Non-aqueous microemulsions for drug delivery

Palatable liquid therapeutic microemulsion wherein a drug dissolved in propylene glycol is dispersed in fatty ester. Lecithin is the emulsifier.

BACKGROUND OF THE INVENTION 
Liquid administration of drugs is convenient and often advantageous, 
especially when dealing with children or the elderly for whom pill 
swallowing can be difficult or even hazardous. Unfortunately, many drugs 
are not soluble in water, while water solution of others such as ibuprofen 
may have a very unpleasant taste. Some drugs, such as aspirin, are either 
unstable in the presence of water or are insoluble in water and therefore 
cannot be incorporated into aqueous formulations. To overcome these 
various problems a water-free liquid preparation of a number of drugs 
would be desirable. 
SUMMARY OF THE INVENTION 
The invention is a nonaqueous emulsion useful for drug delivery which 
largely overcomes the problems mentioned above with water-unstable and/or 
unsavory drugs. For example, use of the invention, a very palatable 
ibuprofen formulation can be made in which only one teaspoon contains a 
normal child's dose. 
The emulsion contains a drug dissolved in a suitable non-aqueous internal 
phase solvent, such as propylene glycol, dispersed, with a suitable 
emulsifier such as lecithin in an alkyl fatty acid ester. Excipients such 
as sweeteners, flavoring agents and taste masking materials can also be 
included. 
A key feature of the invention is its ability to prevent the 
crystallization of the drug from the internal phase, even when the level 
of drug in that phase is above saturation levels.

DETAILED DESCRIPTION OF THE INVENTION 
The nonaqueous, internal phase of the emulsion is a polar, 
pharmaceutically-acceptable oxygen-containing liquid such as C.sub.2 
-C.sub.30, preferably C.sub.2 -C.sub.20 polyhydric alcohols, poly(ethylene 
or propylene) glycols with 4-200 repeating units, and the C.sub.1 -C.sub.5 
ether or C.sub.2 -C.sub.30, preferably C.sub.2 -C.sub.20 ester derivatives 
of any of the foregoing. Examples of such materials include glycerin, 
propylene glycol, polyethylene glycol 200, 400, 600, 1500, 4000 and 6000 
with the number correlating approximately with the number of repeating 
units and ranging from 4 to 200, ethylene glycol dimethyl ether, 
tetraethylene glycol dimethyl ether, triacetin, medium chain (C.sub.6 
-C.sub.10) triglycerides such as tricaprylin (caprylic acid ester of 
glycerol, and propylene glycol C.sub.8 diester (Captex 200). Preferably 
the internal phase is a C.sub.2 -C.sub.10 polyhydric alcohol, a 
polyethylene glycol with n=4-80, or the methyl or ethyl ethers thereof. 
The drug is dissolved in the internal non-aqueous phase. By drug is meant 
any therapeutic agent such as hormones, vitamins, enzymes, drugs, etc. 
Typical drugs which are suitable include aspirin, ibuprofen, piroxicam, 
cimetidine, fat soluble vitamins and steroids such as estrogen and 
vitamins A, D and E. Preferably the drug is aspirin, ibuprofen, or 
cimetidine. In addition, other water sensitive compounds such as aspartame 
would have increased stability in such non-aqueous systems. 
One of the key advantages of our invention is that the non-aqueous solution 
of the drug can be supersaturated. The solvent is heated to about 
80.degree. C., i.e., a temperature at which about 2-4 times or more the 
amount of drug that would form a saturated solution at room temperature is 
dissolved in the solvent. When such solutions are cooled to room 
temperature the drug ordinarily would crystallize out; however, once 
incorporated into the microemulsion, it remains as a supersaturated 
solution. 
The emulsion also contains lecithin as the emulsifier. Egg or soya lecithin 
is suitable. Lecithin itself is a solid but is also available commercially 
as a liquid by having been mixed with oil such as soybean oil. These 
liquid lecithins are suitable and, indeed, are preferred. Attempts to 
accomplish the same liquefying effect by using some of our lower alkyl 
fatty ester have resulted in slightly cloudy emulsions, but we think this 
is merely a matter of technique. 
The continuous phase of the emulsion is a lower alkyl ester of a C.sub.8 
-C.sub.22 fatty acid such as ethyl palmitate or a triglyceride. The alkyl 
is C.sub.1-5 preferably C.sub.1-3. Monoesters are preferred because di or 
triesters such as soybean oil tend to be more oily in taste and texture, 
although even this can be masked. 
Sweeteners such as saccharin, aspartame (depending on the temperature used 
in preparation), sorbitol, corn syrup, etc. and other taste maskers such 
as the oils of peppermint and sweet orange, clove, cherry syrup, etc. can 
be included in the formulation. These agents can be added to any one or 
more of the components of the emulsion to insure their effectiveness 
throughout the whole emulsion. 
The relative amount of the ingredients in the formulation will vary but is 
generally as follows, with all percentages being volume percentages unless 
otherwise noted. 
The continuous phase, including any used as lecithin vehicle, predominates 
relative to the internal phase and is usually 33-70% with the internal 
phase being 1-20%. The actual lecithin, i.e., excluding vehicle, will be 
20-60%. Preferably the continuous phase is 40-65%, the internal phase 
5-20%, and the actual liquid lecithin 25-45%. 
The drug is usually 0.1-15 weight percent of the drug-internal phase 
solution. Masking agents, when used, will usually be less than three 
percent, preferably 0.1-2 percent. 
Our emulsion is a microemulsion. It forms spontaneously with gentle mixing 
such as hand shaking. High shear mechanical mixing devices are not 
required. In addition, the emulsion is clear and looks and acts as a 
single phase. It is stable indefinitely and this stability is evident up 
to at least 45.degree. C., well above any temperature likely to be 
encountered between manufacture and use. 
The following describes the preparation of an emulsion typical of our 
invention, in which the term volume refers to microliters. 
Ibuprofen is dissolved in hot, 80.degree. C., 1,2-propylene glycol to make 
a 30.8 wt. % solution. 95 volumes of this hot ibuprofen solution is mixed 
with 450 volumes of room temperature lecithin. The latter is "Centrophase 
31" special soybean (food grade) from Central Soya Company to which has 
been added 0.6 wt. % aspartame. This lecithin is 60-64% soya lecithin 
(acetone insolubles), the balance being essentially soybean oil. It is 
liquid. 
The mixture is immediately gently hand mixed at room temperature by means 
of a stirring rod. After five minutes a clear preparation forms. Its 
spontaneous formation indicates a glycol-lecithin soybean oil 
microemulsion but this is not, in this case, our final product. When 
certain applications require the use of this first microemulsion, the 
formulation can be stopped at this point. Stirring continues for another 
five minutes as 5 volumes oil of sweet orange are added. Stirring 
continues for another ten minutes as 450 volumes ethyl palmitate are 
stirred in. A final microemulsion (179185) of the ibuprofen-propylene 
glycol soybean oil phase in the fatty ester is obtained. The final 
microemulsion is clear, stable, and behaves as a solution. 
It is to be noted in the above procedure that even though the glycol 
contains about four times as much ibuprofen as could be dissolved at room 
temperature, no ibuprofen crystallizes out of the glycol solution when the 
latter is mixed with the lecithin. If the glycol is cooled to room 
temperature before mixing with the lecithin, ibuprofen crystals do appear. 
In any event, having both the glycol and lecithin hot before mixing is 
better practice, even though the above shows it is not always necessary, 
and may even be required at higher drug concentrations. 
The emulsion prepared above is sweet tasting with an agreeable quality or 
feel. It contains 140 milligrams ibuprofen (a child's dose) in five 
milliliters of emulsion, the latter being equal to one teaspoon. Without 
the supersaturation of the glycol, the dosage would be greater than a 
tablespoon and much more difficult to administer to a child. With higher 
supersaturation of the glycol the dosage would be less than a teaspoon and 
would be even more easy to administer to a child. 
Another emulsion (179162) was made in essentially the same manner except 
that the internal phase was 90 volumes of a propylene glycol solution 
containing 37.5% (wt) ibuprofen and 0.3% aspartame to which is then added 
10 volumes clove oil. The emulsifier was 450 volumes "Centrophase 31" to 
which was added 10 volumes clove oil. Finally, the ethyl palmitate (450 
volumes) contained 0.3% aspartame and 10 volumes added clove oil. The 
results are essentially the same with respect to emulsion formation and 
emulsion quality. 
The same results are also obtained in making an emulsion (179157) in which 
the internal phase is 90 volumes of a 23.8 wt. % solution of cimetidine in 
propylene glycol which is added to 450 volumes Centrophase 31 lecithin. 
After the first emulsion of these components forms excipients aspartame 
(0.3 wt. % overall) 7.5 volumes cherry flavor and 2.5 volumes vanilla 
flavor are added. The external phase is 450 volumes ethyl palmitate. 
Finally, an emulsion (179183) is made the same way as above with an 
internal phase of one volume of a 20% aspirin solution (wt.) in triacetin. 
4.5 volumes of the sam lecithin and 4.5 volumes ethyl palmitate are used. 
The results are substantially the same as above. In this example the term 
volumes refers to milliliters.