Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2001-05-17
2004-09-21
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S499000, C424S500000, C424S501000, C424S502000, C424S422000, C424S423000, C424S424000, C424S425000, C424S426000, C424S484000
Reexamination Certificate
active
06793938
ABSTRACT:
BACKGROUND OF THE INVENTION
The invention relates to lipid/polymer-containing biodegradable pharmaceutical compositions which are designed to provide controlled release of encapsulated physiologically active substances.
Delivery systems offer the advantage of improved bioavailability and a higher therapeutic index over a prolonged period of time for physiologically active substances. Two major classes of drug-delivery systems are formed from either biodegradable polymers or lipids (Langer, R.,
Nature
392: 5-10, 1998). Polymer-based drug-delivery systems have been developed as microspheres for injection, implants, transdermal patches, and aerosols for inhalation (Domb et al.,
Handbook of Biodegradable Polymers
, Harwood Academic Publishers, Amsterdam, 1997; Putney et al.,
Nature Biotechnology
16: 153-157, 1998; Edwards et al.,
Science
276: 1868-1871, 1997). Lipid-based drug delivery systems have been developed as unilamellar, multilamellar (Gregoriadis,
Liposome Technology
, Vols. I, II, III, CRC Press, Boca Raton, Fla., 1993) and multivesicular liposomes (U.S. Pat. No. 5,422,120 to Kim; U.S. Pat. No. 5,723,147 to Kim et al.; U.S. Pat. No. 5,767,627 to Sankaram et al.; U.S. patent application Ser. No. 08/305,158; U.S. patent application Ser. Nos. 08/723,583, 08/925,532, 08/792,566, and 08/925,531).
One of the limitations of using biodegradable polymers is that pharmaceutical compositions such as microspheres prepared from biodegradable polymers require storage under anhydrous conditions due to their susceptibility to hydrolysis. As a result, a typical pharmaceutical package of microspheres for injection consists of one vial with an anhydrous formulation of a biodegradable polymer and a physiologically active substance as a solid dosage form and another vial with an aqueous reconstitution medium (e.g., Lupron Depot,
Physicians Desk Reference
, pp. 2739-2746, Medical Economics Company, Inc., Montvale, N.J., 1997). The contents of the two vials are mixed immediately prior to injection.
Microspheres are prepared by a single emulsification process (U.S. Pat. No. 4,389,330 to Tice et al.; U.S. Pat. No. 3,691,090 to Kitajima et al.), a double emulsification process (Edwards et al.,
Science
276: 1868-1871, 1997), a phase inversion microencapsulation process (Mathiowitz et al.,
Nature
386: 410-413, 1997), or an atomization-freeze process (Putney and Burke,
Nature Biotechnology
16: 153-157, 1998). In the single emulsification process, a volatile organic solvent phase containing a biodegradable polymer, an aqueous solution necessarily containing an emulsifier such as polyvinyl alcohol, and a physiologically active substance are homogenized to produce an emulsion. The solvent is evaporated and the resulting hardened microspheres are freeze-dried.
In the double emulsification process, an aqueous solution which may contain a physiologically active substance and an volatile organic solvent phase containing a biodegradable polymer are homogenized to form an emulsion. The emulsion is mixed with another aqueous solution, which contains an emulsifier such as polyvinyl alcohol. Evaporation of the solvent and freeze-drying produces microspheres.
In the phase inversion microencapsulation process, drug is added to a dilute polymer solution in a solvent (e.g. dichloromethane) which is then poured rapidly into an unstirred bath of another liquid (e.g. petroleum ether) causing nano- and microspheres to form spontaneously. In the atomization-freeze process, micronized solid physiologically active substance is suspended in a solvent phase containing a biodegradable polymer that is then atomized using sonication or air-atomization. This produces droplets that are then frozen in liquid nitrogen. Addition of another solvent in which both the polymer and the drug are insoluble extracts the solvent from the microspheres.
Microspheres prepared by the single-emulsification process or the double-emulsification process methods can be aerosolized (Edwards et al.,
Science
276: 1868-1871, 1997). Addition of dipalmitoyl phosphatidylcholine to the solvent phase increases particle size, porosity, and efficiency of aerosolization and decreases the mass density. However, formation of the large porous particles still requires an emulsifier such as polyvinyl alcohol. Sucrose stearate, magnesium stearate, aluminum tristearate, sorbitan fatty esters, and polyoxyethylene fatty ethers have been used as droplet stabilizers in a solvent evaporation method for producing microspheres from acrylic polymers (Yuksel et al.,
J. Microencapsulation
14: 725-733, 1997). Poloxamer 188, or Pluronic F68, has been used as a nonionic surfactant in the primary emulsion, in addition to polyvinyl alcohol in the second aqueous phase, for producing microspheres from poly(lactide) using a double emulsification process (Nihant et al.,
Pharm. Res.
11: 1479-1484, 1994). The hydrophilic additives, 2-hydroxypropyl &bgr;-cyclodextrin, methyl &bgr;-cyclodextrin, Pluronic F-127, L-tartaric acid dimethyl ester, and a hydrophobic additive, beeswax (which consists of esters of long-chain monohydric alcohols with even-numbered carbon chains, esterified with long-chain acids, also having even numbers of carbon atoms) were used to produce poly(lactide-glycolide) double-layer films (Song et al.,
J. Controlled Rel.
45: 177-192, 1997).
SUMMARY OF THE INVENTION
The invention is based on the discovery that biodegradable microspheres can be produced which include both polymer and lipid components, and are free of surfactants introduced into a second aqueous phase of the microspheres. A typical surfactant which heretofore had been introduced into the second aqueous phase is polyvinyl alcohol. Production of the biodegradable microspheres of the invention involves substantial or complete removal of volatile organic solvent from the microsphere walls. The microspheres can be loaded with physiologically active substances, which are released in vitro and in vivo. The rate of release can be easily controlled by adjustments of the lipid/polymer ratio. Previously available microsphere compositions required a change in the identity of the polymer.
In one aspect, the invention provides a lipid/polymer-containing pharmaceutical composition including a biodegradable microsphere which includes at least one type of biodegradable polymer which is soluble in organic solvents, and at least one type of lipid. Also included in the composition is a physiologically active substance which is releasable from the biodegradable microsphere. The composition is preferably substantially free of volatile organic solvent, and most preferably substantially free of polyvinyl alcohol. The compositions can be in the form of an aqueous suspension, or alternatively in the form of a solid dosage, such as in the tablet, capsule, wafer, transdermal patch, suture, implant, or suppository form.
The biodegradable polymers can be homopolymers such as polylactides, polyglycolides, poly(p-dioxanones), polycaprolactones, polyhydroxyalkanoates, polypropylenefumarates, polyorthoesters, polyphosphate esters, polyanhydrides, polyphosphazenes, polyalkylcyanoacrylates, polypeptides, or genetically engineered polymers. At the same time, the biodegradable polymers can be copolymers (random or block) such as poly(lactide-glycolides), poly(p-dioxanone-lactides), poly(p-dioxanone-glycolides), poly(p-dioxanone lactide-glycolides), poly(p-dioxanone-caprolactones), poly(p-dioxanone-alkylene carbonates), poly(p-dioxanone-alkylene oxides), poly(p-dioxanone-carbonate-glycolides), poly(p-dioxanone-carbonates), poly(caprolactone-lactides), poly(caprolactone-glycolides), poly(hydroxyalkanoates), poly(propylenefumarates), poly(orthoesters), poly(ether-esters), poly(ester-amides), poly(ester-urethanes), polyphosphate esters, polyanhydrides, poly(ester-anhydrides), polyphosphazenes, polypeptides and genetically engineered copolymers. The lipids of the pharmaceutical compositions can be zwitterionic lipids, acidic lipids, cationic lipids, sterols, or triglycerides of many types, including many phospholipids.
The phy
Gardner Diane L.
Nolan-Baron Liliana Di
Page Thurman K.
Paul Hastings Janofsky & Walker LLP
Skye Pharma, Inc.
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