Method of enhancing the administration of pharmalogically active agents

According to the method of the invention, the parenteral administration of water-insoluble pharmacologically active agents is enhanced wherein the agents are administered in the lipoid phase of a carrier emulsion comprising a microemulsion of a finely dispersed lipoid in an aqueous phase. The lipoid preferably has a mean particle size below 1 micron. This makes it possible to administer water-insoluble agents in high concentrations, and thus a lower dose, whereby a rapid onset of the pharmacological effect is accompanied by a markedly reduced incidence of injury to body tissues.

BACKGROUND OF THE INVENTION 
It is now a well established fact that a prerequisite for the action of a 
drug is its ability to penetrate the lipid cell membranes. A substance can 
act only through its undissociated, lipid soluble part. This sets a 
limitation for the intravenous administration of compounds with a pK.sub.a 
value far from the physiological pH range. On the other hand, a drug has 
to be dissolved in a physiological vehicle, which normally is an isotonic 
aqueous solution. Thus, many drugs can only be administered orally as 
tablets or as suspensions, despite the fact that there is a marked 
therapeutic need for a parenteral route of administration. 
The degree of protein binding differs from drug to drug and from species to 
species. The albumin bound part of a drug may be regarded as a floating 
depot, but it has no pharmacological effect per se. Repeated 
administrations sooner or later give a saturation of the albumin binding 
capacity and finally enough free drug to give a pharmacological effect. 
The physiological mechanism of the fat transport in the blood and lymph is 
by chylomicrons with a median particle diameter between 0.2 and 0.3 .mu.m 
(range 0.05 - 0.50 .mu.m) and containing phospholipids and protein in the 
membrane. 
In the administration of pharmacologically active agents, it has up to now 
mostly been necessary to use water-soluble agents or to transform the 
agents into a water-soluble form, so that a solution can be obtained 
having the properties required for the administration. The use of the 
agents in a water-soluble form, however, has often had several 
disadvantages. For instance, the aqueous solutions may often be acidic or 
basic, which may cause side effects. Also, it may sometimes be difficult 
to attain a desired effect, as the solutions cannot be tolerated by the 
patient. 
It has long been postulated that a higher degree of lipophilisity will 
support an increased pharmacological action of a pharmacon. In 1937 Meyer 
said that "Narcosis commences when any chemical indifferent substance has 
attained a certain molar concentration in the lipids of the cell." Until 
now, it has been difficult to deny or accept this theory as there was no 
way to administer these lipophilic and hydrophobic substances so that the 
pharmacokinetics of the compounds could not be investigated. 
It is known from Remington's Pharmaceutical Sciences, 13th Edition, 1965, 
Page 228, Column 2, Line 23, that "Most stable emulsions have particle 
sizes in the range of 0.25 to 5.0 microns (.mu.)." However, the reference 
is to emulsions in general without any appreciation of the utilization of 
such emulsions for the parenteral administration of oil-soluble 
pharmacologically active agents, and more specifically there is no 
appreciation that such emulsions can be utilized as a carrier emulsion to 
enhance the parenteral administration of oil-soluble pharmacologically 
active agents whereby a lower dose rate can be utilized than heretofore to 
achieve a given effect. 
U.S. Pat. No. 2,972,565 to Zilversmit discloses fat concentrates for use in 
the preparation of fat-in-water emulsions when diluted with water and 
disclosed as suitable for intravenous administration. However, we have 
made extensive tests in accordance with the examples of the Zilversmit 
patent, and all tests have ended in failure. Even with the use of modern 
high-speed emulsifying equipment, it has not been possible to prepare 
emulsions from Zilversmit's concentrates which have had the small and 
uniform particle size which is essential in accordance with the present 
invention. When administering placebo emulsions of this type to mice, up 
to 50% of the test animals have died. The teachings of the patent to 
Zilversmit cannot be considered to lead one skilled in the art to the 
present method of enhancing the parenteral administrations of oil-soluble 
pharmacologically active agents. 
DESCRIPTION OF THE INVENTION 
The present invention now refers to a new method of enhancing the 
administering of water-soluble pharmacologically active agents. According 
to the invention, a method of administering a pharmacologically active, 
oil soluble agent having a diagnostic or therapeutic effect is disclosed 
which comprises the steps of dispersing a pharmacologically acceptable 
lipoid in a pharmacologically acceptable aqueous solution to form an 
oil-in-water emulsion for stabilizing the dispersion of the lipoid in the 
form of particles substantially less than 4 microns in diameter, and 
generally of a mean particle size not over 1 micron, predominantly 
dissolving the active agent in the lipoid, and parenterally administering 
the emulsion with the active agent dissolved in the lipoid phase thereof. 
Through this method, an enhanced diagnostic or therapeutic effect is 
achieved with a rapid onset accompanied by a reduced incidence of injury 
to body tissues. 
By the present invention, the disadvantages mentioned in the background of 
the invention can be avoided, as the active agents are administered 
dissolved or dispersed in a system of at least one finely dispersed 
hydrophobic component in at least one hydrophilic component, and primarily 
then in an emulsion or suspension of a pharmacologically inert fat or oil 
in an aqueous phase. Also, the agents may be used here without affecting 
the pH or the osmotic pressure of the aqueous phase, as the agent will 
mainly be present in a dissolved or dispersed state in the hydrophobic 
phase, and will not have any effect on pH or osmotic pressure. Because of 
this, the method of administration according to the invention will cause a 
lower occurrence of injuries to the body tissues. In most cases, the agent 
also gives a stronger effect and more rapid onset. Unexpectedly, this 
permits a smaller amount of the agent, i.e. a lower dose, to be used to 
achieve or maintain an effect that would otherwise require a significantly 
higher dose. 
The aforementioned protein binding will also be reduced, as the agent is 
not in close contact with the proteins. A longer duration of the effect is 
also obtained in those cases where the agent normally is attacked rapidly 
by enzymes in metabolic processes. This is a very important characteristic 
of the present invention: a rapid onset and a good effect with a longer 
duration than for the water-soluble salt of the agent. It is a well known 
fact that the previous use of oil in injections has resulted in a slow 
release of the active agent from the site of injection in order to protect 
the patient from side effects due to overdosage. See U.S. Pat. No. 
3,240,670 (column 1, line 17). 
In the past, it has been the opinion of those skilled in the art that for 
parenteral injections, especially then intravenous injection, only aqueous 
systems could be used. See, for instance, "Husa's Pharmaceutical 
Dispensing", Mack Publishing Company, Easton, Pa. (1966). However, it has 
now been shown that provided the necessary precautions are taken, it is 
not only possible to use the new method of administration by parenteral 
injection, but even that superior results are attained. In view of the 
prior art, this is unexpected. 
In the use of fat emulsions for intravenous nutrition, a possibility may 
also be stressed. In accordance with the invention, water-insoluble agents 
for therapeutic or diagnostic purposes may be administered to the patient 
simultaneously with the infusion of the fat emulsion. 
It may occur that the active agent is not completely dissolved in the 
hydrophobic phase. It may have a greater affinity to the hydrophobic phase 
on account of its hydrophobic properties, but depending upon the 
distribution equilibria, both of the phases may contain the active agent. 
However, according to the most preferred embodiment, the agent is present 
predominantly as a fraction of the lipoid in the hydrophobic phase, in a 
dissolved state. 
The method of the invention comprises most of the administration ways known 
in the medical art, but is especially intended for parenteral 
administration, preferably then intravenously, but also intramuscularly or 
subcutaneously. Examples of administration methods, other than those 
mentioned above, are the following: 
Parenterally: 
intradermally 
intraarterially 
intraspinally 
intrathecally 
intrapleurally 
intraperitoneally 
intrasynovially 
Locally 
The local administration mentioned above is not intended to refer to 
external local or topical administration, such as an unguent or cream, but 
rather to an internal local administration, such as directly in an 
operation wound and the like, where the emulsion with the active agent 
gets in a direct contact with the blood and lymph vessels. 
The active agents with a therapeutic and/or diagnostic effect, which are to 
be used in the method of the invention, can be of very varying types, and 
the selection of these agents is only restricted by the conditions that 
they must be compatible with the vehicle system of several phases and that 
no harmful side effects may arise. In all cases an agent will be used 
which is soluble in the hydrophobic phase, such as an oil-soluble agent, 
but the agents may then also be partly soluble in the hydrophobic phase 
and be present in it with the other part as an emulsion or suspension on 
account of their greater affinity to this phase. It is also possible to 
administer simultaneously oil-soluble and water-soluble agents, each of 
these primarily being present in the phase to which they have the greatest 
affinity. However, that condition must always be satisfied that it must 
always be possible to combine the various components to a stable system 
with the desired properties, and no harmful side effects must arise. 
At room temperature, the active agents are usually solids or liquids with a 
boiling point above 140.degree. C in order to avoid transport from the 
blood system through the capillaries in the lungs. They may also be lower 
boiling liquids, the salt form of which is solid. In any case, it is 
necessary that the agents are oil soluble. 
Pharmacologically active agents which may be administered in accordance 
with the present invention, may be selected, but are not limited to the 
following groups: 
Centrally and peripherally acting agents: 
depressants 
anaesthetics 
analgetics 
stimulants 
spasmolytics 
muscle relaxants 
vasodepressants 
X-ray contrast agents 
In addition to the active agent or agents and the hydrophilic component, 
which consists of an aqueous solution, and the hydrophobic component, 
which consists of a pharmacologically inert lipoid, the compositions of 
the invention may contain other substances. These may for instance be 
preservatives, agents for pH adjustment, and agents for adjustment of the 
osmotic pressure. One of the most important additives will consist of one 
or more agents for achieving a stable dispersion of the hydrophobic phase 
in the hydrophilic phase. Many emulsifiers and suspension agents of a 
natural as well as synthetic origin may be used. 
The preparations according to the method of the invention may contain from 
1 up to 10 hydrophilic components, and usually they contain about 5 
hydrophilic components. 
As has been indicated above, the carrier or vehicle for the preparations 
according to the invention consists of a system of at least one 
hydrophobic component finely dispersed in at least one hydrophilic 
component. In most cases, the vehicle will consist of an emulsion or 
suspension of a fat or an oil in an aqueous solution, both phases of 
course being pharmacologically acceptable. For these certain conditions 
must be fulfilled. In a finely dispersed system which is to be introduced 
into the blood vessels, all the particles must have a diameter below 4 
microns, as they will otherwise get stuck in the capillary vessels. A 
particle size of 1 micron or less is a salient aspect, and this also makes 
the system more stable. Moreover, the system must also be of such a type 
that the particles do not form aggregates. Furthermore, the vehicle system 
must also be able to withstand autoclaving and preferably also freezing, 
and it must have such a composition and such properties that it can be 
stored for a long time without physical and chemical breakdown. It is of 
course also an important requirement that the vehicle system itself must 
not cause undesirable effects. 
In the vehicle systems most commonly used, which consists of an emulsion or 
suspension of a pharmacologically inert oil or fat in an aqueous solution, 
the hydrophobic component usually consists of a fat or an oil of vegetable 
or animal origin, such as soybean oil, cottonseed oil, coconut oil or 
olive oil. In order to obtain a stable system, it is furthermore necessary 
to include stabilizers of a natural or synthetic origin, such as 
phosphatides, polypropylene glycol, polyethylene glycol, polyglycerol 
monooleate, etc. The emulsions or suspensions used usually have a fat 
content of 0.1 - 99 per cent by weight, depending on the form of 
application. The amount of stabilizer in the compositions is determined by 
the properties of the system and depends on the nature of the dissolved 
active agent and usually lies between 0.1 and 20 weight per cent. 
For the purposes of the invention, suitable fat emulsions have been 
prepared, and one example of such emulsions is described in the U.S. Pat. 
No. 3,169,094. This emulsion consists of soybean oil in water with native 
egg phosphatides added as a stabilizer, and it has proved to be free from 
harmful side effects also when administered in such large quantities as 
are required in intravenous fat nutrition. Other oils or fats and other 
stabilizers may also be used for the purposes of the invention, even if 
they give side effects when used for intravenous nutrition, as they are 
administered in much smaller quantities when used as vehicles for 
pharmaceutically active agents. 
The invention is further illustrated by the following examples, which, 
however, are not limitative.

EXAMPLE 1 
5 g of phenyramidol base is dissolved in 95 g of soybean oil. An emulsion 
is prepared of 20 g of such a soybean oil solution, 1 g of egg 
phosphatides, 2.5 of glycerol and 0.5 g of Myrj 52 (a registered trade 
mark for a nonionic emulsifier consisting of a polyoxyethylene derivative 
of fatty acids, from Atlas Co, described on page 709 of the Merck Index, 
8th Ed., and on page 389 of the Extra Pharmacopoeia, Martindale, 26th 
Ed.), and sterile water to 100 ml. In the preparation, the conventional 
precautions for the preparation of bacteriologically acceptable injection 
solutions must be observed. 
In pharmacological testing on mice, this composition shows a better effect 
than an aqueous solution of phenyramidol hydrochloride. Furthermore, the 
aqueous solution also has a lower pH value. 
EXAMPLE 2 
3.75 g hexobarbital 
10 g soybean oil 
25 g ethanol 
1 g egg phosphatides 
0.5 g Myrj 52 (same product as in Example 1) 
Sterile water to 100 ml 
An emulsion with the above composition is prepared in the same manner as in 
Example 1. In the finished emulsion, the majority of the particles have a 
size below 1 micron. 
EXAMPLE 3 
Mecamylamine (3-methylaminoisocamphane hydrochloride) is a 
ganglion-blocking secondary amine, and as a base, it is an oily liquid 
which is soluble in lipids. Its toxicity (LD.sub.50) after intravenous 
administration has been estimated in male albino mice of the NMRI strain 
in accordance with the method of the Nordic Pharmacopoeia. The following 
preparations were used: 
Mecamylamine hydrochloride, 1% dissolved in saline 
Mecamylamine base, dissolved in soybean oil and emulsified in the 
conventional way. Final concentration 1%. 
Mecamylamine base, directly emulsified in 5.5% glucose solution with the 
aid of Pluronic F-68 (a registered trade mark for a nonionic emulsifier 
consisting of a block polymer of ethylene oxide and propylene oxide, from 
Wyandotte Chemical Corporation, described on page 392 of the Extra 
Pharmacopoeia, Martindale, 26th Edition) and an ultrasonic apparatus 
(20.000 Hz). Final concentration 1%. 
The injections were given in the dorsal tail vein at a speed of 0.1 ml per 
5 seconds. The results are listed in Table 1. 
TABLE I 
______________________________________ 
Intravenous toxicity of different mecamylamine 
preparations in mice. 
LD.sub.50.sup.1) 
Survival time 
Preparation mg/kg sec. .+-. S.E. 
______________________________________ 
Mecamylamine HC1 
16.3 55 .+-. 5.1 
(15.5 - 17.6) -Mecamylamine in oil.sup.2) 
15.4 52 .+-. 3.1 
emulsion (Intralipid) 
(14.8 - 16.1) 
Mecamylamine in water 
11.9 56 .+-. 3.8 
emulsion (11.4 - 12.4) 
______________________________________ 
.sup.1) Fiducial limits at P = 0.05 
.sup.2) "Intralipid" is a registered trade mark for a fat emulsion for 
intravenous nutrition. It is described in U.S. Pat. No. 3,169,094. 
The intravenous toxicity of mecamylamine hydrochloride has earlier been 
found to be, by Stone et al.: 21.0 mg/kg Stone, C. A., Torchiana, M. L., 
Navarro, A. and Beyer, K. H.: "Ganglionic blocking properties of 
2-methylaminoisocamphane hydrochloride (Mecamylamine), a secondary amine", 
J. Pharmacol. Exptl. Therap.: 169-183 (1956)! and by Corne & Edge: 12.9 
mg/kg Corne, S. J. and Edge, N. D.: "Pharmacological properties of 
pempidine (1,2,2,6,6-pentamethylpiperidine, a new ganglio-blocking 
compound", Brit. J. Pharmacol.: 13: 339-349 (1958)!, which statistically 
does not differ from the above results. 
All the quantal log-dose-response lines had the same slope and a comparison 
between the hydrochloride and the two emulsions showed a slight increase 
in toxicity for the pure base preparation, 138% (125-150%), but no 
difference for the soybean oil preparation, 106% (99-113%), the fiducial 
limits given at P = 0.05. 
As can be seen from the table, there was no difference in survival time 
(the time from the injections to death) between the preparations. 
To summarize, it can be stated that the toxic effects of mecamylamine have 
not been altered to any notable degree by the different galenic 
modifications used. 
EXAMPLE 4 
The question to be considered here is the influence of protein binding on a 
drug, which is dissolved in the oil phase of an emulsion. Quinidine is 
bound to plasma albumin to an extent of about 80%, and the therapeutic use 
of its water soluble salts by intravenous injection may therefore be 
hazardous. The individual rate and speed of albumin binding seems to be 
more important than the magnitude of the dose given. 
A male mongrel dog with an irregular heart rate, between 60 and 130 beats 
per minute, was anaesthesized with urethane, and blood pressure, 
ventilation, heart rate and ECG were recorded. 
Quinidine base, dissolved in soybean oil suspended in water with a final 
concentration of 0.3% was injected into the femoral vein (1 mg/kg). A few 
seconds after the injection was finished, the heart rate was regulated, 
and this effect persisted for about 30 minutes. 
When a placebo emulsion was administered, no effect could be registered, 
but when the quinidine injection was repeated, there was again a 
regulation, which persisted for about one hour. 
These results have been followed up in strophantine induced arrythmias in 
dogs, and it is found that quinidine base dissolved in oil and emulsified 
in water is a better and safer preparation for intravenous injections than 
aqueous solutions of the quinidine salts. 
______________________________________ 
Example 5: Hexobarbital 1 % 
______________________________________ 
Hexobarbital 1. % 
Phospholipids 0.5 % 
Span 80.sup.1) 0.05 % 
Oleic acid 2.5 % 
Soybean oil 17.5 % 
Glycerol 2.5 % 
Tween 80.sup.2) 
0.05 % 
Sterile water to 100 % 
______________________________________ 
.sup.1) Span 80 is a registered trade mark for an emulsifier, consisting 
of sorbitan esters of long chain fatty acids; page 973, The Merck Index, 
Eighth Edition, 1968 
.sup.2) Tween 80 is a registered trade mark for an emulsifier, consisting 
of polyoxyethylene sorbitan monooleate; page 973, The Merck Index, 8th 
Ed., 1968 
The emulsion has an instant action when administered intravenously. 
Rats: At a dose of 60 mg/kg, the animals fall asleep without excitation. A 
constant supply of 35 mg/kg gives continuous sleep and after interruption 
of the infusion, the animals wake up after about 3 min. 
Cats: The effects of the emulsion on the blood pressure when given 
intravenously in a dose of 5-10 mg/kg was registered on a 
chloralose-anaesthetized cat. The emulsion and a solution of sodium 
hexobarbital both gave a depression of about 60 mm Hg with about the same 
duration. 
Mouse: The sleeping time after a single dose injection of the emulsion was 
shorter than the sleeping time after injection of an aqueous solution of 
sodium hexobarbital: 
______________________________________ 
Sleeping time 
Dose emulsion sodium salt 
______________________________________ 
72 mg/kg 130 sec. 172 sec. 
86 mg/kg 583 sec. 905 sec. 
______________________________________ 
In accordance with common practice, the sleeping time has been set as the 
duration of the loss of the righting reflex. 
______________________________________ 
Example 6: Chloralose 0.5 % 
______________________________________ 
Chloralose 0.5 % 
Soybean oil 10. % 
Monoglycid 18/98 10. % 
Pluronic F-68 0.5 % 
Glycerol 2.5 % 
Sterile water to 100 % 
______________________________________ 
In rats, an instant sleeping effect was obtained. 
______________________________________ 
Example 7: Tribromoethanol 2 % 
______________________________________ 
Tribromoethanol 2. % 
Soybean oil 10. % 
Span 80 0.14 % 
Tween 80 0.36 % 
Phospholipids 0.5 % 
Glycerol 2.5 % 
Sterile water to 100 % 
______________________________________ 
In rabbits, 80 mg/kg, administered intravenously slowly (5 minutes) gives a 
light sleep with an onset time of 30 seconds and a duration of 9 minutes. 
The awakening was without remarks. 
The following preparations have also been prepared and administered by 
parenteral injection with good results: 
______________________________________ 
Example 8: Pentazocine 
______________________________________ 
Pentazocine 0.05 g 
Soybean oil 10. g 
Pluronic F-68 0.5 g 
Glycerol 2.5 g 
Sterile water to 100 ml 
______________________________________ 
______________________________________ 
Example 9: Phenylbutazone 
______________________________________ 
Phenylbutazone 2. g 
Soybean oil 10. g 
Acetylated monoglycerides 
10. g 
Glycerol 2.5 g 
Pluronic F-68 0.5 g 
Sterile water to 100 ml 
______________________________________ 
______________________________________ 
Example 10: Cyclandelate 
______________________________________ 
Cyclandelate 0.2 g 
Soybean oil 15. g 
Phosphatides 0.5 g 
Pluronic F-68 0.5 g 
Glycerol 2.5 g 
Sterile water to 100 ml 
______________________________________ 
Cyclandelate (3,5,5-trimethylcyclohexyl mandelate) which is almost 
completely insoluble in water has been administered intraarterially in the 
hind leg of cats anaesthetized with chloralose, and in doses of about 1-2 
mg/kg body weight, causing a marked vasodilation within a few seconds, 
especially in noradrenaline induced vasoconstriction. The systemic effect 
(heart rate, blood pressure, etc.) on the circulation of the cats was 
negligible within the dose range used. It has not been possible earlier to 
demonstrate this marked local vasodilating effect, as it has not been 
possible earlier to administer cyclandelate by injection. 
______________________________________ 
Example 11: Benzocaine 
______________________________________ 
Benzocaine 2. g 
Soybean oil 10. g 
Monoglyceride 10. g 
Glycerol 2.5 g 
Span 65 0.5 g 
Sterile water to 100 ml 
______________________________________ 
______________________________________ 
Example 12: Secobarbital 
______________________________________ 
Secobarbital 1.5 g 
Soybean oil 15. g 
Monoglyceride 5. g 
Glycerol 2.5 g 
Sterile water to 100 ml 
______________________________________ 
______________________________________ 
Example 13: Quatacaine 
______________________________________ 
Quatacaine 0.5 g 
Soybean oil 20. g 
Pluronic F-108 1. g 
Glycerol 2.5 g 
Sterile water to 100 ml 
______________________________________ 
______________________________________ 
Example 14: Lidocaine 
______________________________________ 
Lidocaine 2. g 
Soybean oil 15. g 
Myvacet 9-40 5. g 
Pluronic F-108 1. g 
Glycerol 2.5 g 
Sterile water to 100 ml 
______________________________________ 
"Myvacet 9-40" is a registered trade mark for acetylated monoglycerides, 
sold by Distillation Products Co. 
______________________________________ 
Example 15: Thiopental 
______________________________________ 
Thiopental 0.75 g 
Soybean oil 20. g 
Myvacet 9-40 7.5 g 
Pluronic L-81 1. g 
Glycerol 2.5 g 
Sterile water to 100 ml 
______________________________________ 
______________________________________ 
Example 16: Pentobarbital 
______________________________________ 
Pentobarbital 0.75 g 
Soybean oil 20. g 
Myvacet 9-40 7.5 g 
Pluronic F-88 1. g 
Glycerol 2.5 g 
Sterile water to 100 ml 
______________________________________ 
EXAMPLE 17 
In this example, the acute toxicity (LD.sub.50) and the anticonvulsant 
activity of various diazepam formulations has been investigated in mice. 
In accordance with the invention, a diazepam emulsion was prepared with 
the followng composition: 
______________________________________ 
Diazepam (WHO) 0.5 g 
Soybean oil 15.0 g 
Acetylated monoglycerides 
5.0 g 
Egg yolk phosphatides 
1.2 g 
Glycerol 2.5 g 
Distilled water to 100.0 ml 
______________________________________ 
This formulation was compared to a commercial diazepam formulation for 
injection, which is sold under the registered trade mark Valium from 
Hoffman La Roche & Co. This commercial diazepam formulation contains 5 
mg/ml of diazepam dissolved in an aqueous mixture containing 41.4% 
propylene glycol, 8.06% ethanol, 1.57% benzyl alcohol, 0.12% benzoic acid 
and 4.88% sodium benzoate. It is necessary to use this mixture, as 
diazepam is not soluble in water alone. 
The test results showed that the two formulations had nearly equal 
anticonvulsant activities, but that the diazepam formulation of the 
invention had an LD.sub.50 of 283.3 mg/kg, while the LD.sub.50 of the 
commercial diazepam formulation was 83.4 mg/kg. It is believed that the 
solvents necessary in the commercial diazepam formulation contribute in a 
large degree to its greater toxicity, and this has been confirmed in a 
test with a placebo solution using only the solvents of the commercial 
diazepam formulation. This placebo solution had an LD.sub.50 of 90.5 
mg/kg. 
Thus, it has been shown that the administration in accordance with the 
invention can be made much safer than in prior methods. 
EXAMPLE 18 
This example shows how the incidence of injuries in the form of 
thrombophlebitis is drastically reduced through the present invention. 
Thrombophlebites are inflammations in the venous walls, and they can 
sometimes have quite serious consequences. At intravenous injections, 
however, they have been such a common occurrence and their appearance has 
sometimes not even been noted, but they have been considered as an 
unavoidable evil. In the use of barbiturates for intravenous anaesthesia, 
the rate of thrombophlebitis within two weeks after injection has been 
found to be from 10 to 30 percent. 
In a comparative test, a commercial 5.5% water solution of Narkotal, trade 
mark for pronarcon or 5-(2-bromoallyl)-5-isopropyl-1-methylbarbituric 
acid, was administered intravenously to 53 patients. It was found that 
within a week, 16 of the patients, i.e. 30%, developed symptoms of 
thrombophlebitis. In another test, an emulsion prepared in accordance with 
the invention and containing 1.5 percent secobarbital in the oil phase was 
administered intravenously in the same way to 62 patients. It was found 
that none of these patients developed any thrombophlebitis symptoms. This 
clearly shows that the risk of injuries to the tissues is markedly 
decreased in the method of the invention. 
EXAMPLE 19 
This example shows that it is preferred that the active agent used has a 
boiling point above 140.degree. C. 
An emulsion composition was prepared containing 5 percent of methoxyflurane 
(2,2-dichloro-1,1-difluoroethyl methyl ether; b.p. 105.degree. C) in a 
carrier system of soybean oil emulsified in water with the help of egg 
phosphatides. This formulation was administered to mice, and the LD.sub.50 
value was found to be 150.4 mg/kg. 
It was not possible to establish a relation between the sleeping time and 
the administered dose. Within a dose range from 118 to 190 mg/kg, the 
surviving animals slept from 0.6 to 2.0 minutes. There was, however, no 
correlation between the magnitude of the dose and the sleeping time, and 
therefore, this cannot be considered as a genuine effect. The reason for 
this is that the methoxyflurane was eliminated through the respiratory 
tract so quickly that the pharmacological effect was not obtained. 
As discussed, a salient aspect of the invention resides in the fact that 
the mean particle size of the lipid particles comprising the inner phase 
of the carrier emulsion utilized in carrying forth the present method is 
preferably not over 1 mm. To facilitate the practice of the present 
invention the following method is discussed as being suitable for the 
predetermination of the particle size distribution. 
A convenient method to determine the size distribution pattern in 
particulate formulations has been published by Groves, Yalabik and Tempel 
Powder Technology 11, 245 - 255, 1975. It's application in lipid emulsion 
formulations was described by Groves and Yalabik Powder Technology, 
presently in press. The method uses a laser beam and photodetector as the 
sensing system for the lipid particles in a centrifugal field and the size 
distribution is calculated by using the centrifugal analogue of Stokes' 
law. 
The laser photosedimentometer was used to determine the particle size 
distribution of seven different emulsions of types according to the 
present invention. The factor d.sub.st(50) (Stokes' diameter) is 
calculated in the particle size determinations. This value indicates the 
mean diameter (at 50%) and the width of the distribution is expressed by 
the slope (standard deviation) in Table II. 
TABLE II 
______________________________________ 
Stokes' diameter 
Emulsion type .sup.d st(50) in .mu.m 
Slope 
______________________________________ 
(1) Fat emulsion 10% 
0,15 0,42 
(2) Fat emulsion 20% 
0,23 1,56 
(3) Fat emulsion 50% 
0,50 1,40 
(4) Emulsion with 
Soy bean + Pluronic F 108 
0,13 2,43 
(5) Emulsion with Soy bean 
oil + Pluronic F 68 
0,63 1,43 
(6) Diazepam emulsion 
0,19 1,41 
(7) Placebo emulsion 
to diazepam 0,25 1,52 
______________________________________ 
While it is believed that the unexpected result obtained by the practice of 
the method of the present invention is apparent from the foregoing 
specific Examples, particular attention is directed to, for instance, the 
enhanced administration of the pharmacological agents diazepam and 
barbituates, see Examples 17 and 18 respectively. 
From a consideration of Example 17 it will be seen that the acute toxicity 
of diazepam when administered parenterally in accordance with the present 
invention is substantially lower than than of diazepam administered by a 
prior parenteral method. In Example 18 it will be seen that the use of 
barbituates for intravenous anaesthesia administered parenterally in 
accordance with the present method resulted in a marked decrease of risk 
of injury to tissues, namely inflammation of the venous walls thereby 
greatly enhancing the administration of barbituates for intravenous 
anaesthesia.