present in the isolated, washed organ (no doubt, bound in the lipid barrier) prior to the admin istration of the surfactant.

In like manner, substantially the same results were also achieved with the intact dog when the above procedure was repeated using this particular animal instead of the aforesaid isolated organ.

Example IV The procedure described in Example I is repeated in dogs using other compounds in place of adrenaline. Thus, for instance, the following compounds have been used on an individual basis: nor-adrenaline, tube or bamboo curare, pot curare and gourd or calabash, lidocaine, serotonin and digitoxin. In each case, the results obtained are substantially the same as those reported previously for adrenaline in Example 1.

Example V The procedure of Example I is followed except that other surface-active agents are employed in place of Triton X100 and these are listed below as follows:

In each and every case, the results obtained are substantially the same as those reported previously in Example I.

' Example VI Example VII The procedure described in Example II was repeated using other isolated organs in place of that of the frogs heart. Among the organs specifically tested in this manner are the hearts of dogs and eels, as Well as muscle and nerve preparations taken from all three species of animals. In each and every case, the results obtained are substantially identical with those for the frog heart.

What is claimed is:

1. A method for pofentiating the physiological effect of a drug which is bound by a lipid barrier layer at the receptor site, said method comprising the step of parenterally administering to an animal, a drug selected from the group consisting of adrenaline, nor-adrenaline, curare, lidocaine, serotonin and digitoxin in conjunction with a non-toxic surface-active agent of the formula RQWCHQCHQDOH wherein R is an alkyl radical of from one to eighteen carbon atoms and n is an integer of from one to thirty, inclusive, said surface-active agent being present in an amount of from about 0.1% to about 10% by weight based on the drug.

2. A method as claimed in claim 1 wherein the surface-active agent is administered simultaneously with the drug by admixture therewith.

3. -A method as claimed in claim 1 wherein the surfaceactive agent is administered separately and up to 15 minutes subsequent to the administration of the drug.

4. A method as claimed in claim 1 wherein R is nonyl and 11:6.

5. A method as claimed in claim 1 wherein R is 6. A method as claimed in claim 5 wherein the drug employed is adrenaline.

7. A method as claimed in claim 5 wherein the drug employed is lidocaine.

8. A method as claimed in claim 5 wherein the drug employed is serotonin.

9. A method as claimed in claim 5 wherein the drug employed is digitoxin.

10. A method as claimed in claim 1 wherein R is nonyl, n equals 6 and and the drug is adrenaline.

References Cited UNITED STATES PATENTS 2,767,116 10/1956 Cheney 167-82.9 2,803,583 8/1957 Petersen 16758.l 2,976,213 3/1961 Murphey l6758.1 3,228,834 l/l966 Gans 167-58.1

OTHER REFERENCES C. A., vol. 60, p. 16371 f (1964).

ALBERT T. MEYERS, Primary Examiner.

S. I. FRIEDMAN, Assistant Examiner.

US. Cl. X.R.