Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
1998-12-22
2001-05-08
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S486000, C514S772400, C436S071000
Reexamination Certificate
active
06228399
ABSTRACT:
This invention relates to compositions and procedures that yield sub-micron and micron 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, and one or more non-ionic, anionic or cationic surfactants coated or adhered onto the surfaces of the water insoluble-compound particles. The combination of phospholipids and surfactants allows the formation and stabilization of the sub-micron and micron size compound particles via hydrophilic, lipophilic and electrostatic interactions and therefore prevent these particles from 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 and ophthalmic routes of delivery. Water insoluble compounds 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, more preferably <0.1 mg/ml. It is desirable that the drug is stable in water as a dispersion; otherwise a lyophilized or spray-dried solid form may be desirable.
As used herein, “micro” refers to a particle having diameter of from nanometers to micrometers. Microparticles, as used herein, refer to solid particles of irregular, non-spherical or spherical shapes. Formulations containing these microparticles provide some specific advantages over the unformulated 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, ophthalmic formulation of drugs that otherwise could not be formulated for nasal or ocular use.
Current technology for delivering insoluble drugs as described in U.S. Pat. Nos. 5,091,188; 5,091,187 and 4,725,442 focuses on (a) either 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 over time because of the dissolution and reprecipitation phenomenon known as the “Oswald ripening”.
DESCRIPTION OF THE INVENTION
The present invention focuses on preparing submicron to micron size particles using a combination of surface modifier(s) with a phospholipid, and how the growth of particle size, and hence storage stability, is controlled by adding a combination of surface modifier(s) with a phospholipid to the formulation.
The use of a surface modifier or combination of surface modifiers in addition to a phospholipid is characterized by its ability to result in volume weighted mean particle size values that are (i) 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) provide compositions resistant to particle size growth on storage. While resistance to particle size growth on storage was an objective of this invention we were surprised to observe a significant reduction in particle size with the addition of the surfactant. In order to achieve the advantages of the present invention it is necessary that the phospholipid and the surfactant both be present at the time of particle size reduction or precipitation.
Another aspect of the present invention includes free-flowing powders of poorly soluble or insoluble drug substances such as cyclosporin as well as solid dosage forms of these powders, for instance in the form of compressed tablets and the like. Surprisingly we have found that microparticulate formulations exhibit enhanced stability and bioavailability as illustrated in the data that follows.
Although we do not wish to be bound by any particular theory, it appears that these surface modifiers generally, that is phospholipids and one or more surfactants, adsorb to the surfaces of drug particles, and (a) convert lipophilic to hydrophilic surfaces with increased steric hindrance/stability, and (b) possibly modify zeta potential of surfaces with more charge repulsion stabilization. The concentrations of surface modifiers used in the process described here are normally above their critical micelle concentrations (CMC) and hence facilitate the formation of sub-micron to micron particles by stabilizing the particles.
Phospholipid and surface modifier(s) are adsorbed onto the surfaces of drug particles in sufficient quantity to retard drug particle growth, reduce drug average particle size from 5 to 100 &mgr;m 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.
The concentration of phospholipid or surface modifier in the suspension or solid dosage form can be present in the range of 0.1 to 50%, preferably 0.2 to 20%, and more preferably 0.5 to 10%.
The formulations prepared by this invention may be dried, e.g., by lyophilization, fluid or spray drying, into powders, which can be resuspended or filled into capsules or converted into granules or tablets with the addition of binders and other excipients known in the art of tablet making.
By industrially useful insoluble or poorly soluble compounds we include biologically useful compounds, imaging agents, pharmaceutically useful compounds and in particular drugs for human and veterinary medicine. Water insoluble compounds are those having a poor solubility in water, that is less than 5 mg/ml at a physiological pH of 6.5 to 7.4, although the water solubility may be less than 1 mg/ml and even less than 0.1 mg/ml.
Examples of some preferred water-insoluble drugs include immunosuppressive agents such as cyclosporins including cyclosporine (cyclosporin A), immunoactive agents, antiviral and antifungal agents, antineoplastic agents, analgesic and anti-inflammatory agents, antibiotics, anti-epileptics, anesthetics, hypnotics, sedatives, antipsychotic agents, neuroleptic agents, antidepressants, anxiolytics, anticonvulsant agents, antagonists, neuron blocking agents, anticholinergic and cholinomimetic agents, antimuscarinic and muscarinic agents, antiadrenergic and antiarrhythmics, antihypertensive agents, antineoplastic agents, hormones, and nutrients. A detailed description of these and other suitable drugs may be found in
Remington's Pharmaceutical Sciences
, 18th edition, 1990, Mack Publishing Co. Philadelphia, Pa.
The phospholipid may be any natural or synthetic phospholipid, for example phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol, phosphatidic acid, lysophospholipids, egg or soybean phospholipid or a combination thereof. The phospholipid may be salted or desalted, hydrogenated or partially hydrogenated or natural semisynthetic or synthetic. Examples of commercially available phospholipids include but are not limited to egg phospholipids P123 (Pfanstiehl), Lipoid E80 (Lipoid); and hydrogenated soy phospholipids Phospholipon 90H and 100H (Natterman) and 99% pure soy phosphatidyl choline (Avanti Polar Lipids).
Examples of some suitable surface modifiers include: (a) natural surfactants such as casein, gelatin, tragacanth, waxes, enteric resins, paraffin, acacia, gelatin, cholesterol esters and triglycerides, (b) nonionic surfactants such as polyoxyethylene fatty alcohol ethers, sorbitan fatty acid esters
Parikh Indu
Selvaraj Ulagaraj
Fubara Blessing
Nixon & Vanderhye
Page Thurman K.
Research Triangle Pharmaceuticals
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