Cyclosporin formulations of mono or diglyceride fatty acid

Cyclosporins are useful immunosuppressive, anti-fungal and antiphlogistic agents which are relatively insoluble in water and aqueous fluids (including body fluids). They may be rendered more soluble or dispersible in aqueous media by first dissolving them in at least one mono- or di- glyceride of a C.sub.6 -C.sub.10 fatty acid, and the resulting solution can then easily be emulsified in water or an aqueous fluid.

BACKGROUND TO THE INVENTION 
The present invention relates to a novel pharmaceutical composition wherein 
at least one cyclosporin, which is the active ingredient, is accompanied 
by a solubilising agent which is a mono- or di- glyceride of an 
intermediate molecular weight fatty acid (i.e. a fatty acid having from 6 
to 10 carbon atoms). 
The cyclosporins are a homologous group of biologically active 
oligopeptides, which are metabolites produced by certain fungi imperfecti. 
Cyclosporin A is the best known member of this group, but cyclosporins B 
to I have also so far been identified, and the commercially available 
product may contain a mixture of several individual cyclosporins. They all 
share a cyclic peptide structure consisting of 11 amino acid residues with 
a total molecular weight of about 1,200, but with different substituents 
or configuration of some of the amino acids [Merck Index, 2748, 10th Ed.; 
Helv. Chim. Acta 60, 1568-1578 (1977); Helv, Chim. Acta 65, 1655-1677 
(1982)]. 
For convenience, the term "cyclosporin" (in the singular and without 
further qualification) will be used hereinafter to designate the 
cyclosporin component of the composition of the present invention. 
However, it should be understood that, as used with reference to the 
invention, this term is intended to include any individual member of the 
cyclosporin group, as well as mixtures of two or more such individual 
cyclosporins whether of two or more such individual cyclosporins whether 
in the form of commercially available mixtures or otherwise. 
Cyclosporin has immunosuppressive, antifungal and antiphlogistic 
activities, but has so far been primarily used therapeutically for its 
immunosuppressive activity. In its therapeutic use as an 
immunosuppressive, it is currently used either orally or by injection. 
However, since the solubility of cyclosporin in water is extremely low 
(e.g 20 .mu.g/ml to 30 .mu.g/ml for cyclosporin A), both types of 
formulation are prepared as an oily solution containing ethanol. Even so, 
the bioavailability of its oral preparations is extremely low, generally 
below 30% [K. Takada et al. Drug Delivery System 1, No. 1, 1-7 (1986)]. 
This is believed to be due to the separation of cyclosporin as a solid 
immediately after it comes into contact with water, e.g. in the mouth or 
in the gut. Injectable preparations of cyclosporin formed as an oily 
solution containing ethanol have first to be diluted with physiological 
saline before intravenous administration. In the case of intravenous 
administration, however, it is clearly not merely undesirable but highly 
dangerous for cyclosporin to separate out on contact with water. 
Accordingly, a surface active agent, such as a polyoxyethylated castor 
oil, is added as a solubilizer to injectable preparations in order to 
prevent the cyclosporin from separating out. However, the addition of 
surface active agents, such as polyoxyethylated castor oil, to injectable 
preparations can give rise to safety problems. 
Cyclosporin is effective in the treatment of the ocular symptoms of 
Behcet's Syndrome. When it is administered orally for the treatment of 
these symptoms and relies upon systemic circulation to reach the eyes, the 
side effects of the drug may cause various adverse reactions, such as 
hypertrichosis or renal dysfunction. However, when oily preparations 
containing cyclosporin are applied directly to the eyes, irritation or a 
clouded visual field may frequently result. Hence, cyclosporin is, in 
reality, of little practical use in the treatment of the ocular symptoms 
of Behcet's Syndrome, for which it would otherwise be very well suited. 
Moreover, if it were possible to prepare a formulation suitable for 
topical application to the eyes, it would be expected to have various 
other uses in addition to the treatment of the ocular symptoms of Behcet's 
Syndrome. For example, from its pharmacological mode of action, it is 
thought that it could be useful during keratoplasty as well as in the 
treatment of herpetic keratitis and spring catarrh. 
One way of overcoming the problem of inadequate water solubility would be 
to dissolve sufficient cyclosporin in an aqueous solvent system so as to 
reach an effective concentration for treatment. Such a solvent system 
should not contain any additive, such as a surface active agent, which 
could give rise to safety problems. If this could be achieved, the 
cyclosporin would already be in an aqueous solution and its contact with 
bodily fluids would merely constitute dilution, so that it would not 
immediately separate out when contacted with the water of such fluids. 
However, so far it has been very difficult to make any such preparation 
because cyclosporin has an extremely low solubility in water and has a 
cyclic structure with a molecular weight significantly greater than 1,000, 
with the result that insufficient can be dissolved to be effective for the 
desired treatment. Table 1 shows the solubility of cyclosporin A in 
various kinds of solvents, from which it can be seen that the solubility 
pattern seems quite unique. 
TABLE 1 
______________________________________ 
Solubility Solubility of 
parameters cyclosporin A 
Solvent .delta.d 
.delta.p .delta.h 
[mg/ml] 
______________________________________ 
Methanol 7.4 6.0 10.9 &gt;1000 
Ethanol 7.7 4.3 9.5 &gt;1000 
Acetonitrile 7.5 8.8 3.0 &gt;1000 
Ethyl acetate 7.4 2.6 4.5 &gt;1000 
Benzene 8.9 0.5 1.0 400 
Tetrahydrofuran 
8.2 2.8 3.9 400 
Acetone 7.6 5.1 3.4 100 
Propylene glycol 
8.2 4.6 11.4 100 
Isopropanol 7.7 3.0 8.0 50 
Cyclohexane 8.2 0.0 0.0 20 
Hexane 7.2 0.0 0.0 &lt;10 
Water 6.0 15.3 16.7 &lt;1 
______________________________________ 
In the above Table, .delta.d, .delta.p and .delta.h are measures of 
dispersion force, polarity and hydrogen bonding, respectively. 
In view of these solubility properties, it has, in the past, been 
considered not merely difficult but practically impossible to design 
reasonably a pharmaceutical composition containing cyclosporin dissolved 
in an aqueous medium. 
Although the cyclosporins have demonstrated some solubility in oily 
preparations containing higher fatty acid glycerides, such as olive oil, 
peanut oil and/or castor oil, these frequently produce an unpleasant 
sensation when applied to the eye because of stimulation or the 
viscousness which is characteristic of these oils. 
We have previously proposed in USSN 201 579, filed 1st of June, 1988, to 
solubilise cyclosporin by using it in admixture with at least one 
.alpha.-cyclodextrin and/or derivative thereof; however, that previous 
proposal differs from the present invention in that it actually 
solubilises the active compound, whereas, in the present invention, the 
active compound is dissolved in a glyceride, which may then be emulsified 
in water. 
It is known that intermediate molecular weight fatty acid triglycerides and 
higher fatty acid glycerides can be employed in cyclosporin compositions 
[see, for example, U.S. Pat. No. 4,388,307], but these glycerides are 
unsatisfactory for use as envisaged by the present invention, and this is 
demonstrated later herein. 
In Belgian Pat. No. 895 724, there is disclosed the use of a derivative of 
the cyclosporins, namely dihydrocyclosporin D, in the treatment of 
multiple sclerosis, and, among many others, there are described gelatine 
capsules in which the dihydrocyclosporin D is dissolved in a non-aqueous 
mixture of ethanol, Imwitor (trade mark) 742 and Maisine. However this 
differs from the present invention in that there is no suggestion that the 
composition is or need be dissolved or dispersed in water. Furthermore, 
these compositions only attain solubility of the cyclosporin by the 
inclusion of additional cyclosporin solvents, in particular ethanol and 
(in the case of Example 1) the cyclosporin solubilising agent Labrafil 
2152. Similar considerations also apply to other formulations comprising 
cyclosporins known from the art, e.g. as herein discussed. 
We have now found that the cyclosporins have excellent solubility in the 
mono- and di- glycerides of intermediate molecular weight fatty acids, 
which are easily emulsified in water, and which can thus substantially 
improve the dispersibility of cyclosporin in water and aqueous media. It 
is considered that this is most surprising in view of the difficulties 
experienced with higher fatty acid glycerides and even with the 
triglycerides of intermediate molecular weight fatty acids. 
BRIEF SUMMARY OF INVENTION 
It is an object of the present invention to provide a pharmaceutical 
composition in which the cyclosporin is solubilised in a non-irritating 
base, which enables the cyclosporin to be dispersed with ease in water or 
aqueous media, for example bodily fluids. 
Thus, in accordance with the present invention, there is provided, as a new 
composition of matter, a pharmaceutical composition comprising at least 
one cyclosporin in admixture with an amount of at least one intermediate 
molecular weight fatty acid mono- or di-glyceride sufficient to dissolve 
the cyclosporin. 
The invention also provides a method of suppressing the mammalian immune 
system by administering to a mammal, especially a human being, an oily 
solution or aqueous emulsion comprising an effective amount of at least 
one cyclosporin in association with sufficient of at least one 
intermediate molecular weight fatty acid mono- or di- glyceride to 
dissolve said cyclosporin. 
The invention still further provides a method of treating the ocular 
symptoms of Behcet's Syndrome by administering to the eye of a mammal, 
especially a human being, a composition, preferably in the form of an oily 
solution or aqueous emulsion, comprising an effective amount of at least 
one cyclosporin in association with sufficient of at least one 
intermediate molecular weight fatty acid mono- or di- glyceride to 
dissolve said cyclosporin. 
DETAILED DESCRIPTION OF THE INVENTION 
As currently commercially available, cyclosporin is supplied as a mixture 
in which the principal ingredient is cyclosporin A and which also contains 
a certain, but much smaller, quantity of the other cyclosporins, 
specifically cyclosporins B, C, D and G. However, as already explained, 
the present invention can be applied either to a pure cyclosporin (whether 
cyclosporin A or another member of the cyclosporin group) or to a mixture 
of individual cyclosporins, such as the above-mentioned commercial 
mixture. 
The effectiveness of the intermediate molecular weight fatty acid mono- and 
di- glycerides is rather unexpected in view of the disadvantages 
associated with the use of other closely related compounds. 
Thus, higher fatty acid glyceride preparations are defective because of the 
reasons given above. On the other hand, lower fatty acid glycerides are 
ill-tasting and smell offensive, and, as these glycerides are naturally 
soluble in water, a mixed solvent of water and a lower fatty acid 
glyceride can hardly be expected to dissolve cyclosporin. Moreover, 
comparing the various intermediate fatty acid glycerides with each other, 
the triglycerides show a significantly lower ability to dissolve the 
cyclosporins and thus disperse them in water. 
On the contrary, an oily preparation composed of an intermediate molecular 
weight fatty acid mono- or di-glyceride and cyclosporin has the advantages 
of being capable of containing a high concentration of cyclosporin, of 
being emulsified easily with water in the absence of a surface active 
agent or in the presence of a highly safe (i.e. weakly emulsifying) 
surface active agent, and of having a high stability on standing. 
There is no particular restriction on the nature of the intermediate 
molecular weight fatty acid mono- or di- glyceride used in the present 
invention, and any mono- or di- glyceride of an intermediate molecular 
weight fatty acid having from 6 to 10 carbon atoms may be used. Examples 
of preferred intermediate molecular weight fatty acids include: caproic 
acid, 4-methyl-pentanoic acid, enanthic acid, 5-methylhexanoic acid, 
2-ethylhexanoic acid, caprylic acid (more properly named "octanoic acid"), 
6-methylheptanoic acid, pelargonic acid, capric acid and 8-methylnonanoic 
acid. The more preferred fatty acids contain from 8 to 10 carbon atoms, 
most preferably 8 carbon atoms. 
Thus, the mono- and di- glycerides of fatty acids containing 8 carbon atoms 
are still more preferred, and the diglycerides of fatty acids containing 8 
carbon atoms are most preferred. 
Because there are three positions on the glycerin molecule to which the 
fatty acid residues may attach, mono- and di- glycerides can exist in the 
form of symmetric .beta.-monoglycerides and .alpha.,.alpha.'-diglycerides 
as well as asymmetric .alpha.-monoglycerides and 
.alpha.,.beta.-diglycerides. The present invention embraces the use of all 
of these glycerides, and the exact nature of these isomers and whether a 
single such compound or a mixture of such compounds is employed is not 
critical to the invention. 
Also, in the case of the diglycerides, the fatty acid residues may be the 
same as each other, or they may be mixed diglycerides in which there are 
two different kinds of fatty acid residues. The present invention embraces 
the use of all of these glycerides. 
It is also possible to use a single one of these intermediate molecular 
weight fatty acid mono- or di- glycerides or to use a mixture of any two 
or more thereof. 
The amount of the intermediate molecular weight fatty acid mono- or di- 
glyceride employed in this invention is not particularly restricted, and 
this amount may vary, depending on the kind of intermediate molecular 
weight fatty acid mono- or di- glyceride employed and the kind of 
formulation employed. For example, because of the strong emulsifiability 
of mono- and di- glycerides, an oily preparation containing only 
cyclosporin and at least one mono- and/or di- glyceride can be 
administered at a concentration of nearly 100% because it will change to 
an almost completely emulsified state in vivo. 
However, in general, it is preferred to use the composition of the present 
invention in the form of an emulsion in the presence of water. In this 
case, the non-aqueous components are preferably present in amounts of 
about 50% by weight or less, more preferably about 25% or less, of the 
whole composition. If the preparation is to be applied topically, the 
non-aqueous components are preferably present in an amount of 1% by weight 
or less. 
The weight ratio of the intermediate molecular weight fatty acid mono- 
and/or di- glycerides to the cyclosporin used in this invention is 
preferably from 1:0.1 to 1:1, more preferably from 1:0.1 to 1:0.5, and 
most preferably from 1:0.25 to 1:0.5. 
If the preparation takes the form of an emulsion, a surface active agent 
may also be employed, if desired, in order to improve the stability on 
standing of the emulsion and the absorption in vivo of the active agent, 
by decreasing the sizes of the oil particles. Preferred examples of the 
surface active agents which may be employed include: 
polyoxyethylene-polyoxypropylene glycol; and phospholipids, such as 
lecithin. However, there is no particular restriction on the nature of any 
such added surface active agent, provided that it is highly safe. 
It is also possible in accordance with the present invention to use an 
intermediate molecular weight fatty acid mono- or di- glyceride in 
admixture with any other vegetable oil, or to improve the preparation 
containing these basic substances by adding conventional additives, such 
as a pH adjuster, an osmotic pressure adjuster, an antiseptic, a surface 
active agent, a perfume or a corrigent. 
The composition of the present invention may be provided in the form of an 
oily solution of the cyclosporin and the intermediate molecular weight 
fatty acid mono- or di- qlyceride together with a suitable vehicle, or in 
the form of an aqueous emulsion thereof. It is also possible to provide 
the composition as a powdery product by spray-drying or freeze-drying such 
an emulsion. 
The oily solution and aqueous emulsion preparations of the present 
invention can be employed for oral administration or for administration by 
injection; they can also be applied to the eye without any trouble. The 
powdery product can not only be employed for oral administration, for 
injection or for application to the eye by dissolving it before use, but 
it can also be used as the material for oral solid preparations, such as 
powders, granules, capsules and tablets, and for suppositories. 
In the case of an oily solution or aqueous emulsion, the concentration of 
cyclosporin is preferably from 0.1 to 500 mg/ml, and more preferably from 
0.2 to 200 mg/ml. 
The compositions of the invention will, of course, be formulated in 
conventional pharmaceutical forms appropriate to the intended route of 
administration, for example as formulations for oral administration or for 
topical administration, especially to the eyes. However, appropriate 
formulations are well known in the art and require no further explanation 
here.

The invention is further illustrated by the following Examples, Test 
Examples and Experiments. In the following, all parts and percentages are 
by weight. The cyclosporin samples used in the Examples, Test Examples and 
Experiments were supplied by Sandoz Ltd., Switzerland. The commercially 
available "Sandimmune" (Trade name) contains the same kind of cyclosporin 
compound as was used in these Examples. Test Examples and Experiments. 
TEST EXAMPLE 1 
Emulsifiability 
The mixed triglyceride of caprylic acid and capric acid (Trade name: ODO; 
obtainable from The Nisshin Oil Mills, Ltd.), castor oil, olive oil and 
peanut oil were examined for emulsifiability. 
The emulsion was composed of 10 weight % or 20 weight % of the glyceride, 0 
weight %, 1.2 weight % or 2 weight % of a surface active agent (Pluronic 
F68, a trade name for a material obtainable from Asahi Denka Kogyo K.K. or 
dipalmitoylphosphatidylcholine obtainable from Nippon Oils & Fats Co., 
Ltd.). the balance being a physiological saline solution. 
Each solution was emulsified by using a Physcotron emulsifier (a trade name 
for an emulsifier obtainable from Niti-on Irika Kikai Co., Ltd.), and the 
condition of each emulsion was judged by the naked eye. Judging from the 
separation between oil and water, the mixed triglyceride of caprylic acid 
and capric acid was found to be the best among the 4 kinds of glycerides, 
regardless of the compositions, and a great difference could be observed 
between the emulsifiability of this and the emulsifiability of castor oil, 
olive oil or peanut oil. Although the mixed triglyceride of caprylic acid 
and capric acid is not included in this invention, even this intermediate 
molecular weight fatty acid triglyceride was found to exhibit far better 
emulsifiability than did any of the higher fatty acid glycerides. 
TEST EXAMPLE 2 
Emulsifiability 
1 ml of an intermediate molecular weight fatty acid glyceride and 9 ml of 
water were placed in a test tube, and the test tube was shaken lightly to 
examine the emulsifiability of the intermediate molecular weight fatty 
acid glyceride. 
The intermediate molecular weight fatty acid glycerides examined in this 
Example were caprylic acid mono-, di- and tri- glycerides and caproic acid 
diglyceride. 
Caprylic acid monoglyceride was emulsified in a manner very close to 
self-emulsification. There was little separation between oil and water and 
the emulsion was very stable. 
Caprylic acid triglyceride was emulsified only after vigorous shaking by 
hand, but the emulsion tended to separate into oil and water after it had 
been allowed to stand for some time. 
Caproic acid diglyceride and caprylic acid diglyceride both showed an 
intermediate emulsifiability between the two mentioned above. 
In short, good emulsifiability was observed in the following order: 
caprylic acid monoglyceride, caproic acid diglyceride, caprylic acid 
diglyceride and caprylic acid triglyceride. 
TEST EXAMPLE 3 
Solubility 
Table 2 below shows the solubility of cyclosporin in each of the glycerides 
at room temperature. 
TABLE 2 
______________________________________ 
Glyceride Solubility [mg/ml] 
______________________________________ 
Peanut oil 50 
Olive oil 10 
Soybean oil 20 
Castor oil 250 
Mixed triglyceride of caprylic 
50 
acid and lauric acid 
(trade name Miglyol 812, Huls 
Troisdorf A.G.) 
Mixed triglyceride of caprylic 
50 
acid and capric acid 
(trade name ODO, The Nisshin 
Oil Mills, Ltd.) 
Caprylic acid diglyceride 
520 
(trade name Sunfat GDC, 
Taiyo Kagaku Co., Ltd.) 
Caprylic acid monoglyceride 
550 
(The Nisshin Oil Mills, Ltd.) 
Caproic acid diglyceride 
510 
(Nikko Chemical Co., Ltd.) 
______________________________________ 
TEST EXAMPLE 4 
Solubility 
The solubility of cyclosporin in four kinds of glycerides at 45.degree. C. 
is shown in Table 3 below. 
TABLE 3 
______________________________________ 
Glycerides Solubility [mg/ml] 
______________________________________ 
mixed triglyceride of caprylic 
130 
acid and capric acid 
(Trade name: ODO; The Nisshin 
Oil Mills, Ltd.) 
Lauric acid monoglyceride 
300 
(Trade name: Sunsoft 757; Taiyo 
Kagaku Co., Ltd.) 
Oleic acid monoglyceride 
400 
(Trade name: MGO; Nikko Chemical 
Co., Ltd.) 
Capric acid monoglyceride 
600 
(Trade name: Sunsoft 767; Taiyo 
Kagaku Co., Ltd.) 
______________________________________ 
From the results reported above in Test Examples 3 and 4, it can be seen 
that the solubility of cyclosporin in intermediate molecular weight fatty 
acid glycerides (in which the fatty acid contains from 6 to 10 carbon 
atoms) was particularly high in the mono- and di- glycerides, as compared 
with the hiqher fatty acid glycerides and the intermediate molecular 
weight triglycerides. 
EXAMPLE 1 
An emulsion containing cyclosporin was prepared. It was composed of one 
part of cyclosporin, 2 parts of caprylic acid diglyceride (Trade name: 
Sunfat GDC), 1 part of Pluronic F68 and 96 parts of physiological saline 
solution, a total of 100 parts. Two kinds of solutions, one in which 
cyclosporin was dissolved in Sunfat GDC, and the other in which Pluronic 
F68 was dissolved in the physiological saline solution, were mixed 
together and emulsified by ultrasonic treatment. The size of the oil 
particles in the resulting emulsion was not larger than 1 .mu.m. No 
separation of cyclosporin could be observed. 
EXAMPLE 2 
An emulsion containing cyclosporin was prepared. It was composed of 2 parts 
of cyclosporin, 5 parts of caprylic acid diglyceride (Trade name: Sunfat 
GDC), 1.2 parts of soy lecithin (Trade name: Lecinol S-10EX; Nikko 
Chemicals Co., Ltd.) and 91.8 parts of physiological saline solution, a 
total of 100 parts. Two kinds of solutions, one in which cyclosporin was 
dissolved in Sunfat GDC, and the other in which soy lecithin was mixed 
with the physiological saline solution, were mixed together, and 
emulsified by ultrasonic treatment. 
The resulting emulsion was slightly viscous and the size of the oil 
particles was not larger than 1 .mu.m. No separation of cyclosporin could 
be observed. 
EXAMPLE 3 
An emulsion containing cyclosporin was prepared. It was composed of 0.1 
part of cyclosporin, 0.25 part of caprylic acid diglyceride (Trade name: 
Sunfat GDC), 2 parts of Pluronic F68 and 97.65 parts of physiological 
saline solution, a total of 100 parts. Two kinds of solutions, one in 
which cyclosporin was dissolved in Sunfat GDC, and the other in which 
Pluronic F68 was dissolved in the physiological saline solution, were 
mixed together and treated 5 times using a laboratory homogenizer 
[Manton-Gaulin 15M-8TA (Gaulin Corporation)]at 300 kg/cm.sup.2. The size 
of the oil particles was not larger than 1 .mu.m. 
EXAMPLE 4 
An emulsion containing cyclosporin was prepared. It was composed of 5 parts 
of cyclosporin, 10 parts of caprylic acid diglyceride (Trade name: Sunfat 
GDC), 1 part of Pluronic F68 and 84 parts of purified water, a total of 
100 parts. Two kinds of solutions, one in which cyclosporin was dissolved 
in Sunfat GDC, and the other in which Pluronic F68 was dissolved in 
purified water, were mixed together, and emulsified by ultrasonic 
treatment. The resulting emulsion was slightly viscous, and the size of 
oil particle was not larger than 1 .mu.m. 
EXAMPLE 5 
Following the procedures described in Examples 1, 2, 3 and 4. Similar 
emulsions were obtained from caproic acid diglyceride and caprylic acid 
monoglyceride after similar treatment. The results were very similar. 
EXPERIMENT 1 
The emulsion preparation prepared as described in Example 3 was applied to 
the right eye of a male Japanese white rabbit 10 times at intervals of 30 
minutes, and at a dose of 0.05 ml each time. Thirty minutes after the 
final application, the tissue was exised. At the time of obtaining the 
corneal sample, the corneal epidermis was removed in order to obtain such 
a sample as free as possible from cyclosporin adsorbed on the surface. The 
mean cyclosporin levels in the tissues of three eye samples were 3400 
ng/ml and 700 ng/ml for the corneal parenchyma and for the ciliary body 
respectively. Therefore, the transfer of cyclosporin into the eye tissue 
was established. Cyclosporin was analyzed quantitatively using a 
radio-immunoassay kit (Sandoz Ltd.) 
EXPERIMENT 2 
The emulsion prepared in Example 4 or Sandimmun Drink Solution (Sandoz 
Pharmaceutical Co. Ltd.& Sankyo Co., Ltd., which was used as control and 
which is available commercially), each containing cyclosporin, was 
administered orally at a dose of 10 mg/kg (calculated as cyclosporin) to a 
Beagle dog which had been previously fasted. Blood samples were taken at 
the times shown in Table 4 below to determine the blood cyclosporin 
levels, using a radioimmunoassay kit (Sandoz Ltd.). 
TABLE 4 
______________________________________ 
Blood cyclosporin level [ng/ml] 
(the mean value from 2 dogs) 
Time after 24 
administration 
0 1 2 3 4 6 hours 
______________________________________ 
Sample 
Sandimmun &lt;30 &lt;30 310 310 280 180 40 
Drink 
Solution 
Emulsion of 
&lt;30 210 370 580 480 350 40 
Example 4 
______________________________________ 
It was demonstrated that the emulsion of this invention brought about good 
absorbability compared with the control. 
As will be appreciated from the foregoing description and, in particular, 
the above Examples illustrating the present invention, the specific 
teachings of the present invention enable the preparation of 
pharmaceutical compositions comprising cyclosporins in solution in 
selected mono- and di- glycerides, which are capable of directly forming 
aqueous emulsions, as well as pharmaceutical compositions comprising such 
aqueous emulsions, without any need for any additional co-solvent 
component for the cyclosporin, e.g. without the need for the addition of 
ethanol or of any other solubiliser for the cyclosporin. 
In a particular aspect, the present invention also provides: a 
pharmaceutical composition in accordance with the invention, e.g. as 
herein described, claimed or exemplified, which is free or substantially 
free from ethanol and/or from any trans-esterification product of a 
vegetable oil (whether natural or hydrogenated) tri-glyceride and a 
polyalkylene polyol. 
Preferably the compositions in accordance with this aspect of the present 
invention are free or substantially free from any further solubiliser or 
co-solubiliser for the cyclosporin.