Incorporation of active substances in carrier matrixes

Details Incorporation of active substances in carrier matrixes Incorporation of active substances in carrier matrixes

1999-04-30

2002-04-16

Azpuru, Carlos (Department: 2165)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Particulate form

C424S451000, C424S464000, C424S502000, C264S004300, C264S004330, C264S004600, C428S402210

Reexamination Certificate

active

06372260

ABSTRACT:

FIELD OF INVENTION
The present invention relates to a process for the preparation of a formulation which comprises an active substance associated with a carrier by forming an emulsion of the components and precipitating the system by using a fluid gas technique. The invention also relates to the formulation obtained by this process.
BACKGROUND OF THE INVENTION
Several solutions to the problem of incorporation of active substances in carrier matrixes in order to obtain particle systems have been suggested. Such systems can be utilized in, for instance, immediate release formulations, modified release formulations, extended release formulations, pulsed release formulations, etcetera.
Some examples of such techniques are:
hot melt microencapsulation (Schwope et al
Life Sci
. 1975, 17,1877)
interfacial polymerisation (Birrenbach and Speiser,
J. Pharm.Sci
. 1976, 65, 1763, Thies,
In Encyclopedia of Chemical Technology,
4 ed. Ed. Kirk-Othmer, 1996, 16, p. 632)
solvent evaporation methods (Cleland, In Vaccine Design.
The subunit and adjuvant approach
, Eds: Powell and Newman Plenum Press, New York; 1995, 439)
solvent extraction (Cleland, In Vaccine Design.
The subunit and adjuvant approach
, Eds: Powell and Newman Plenum Press, New York; 1995, 439)
spray drying (WO 94/15636)
An important step in the preparation of such systems is the incorporation step of the active substance. The choice of preparation method for the release system depends on the kind of active substance that is going to be incorporated and the desired release properties of the active substance from the delivery system. All techniques listed above have their advantages and disadvantages. Thus, the hot melt microencapsulation method is unsuitable for thermosensitive active substances. A drawback with the interfacial polymerisation method is that the highly reactive monomers in the water immiscible solvent can react both with the core material and with the encapsulated active substance. A drawback with the solvent evaporation process method is that the method is time consuming and that it only can be performed batch wise. As in the solvent evaporation technique, the extraction method is also time-consuming as it can only be performed batch wise. A drawback with the spray drying method is that it is difficult to produce particles in the nanometer size range. This method is also unsuitable for thermosensitive substances or oxidative sensitive active substances because of the exposure of heat and air in the process.
Supercritical fluid technology has advanced in the recent years. Briefly, a supercritical fluid can be defined as a fluid at or above its critical pressure and critical temperature simultaneously. The physicochemical properties of supercritical fluids are flexible with temperature and pressure and could be selected to suit a given application. There are several new techniques used today, one is known as rapid expansion of supercritical solutions (RESS) and another is known as gas anti-solvent precipitation (GAS). In the GAS technique a substance of interest is dissolved in a conventional solvent, a super-critical fluid such as carbon dioxide is introduced into the solution, leading to a rapid expansion of the volume of the solution. As a result, the solvent power decreases dramatically over a short period of time, triggering the precipitation of particles. Cf J. W. Tom and P. G. Debenedetti in J. Aerosol Sci., 22 (1991), 555-584; P. G. Debenedetti et al in J. Controlled Release, 24 (1993), 27-44 and J. W. Tom et al in ACS Symp Ser 514 (1993) 238-257; EP 437 451 (Upjohn) and EP 322 687 (Schwarz Pharma). A modification of the GAS system has recently been developed (WO 95/01221 and WO 96/00610). It is called the SEDS (solution enhanced dispersion by supercritical fluid) process, which utilises supercritical fluid technologies for particle formation.
Protein can be incorporated in the carrier matrixes, like other active substances, using the encapsulation methods listed above. The protein is dissolved in a water phase, suspended or directly dissolved in the phase containing the carrier. A disadvantage with proteins dissolved in organic solvents is the low solubility of proteins in organic solvents and / supercritical fluids/modified supercritical flows (Stahl et al, “Dense Gas Results”,
Fluid Phase Equilibra
, 1983, 10, 269). Another disadvantage with the protein directly dissolved or suspended in the organic solvent is that the organic solvent may unfold or denature the protein. (Dill and Shortle
Ann. Rev. Biochem
., 1991, 60, 795-825). This may lead to a loss of therapeutic effect, e.g. inmunological effect.
In supercritical fluid techniques, the proteins have been dissolved directly-in DMSO for preparation of pure protein particles (Winters et al.,
J.Pharm.Sci
., 1996, 85, 586-594 and
Pharm.Res
., 1997, 14, 1370-1378) or in co-precipitation with polymer, with both, the polymer and the protein, dissolved in DMSO (WO9629998 and Bertucco et al.
In High Pressure Chemical Engineering
, 1996, 217-222). Even a mixture of ethanol and water has been used as a solvent for a protein and a polymer in SAS (EP0542314 and Tom et al.,
In Supercritical Fluid Engineering Science
, ACS Symposium Series, 1993, 514, 238-257).
Protein particles have been prepared from water solution in the SEDS technique using a three-component nozzle, where the protein solution in water is first co-introduced with ethanol and then mixed with supercritical carbon dioxide (WO9600610) in the nozzle. Even if the contact time between~the aqueous solution and the ethanol is very short, it may cause destruction of the protein conformation.
Low molecular weight substances have also been co-precipitated with polymers with supercritical fluid techniques. In EP322687 is presented the preparation of a drug form which comprises an active substance and carrier with anti-solvent technique and with RESS (Kim et al.
Biotechnol Prog
1996, 12, 650-661, Chou and Tomasko,
The
4
th
Int.Symp. on Supercritical Fluids
, Sendai, Japan, 1997, 55). Here, in the anti-solvent technique, the active substance and carrier are dissolved or dispersed in the same liquid medium and combined with supercritical fluid. Examples include in these documents only refer to incorporation of hydrophobic compounds in L-PLA spheres. Nothing about the compounds in aqueous phase was mentioned, as well as, in other studies reported on PCA (Bodmeier et al.,
Pharm.Res
., 1995, 12, 1211-1217), SAS (Bertucco et al.
In High Pressure Chemical Engineering
, 1996,217-222), GAS (Chou and Tomasko,
The
4
th
Int.Symp. on Supercritical Fluids
, Sendai, Japan, 1997,55) or ASES (Bleich and Müller,
J. Microencapsulation
, 1996,13, 131-139).
DISCLOSURE OF THE INVENTION
It has now been found that it is possible to associate an active substance or substances with a carrier system by forming an emulsion of the components and precipitating the system by using a fluid gas technique. The active substance or active substances are incorporated within and/or around the carrier system, which includes that the carrier can also surround the active substance or active substances.
This improved method for preparing active substance containing carrier systems is based on the use of emulsions. The emulsion is a mixture of two non-miscible liquids, or phases, where one liquid is finely dispersed in another liquid One of the liquids is.more polar, for instance water or aqueous phase, in comparison to the other liquid, for instance an organic solvent or a mixture of solvents (oil phase, here called the non-aqueous phase). The emulsion can be either kinetically stable (macroemulsion) or a thermodynamically stable (microemulsion), or combination thereof . In order to stabilise the emulsion an emulsifier, either alone or in combination with other emulsifiers, such as but not limited to, surfactants, polymers, lipids can be used. The emulsifiers are dissolved in either the aqueous phase and/or the non-aqueous phase. The active substance or substances, which is/are going to be incorporated or/and associated to the car

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