Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Liposomes
Reexamination Certificate
1998-12-22
2001-07-10
Kishore, Gollamudi S. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Liposomes
C424S400000, C514S002600, C514S021800, C514S937000, C514S943000
Reexamination Certificate
active
06258377
ABSTRACT:
The present invention relates to preparations of substances in hydrophobic solvents in which they would normally be soluble and to processes for obtaining these preparations. In particular, the invention relates to preparations of hydrophilic species in mixtures of medium chain monoglycerides (MCMs) and diglycerides.
The invention in particular applies to hydrophilic macromolecules which would not normally be soluble in oils or other hydrophobic solvents.
For many applications, e.g. in the pharmaceutical sciences, in food technology or the cosmetics industry, work with proteins and similar macromolecules presents problems because their hydrophilicity and high degree of polarity limit the extent to which they can interact with or incorporate into lipid phases. Many natural systems employ lipidic barriers (eg skin, cell membranes) to prevent access of hydrophilic molecules to internal compartments; the ability to disperse proteins in lipidic vehicles would open up a new route to introduction of these macromolecules into biological systems, whereby the lipid medium containing the protein can integrate with the hydrophobic constituents of barriers, instead of being excluded by them.
We have previously disclosed, in WO-A-9513795, WO-A-9617593 and WO-A-9617594, methods for preparing hydrophobic preparations where a hydrophilic species is solubilised in a hydrophobic phase in which it would not normally be soluble. In particular, these methods are suitable for solubilising proteins.
Although the above-described preparations provide simple and efficient methods for solubilising macomolecules such as proteins, we have now found that the macromolecule delivery properties of the preparations can be improved by the use of a particular oil phase and, optionally, particular amphiphiles. This is particularly advantageous when the macromolecule to be solubilised is a protein, eg a pharmaceutically active protein, since the preparations disclosed herein provide not only enhanced uptake of the therapeutic macromolecule but also good dose repeatability.
Thus, in a first aspect, the present invention provides a hydrophobic preparation comprising:
(i) an oil phase comprising one or more medium chain monoglycerides; and
(ii) at least one amphiphile;
(iii) a hydrophilic species solubilised or otherwise dispersed in the mixture of glycerides;
wherein the hydrophilic species is one that is not normally soluble in the one or more monoglycerides.
In the context of the present invention “hydrophobic preparation” is a preparation in which the hydrophilic species is not present in aqueous phase. Such a hydrophobic preparation is particularly suitable for use in orally delivering a hydrophilic macromolecule such as a protein.
The prior art does contain a number of examples of the use of medium chain monoglycerides as permeation enhancers in the intestine (Sekine et al,
J.Pharmacobiodyn.,
7:856-63 (1984); Higkai et al,
J.Pharmacobiodyn.,
9:532-9 (1986); Unowsky et al, Chemotherapy, 34:272-6 (1988); Watanabe et al,
J.Pharm.Sci.,
77:847-9 (1988); Yeh et al,
Pharm.Res.,
11:1148-54 (1994); Constinides et al,
Pharm.Res.,
11:1385-90 (1994)). However, in every case the formulations disclosed are ones where the active principle/drug is solubilised in an aqueous phase. In fact until the methods disclosed in, inter alia, WO-A-9513795 preparations where a hydrophilic species was truly and readily solubilised in a hydrophobic phase, with retention of biological activity, were not available.
Preparations in accordance with the invention will generally have no bulk aqueous phase and may have no free water molecules.
In a preferred embodiment the oil phase i) will compose a mixture of medium chain mono- and diglycerides. Suitably, medium chain glycerides useful in the present invention have chain lengths of 8 to 10 carbon atoms, for example, they can comprise straight chain saturated fatty acids. In another embodiment the oil phase i) may comprise one or more medium chain monoglycerides together with at least one other component such as oleic acid, glycerol mono-oleate or gelucides. For both these embodiments the essential component will be the medium chain monoglyceride(s). Whether medium chain monoglyceride(s) are used alone or as mixtures of glycerides or the like, the oil component used should be such that the amount of monoglyceride(s) present should be maximised while ensuring that the oil component remains liquid at a temperature of 45° C. or lower. In particular, monoglyceride(s) can make up 40-90% of the total amount of oil present, preferably 60-70%. An example of a suitable mixture of glycerides is Akoline MCM™ which contains both medium chain mono- and diglycerides, available from Karlshamns Sweden AB, S/374 82 Karlsbamn, Sweden.
Preferably, the ratio of amphiphile:macromolecule is in the range 1:1 to 20:1 by weight and more preferably in the range 2:1 to 8:1 by weight.
Examples of suitable amphiphiles include phospholipids such as phosphatidyl choline, phosphatidic acid, phosphatidyl glycerol, phosphatidyl ethanolamine and lyso-derivatives of these, octyl glucoside and other glycolipids, tocopherol succinate and cholesterol hemisuccinate. Other suitable amphiphiles include phosphatidyl serine, sodium docusate and hydroxypropyl cellulose. More than one amphiphile may be used.
In one preferred embodiment the amphiphile used is a bile salt. In the present invention it should be understood that the terms bile salt and bile acid are used interchangeably because whether the salt or its conjugate acid is present will depend on the pH of the surrounding environment.
Bile salts are naturally occurring surfactants. They are a group of compounds with a common “backbone” structure based on cholanic acid found in all mammals and higher vegetables. Bile salts may be mono-, di- or tri-hydroxylated; they always contain a 3&agr;-hydroxyl group whereas the other hydroxyl groups, most commonly found at C
6
, C
7
or C
12
, may be positioned either above (&bgr;) or below (&agr;) the plane of the molecule.
Within the class of compounds described as bile salts are included amphiphilic polyhydric sterols bearing carboxyl groups as part of the primary side chain. The most common examples of these in mammals result from cholesterol metabolism and are found in the bile and, in derivatised form, throughout the intestine.
In the context of this specification, the term may also apply to synthetic analogues of naturally occurring bile salts which display similar biological effects, or to microbially derived molecules such as fusidic acid and its derivatives.
The bile salt (or salts) may be either unconjugated or conjugated. The term “unconjugated” refers to a bile salt in which the primary side chain has a single carboxyl group which is at the terminal position and which is unsubstituted. Examples of unconjugated bile salts include cholate, ursodeoxycholate, chenodeoxycholate and deoxycholate. A conjugated bile salt is one in which the primary side chain has a carboxyl group which is substituted. Often the substituent will be an amino acid derivative which is inked via its nitrogen atom to the carboxyl group of the bile salt. Examples of conjugated bile salts include taurocholate, glycocholate, taurodeoxycholate and glycodeoxycholate.
Thus, in the present invention examples of suitable bile salts include cholate, deoxycholate, chenodeoxycholate and ursodeoxycholate, with ursodeoxycholate being particularly preferred. Other bile salts which may be employed include taurocholate, taurodeoxycholate, taurouodeoxycholate, taurochenodeoxycholate, glycholate, glycodeoxycholate, glycoursodeoxycholate, glycochenodeoxycholate, lithocholate, taurolithocholate and, glycolithocholate.
In the present invention the term “hydrophilic species” relates to any species which is generally soluble in aqueous solvents but insoluble in hydrophobic solvents. The range of hydrophilic species of use in the present invention is diverse but hydrophilic macromolecules represent an example of a species which may be used.
A wide variety of macromolecules is sui
Kirby Christopher John
New Roger Randal Charles
Kishore Gollamudi S.
Pennie & Edmonds LL
Provalis UK Limited
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