Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2000-08-29
2002-01-08
Dees, Jose′ G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S490000
Reexamination Certificate
active
06337092
ABSTRACT:
This invention relates to compositions and processes that provide sub-micron and micron size stable particles of water-insoluble or poorly soluble drugs or other industrially useful insoluble compounds. The compositions of this invention include combinations of natural or synthetic phospholipids, a charged surface modifier such as a highly purified charged phospholipid, and a block copolymer coated or adhered onto the surfaces of the water insoluble-compound particles. The combination of charged surface modifier and block copolymer allows the formation and stabilization of the sub-micron and micron size compound particles. The particles are stabilized by the charged surface modifier which provides electrostatic stabilization, and by the block copolymer which provides steric stabilization. The combination of charged surface modifier and block copolymer stabilize these particles with respect to particle growth, aggregation or flocculation.
BACKGROUND OF THE INVENTION
There is a critical need in the pharmaceutical and other biological based industries to formulate water-insoluble or poorly soluble substances into formulations for oral, injectable, inhalation, ophthalmic, and other routes of delivery. Water insoluble substances are those having poor solubility in water, that is <5 mg/ml at physiological pH (6.5-7.4). Preferably their water solubility is <1 mg/ml, and more preferably <0.1 mg/ml. Water-insoluble or poorly soluble substances as used herein include water-insoluble or poorly soluble pharmaceutical compounds and water-insoluble or poorly soluble drugs.
It is desirable that a water-insoluble or poorly soluble substance be stable when formulated as a dispersion, for example as a dispersion in an aqueous medium such as water. It is also desirable that a formulation of a water-insoluble or poorly soluble substance be stable when formulated as a dispersion. Alternatively, a dry formulation of the substance such as a lyophilized or spray-dried solid form of the formulation can be desirable.
As used herein, “micro-” refers to the largest cross section or diameter such as that of a particle having a cross section or diameter of from nanometers to micrometers. Thus, microparticles, as used herein, refer to solid particles having a cross section or diameter of from nanometers to micrometers and are of irregular or non-spherical or substantially spherical shapes. Drug formulations containing these microparticles provide some specific advantages over unformulated and non-micronized drug particles which include improved oral bioavailability of drugs that are poorly absorbed from GI tract, development of injectable formulations that are currently available only in oral dosage form, less toxic injectable formulations that are currently prepared with organic solvents, sustained release of intramuscular injectable drugs that are currently administered through daily injection or constant infusion, and preparation of inhaled or ophthalmic formulation of drugs that otherwise could not be formulated for nasal/oral inhalation or ocular use.
Current technologies for delivering insoluble drugs as described in U.S. Pat. Nos. 5,091,188; 5,091,187; and 4,725,442 focus either on (a) coating small drug particles with natural or synthetic phospholipids or (b) dissolving the drug in a suitable lipophilic carrier and forming an emulsion stabilized with natural or semisynthetic phospholipids. One of the disadvantages of these formulations is that certain drug particles in suspension tend to grow larger over time because of the dissolution and reprecipitation phenomenon known as “Ostwald ripening” or particle growth. As the solvent or medium surrounding the particle becomes saturated with solute such as a drug, the larger particles grow and become even larger as seen, for example in Luckham, Pestic. Sci., (1999) 25, 25-34.
Another approach, as described in a series of patents uses cloud point modifier(s). In U.S. Pat. Nos. 5,298,262; 5,326,552; 5,336,507; 5,304,564 and 5,470,583 a poorly soluble drug or diagnostic agent has adsorbed on its surface both a cloud-point modifier and a non-crosslinked nonionic surfactant. The role of the cloud point modifier is to increase the cloud point of the surfactant such that the resulting nanoparticles are resistant to particle size growth upon heat sterilization at 121° C.
U.S. Pat. No. 5,922,355 discloses the preparation of submicron size particles of pharmaceutical or other water-insoluble or poorly water-insoluble substances using a combination of one or more surface modifiers/surfactants such as polaxomers, poloxamines, polyoxyethylene sorbitan fatty acid esters and the like together with natural or synthetic phospholipids. Particles so produced have a volume weighted mean particle size at least one-half smaller than obtainable using a phospholipid alone. Compositions so prepared are resistant to particle size growth on storage. Phospholipid and surface modifier(s) are adsorbed on to the surfaces of drug particles in sufficient quantity to retard drug particle growth, reduce drug average particle size from 5 to 100 micrometers to sub-micron and micron size particles by one or combination of methods known in the art, such as sonication, homogenization, milling, microfluidization, precipitation or recrystallization or precipitation from supercritical fluid, and maintain sub-micron and micron size particles on subsequent storage as suspension or solid dosage form. In U.S. Pat. No. 5,922,355, the second surface modifier may function to suppress Ostwald Ripening, to help maintain particle size, to increase storage stability, to minimize sedimentation, and to decrease the particle growth during lyophilization and reconstitution. The second surface modifier adheres or coats firmly onto the surface of water-insoluble drug particles, and modifies interfaces between the particles and the liquid in the formulations. It increases the interface compatibility between water-insoluble drug particles and the liquid, and it may possibly orient preferentially with hydrophilic portions projected into aqueous medium and with lipophilic portions strongly adsorbed at the water-insoluble drug particle surfaces.
In U.S. Pat. No. 5,922,355, the use of a surface modifier or combination of surface modifiers in addition to a phospholipid provides (i) volume weighted mean particle size values that are at least 50% and preferably about 50-90% smaller than what can be achieved using phospholipid alone without the use of a surfactant with the same energy input, and (ii) compositions resistant to particle size growth on storage.
DESCRIPTION OF THE INVENTION
The present invention focuses on submicron to micron size particles or microparticles coated with a natural phospholipid which particles are prepared using a combination of electrostatic and steric stabilization from at least one charged surface modifier and at least one block copolymer respectively. The growth in size of the particles, and hence their storage stability, is controlled by a combination of electrostatic and steric stabilizing materials.
In particular, this invention describes a pharmaceutical composition comprising electrostatic and steric-stabilized particles having diameters of about 0.05 to about 10 microns of a water-insoluble or poorly soluble drug, said particles having phospholipid coated surfaces and being stabilized with a combination of a charged surface modifier and a block copolymer, wherein the diameter of said particles is greater than about 50% but less than 100% of the diameter of particles comprising said poorly soluble drug and said phospholipid coated surfaces prepared by otherwise identical means in the absence of said combination of charged surface modifier and block copolymer, and wherein the charged surface modifier provides electrostatic stabilization and the block copolymer provides steric stabilization that minimize particle size growth caused by Ostwald ripening and particle aggregation and provides for small particle formation.
In addition, this invention describes a pharmaceutical composit
Khan Sheema
Pace Gary W.
Dees Jose′ G.
George Konata M.
Nixon & Vanderhye
RTP Pharma Inc.
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