United States Patent:   5,980,936

Assignee:  Alliance Pharmaceutical Corp. (San Diego, CA)

Filed:  August 7, 1997

Multiple emulsions comprising a discontinuous emulsified phase incorporating a highly polar liquid, a second component selected from the group consisting of fluorocarbons and hydrocarbons and a continuous hydrophobic phase are disclosed. In preferred embodiments, the hydrophobic phase may comprise a fluorocarbon or hydrocarbon. Additionally, the stable multiple emulsions of the present invention may further incorporate a bioactive agent and are particularly suitable for drug delivery including pulmonary drug delivery.

SUMMARY OF THE INVENTION

The present invention accomplishes these and other objectives by providing unique multiple emulsions which may be used for the administration of bioactive agents. In preferred embodiments, the invention comprises multiple emulsions having a continuous hydrophobic phase and a discontinuous emulsified phase. That is, the discontinuous phase of the disclosed multiple emulsions comprises an emulsified phase incorporating a polar liquid (W) and a second component selected from the group of hydrocarbons (HC) and fluorocarbons (FC). By "emulsified" it is meant that the two components (either W and HC or W and FC) are subjected to sufficient energy, preferably in the presence of a first dispersant, to provide a substantially homogeneous suspension of an immiscible liquid in a continuous liquid carrier. In accordance with the teachings herein, the discontinuous emulsified phase may comprise a W-in-FC emulsion, a W-in-HC emulsion, a FC-in-W emulsion or a HC-in-W emulsion. The selected emulsion is then dispersed in a continuous hydrophobic phase, preferably in the presence of a second dispersant, to provide stable multiple emulsions for the delivery of bioactive agents. Preferably, the continuous hydrophobic phase comprises a liquid hydrophobic compound selected from the group consisting of hydrocarbons and fluorocarbons.

It should be appreciated that the discontinuous emulsified phase preferably comprises two distinct phases of one immiscible liquid dispersed in another. By immiscible it is meant than one liquid is at least partially insoluble in the other liquid. As set forth above, one of the phases making up the emulsified phase is a polar liquid while the other is selected from the group consisting of hydrocarbons and fluorocarbons. In preferred embodiments the polar liquid will be aqueous or aqueous based. However, other polar liquids such as, for example, alcohols, alkyl sulfoxides and combinations thereof may be compatible with the present invention. In particular short chain alcohols (i.e. carbon chain length .ltoreq.4 carbons) and alkyl sulfoxides such as dimethylsulfoxide may be suitable for use with or without the addition of water. As such, the terms "aqueous" and "polar liquid" may be used interchangeably throughout the instant specification unless the context of the passage indicates differently. The letter W shall be held to mean any polar liquid including aqueous solutions.

In any case those skilled in the art will appreciate there is a distinct first interface separating the two components of the discontinuous emulsified phase. Preferably the first dispersant is largely deposited at the first interface to stabilize the emulsified phase and allow it to maintain its distinct homogenous configuration when it is dispersed in the hydrophobic continuous phase of the multiple emulsions.

In this regard, dispersion of the discontinuous emulsified phase in the hydrophobic continuous phase provides the multiple emulsions of the present invention. Preferably, the multiple emulsions further comprise a second dispersant largely deposited at the interface between the discontinuous emulsified phase and the continuous hydrophobic phase. As indicated above, the continuous hydrophobic phase may comprise either a hydrocarbon or a fluorocarbon.

As used herein, the term "dispersant" shall be held to mean any single surfactant, emulsifying agent or surfactant system that is capable of reducing the interfacial tension between distinct phases. It will be appreciated that the first and second dispersants used in the disclosed multiple emulsions may be the same or different.

Accordingly, in keeping with the teachings herein the multiple emulsions of the invention may comprise W-in-FC-in-HC emulsions, FC-in-W-in-HC emulsions, HC-in-W-in-FC emulsions and W-in-HC-in-FC emulsions. Consistent with the scope of the instant disclosure, the hydrocarbon or fluorocarbon of the continuous hydrophobic phase may be the same or different than the hydrocarbon or fluorocarbon incorporated in the discontinuous emulsified phase. Similarly, the first dispersant may be the same or different than the second dispersant. In any case, the multiple emulsions may be combined with bioactive agents to provide stable bioactive multiple emulsions having extended shelf-lives, enhanced bioavailability and prolonged delivery profiles.

Accordingly, one aspect provided by the present invention are stable multiple emulsions for the delivery of bioactive agents comprising:

a discontinuous emulsified phase comprising a first dispersant a polar liquid and a second component selected from the group consisting of fluorocarbons and hydrocarbons;

a continuous phase comprising a liquid hydrophobic compound; and

an effective dispersing amount of a second dispersant wherein said discontinuous emulsified phase is immiscible in said liquid hydrophobic compound.

In preferred embodiments the discontinuous emulsified phase will comprise an FC-in-W emulsion, a W-in-FC emulsion, a HC-in-W emulsion or a W-in-HC emulsion. Moreover, the continuous hydrophobic phase is selected from the group consisting of hydrocarbons and fluorocarbons. Of course those skilled in the art will appreciate that the disclosed multiple emulsions may further comprise effective dispersing amounts of a first and second dispersants and at least one bioactive agent.

A wide variety of hydrocarbons and hydrocarbon derivatives may be used to form the preparations of the present invention. As used herein, the term "hydrocarbon" is held to mean any compound, including bioactive agents, which are capable of being dispersed in, or of dispersing, the other disclosed components of the multiple emulsions. That is, the hydrocarbon itself may be a bioactive agent or drug although non-bioactive hydrocarbons are compatible with the teachings herein. In any case, the selected hydrocarbon is preferably biocompatible and readily available from natural or synthetic sources.

Hydrocarbons compatible with the present invention include saturated or unsaturated hydrocarbons (cyclic, aliphatic or aromatic), or hydrocarbon derivatives including substituted and unsubstituted compounds (e.g. alcohols, aldehydes, ketones, amines, ethers, amides, etc.). Lipophilic bioactive compounds that may be incorporated using the disclosed dispersing agents, such as selected steroidal compounds, aminoglycosidic compounds and cholesterol derivatives are also hydrocarbons for the purposes of the invention. Yet other compatible hydrocarbons include paraffins, lipids, waxes, glycerides, fatty acids, natural and synthetic hydrocarbons and derivatives thereof. Preferred natural hydrocarbons may be selected from the group consisting of canola oil, soybean oil, olive oil, corn oil, castor oil, safflower oil and sunflower oil.

Similarly it will be appreciated that the term "fluorocarbon" is used in a broad sense and comprises any highly fluorinated compound such as a linear, branched, cyclic, saturated or unsaturated fluorinated hydrocarbon, optionally containing at least one heteroatom and/or bromine or chlorine atom, wherein at least 30% of the hydrogen atoms of said hydrocarbon compound have been replaced by fluorine atoms. Particularly preferred embodiments comprise perfluorocarbons. Fluorocarbons compatible with the present invention are generally selected for beneficial physical characteristics such as low toxicity, low surface tension, high spreading coefficient and the ability to transport gases.

The multiple emulsions of the present invention may be formed using conventional emulsification procedures well known to those skilled in the art. In this regard it will be appreciated that the desired multiple emulsions can be formed using ultrasound, microfluidization, high pressure homogenization or any other appropriate method. Preferably, a two step process is used wherein the discontinuous emulsified phase is formed and then dispersed in the continuous hydrophobic phase. In such cases the energy imparted during the second step is preferably such that it does not substantially disrupt the emulsion formed during the first step.

Accordingly, another aspect of the invention is directed to methods for forming a stable multiple emulsion comprising the steps of:

emulsifying a first dispersant a polar liquid and a second component selected from the group consisting of fluorocarbons and hydrocarbons to provide an emulsified disperse phase; and

dispersing said emulsified disperse phase in a continuous phase comprising a hydrophobic compound and an effective dispersing amount of a second dispersant wherein said emulsified disperse phase is immiscible in said hydrophobic compound.

In preferred embodiments incorporated dispersants are selected from non-fluorinated surfactants and fluorinated surfactants. As previously alluded to, the included dispersants may be the same or different depending on the selected emulsion components and the desired configuration of the multiple emulsion. Of course those skilled in the art will appreciate that any dispersant or dispersants which provide the desired multiple emulsion may be incorporated in the preparations of the present invention. The first dispersant, deposited at the first interface (between the W and HC or FC) in the discontinuous emulsified phase often, but not necessarily has a high hydrophilic-lipophilic balance (HLB). Preferably the first dispersant is selected from the group consisting of phospholipids, poloxamers (such as pluronics), poloxamines (such as tetronics) and sorbitan esters. In particularly preferred embodiments the first dispersant is a phospholipid or combination of phospholipids such as egg yolk phospholipid (EYP).

The second dispersant, optionally deposited at the interface between the discontinuous emulsified phase and the continuous hydrophobic phase, may also be a non-fluorinated surfactant. This is particularly preferred when the discontinuous phase exhibits an aqueous exterior so the second interface is between the aqueous component and the hydrophobic continuous phase. Conversely, when the discontinuous emulsified phase exhibits a HC or FC exterior (i.e. in a W-in-FC-in-HC emulsion), fluorinated surfactants are preferred. In such embodiments, the second dispersant may be selected from the group consisting of semi-fluorinated alkanes or alkenes and perfluoroalkylated surfactants. In particularly preferred embodiments, the dispersing agent is selected from the group consisting of diblock compounds having a fluorinated region and a hydrogenated region. In other preferred embodiments, the second dispersant may be selected from fluorinated surfactants such as those described in "Fluorinated Surfactants Intended for Biomedical Uses," J. Greiner, J. G. Riess and P. Vierling in Organofluorine Compounds in Medical Chemistry and Biomedical Applications, R. Filler, T. Kobayashi and Y. Yagupolski (eds.), Elsevier, 339-380 (1993).

In yet another aspect, the present invention provides methods for delivering a bioactive agent to a patient using the disclosed multiple emulsions. As used herein, the term bioactive agent is defined to mean any pharmaceutical compound or composition, including diagnostic and therapeutic agents as well as physiologically acceptable gases such as oxygen or nitric oxide, which may be administered to an animal to treat a disorder or disease. In general the methods comprise:

providing a bioactive multiple emulsion comprising an discontinuous emulsified phase having therein a first dispersant a polar liquid and a second component selected from the group consisting of fluorocarbons and hydrocarbon oils, said emulsified phase dispersed in a continuous phase comprising a hydrophobic compound and an effective dispersing amount of a second dispersant wherein said bioactive multiple emulsion further comprises at least one bioactive agent; and

administering said bioactive multiple emulsion to a patient.

In accordance with the teachings herein the bioactive preparations of the present invention may be administered to a patient using a route of administration selected from the group consisting of topical, subcutaneous, pulmonary, synovial, intramuscular, intraperitoneal, nasal, vaginal, rectal, aural, oral and ocular routes. Due to the physical characteristics of the bioactive multiple emulsions (i.e. the hydrophobic continuous phase comprising either a HC or FC), pulmonary administration (when FC) and administration to the gastrointestinal tract (when HC and FC) of these preparations is particularly preferred.

Pharmaceutically effective amounts of both lipophilic bioactive agents and those which are soluble in water may be advantageously delivered using the preparations of the present invention. Preferably, water soluble bioactive agents are delivered in combination with a lipophilic or hydrophobic agent although single bioactive agents may also be delivered effectively. In each of the aforementioned embodiments, bioactive agents compatible with the present invention include, but are not limited to, respiratory agents, bronchodilators, bronchoconstrictors, antibiotics, antivirals, mydriatics, antiglaucomas, anti-inflammatories, antihistaminics, antineoplastics, anesthetics, ophthalmic agents, enzymes, cardiovascular agents, polynucleotides, genetic material, viral vectors, immunoactive agents, imaging agents, immunosuppressive agents, peptides, proteins, physiological gases, gastrointestinal agents and combinations thereof.

Pharmaceutically effective amounts of the selected bioactive agents may be determined using techniques well known in the art. Additional, stabilizers, solubilizing agents or co-solvents such as, for example, natural and synthetic polymers, diblocks, polyethylene glycol, sorbitan esters poloxamers such as pluronics or poloxamines can be used to facilitate the incorporation of the selected bioactive agents or agents into one or the other phase of the preparation. It will further be appreciated that the bioactive agents may be incorporated in the form of relatively insoluble solid particulates or associated with insoluble polymeric particulates.

Claim 1 of 30 Claims

1. A stable multiple emulsion for the delivery of bioactive agents comprising:

a discontinuous emulsified phase comprising a first dispersant, a polar liquid and a second component selected from the group consisting of fluorocarbons and hydrocarbon oils wherein the second component is dispersed in the polar liquid or the polar liquid is dispersed in the second component;

a continuous phase comprising a hydrophobic compound; and

an effective dispersing amount of a second dispersant wherein said discontinuous emulsified phase is immiscible in said hydrophobic compound.

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