Sustained release delivery of water soluble bio-molecules and drugs using phosphokipid-coated microcrystals, microdroplets and high-concentration lipsomes

Abstract

The novel uses of the phospholipid-coated microcrystal in the delivery of water-soluble biomolecules such as polypeptides and proteins. The proteins are rendered insoluble by complexation and the resulting material forms the solid core of the phospholipid-coated particle. Alternatively, the proteins, bio-molecules or drugs can be entrapped in water-soluble form between the membranous layers of the coated microcrystal. All types of phospholipid microcrystals can incorporate 5 nm to 10 um diameter iron oxide particles to allow for manipulation by magnetic fields. Water-soluble bio-molecules including proteins, peptides, and drugs can be entrapped and retained with long shelf life in liposomes at high concentrations, provided that the phospholipid concentration is greater than 10% (w/v) such that greater than 50% of the system volume is enclosed within phospholipid membranes. Both the phospholipid-coated microcrystal and the phospholipid-coated microdroplet can be used as vaccine adjuvants.

What is claimed is: 
     
       1. A pharmaceutical delivery system for a water-soluble biological molecules consisting essentially of a syringable, injectable aqueous suspension of solid particles of the bio-molecule in a complexed water-insoluble form, the solid particles having diameters or maximal dimensions of about 0.05 um to about 10 um, coated with a 0.3 nm to 3.0 um thick layer of a membrane-forming amphipathic lipid which stabilizes the bio-molecules in complexed solid form against coalescence and renders the bio-molecule in solid form, which composition is substantially devoid of uncoated particles. 
     
     
       2. A pharmaceutical delivery system for a water soluble biological molecules consisting essentially of a syringable, injectable aqueous suspension of solid particles of the bio-molecule an a complexed water-insoluble form. the solid particles having diameters or maximal dimensions of about 0.05 um to about 10 um, coated with a 0.3 nm to 3.0 um thick encapsulating primary layer consisting of coating and enveloping layers of a membrane-forming layer of first a membrane-forming amphipathic lipid which stabilizes the bio-molecules in complexed solid form against coalescence and renders the bio-molecules in complexed solid form, and 25 nm to 3.0 um thick secondary layer consisting of second membrane-forming amphipathic lipid in vesicular form associated with and surrounding but not enveloping the lipid-encapsulated solid-form bio-molecules, which composition is substantially devoid of uncoated particles. 
     
     
       3. A pharmaceutical delivery system for water-soluble drugs or biological molecules consisting essentially of a syringable, injectable aqueous suspension of solid particles of a pharmacologically-acceptable water-insoluble substance, the solid particles having diameters or maximal dimensions of bout 0.05 um to about 10 um, coated with a 0.3 nm to 3.0 um thick layer of a membrane-forming amphipathic lipid which stabilizes the solid particles of a pharmacologically-acceptable water-insoluble substance against coalescence, wherein the water-soluble drug or bio-molecules are entrapped within the layers of membrane-forming lipid. 
     
     
       4. A pharmaceutical delivery system for a water-soluble drug or biological molecules consisting essentinally of a syringable, injectable aqueous suspension of solid particles of a pharmacologically-acceptable water-insoluble substance, the solid particles having diameters or maximal dimensions of about 0.05 um to about 10 um. coated with a 0.3 nm to 3.0 um thick encapsulating primary layer consisting of coating and enveloping layers of a membrane-forming amphipathic lipid which stabilizes the pharmacologically-acceptable substance in solid form against coalescence, wherein the water-soluble drug or bio-molecules are entrapped within the layers of membrane-forming lipid. 
     
     
       5. The compositions, of claim 1, 2, 3 or 4 wherein the solid particles also contain magnetic iron oxide (Fe 3  O 4 ) particles having diameters maximal dimension of about 5 nm to about 10 um. 
     
     
       6. A syringable, injectable pharmaceutical composition consisting essentially of an aqueous suspension of crystals or solid particles of a pharmacologically active water-insoluble drug substance in solid Form, the solid particles having diameters or maximal dimensions of about 0.05 um to about 10 urn, coated with a 0.3 nm to 3.0 um thick layer of a membrane-forming amphipathic lipid which stabilizes the drug substance from coalescence and renders the drug substance in solid form less irritating to living tissue, which composition contains colloidal iron oxide (Fe 3  O 4 ) particles of about 5 nm to about 10 um diameters or maximal dimensions, which composition is substantially devoid of uncoated crystals or drug or iron oxide particles. 
     
     
       7. A syringable, injectable pharmaceutical composition consisting essentially of an aqueous suspension of solid particles of a pharmacologically active water-insoluble drug substance in solid form, the crystals or solid particles having diameters or maximal dimensions of about 0.05 um to about 10 um, coated with a 0.3 nm to 3.0 um thick encapsulating primary layer consisting or coating and enveloping layers of a membrane-forming amphipathic lipid, which stabilizes the drug substance from coalescence, and 25 nm to 3.0 um thick secondary layer consisting or a membrane-forming amphipathic lipid in vesicular form associated with and surrounding but not enveloping the lipid-encapsulated drug particles, which composition contains colloidal iron oxide (Fe 3  O 4 ) particles of about 5 nm to about 10 um diameters or maximal dimensions, which composition is substantially devoid of uncoated crystals or drug or iron oxide particles. 
     
     
       8. A solid pharmaceutical composition consisting essentially of the compositions of claims 1, 2, 3 or 4, devoid of water which, when water is added, gives an aqueous suspension. 
     
     
       9. The compositions of claims 1, 2, 3 or 4, in which the crystals or particles are wetted with a water-immiscible oil of up to 0.25 gram per gram crystalline or solid substance, to facilitate contact between the solid substance and the primary of amphipathic membrane-forming lipid, or to slow the rate of dissolution of crystals or solid substance or to otherwise modify the rate of release of pharmacologically-active substance. 
     
     
       10. The composition of claim 1, 2, 3 or 4, in which the bio-molecule is an antigen. 
     
     
       11. The composition of claim 10 in which the antigen is a bacterial membrane or a viral coat fragment. .Iadd. 
     
     
       12.  An orally administrable pharmaceutical composition consisting essentially of a free-flowing aqueous suspension of solid particles of a pharmacologically active water-insoluble drug substance in solid form, the solid particles having diameters of about 0.05 μm to about 10 μm, coated with a 0.3 nm to 3.0 μm thick layer of a membrane-forming amphipathic lipid which stabilizes the drug substance from coalescence. .Iaddend..Iadd.13. An orally administrable pharmaceutical composition consisting essentially of a free-flowing aqueous suspension of crystals or solid particles of a pharmacologically active water-insoluble drug substance in solid form, the crystals or solid particles having diameters or maximal dimensions of about 0.05 μm to about 10 μm, coated with a 0.3 nm to 3.0 μm thick encapsulating primary layer consisting of coating and enveloping layers of a membrane-forming amphipathic lipid, which stabilizes the drug substance from coalescence and a 25 nm to 3.0 μm thick secondary layer consisting of a membrane-forming amphipathic lipid in vesicular form associated with and surrounding but not enveloping the lipid-encapsulated drug particles, which composition is substantially devoid of uncoated crystals or particles. .Iaddend..Iadd.14. Composition of claim 12, in which the water-insoluble drug substance in a water-soluble drug or biomolecule is rendered water-insoluble by complexation with a pharmaceutically acceptable compound producing a crystalline or solid form. .Iaddend..Iadd.15. Composition of claim 13, in which the water-insoluble drug substance is a water-soluble drug or biomolecule is rendered water-insoluble by complexation with a pharmaceutically acceptable compound producing a crystalline or solid form. .Iaddend..Iadd.16. The compositions of claim 12, 13, 14 or 15, wherein the solid particles comprise a pharmacologically-acceptable substance in solid form and wherein water-soluble drug or biomolecules are entrapped between the layers of the membrane-forming amphipathic lipid. 
     
     
        .Iaddend..Iadd.17.  An anhydrous orally administrable pharmaceutical composition in solid form which will produce the free-flowing aqueous suspensions of claim 12, 13, 14 or 15 when water is added. .Iaddend..Iadd.18. A lyophilized orally administrable pharmaceutical composition in solid form prepared by lyophilization of the compositions of claims 12, 13, 14 or 15. .Iaddend.