Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Liposomes
Reexamination Certificate
1996-02-23
2001-06-12
Kishore, Gollamudi S. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Liposomes
C424S400000, C514S937000, C514S393000
Reexamination Certificate
active
06245349
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to drug delivery compositions useful for the administration of lipophilic and amphipathic drugs. More specifically, the drug delivery compositions are characterized as being lipid nanoparticles that are stable upon storage and also upon dilution in aqueous buffer.
BACKGROUND OF THE INVENTION
The formulation of lipophilic, amphipathic, or sparingly water soluble drugs into parenteral and pulmonary dosage forms has proven to be difficult. Successful drug delivery vehicles must be capable of maintaining the drug in its dissolved state over an extended storage period. It is also important that the drug delivery vehicle itself remain stable over the storage period.
Commonly employed delivery vehicles for such drugs include liposome and liposphere compositions. Exemplary of such systems are those drug delivery vehicles set forth in U.S. Pat. Nos. 5,395,619, 5,340,588, and 5,154,930. However, these systems suffer from serious drawbacks. As noted in U.S. Pat. No. 5,395,619, liposome compositions are rapidly cleared from the bloodstream, and various modifications to the liposome systems have been proposed to remedy this problem such as formulating with ganglioside G
M1
, coating with polyethylene glycol chains, or attaching polymer compounds to the phospholipid.
Lipid emulsions have also been proposed as alternative delivery vehicles for such drugs. However, the emulsion particle size, generally ranging from about 200 to 1,000 nm, cause these compositions to be readily removed from the blood stream where they tend to accumulate predominately in the liver and spleen. The particle size of the lipid emulsions also precludes the use of filters to sterilize the compositions, thus heat sterilization must be used, which is detrimental to various drugs. From a manufacturing standpoint, lipid emulsions are not preferred due to the requirement of high shear equipment.
Amphipathic drugs containing both hydrophilic and hydrophobic moieties in their structures are frequently poorly soluble in pharmaceutically acceptable oils or aqueous buffers and therefore require administration in potentially irritating compositions containing alcohols or alcohol/surfactant mixtures.
Microemulsions have also been proposed as drug delivery compositions. Microemulsions are generally defined as those systems containing a lipophilic and a hydrophilic component wherein the average particle size of the dispersed phase is below about 150 nm. Microemulsions are further characterized as being clear or translucent solutions. The clarity and particle size characteristics distinguish microemulsions from emulsions. The smaller particle size range of microemulsions enables them to be retained in the blood system for a longer period of time than emulsions. However, microemulsions are generally not dilutable with aqueous fluids, such as certain bodily fluids and buffer solutions, and form emulsions upon contacting such fluids. Various microemulsions are also sensitive to temperature and are not stable outside of room temperature conditions.
A need therefore exists in the art of drug delivery to develop a vehicle that can be used with lipophilic and amphipathic materials and that can be stored at various temperatures for extended periods of time and that can be filter sterilized. The vehicle should also be dilutable with an aqueous fluid such as blood or a buffer solution and still retain these characteristics.
SUMMARY OF THE INVENTION
The present invention provides drug delivery compositions in both concentrated and diluted forms for use as vehicles in the administration of various active agents. The drug delivery compositions are primarily designed for use with lipophilic, amphipathic, and sparingly water soluble active agents, preferably drugs. The drug delivery compositions are to be administered to an animal to effect uptake of the active agent. The primary mode of administration is by intravenous, intra-arterial, intrathecal, intraperitoneal, intraocular, intra-articular, intramuscular or subcutaneous injection. The preferred routes are intravenous, intrathecal or intra-arterial injection. The most preferred routes are intravenous or intra-arterial injection.
The concentrated drug delivery compositions can be formulated with or without an oil component. If present, the oil component can constitute up to about 50 percent by weight of the concentrated composition. The concentrated delivery compositions contain between 3 and 50 percent by weight phospholipid, between 3 and 50 percent by weight of a compound selected from the group consisting of propylene glycol and polyethylene glycol having a weight average molecular weight of from 200 to 4000, and mixtures thereof, and between 3 and 50 percent by weight of a high HLB surfactant having an HLB value of at least about 12. The concentrated compositions contain an active agent, preferably a drug, in an amount of from about 0.1 to about 50 percent by weight. The concentrated compositions can also contain an aqueous component, generally water or a buffer solution, in an amount up to about 15 percent by weight.
Standard pharmaceutical preservatives may be added to either the concentrate or the diluted microemulsion formulations. These may include antioxidants, such as a-tocopherol or ascorbate, and antimicrobials, such as parabens, chlorobutanol or phenol. The preservatives are generally present in an amount of from about 0.1-0.3% by weight.
The concentrated drug delivery compositions can be stored at various temperatures while retaining the active material in its active state. It is preferred, however, to conduct the storage of the delivery composition in its diluted form. The diluted form is prepared by adding an aqueous liquid, preferably water or a buffer solution, to the concentrated composition. The diluted oil-in-water microemulsions form spontaneously, without the need for high shear mixing equipment, upon the addition of the aqueous liquid to the concentrated compositions. The final water content of the diluted composition is at least about 80 percent by weight. The diluted composition can contain between 0.1 and 10 percent by weight phospholipid, between 0.1 and 15 percent by weight of a compound selected from the group consisting of propylene glycol and polyethylene glycol having a weight average molecular weight of from 200 to 4000, and mixtures thereof, between 0.1 and 10 percent by weight of a high HLB surfactant having an HLB value of at least about 12, and an active agent, preferably a drug, in an amount of from about 0.01 to about 5 percent by weight. If present, the oil component can constitute from about 0.1 to about 10 percent by weight of the diluted composition.
The diluted drug delivery compositions are characterized as being nanoparticle compositions. The number average particle size of these compositions is below about 100 nm. These compositions are also characterized as generally being clear or translucent. These compositions can be stored at freezing conditions, refrigeration conditions, room temperature conditions, and at elevated temperature conditions without concomitant loss of their particle size characteristics. These compositions can be heat or filter sterilized.
The present invention also provides for the administration of the diluted drug delivery composition to an animal to effect administration of the active agent. Modes of administration include intra-arterial, intrathecal, intraperitoneal, intraocular, intra-articular, intramuscular or subcutaneous injection. The preferred routes are intravenous, intrathecal or intra-arterial injection. The most preferred routes are intravenous or intra-arterial injection. The present invention further provides for methods of preparing the diluted drug delivery compositions by the disclosed path dependency sequence.
A benefit of the compositions of the present invention is that the concentrated compositions can be transformed into the diluted oil-in-water microemulsion compositions without the need for high shear mixing equipment. As such, the concentrated
Tustian Alex K.
Yiv Seang H.
Elan Corporation PLC
Kishore Gollamudi S.
Synnestvedt & Lechner LLP
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