Controlled release composition forming a reversed micellar (L2) structure or a normal micellar (L1) structure

A controlled-release composition for a biologically active material, characterized in that it comprises a mixture of: a) monocaproin, optionally in admixture with moncaprylin and/or monocaprin, and b) a polar liquid selected from the group consisting of such polar liquids which are capable of forming an L2 phase with a), and c) a biologically active material dissolved or dispersed in said mixture of a) and b), a) being present in the composition, based on the total weight of a)+b), in an amount of from the lower limit where the mixture of a) and b) forms a reversed micellar (L2) structure and up to 100% by weight of a), with the further proviso that said mixture of a) and b) is essentially within that specific domain of the L2 structure, in a phase diagram, where said L2 structure will change to a normal micellar (L1) structure if contacted with an external polar liquid. Said composition is preferably used as a medial composition.

TECHNICAL FIELD 
the present invention is within the field of encapsulating biologically 
active materials in order to obtain a controlled, or sustained, release 
thereof as is desirable within many different technical fields, such as 
for instance to have a longer lasting or delayed effect of a 
pharmaceutically active material. More specifically the invention is based 
on a novel encapsulating or carrier material or system which enables a 
highly reproducible sustained release (reduced biological variability) of 
biologically active compounds. With reference to last-mentioned property 
the term "controlled release" will be generally used throughout 
description and claims to emphasize the fact that by the present invention 
the desired sustained release of the active compound can be obtained in a 
controlled way. 
BACKGROUND OF THE INVENTION 
About thirty years ago one of the inventors, K. Larsson, in Z. phys. Chem. 
56 (1967), 173, reported that the aqueous system of monocaproin, which is 
a lipid the complete name of which is glycerolmonohexanoate or 
glycerolmonocapronate, forms one single liquid phase at all compositions. 
At that time this was a unique and remarkable behaviour of a single 
amphiphilic (surfactant) molecule; only mixtures of surfactants and 
cosurfactants were known to exceptionally show such lack of a phase 
transition when the composition was changed from anhydrous towards pure 
water. 
Recent work within the field of drug delivery, with special regard to 
molecules that need to be protected against enzymatic degradation (like 
peptides), has shown that so called microemulsions or L2-phases provide a 
useful carrier system. An example of such an L2-system is disclosed in 
European patent specification No. 314 689, which discloses the utilization 
of C.sub.16-22 -monoglycerides interacting with C.sub.16-22 -triglycerides 
and a polar liquid. 
although the phase properties of monocaproin have been known for a very 
long time, however, it has not been realized earlier that this unusual 
micellar phase can provide a highly efficient carrier in connection with 
for instance drug delivery, as far as is known to applicant. The main 
reason probably is that a molecule with such a short hydrocarbon chain is 
regarded more as an organic solvent than as a lipid and has, therefore, 
not been expected to provide efficient solubilization power of drugs into 
an association-colloid type of structure. 
When amphiphilic systems forming ordinary micellar solutions (L1-solution) 
have been used in drug delivery, relatively long hydrocarbon chains have 
also been involved; cf. K. A. Johnson, G. B. Westermann-Clark, and D. 
Shaf, Pharmaceut. Res. 6 (1989), 239. 
Furthermore, it can be added that Ericsson and Hegg in Progr. Colloid & 
Polymer Sci. 70 (1985), 92, have reported a study of the surfactant 
behaviour of 1-monocaproin and its interaction with ovalbumin in a diluted 
water solution. The critical micellar concentration (cmc) of monocaproin 
was found to be 160 mM. Their result demonstrated that there is no 
molecular interaction between this specific protein and monocaproin. We 
have now unexpectedly found that the micellar system according to the 
present invention exhibits full compatibility with any protein also at 
high concentrations, i.e. even up to and including the region where the 
L1-type of structure changes to the L2-type of structure. 
GENERAL DESCRIPTION OF THE INVENTION 
Thus the present invention is based on the unexpected finding that 
monocaproin is highly efficient in solubilizing amphiphilic biologically 
active materials, especially drug molecules, and that the successive 
change from an L2-type of micellar solution into an L1-type thereof 
without any phase separation provides a useful mechanism for protecting 
molecules which are sensitive to enzymatic degradation, and also for 
sustained release, particularly in drug administration, for instance oral 
administration. 
It has also been found that lipase degradation of the new compositions 
according to the present invention is extremely slow compared to 
previously disclosed glyceride-based formulations. As is realized by a 
person skilled in the art this is a very significant factor in especially 
oral drug carrier systems. 
A pronounced problem in the oral delivery of drugs by lipid-based 
formulations is furthermore the interference between the lipids of the 
drug formulation and the lipids in foods. In order to accomplish a 
reproducible drug uptake it is therefore advisable and sometimes even 
necessary to take the drug on an empty stomach, which may of course be 
disadvantageous. Fats and oils in foods are often covered by a surface 
layer of amphiphilic molecules, usually polar lipids, and these surface 
lipids and the dominating core of oils/fats are always in an emulsified 
state in the gastrointestinal tract. A general complication in connection 
with previously known drug delivery systems based on lipids is that these 
emulsions originating from the food will interact with the drug carrier 
system, which means that the food composition can influence upon the drug 
uptake. 
A most remarkable and unexpected property of monocaproin, contrary to 
previously described lipid systems, is that the aqueous phase thereof does 
not solubilize triglyceride oils or fats, and not even so called medium 
chain triglycerides or pure tricaprylin. 
An addition factor to consider in oral administration of drugs is the 
phospholipid surface layer covering the gastric and the intestinal mucous 
layer; cf. B. A. Hills, The Biology of Surfactant, Cambridge University 
Press, Cambridge, (1988). the new micellar composition according to the 
present invention has such a small interaction with these phospholipids 
that said interaction can be neglected in a corresponding drug carrying 
system, which is contrary to the situation in connection with the 
previously known lipid drug carriers. 
More specifically, according to the first aspect of the invention, there is 
accomplished a new controlled-release composition for a biologically 
active material, which composition is characterized in that it comprises a 
mixture of: 
a) monocaproin, optionally in admixture with a monoglyceride selected from 
the group consisting of C.sub.6 -C.sub.10 -fatty acid monoglycerides, i.e. 
monocaprylin and/or monocaprin, and 
b) a polar liquid selected from the group consisting of such polar liquids 
which are capable of forming an L2 phase with a), and 
c) a biologically active material dissolved or dispersed in said mixture of 
a) and b), a) being present in the composition, based on the total weight 
of a)+b), in an amount of from the lower limit where the mixture of a) and 
b) forms a reversed micellar (L2) structure and up to 100% by weight of 
a), with the proviso that said mixture of a) and b) is also essentially 
within that specific domain of the L2 structure, in a phase diagram, where 
said L2 structure will change to a normal micellar (L1) structure if 
contacted with an external polar liquid. 
Thus, if firstly considering the binary system monocaproin-water said 
system shows micellar molecular assemblies at all concentrations in the 
temperature range between about room temperature and about 100.degree. C., 
with an inverted L2-type of structure, which continuously goes over to an 
ordinary micellar solution (L1) when raising the proportion of water. 
These two micellar phases are highly efficient solubilizers of lipophilic 
materials and the continuous phase change L2.fwdarw.L1 has been shown to 
give an outstanding sustained or controlled release of the lipophilic 
substance, as well as the additional advantages referred to above. 
With reference to the specific embodiment where a binary system of 
monocaproin and water is utilized it should be emphasized that the 
invention is applicable also up to the extreme end with 100% of 
monocaproin, i.e. the invention also covers the case where there is in 
fact no water or other polar liquid present at the beginning. This is an 
important advantage contrary to earlier known aqueous formulations as 
ordinary capsules do not allow water. 
As concerns the statement that the mixture of a) and b) is also 
"essentially" within that specific domain of the L2-structure where a 
change to an L1-structure only is accomplished in contact with an external 
polar liquid, this means that it may be borderline cases where a specific 
application permits the presence of a second phase, e.g. L.sub..alpha., in 
a minor or negligible amount. No specific figure can be given here, but 
that aspect is easily considered by a person skilled in the art from case 
to case. 
A very important feature in connection with the release or delivery 
applications in accordance with the invention also is that we have found 
that water can be replaced with any other polar liquid that is capable of 
forming the L2-phase referred to in connection with the invention. Thus, 
it has been found that also with other polar liquids the same type of 
association-colloid structures exist with said continous phase change from 
L2 to L1. 
In the case of low solubility of a desired biologically active material it 
has been found that the solubilization can be increased by the addition of 
C.sub.8 -C.sub.10 -fatty acid monoglycerides, provided that said addition 
is made in such a way that it does not influence upon the uniqe one-phase 
behaviour. Thus, the addition has to be kept within that specific part of 
the L2-domaine which, when contacted with water or any other polar liquid 
from the surroundings e.g. the intestin or the stomach, will cause the 
desired continous phase change from L2 to L1. The specific composition to 
be used in each separate case is easily determined by a person skilled in 
the art by using a phase diagram, as will be illustrated further below in 
connection with the figure. 
In connection with the general inventive idea it could also be added that 
in principle the C.sub.4 -monoglyceride, i.e. monobutyrin, can be expected 
to act in a way similar to that of monocaproin. However, in practice it 
does not seem to be any realistic alternative, inter alia for such reasons 
as being instable and having an unpleasant taste and smell. 
With reference to preferable embodiments of the composition according to 
the invention the following ones can be referred to. 
As concerns the optional presence of said C.sub.8 -C.sub.10 -fatty acid 
glyceride the difference in the effect of added monocaprin as compared to 
monocaprylin is quite small when considering the extent of the one-phase 
region used in the present invention. A slightly higher ratio of said 
long-chain monoglyceride/monocaproin is possible without the occurence of 
a second phase when using monocaprylin as compared to monocaprin. Another 
difference that may be referred to in this connection is that the second 
phase occuring in these systems, which is the lamellar liquid-crystalline 
phase L.sub..alpha. at 25-25.degree. C., melts into a separate L2-phase in 
the monocaprylin system when the temperature is increased towards 
40.degree. C. 
Apart from using the pure compounds monocaprylin and/or monocaprin said 
optional ingredients of the composition according to the invention may 
also be used in the form of a technical monoglyceride mixture prepared 
from so called medium chain triglycerides, which mixture should give an 
intermediate behaviour as compared to that of monocaprin or monocaprylin 
descried above. 
The polar liquid used as ingredient b) of the composition according to the 
invention is preferably selected from the group consisting of water, 
glycerol, ethylene glycol and propylene glycol. Another useful polar 
liquid is a lower alkanol such as ethanol. 
As concerns the external polar liquid referred to in connection with the 
change from an L2-structure into an L1-structure said liquid generally is 
gastric juice or other body fluid in connection with the drug aspect of 
the invention, but as the invention is not strictly limited to a 
controlled release of drugs only, said polar liquid may also well be any 
of the polar liquids referred to above. Thus, said external polar liquid 
is also preferably water, glycerol, ethylene glycol or propylene glycol, 
also in connection with non-medical uses of the composition claimed, where 
sustained release of a biologically active ingredient is desired. 
The biologically active material is generally selected from the group 
consisting of amphiphilic and lipophilic materials and preferably 
pharmaceutical lipophilic compounds. Examples of such pharmaceutical 
compounds in connection with which the invention is especially preferable 
are antibiotics, proteins, peptides, steroids, vitamins, nucleic acids and 
vaccines. 
An especially interesting biological active compound is a protein or a 
peptide, preferably cyclosporin, desmopressin (dDAVP) or vasopressin or 
calcitonins. A highly preferable use of said cyclosporin in connection 
with the invention is as an immunosuppresive drug. 
As has been described above ingredient a) of the composition claimed can be 
present up to 100% by weight, based on the total weight of a)+b). 
Generally this means that a) is present within the range of 50-100% by 
weight, more preferably 80-100% by weight. 
The biologically active material is preferably present in the composition 
according to the invention in an amount of 0.1-20, more preferably 0.2-12, 
% by weight based on the total weight of a)+b). 
Lipases in saliva, in gastric mucosa and of course the strongly dominating 
pancreatic lipase degrade lipids in oral drug delivery systems based on 
lipids. It is well known that lipases also attack other lipids than 
triglycerides, for example phospholipids, galactolipids, diglycerides and 
monoglycerides (the 1-isomer). A requirement for the enzymatic degradation 
(to take place with a reasonable velocity) is the existence of an 
interphase between water and the actual lipid phase where the lipase is 
localized. An interesting feature of our new composition or system is the 
lack of such an interphase. This means that the protection of substances 
in the gastrointestinal system is much more effective than in lipid 
systems forming separate phases which are coexisting with an aqueous 
phase. This property must be considered of outmost importance in 
protecting peptides in oral delivery. 
In order to increase the life-time of the monocaproin micelles in the 
intestinal system the addition of minor amounts of food emulsifiers can be 
used to improve the protection of the drug against the intestinal enzymes. 
Therefore, another preferable embodiment of the invention is represented 
by a composition which contains a food emulsifier, preferably an 
emulsifier which contains a polyoxyethylene chain. 
Still another preferable embodiment of the invention is a composition 
wherein said monocaproin comprises either the 1-isomer or the 2-isomer, 
i.e. where the monocaproin is essentially pure 1-monocaproin or 
essentially pure 2-monocaproin. 
Since, the invention is of special importance in connection with drug 
delivery another aspect of the invention is represented by a composition 
as previously defined for use as a medical composition, i.e. primarily for 
the controlled release of a biologically active material in the form of a 
drug or medical compound. 
Preferable embodiments of such a composition are those embodiment which 
have already been disclosed in connection with the controlled-released 
composition per se. Thus, they will not be repeated here. 
In connection with the medical composition it should, however, be added 
that it is preferably adapted for oral delivery of the drug. Such an 
embodiment is especially interesting in connection with proteins, since 
proteins in aqueous solution have a tendency to unfold at the air-water 
interphase, but when monocaproin is present above CMC (critical micell 
concentration), it will squeeze out the proteins from the air/water 
interphase. Such a drug delivery system therefore also has a protective 
effect on protein stability. 
If the protein, or other medical substance is unstable in an aqueous 
solution the present invention is preferably utilized with propylene 
glycol or glycerol as said polar liquid because such a system is more 
stable than a water-monocaproin system. Thus, as glycerol-monocaproin form 
the same type of association colloids as water-monocaproin, the former 
system is preferred in oral delivery of such proteins. 
Furthermore, the finding that monocaproin can reduce the interfacial 
tension without solubilizing usual lipids means that it can increase the 
penetration through the skin without destroying the physiologically 
important lipid barrier on stratum corneum. Drug delivery by the micellar 
system according to the present invention through the skin therefore 
represents an application particularly well suited to situations when fast 
and efficient drug penetration is desired. That is, still another 
preferably embodiment of the medical composition claimed is a composition 
which has been adapted for transdermal delivery of the drug. 
According to still another aspect of the invention it can be defined as the 
use of a composition as defined above for the manufacture of a medicament 
comprising a protein or a peptide as the active medical compound and 
adapted for oral or transdermal administration of said medical compound. 
An especially interesting medical compound in this context is clyclosporin, 
primarily for use as an immunosuppresive drug. 
For biologically active non-medical materials the invention can also be 
defined as the use of a composition as defined above for the controlled 
release of said non-medical material. 
An example of such a non-medical material is an enzyme for a biotechnology 
application, but various other materials and applications are of course 
possible within the scope of the invention as is realized by a person 
skilled in the art. 
The invention also relates to a method of preparing the controlled-release 
composition defined, which method generally comprises mixing a) and b) so 
as to form an L2-structure as defined and dissolving or dispersing c) 
therein during or after said mixing of a) and b) so as to obtain said 
controlled-release composition. 
This general method of preparing the composition should cause the skilled 
artisan no problem and further details in this context should not be 
needed here. 
However, it could be added that in a case where there may be an interaction 
between the biologically active material and ingredient a) of the 
composition, a preferable embodiment of the method comprises forming said 
L2-structure of a) and b) and keeping it separate from c) up to the moment 
of use, preferably in a two-compartment delivery system, and then 
dissolving or dispersing c) in said L2-structure when the 
controlled-release composition is to be utilized. 
Finally, another aspect of the invention, which is also based on the 
finding of the outstanding properties of monocaproin as a carrier for a 
protein or a peptide, is represented by a composition for use as a nasal 
medical composition, which is characterized in that it comprises a protein 
or peptide included in an spray delivery composition comprising a mixture 
of 
a) monocaproin, optionally in admixture with monocaprylin and/or 
monocaprin, and 
b) a polar liquid, which is preferably selected from the group consisting 
of water, glycerol, ethylene glycol and propylene glycol, a) and b) being 
present in the composition in such a mutual ratio that they form a 
micellar structure in an aerosol form. 
Thus, according to this aspect of the invention a) can be present in such a 
small amount only that a normal micellar (L1)structure is at hand already 
from the beginning in said nasal composition. In other words the protein 
or peptide may in fact be ready for delivery or release already in the 
spray composition. However, this spray delivery aspect of the composition 
works also up in the micellar L2-structure range. Generally this means 
that a) can be present in such a spray delivery composition in an amount 
of about 2-70, preferably 2-50, more preferably 2-20% by weight, based on 
the total weight of a)+b). 
Said aerosol composition for use as a nasal medical composition preferably 
comprises or essentially consists of insulin as said protein or peptide. 
Another way of expressing the invention is by a method of administering to 
a mammal, especially man, a biologically active material, which method 
comprises providing a composition as defined above and administering an 
effective amount thereof to the body of said mammal, whereby a controlled 
release of said composition is obtained.

EXAMPLES 
Example 1 
86 mg of cyclosporin A was dissolved in 860 mg of monocaproin. To the 
solution 20 g of water was added. 
Microscopic inspection of the sample in polarized light showed no 
birefringence. This shows that the cyclosporin has been dissolved in the 
monocaproin phase. 
Example 2 
Cyclosporin in an amount of 9 g was dissolved in 91 g of monocaproin. The 
solution obtained was transferred to 100 mg gelatin capsules covered by a 
solid fat film acting as a protection during the passage of the capsule 
through the gastric region. 
Example 3 
A solution was prepared from 30 g of monocaprin in 60 g of monocaproin. 
This solution was added to a heparin-solution containing 10 000 IE/ml. 
This preparation for oral heparin delivery is supplied via the same kind 
of capsules as in example 2. 
Example 4 
The human insulin preparation Insulatard from Novo Nordisk with 100 IE/ml 
was converted to a preparation for nasal delivery as a spray merely by 
adding monocaproin in a concentration of 4% (w/w). 
Example 5 
A homogenous sample was prepared by mixing an aqueous solution of the 
peptide dDAVP (desmopressin) (1070 .mu.g/ml) with monocaproin 
(monohexanoin from Larodan, Malmo, Sweden) in the weight ratio of 1 to 9, 
to give a final concentration of 107 .mu.g/ml. 1 mg/kg bodyweight of this 
solution was fed intragastrically to eight rats, as was a corresponding 
saline solution of dDAVP. 
The bioavailabiliyt of dDAVP was 2.0% from the monocaproin containing 
solution and 0.2% from the saline solution. 
Thus, what can be seen from this Example is a drastic increase of the 
bioavailability of the peptide by the composition according to the 
invention. 
Example 6 
Many galenic formulations of drugs contain polar solvents. In order to 
demonstrate the excellent miscibility of monocaproin with polar solvents, 
the following mixtures were prepared and inspected visually. The Table 
below shows the results. The clear, low viscous appearance confirms that 
it is a solution. 
TABLE 
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% (w/w) Polar 
% Mono- 
Polar solvent 
solvent caproin Appearance 
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Ethanol 10 90 clear, low viscous 
Propylene Glycol 
10 90 clear, low viscous 
Ethanol/ 5 
Propylene Glycol 
5 90 clear, low viscous 
Ethanol 90 10 clear, low viscous 
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