HK1118464A - Pharmaceutical formulations for minimizing drug-drug interactions - Google Patents

Description

Pharmaceutical formulations for minimizing drug-drug interactions

Cross Reference to Related Applications

This application claims the benefit of U.S. provisional patent application No. 60/690,322 filed on day 14, 6/2005.

Technical Field

[001] The present invention relates generally to the minimization of drug-drug interactions. More specifically, a pharmaceutical combination is provided that overcomes pharmacokinetic drug-drug interactions.

Background

[002] Drug-drug interactions occur when a drug administered to the body induces interactions with another administered drug and modifies the effects of the latter, as well as when both drugs are present in the body at the same time. During drug-drug interactions, one drug exhibits an increase or decrease in therapeutic response upon interaction with another drug.

[003] Drug-drug interactions are classified as either pharmacokinetic or pharmacokinetic. Pharmacokinetic drug-drug interactions typically occur when one drug enhances or attenuates the effect of the other at its site of action without a change in the concentration of the drug in the body. Pharmacokinetic interactions typically involve two or more drugs with similar or antagonistic effects, which affect the sensitivity of a patient to each drug treatment. Pharmacokinetic drug-drug interactions occur when one drug enhances or interferes with the absorption, distribution, excretion or metabolism of another drug that is also present in the body. Pharmacokinetic drug-drug interactions often result in changes in pharmacokinetics.

[004] While enhancing or interfering with the absorption of one drug in the gastrointestinal tract, the presence of another drug resident in the body at the same time generally increases or decreases the bioavailability of the previous drug by (1) modifying gastrointestinal motility, gastrointestinal pH, or gastrointestinal bacterial flora; (2) forming chelates or complexes that are difficult or easy to absorb; (3) induce damage to the gastrointestinal mucosa, or (4) elicit a binding response that modifies the physiochemical properties of the drug of interest. One method of overcoming absorption complications involves staggering the time of administration of the drugs individually.

[005] When the distribution of one drug is disturbed, another drug co-present in the body typically displaces the drug from plasma proteins or tissue binding sites. More specifically, the drugs compete with each other for protein or tissue binding sites. One drug with higher affinity to the binding site replaces the other drug at the binding site.

[006] While enhancing or interfering with the excretion of one drug, the concomitant presence of another drug in the body competes with the drug for anionic and cationic carriers, which results in changes in glomerular filtration rate, active tubular secretion, urine pH, passive tubular reabsorption, and other such renal parameters.

[007] The presence of one drug often modifies the rate of metabolism of resident drugs in the reticuloendothelial system (RES) organs and tissues, including the liver, spleen, and bone marrow, while enhancing or interfering with the metabolism of the other drug. The RES system is also involved in the Mononuclear Phagocyte System (MPS).

[008] Swada et al (U.S. patent No. 6,761,895) describes a method for overcoming absorption, distribution, excretion and metabolic complications. The' 895 patent describes a system for avoiding undesirable interactions between a drug and an accompanying drug by either timed release of the drug or controlling the site of release of the drug to the digestive tract. This patent, purportedly overcoming the metabolic complications, proposes timed release or control of the site of release in the digestive tract, which purportedly allows one of the drugs to reach the liver at a particular time after the concomitant drug has been absorbed by the liver. Thus, the' 895 patent proposes a system that overcomes the metabolic complications without directly modifying the metabolic rate of any drug.

[009] In view of the above, it is an aspect or object herein to provide a pharmaceutical combination for a pharmacokinetic drug-drug interaction comprising a first pharmaceutical component having a specific pharmacokinetic profile in a mammal and a second pharmaceutical component prepared for parenteral administration having a modified pharmacokinetic profile. The aim is that due to the modified formulation of the second pharmaceutical component in the modified drug delivery vehicle the respective pharmacokinetic profiles of the respective pharmaceutical components do not significantly influence each other, or at least the interaction between the profiles is significantly reduced with respect to the second pharmaceutical component not prepared according to the invention.

[0010] Terms such as "first" and "second" are used herein to provide a convenient reference and are not intended to indicate a requirement for a particular order, timing, combination or classification of administration. The term "pharmaceutical combination" is intended to be a broad definition, referring to a combination of different forms of pharmaceutical ingredients, provided that at some point in time each ingredient is present in the mammal at the same time.

[0011] A pharmaceutical combination may include those pharmaceutical ingredients prepared for separate administration and in different compositions. As such, the pharmaceutical component of one composition is administered to the mammal after the separate administration of the other pharmaceutical component of a different composition. For example, a first pharmaceutical composition is provided in a vial (or other unit of administration) and a second pharmaceutical composition is provided in another vial (or other unit of administration), and these first and second compositions are administered separately. Such separate administrations may be at different times and/or by different modes of administration. In addition, a pharmaceutical combination may include those pharmaceutical ingredients prepared for administration together. For example, a first component and a second component may be administered together from a single vial (or other unit of administration) having a mixture of such components. In any such method, it is understood that the first and second components are administered concomitantly.

Summary of The Invention

[0012] In view of the objects of the invention claimed herein, there is provided a pharmaceutical composition for minimizing pharmacokinetic drug-drug interactions, comprising a first pharmaceutical component having a specific pharmacokinetic profile in mammals and a second pharmaceutical component prepared for parenteral administration having a modified pharmacokinetic profile. Typically, the modified second pharmaceutical component has a drug delivery vehicle with a pharmacokinetic profile that is different from the profile of the unmodified formulation. Due to the modification of the composition of the second pharmaceutical component in the modified drug delivery vehicle, the respective pharmacokinetic profiles of the respective pharmaceutical components do not significantly influence each other, or at least the interaction between the respective profiles is significantly reduced with respect to the second pharmaceutical component not obtained according to the modified manufacturing method. In another aspect of this embodiment, the pharmacokinetic profile can be a change in concentration over time. As a result of preparation in a modified drug delivery vehicle, the pharmacokinetic profile of the concentration of the second pharmaceutical component over time is different from that of the same component, which has not been changed in its form. The term "modified drug delivery vehicle" herein refers to a form in which the second pharmaceutical component may be maintained in addition to the usual liquid solution in a different form. Examples of such forms are disclosed below.

[0013] In another aspect of the present disclosure, there is provided a method for minimizing drug-drug interactions in a mammal, comprising the steps of: administering a first pharmaceutical component having a specific pharmacokinetic profile in a mammal; providing a second pharmaceutical component, the second component having a specific pharmacokinetic profile in the mammal in a given formulation, wherein the specific pharmacokinetic profile of the second pharmaceutical component in the given formulation significantly affects the pharmacokinetic profile of the first pharmaceutical component when the first and second pharmaceutical components are present in the mammal at the same time; preparing the second pharmaceutical component as a modified formulation, wherein the modified formulation alters the specific pharmacokinetic profile of the second pharmaceutical component; and parenterally administering the modified formulation of the second pharmaceutical component to the mammal. Thus, when the first pharmaceutical component and the second pharmaceutical component are present in the mammal at the same time, the altered pharmacokinetic profile of the second component does not significantly affect the pharmacokinetic profile of the first pharmaceutical component. The second pharmaceutical component may be administered after the administration of the first pharmaceutical component and/or the order of administration may be reversed or both pharmaceutical components may be administered simultaneously.

[0014] In another embodiment, a pharmaceutical combination for minimizing drug-drug interactions in a mammal is disclosed, comprising a first pharmaceutical component that is metabolized by a specific drug-metabolic mechanism according to a specific metabolic timing, and a second pharmaceutical component that is initially phagocytosed within the RES or MPS. The second pharmaceutical component is subsequently metabolized by a similar drug-metabolic mechanism as the first pharmaceutical component, wherein phagocytosis of the second pharmaceutical component results in a metabolic timing that is different from that of the second pharmaceutical component in the absence of phagocytosis. Thus, the pharmaceutical component formulations of the present invention result in different metabolic timings that minimize pharmacokinetic drug-drug interactions between the first and second pharmaceutical components when present in the mammal at the same time.

[0015] Herein, the metabolic timing is defined as the time-varying concentration profile of a drug component in a cell comprising a drug metabolism mechanism. In some cases, multiple drug components are present such that the total concentration of these components exceeds the capacity of the drug-metabolizing enzyme (i.e., saturation), inhibiting the metabolism of the components. In one aspect of this embodiment, the formulation of one or more components in a modified drug delivery vehicle reduces the sum of the concentrations of the components, thereby reducing the likelihood that the enzyme will become saturated.

[0016] In another aspect, there is provided a method for minimizing drug-drug interactions in a mammal, comprising the steps of: administering to a mammal a first pharmaceutical component that is metabolized by a specific drug-metabolic mechanism according to a specific metabolic timing; providing a second pharmaceutical component which, when administered to a mammal, is metabolized by a similar drug-metabolizing mechanism and according to a similar metabolizing timing as the first pharmaceutical component in a given formulation; modifying the formulation of the second pharmaceutical component, wherein the modified formulation causes phagocytosis of the second pharmaceutical component in the RES or MPS when administered to the mammal; and parenterally administering the modified formulation of the second pharmaceutical component to the mammal. In this embodiment, phagocytosis of the second drug component-modified formulation results in a metabolic timing that is different from that in the absence of phagocytosis, such that the metabolic enzymes common to both drug components are not saturated. Thus, when the first pharmaceutical component and the second pharmaceutical component are present simultaneously in the mammal, the different metabolic timings minimize pharmacokinetic drug-drug interactions between the first and second pharmaceutical components. In addition, the first pharmaceutical component may be administered after the second pharmaceutical component.

[0017] It will be appreciated that the present invention includes many different aspects or features, which may be used alone and/or in combination with other aspects or features. Accordingly, this summary is not an exhaustive identification of various such aspects or features that may be claimed now or hereafter, but rather is a summary of some aspects of the invention to facilitate an understanding of the detailed description that follows. The scope of the present invention is not limited to the specific embodiments described below, but is set forth herein or in the claims set forth hereinafter.

Brief Description of Drawings

[0018] Throughout the specification, reference has been and will be made to the accompanying drawings, wherein like subject matter has like reference numerals, and wherein:

[0019] FIG. 1 is a schematic representation of a method of producing a nanoparticle pharmaceutical composition having an altered pharmacokinetic profile as described in one embodiment herein;

[0020] FIG. 2 is a schematic representation of another method of producing a nanoparticle pharmaceutical composition having an altered pharmacokinetic profile as described in one embodiment herein; and

[0021] fig. 3 is a graph illustrating the intravenous pharmacokinetic profile of itraconazole in the form of a nanosuspension compared to a solution formulation of itraconazole with time variation in concentration.

Detailed description of various embodiments

[0022] Traditional drug combinations may include a number of drug components that may exhibit drug-drug interactions. In conventional drug delivery, two or more drug components may be metabolized by similar drug-metabolizing mechanisms, such as by similar classes of drug-metabolizing enzymes. Thus, if they are present in the mammal at the same time, these drug components will compete for the same class of drug-metabolizing enzymes, thereby causing undesirable drug-drug interactions.

[0023] For example, drug components are often found to be metabolized by the CYP enzyme system (e.g., the cytokine P-450 enzyme localized to liver microsomes). Only a limited number of enzyme molecules make up this system; thus, generally, the capacity of either enzyme molecule is limited. If the co-existing drugs are metabolized by the same enzyme molecule, one drug will interfere with and affect the plasma concentration of the other. This is because enzymes are saturated and do not have the unlimited ability to metabolize all compounds simultaneously.

[0024] Serious side effects result from the concurrent administration of drugs that interfere with the metabolism of other drugs. For example, the concurrent administration of ketoconazole and terfenadine may cause life threatening ventricular arrhythmias. In addition, the concurrent administration of solivudine and fluorouracil has resulted in fatal toxicity. In such instances where one drug causes a decrease in the metabolism of another drug in the liver microsomes, too high a plasma concentration of the first drug results in a high level of toxicity.

[0025] In one aspect herein, a pharmaceutical combination having a first pharmaceutical component and a second pharmaceutical component in a modified formulation, the first pharmaceutical component having a specific pharmacokinetic profile in a mammal is provided. Due to the formulation in the modified drug delivery vehicle, the pharmacokinetic profile of the second pharmaceutical component is altered compared to its unformulated state, and the modified second pharmaceutical component has substantially no or reduced effect on the pharmacokinetic profile of the first pharmaceutical component.

[0026] In another aspect herein, the subject receives the second pharmaceutical component in a formulated state at the same total effective dose as in an unformulated state, but as a result of the formulation, the plasma concentration level of the second pharmaceutical component is reduced as compared to the unformulated state. A decrease in the plasma concentration level of the second drug component in the formulated state results in a decrease in the inhibition of drug metabolism relative to the unformulated state because the second drug component has reduced competition for the drug-metabolizing enzyme with the first drug component. The second component is reconstituted such that the plasma concentration levels are reduced relative to the unmodified state so as to result in reduced inhibition of the general enzyme system. This is accomplished by the extended plasma half-life of the reconstituted drug component relative to its unformulated state. Thus, according to one aspect of the present invention, there is provided a method wherein the unformulated second pharmaceutical component exhibits a given mean plasma concentration over a period of time when administered to a mammal at a selected dose, and wherein the reformulated second pharmaceutical component exhibits a lower mean plasma concentration over a longer period of time when administered to a mammal at the same selected dose.

[0027] In another embodiment, a second pharmaceutical component is provided that is metabolized by a drug-metabolizing enzyme of a similar species as the first pharmaceutical component. To minimize drug-drug interactions, the second pharmaceutical component is formulated for parenteral administration such that it is initially phagocytosed by the RES or MPS. More specifically, when administered parenterally, the second pharmaceutical component is generally not readily soluble in blood, is recognized as a foreign body, and needs to be removed from the systemic circulation. Thus, the second pharmaceutical component is captured by the immobilized macrophages in the RES or MPS by phagocytosis. The organs or tissues usually involved in phagocytosis are liver, spleen and bone marrow. Entrapped within the immobilized macrophages, the drug components dissolve there, allowing them to migrate out of the phagolysosome and then into the extracellular environment. Herein, dissolution refers to the process by which phagolysozome changes the form of a pharmaceutical component such that it can migrate from MPS to the extracellular environment. While not wishing to be bound by theory, such migration may involve passive diffusion of the drug component soluble molecule through a biological membrane, or removal through an extracellular pathway. In addition, macrophages containing the second pharmaceutical component may die, and other macrophages may purge the second pharmaceutical component and repeat the process. In addition, other mechanisms may work simultaneously.

[0028] Thus, phagocytosis, lysis and transport of immobilized macrophages results in the second pharmaceutical component having a different metabolic timing than that of the first pharmaceutical component. Thus, when the first and second pharmaceutical components are present in the mammal at the same time, the different metabolic timings minimize pharmacokinetic drug-drug interactions between the first and second pharmaceutical components.

[0029] While the invention is susceptible of embodiments in many different forms and in many different combinations, there is described herein with specific emphasis instead being placed upon the embodiments of the invention described herein, it being understood that such embodiments are to be considered as illustrative of the principles of the invention and not as limiting the broad aspects of the invention.

[0030] For example, in accordance with the teachings herein, a pharmaceutical combination of the present invention generally comprises a first pharmaceutical component having a specific pharmacokinetic profile and a second pharmaceutical component present in a formulation that alters the pharmacokinetic profile of the second pharmaceutical component relative to its unformulated state.

[0031] The first pharmaceutical component can be administered by a number of routes including, but not limited to, parenteral, oral, buccal, peri-dental, rectal, nasal, pulmonary, topical, transdermal, intravenous, intramuscular, subcutaneous, intradermal, intraocular, intracerebral, intralymphatic, pulmonary, intraarticular, intrathecal and intraperitoneal. In addition, submicron liquid dispersion forms of the drug component can be prepared, including, but not limited to, injections, solutions, delayed release agents, controlled release agents, sustained release agents, pulsatile release agents, and immediate release agents.

[0032] The solid dosage forms of the first pharmaceutical component may also be formulated as tablets, coated tablets, capsules, ampoules, suppositories, lyophilizates, delayed release, controlled release, sustained release, pulsatile release, immediate release and controlled release by patch administration, inhalable powders, suspensions, creams, ointments and other such solid dosage forms.

[0033] The second pharmaceutical component having a modified pharmacokinetic profile is typically a poorly soluble drug, having a water solubility of no more than about 10 mg/ml. Such drugs also pose difficulties in delivering them in injectable form, for example by parenteral administration. To facilitate their delivery, poorly soluble or insoluble drugs and/or their drug delivery vehicles have been modified by the methods discussed herein.

[0034] Methods of modifying the drug itself to make it more suitable for the chosen route of administration include modifying the formulation or molecular structure of the drug. Methods for the modification of poorly soluble or insoluble drug-drug delivery vehicles include the use of salt formation, solid carrier systems, co-solvents/solubilizers, micelles, lipid vesicles, oil-water partitions, liposomes, microemulsions, emulsions and complexes.

[0035] Another method of support modification involves nanoparticles in a suspension of solid particles. Water-insoluble drugs can provide significant stability benefits when formulated as stable suspensions of submicron particles in aqueous media. Precise control of particle size is important to the safety and efficacy of these formulations when used. The particles should not exceed 7 microns in diameter in order to safely pass through capillaries without causing embolisms (Allen et al, 1987; Davis and Taube, 1978; Schroeder et al, 1978; Yokel et al, 1981).

[0036] Thus, in accordance with the teachings herein, to minimize drug-drug interactions between the various drug components in a drug combination, the drug combination can include at least one drug component having a modified pharmacokinetic profile achieved by modification of the drug delivery vehicle of the component. The modification of pharmacokinetic profiles by nanoparticles, nanosuspensions, microemulsions, emulsions, micelles and liposomes is explained in detail below for exemplary purposes only. Furthermore, nanoparticles, nanosuspensions, emulsions, micelles and liposomes each have different phagocytosis and dissolution rates within the RES or MPS. Thus, the rate of dissolution and release by macrophages within the RES or MPS and, indeed, the drug-drug interactions between the drug components within the drug combination can be controlled using varying delivery methods.

Nanoparticles

[0037] To minimize drug-drug interactions among the various drug components in a drug combination in accordance with the teachings of the present invention, the drug combination may include at least one drug component having an altered pharmacokinetic profile achieved by forming nanoparticles of the components.

[0038] Nanoparticles of poorly soluble drug components can be prepared in a number of different ways in accordance with the teachings herein. Such methods of preparing nanoparticles include, but are not limited to, preparation of solvent-free suspensions, replacement of excipients, lyophilization, emulsion precipitation, solvent anti-solvent precipitation, phase inversion precipitation, pH change precipitation, injection precipitation, temperature change precipitation, solvent evaporation precipitation, reaction precipitation, compressed fluid precipitation, mechanical milling of activators, or any other method for producing suspensions of poorly soluble submicron particles, such as those described in U.S. patent No. 6,607,784; 5,560,932, respectively; 5,662,883, respectively; 5,665,331, respectively; 5,145,684; 5,510,118; 5,518,187; 5,534,270; 5,718,388, respectively; and 5,862,999; U.S. patent application publication numbers 2005/0037083; 2004/0245662, respectively; 2004/0164194, respectively; 2004/0173696, respectively; 2004-0022862; 2003/0100568, respectively; 2003/0096013, respectively; 2003/0077329, respectively; 2003/0072807, respectively; 2003/0059472, respectively; 2003/0044433, respectively; 2003/0031719, respectively; 2002/176935, respectively; 2002/0127278, respectively; and 2002/0168402, and commonly assigned and co-pending U.S. patent application serial nos. 60/258,160 and 60/347,548. These patents, patent publications, patent applications, and all other patents, patent publications, patent applications, articles, or other references mentioned herein are incorporated by reference in their entirety and made a part hereof.

I. Nano-suspension

[0039] A method is provided for delivering poorly soluble drugs using a suspension of solid particles, generally involving nanosuspensions. Nanosuspensions typically include an aqueous suspension of nanoparticles of a relatively insoluble pharmaceutical agent. The nanoparticles are also typically coated with one or more surfactants or other excipients for the microparticles to prevent aggregation or flocculation of the nanoparticles. Surfactants commonly used for such coatings preferably include, but are not limited to, ionic surfactants, nonionic surfactants, zwitterionic surfactants, phospholipids, surfactants of biological origin or amino acids and their derivatives.

[0040] One method of preparing nanosuspensions is described by Kipp et al in U.S. patent No. 6,607,784. The' 784 patent discloses a process for preparing submicron-sized particles of an organic compound wherein the solubility of the organic compound in a selected solvent of water miscibility is greater than the solubility in another aqueous solvent. The method described in the' 784 patent generally includes the steps of: (i) dissolving an organic compound in a water-miscible selected solvent to form a solution, (ii) mixing the solution with another solvent to obtain a pre-suspension; and (iii) adding energy to the pre-suspension to form particles having sub-micron dimensions. The particles range in size from about 10nm to about 10 microns, but preferably from about 100nm to about 1000nm or 1 micron. Generally, the average effective particle size can range from about 400nm or less, extending to small micron sizes, and typically no greater than about 2 microns.

[0041] Various nanosuspension embodiments described in detail herein relate to and/or are related to the use of energy augmentation methods to prepare nanosuspensions comprising nanoparticles of poorly soluble drugs. All types of poorly soluble drug components, analogs of drug components, and other equivalent methods of preparing nanosuspensions can be made in submicron form without departing from the spirit of the invention. An energy augmentation method and apparatus for preparing the particle suspension of the present invention is disclosed in the commonly assigned' 784 patent. One general method for preparing suspensions useful in the nanosuspension aspect of the invention is as follows.

[0042] Such processes can be divided into 3 general categories. Each type of process has the following steps: (i) dissolving an organic compound in a water-miscible selected solvent to form a solution, (ii) mixing the solution with another solvent to obtain a pre-suspension; and (iii) adding energy to the pre-suspension to form particles having the average effective particle size described herein.

A. First type of method for the preparation of nanosuspensions

[0043] A first method type of nanosuspension preparation generally involves dissolving a drug component to have an altered pharmacokinetic profile in a water-miscible selected solvent to form a solution. This resulting solution including the drug component may be in an amorphous, semi-crystalline form, or a supercooled liquid state. The selected solvent according to this nanosuspension aspect is a solvent or mixture of solvents in which the organic compound of interest is relatively soluble and which is miscible in the other solvent. Such solvents include, but are not limited to, water-soluble protic compounds in which a hydrogen atom on the molecule is bound to a negatively charged atom, such as oxygen, nitrogen, or the V A group, group VI A, and group VII elements A of the periodic Table of elements. Examples of such solvents include, but are not limited to, alcohols, amines (primary or secondary), oximes, hydroxamic acids, carboxylic acids, sulfonic acids, phosphonic acids, phosphoric acids, amides, and ureas.

[0044] Other examples of selected solvents also include aprotic organic solvents. Some such aprotic solvents can form hydrogen bonds with water, but can only act as proton acceptors because they lack effective proton donating groups. One class of aprotic solvents is the dipolar aprotic solvents as defined by International Union of Pure and Applied Chemistry (IUPACend of Chemical technology, 2nd Ed. 1997):

a solvent having a high relative permittivity (or dielectric constant), greater than ca.15, and a substantial permanent dipole moment, does not provide suitable labile hydrogen atoms to form strong hydrogen bonds, such as dimethyl sulfoxide.

[0045] The dipolar aprotic solvent may be selected from: amides (fully substituted with nitrogen that does not contain a hydrogen atom attached), ureas (fully substituted, no hydrogen atom attached to nitrogen), ethers, cyclic ethers, nitriles, ketones, sulfones, sulfoxides, fully substituted phosphates, phosphonates, phosphoramides, nitro compounds, and the like. Dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), 2-pyrrolidone, 1, 3-Dimethylimidazolidinone (DMI), Dimethylacetamide (DMA), Dimethylformamide (DMF), dioxane, acetone, Tetrahydrofuran (THF), tetrahydrothiophenesulfone (sulfolane), acetonitrile, and Hexamethylphosphoramide (HMPA), nitromethane, and the like, are members of this class.

[0046] Solvents that are generally immiscible with water but have sufficient water solubility in small volumes (no more than 10%) may also be selected as the water-miscible first solvent in these reduced volumes. Examples include aromatic hydrocarbons, olefins, alkanes, and halogenated aromatic substances, halogenated olefins, and halogenated alkanes. Aromatics include, but are not limited to, benzene (substituted or unsubstituted), and monocyclic or polycyclic aromatics. Examples of substituted benzenes include, but are not limited to, xylene (ortho, meta, or para), and toluene. Examples of alkanes include, but are not limited to, hexane, neopentane, heptane, isooctane, and cyclohexane. Examples of halogenated aromatic materials include, but are not limited to, chlorobenzene, bromobenzene, and chlorotoluene. Examples of alkyl halides and alkenes include, but are not limited to, trichloroethane, methylene chloride, Ethylene Dichloride (EDC), and the like.

[0047] Examples of all of the above solvent classes include, but are not limited to: n-methyl-2-pyrrolidone (N-methyl-2-pyrrolidone), 2-pyrrolidone (2-pyrrolidone), 1, 3-dimethyl-2-imidazolidinone (DMI), dimethyl sulfoxide, dimethylacetamide, carboxylic acids (such as acetic acid and lactic acid), aliphatic alcohols (such as methanol, ethanol, isopropanol, 3-pentanol, and N-propanol), benzyl alcohol, glycerin, butylene glycol (1, 2-butylene glycol, 1, 3-butylene glycol, 1, 4-butylene glycol, and 2, 3-butylene glycol), ethylene glycol, propylene glycol, mono-and diacylated glycerides, dimethylisosorbide, acetone, dimethyl sulfone, dimethylformamide, 1, 4-dioxane, tetramethylene sulfone (sulfolane), acetonitrile, nitromethane, tetramethylurea, Hexamethylphosphoramide (HMPA), Tetrahydrofuran (THF), diethyl ether, t-butyl methyl ether (TBME), aromatic hydrocarbons, olefins, alkanes, halogenated aromatics, halogenated olefins, halogenated alkanes, xylene, toluene, benzene, substituted benzenes, ethyl acetate, methyl acetate, butyl acetate, chlorobenzene, bromobenzene, chlorotoluene, trichloroethane, methylene chloride, dichloroethylene (EDC), hexane, neopentane, heptane, isooctane, cyclohexane, polyethylene glycol (PEG), PEG esters, PEG-4, PEG-8, PEG-9, PEG-12, PEG-14, PEG-16, PEG-120, PEG-75, PEG-150, polyethylene glycol esters, PEG-4 dilaurate, PEG-20 dilaurate, PEG-6 isostearate, PEG-8 palmitoyl stearate, PEG-150 palmitoyl stearate, polyethylene glycol sorbitan, PEF-20 sorbitan isostearate, polyethylene glycol monoalkyl ether, PEG-3 dimethyl ether, PEG-4 dimethyl ether, polypropylene glycol (PPG), polypropylene alginate, PPG-10 butanediol, PPG-10 methyl glucose ether, PPG-20 methyl glucose ether, PPG-15 stearyl ether, propylene glycol dicaprylate, propylene glycol laurate, and ethoxylated tetrahydrofurfuryl alcohol (glycofurol).

[0048] One preferred selected solvent is N-methyl-2-pyrrolidone (NMP). Another preferred selected solvent is lactic acid.

B. Second method type of nanosuspension preparation

[0049] A second method type of nanosuspension preparation involves mixing the solution of the first method type with another solvent to precipitate the drug component, resulting in a pre-suspension. In this type of process, the pre-suspension of the drug component becomes crystalline. After the first two steps, the drug component in the pre-suspension is in a friable form, having an average effective particle size (e.g., fine needles and flakes), thereby ensuring that the particles of the pre-suspension are in a friable state in which the organic compound is friable. The compound in the friable state is also more easily and quickly made into particles in the desired size range when compared to methods of handling organic compounds without having it in the friable form.

[0050] Such other solvents for the second type of treatment are typically aqueous solvents. Such an aqueous solvent may be water itself. Such solvents may also include buffers, salts, surfactants, water soluble polymers, and combinations of these excipients.

C. Third method type for the preparation of nanosuspensions

[0051] A third type of treatment for nanosuspension preparation involves the addition of energy to the pre-suspension, which results in the fragmentation and coating of the friable particles. The energy-addition step may be carried out in any mode in which the pre-suspension is subjected to cavitation, shear or impact forces. In a preferred form of the invention, the energy-addition step is an annealing step. Annealing is defined herein as the step of converting a thermodynamically unstable species to a more stable form by a single or repeated application of energy (either direct heating or mechanical stress), followed by thermal relaxation. This reduction in energy can be achieved by a transformation of the solid state from disorder to a more ordered lattice structure. Furthermore, this stabilization can be achieved by rearrangement of the solid-liquid surfactant molecules.

1. Method A for the preparation of nanosuspensions

[0052] As shown in fig. 1, in method a of nanosuspension preparation, a drug component having an altered pharmacokinetic profile is first dissolved in a selected solvent to prepare a first solution. The first solution may be heated from about 30 ℃ to about 100 ℃ to ensure complete dissolution of the pharmaceutical component in the selected solvent.

[0053] Another aqueous solution is provided to which one or more surfactants are added. The surfactant may be selected from ionic surfactants, non-ionic surfactants, cationic surfactants, zwitterionic surfactants, phospholipids or surfactants of biological origin. Suitable surfactants for coating the particles of the invention may be selected from ionic surfactants, non-ionic surfactants, zwitterionic surfactants, phospholipids, surfactants of biological origin or amino acids and their derivatives. The ionic surfactant may be anionic or cationic. The amount of surfactant in the composition is from about 0.01% to 10% w/v, preferably from about 0.05% to about 5% w/v.

[0054] Suitable ionic surfactants include, but are not limited to: alkyl sulfonates, aryl sulfonates, alkyl phosphates, alkyl phosphonates, potassium laurate, sodium lauryl sulfate, alkyl polyoxyethylene sulfates, sodium alginate, dioctyl sodium sulfosuccinate, phosphatidic acid and salts thereof, sodium carboxymethylcellulose, bile acids and salts thereof, cholic acid, deoxycholic acid, glycocholic acid, taurocholic acid, and glycodeoxycholic acid, and calcium carboxymethylcellulose, stearic acid and salts thereof, (e.g., calcium stearate), phosphates, sodium lauryl sulfate, calcium carboxymethylcellulose, sodium carboxymethylcellulose, dioctyl sulfosuccinate, dialkyl esters of sodium sulfosuccinate, sodium lauryl sulfate, and phospholipids.

[0055]Suitable cationic surfactants include, but are not limited to: quaternary ammonium compounds, benzalkonium chloride, cetyltrimethylammonium bromide, chitosan, lauryldimethylbenzylammonium chloride, acylcarnitines hydrochloride, alkylpyridinium halides, cetylpyridinium chloride, cationic lipids, polymethyl methacrylate trimethylammonium bromide, sulfonium compounds, polyvinylpyrrolidone-2-methacrylic acid dimethylaminoethyl methacrylate dimethyl sulfate, cetyltrimethylammonium bromide, phosphine compounds, quaternary ammonium compounds, benzyl-bis (2-chloroethane) ethylammonium bromide, cocotrimethylammonium chloride, cocotrimethylammonium bromide, cocoyldihydroxyethyl ammonium chloride, cocoyldihydroxyethyl ammonium bromide, decyltrimethylammonium chloride, decyldimethyl hydroxyethyl ammonium chloride, C-dimethylhydroxyethyl ammonium chloride bromide, C-alkyl-N-methyl-2-methyl-N-methyl-N_12-15-dimethylhydroxyethylammonium chloride, C_12-15-dimethylhydroxyethylammonium chloride bromide, cocodimethylhydroxyethylammonium chloride, cocodimethylhydroxyethylammonium bromide, tetradecyltrimethylammonium methyl sulfate, lauryl dimethylbenzylammonium chloride, lauryl dimethylbenzylammonium bromide, lauryl dimethyl (oxyethylene)₄Ammonium chloride, lauryl dimethyl (oxyethylene)₄Ammonium bromide, N-alkyl (C)_12-18) Dimethyl benzyl ammonium chloride, N-alkyl (C)_14-18) Dimethyl benzyl ammonium chlorideN-tetradecylmethyl benzyl ammonium chloride monohydrate, dimethyl-bisdecylammonium chloride, N-alkyl and (C)_12-14) Dimethyl 1-naphthylmethylammonium chloride, trimethylammonium alkyltrimethylammonium halides, dialkyl-dimethylammonium salts, lauryltrimethylammonium chloride, ethoxylated alkylaminoalkyldialkylammonium salts, ethoxylated trialkylammonium salts, dialkylbenzenedialkylammonium chloride, N-didecyldimethylammonium chloride, tetradecyldimethylbenzylammonium chloride monohydrate, N-alkyl (C-alkyl)_12-14) Dimethyl 1-naphthylmethylammonium chloride, dodecyldimethylbenzylammonium chloride, dialkylphenylalkylammonium chloride, lauryltrimethylammonium chloride, alkylbenzylmethylammonium chloride, alkylbenzyldimethylammonium bromide, C₁₂Trimethyl ammonium Bromide, C₁₅Trimethyl ammonium Bromide, C₁₇Trimethylammonium bromide, dodecylbenzyltriethylammonium chloride, poly-diallyl-dimethylammonium chloride (DADMAC), dimethylammonium chloride, alkyldimethylammonium halides, tricetyl-methylammonium chloride, decyltrimethylammonium bromide, dodecyltriethylammonium bromide, tetradecyltrimethylammonium bromide, methyltrioctylammonium chloride, "POLYQUAT 10" (mixtures of polymeric quaternary ammonium compounds), tetrabutylammonium bromide, benzyltrimethylammonium bromide, choline esters, benzalkonium chloride, stearkonium chloride, cetylpyridinium bromide, cetylpyridinium chloride, halide salts of quaternized polyethoxyalkylamines, "MIRAPOL" (poly-2) "ALKAQUAT", alkylpyridinium salts, amines, amine salts, imine azolinium salts, protonated propenyl quaternary amides (protonated quaternary ammonium chloride), methylated quaternary ammonium polymers (methylated quaternary polymers), and cationic guar gum, benzalkonium chloride, dodecyltrimethylammonium bromide, triethanolamine, and poloxamines.

[0056]Suitable nonionic surfactants include, but are not limited to: polyoxyethylene fatty alcohol ether, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester, sorbitan ester, glyceride, glyceryl monostearate, polyethylene glycol, polypropylene glycol ester, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, aralkyl polyether alcohol, polyoxyethylene-polypropylene oxide copolymers, poloxamers, poloxamines, methylcellulose, hydroxycellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, noncrystalline cellulose, polysaccharides, starch derivatives, hydroxyethylstarch, polyvinyl alcohol, polyvinylpyrrolidone, triethanolamine stearate, amine oxide, dextran, glycerol, gum arabic, cholesterol, tragacanth, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycol, polyoxyethylene stearates, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose phthalate, noncrystalline cellulose, polyvinyl alcohol, polyvinylpyrrolidone, 4- (1, 1, 3, 3-tetramethylbutyl) phenol polymer in admixture with ethylene oxide and formaldehyde, poloxamer, alkylaryl polyether sulfonate, sucrose stearate and sucrose distearate, C₁₈H₃₇CH₂C(O)N(CH₃)CH₂(CHOH)₄(CH₂OH)₂P-isononylphenoxypoly (glycidol), decanoyl-N-glucamide, N-decyl- β -D-glucopyranoside, N-decyl- β -D-maltopyranoside, N-dodecyl- β -D-glucopyranoside, N-dodecyl- β -D-maltopyranoside, heptanoyl-N-methylglucamide, N-heptyl- β -D-glucopyranoside, N-heptyl- β -D-thioglucoside, N-hexyl- β -D-glucopyranoside; nonanoyl-N-methylglucamine, N-nonyl- β -D-glucopyranoside, octanoyl-N-methylglucamine, N-octyl- β -D-glucopyranoside, octyl- β -D-thioglucopyranoside, PEG-cholesterol derivatives, PEG-vitamin A, PEG-vitamin E, and random copolymers of vinyl acetate and vinylpyrrolidone.

[0057] Zwitterionic surfactants are electrically neutral but have localized positive and negative charges within the same molecule. Suitable zwitterionic surfactants include, but are not limited to, zwitterionic phospholipids. Suitable phospholipids include phosphatidylcholine, phosphatidylethanolamine, diacyl-glyceryl-phosphatidylethanolamine (e.g., ditetradecanoyl-glyceryl-phosphatidylethanolamine (DMPE), dipalmitoyl-glyceryl-phosphatidylethanolamine (DPPE), distearoyl-glyceryl-phosphatidylethanolamine (DSPE), and dioleoyl-glyceryl-phosphatidylethanolamine (DOPE)). Mixtures of phospholipids including anionic and zwitterionic phospholipids may be used in the present invention. Such mixtures include, but are not limited to, lysophospholipids, egg or soy phospholipids or any combination thereof.

[0058]Suitable surfactants of biological origin include, but are not limited to: lipoprotein, gelatin, casein, lysozyme, albumin, casein, heparin, hirudin, or other proteins. Preferred surfactants are combinations of ionic surfactants (e.g., deoxycholic acid) and nonionic surfactants (e.g., polyoxyethylene-polypropylene block copolymers such as poloxamer 188). Another preferred surfactant is a phospholipid such as Lipoid E80 and DSPE-PEG₂₀₀₀Combinations of (a) and (b).

[0059] It is also possible to add a pH adjusting agent such as sodium hydroxide, hydrochloric acid, an amino acid such as glycine, tris buffer or citrate, acetic acid, lactate, meglumine, or the like to the aqueous surfactant solution. The preferred pH of the aqueous surfactant solution is in the range of from about 2 to about 12. Suitable pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, tris buffer, mono-, di-, tricarboxylic acids and salts thereof, citrate buffer, phosphate, glycerol-1-phosphate, glycerol-2-phosphate, acetic acid, lactate, tris (hydroxymethyl) aminomethane, aminosugars, mono-, di-and trialkylamines, meglumine (N-methylglucamine), and amino acids.

[0060] The aqueous surfactant solution may also include an osmotic pressure regulator such as, but not limited to, glycerol, monosaccharides such as glucose, disaccharides such as sucrose, trehalose and maltose, trisaccharides such as raffinose, and sugar alcohols such as mannitol and sorbitol.

[0061] The aqueous surfactant solution of the particle suspension component may also be removed to form dry particles. The method of removing the aqueous medium may be any known method in the art. One example is evaporation. Another example is lyophilization or freeze drying. The dried granules may then be formulated into any acceptable physical form including, but not limited to, solutions, tablets, envelopes, suspensions, creams, lotions, emulsions, aerosols, powders, incorporated into a depot or matrix device for sustained release (such as an implant or transdermal patch), and the like. The aqueous suspensions of the invention may also be frozen to improve stability on storage. Freezing of aqueous suspensions to improve stability is disclosed in commonly assigned and co-pending U.S. patent application publication No. 2003/0077329.

[0062] The drug component solution and the aqueous surfactant solution are then combined. Preferably, the drug component solution is added to the aqueous surfactant solution at a controlled rate. The rate of addition depends on the amount charged and the kinetics of precipitation of the drug components. During the addition, the solution should be constantly stirred. The pre-suspension was prepared using an optical microscope that had observed the formation of amorphous particles, semi-crystalline solids or over-cooled liquids. The method further comprises subjecting the pre-suspension to an annealing step to convert the amorphous particles, the over-cooled liquid or the semi-crystalline solid to a more stable crystalline solid state. The particles obtained have an average effective particle diameter in the range stated above, as determined by dynamic light scattering (light-dependent spectroscopy, laser diffraction, small angle laser light scattering (LALLS), Medium Angle Laser Light Scattering (MALLS)), light screening (for example the Coulter method), rheology or microscopy (light or electron).

[0063] The energy-addition step for producing the nanosuspension involves adding energy by sonication, homogenization, countercurrent flow homogenization (e.g., Mini DeBEE 2000 homogenizer available from beincorporated, NC, where a stream of fluid follows a first path and a structure is inserted into the first path to redirect the fluid in a controlled flow path, causing emulsification or mixing of the fluid along the new path), microfluidization, or other methods of providing impact, shear, or cavitation, including other methods of homogenization. The sample may be cooled or heated at this stage. In a preferred form of this aspect of the invention, the annealing step is effected by homogenization. In another preferred form of this aspect of the invention, annealing may be achieved by ultrasound. In another preferred form, annealing may be achieved by using the emulsification apparatus described in U.S. patent No. 5,720,551.

[0064] Depending on the annealing rate, the temperature of the treated sample is desirably adjusted to be in the range of about 0 ℃ to 30 ℃. Furthermore, in order to achieve the desired phase transition in the treated solid, it may be necessary to adjust the temperature of the pre-suspension during the annealing step to a temperature in the range of about-30 ℃ to about 100 ℃.

2. Method B for preparing nanosuspensions

[0065] As shown in fig. 2, method B for preparing a nanosuspension includes adding a surfactant or a combination of surfactants to the first solution. The surfactant may be selected from the ionic surfactants, nonionic surfactants, cationic surfactants, zwitterionic surfactants, phospholipids, or biological derivatives set forth above. The pharmaceutical suspensions produced using the procedures described herein may be administered directly as an injection solution, provided that a suitable method of solution sterilization is employed. Method B for preparing nanosuspensions generally also includes other processes such as preparation of solvent-free suspensions, replacement of excipients, lyophilization, solvent anti-solvent precipitation, phase inversion precipitation, pH change precipitation, infusion precipitation, temperature change precipitation, solvent evaporation precipitation, reaction precipitation, and compressed fluid precipitation.

Preparation of solvent-free suspensions

[0066] Nanosuspension preparation may alternatively comprise a solvent-free suspension, which may be generated by removal of the solvent after precipitation. This may be accomplished by dialysis, diafiltration, force field fractionation, high pressure filtration or other separation techniques known in the art, such as the following. Complete removal of e.g. lactic acid or N-methyl-2-pyrrolidone is usually accomplished by 1 to 3 successive centrifugations; after each centrifugation the supernatant was decanted and discarded. Fresh suspension vehicle material, free of organic solvent, is added to the residual solids and the mixture is dispersed by homogenization. Other skilled in the art will recognize that other high-shear mixing techniques may be used for this reconstitution step.

Replacement of excipients

[0067] Furthermore, any undesired excipients such as surfactants may be replaced with more desirable excipients by using the separation method described in the paragraph above. After centrifugation or filtration, the solvent and first excipient may be discarded along with the supernatant. Fresh suspension vehicle free of solvent and first excipient may then be added. In addition, new surfactants may be added. For example, a suspension consisting of the drug, N-methyl-2-pyrrolidone (solvent), poloxamer 188 (first excipient), sodium deoxycholate, glycerol and water, after centrifugation and removal of the supernatant, can be replaced with phospholipids (new surfactant), glycerol and water.

Freeze drying

[0068] The suspension may be lyophilized to form a lyophilized suspension for reconstitution into a suspension suitable for administration. To prepare a stable, dry solid, fillers such as mannitol, sorbitol, sucrose, starch, lactose, trehalose or raffinose may be added prior to lyophilization. The suspension may be lyophilized using any suitable procedure for lyophilization, for example: loading at +25 ℃; cooling to-45 ℃ within 1 hour; standing at-45 deg.C for 3.5 hr; average drying was carried out for 33 hours, while continuously increasing the temperature to +15 ℃ under a pressure of 0.4 mbar; finally drying at 0.03 mbar pressure +20 ℃ for 10 hours; and a cryoprotectant: mannitol.

[0069] In addition to the microprecipitation method described above, any other precipitation method known in the art for preparing active agent particles (more preferably, nanoparticles) may be used in conjunction with this method B nanosuspension aspect of the invention. The following is a description of other examples of precipitation methods. The examples are for illustrative purposes and are not intended to limit the scope of the invention.

Solvent anti-solvent precipitation

[0070] Another precipitation technique is solvent anti-solvent precipitation. Suitable solvent anti-solvent precipitation techniques are described in U.S. Pat. nos. 5,118,528 and 5,100,591. The method comprises the following steps:

(1) preparing a liquid phase form of the biologically active substance in a solvent or mixture of solvents to which one or more surfactants may be added; (2) preparing a second liquid phase form of a non-solvent or a mixture of non-solvents, the non-solvent being miscible with the solvent or solvent mixture of the substance;

(3) adding the solutions (1) and (2) while stirring; and (4) removing the unwanted solvent to produce a colloidal suspension of nanoparticles. The' 528 patent describes producing particles of the substance less than 500nm without energy supply.

Phase reversal precipitation

[0071] Another precipitation technique is phase inversion precipitation. One suitable phase inversion precipitation is described in U.S. Pat. Nos. 6,235,224, 6,143,211 and U.S. published patent application No. 2001/0042932. Phase inversion is a term describing the physical phenomenon by which a polymer dissolved in a continuous phase solvent system is converted into a solid macromolecular network in which the polymer is the continuous phase. One method of inducing phase reversal is by adding a non-solvent to the continuous phase. The polymer proceeds from a single phase to an unstable biphasic mixture: polymer rich and polymer lean fractions. The polymer phase-rich non-solvent micelle liquid drop is used as a nucleation point and is coated by the polymer. The' 224 patent describes that phase inversion of the polymer solution under certain conditions can result in the spontaneous formation of discrete particles, including nanoparticles. The' 224 patent describes dissolving or dispersing a polymer in a solvent. The pharmaceutical agent is also dissolved or dispersed in the solvent. In order to effect the crystal seeding step in this method, the reagent is preferably dissolved in a solvent. The polymer, reagent, and solvent collectively form a mixture having a continuous phase, wherein the solvent is continuous. The mixture is then introduced into an at least 10-fold excess of miscible non-solvent, causing the spontaneous formation of reagent micro-embedded particles with an average particle size between 10nm and 10 μm. The particle size is determined by the solvent: the volume ratio of non-solvent, the polymer concentration, the viscosity of the polymer-solvent solution, the molecular weight of the polymer, and the effect of solvent-non-solvent on properties. The method eliminates the step of preparing the microdroplets, for example by forming an emulsion of the solvent. The process also avoids agitation and/or shear forces.

precipitation by pH change

[0072] Another precipitation technique is pH-modified precipitation. The pH-altering precipitation technique typically includes the steps of dissolving the drug in a solution having a pH at which the drug is soluble, followed by the step of altering the pH to a value at which the drug is no longer soluble. The pH may be acidic or basic, depending on the particular pharmaceutical compound. The solution is then neutralized to form a pre-suspension of sub-micron sized particles of the pharmaceutically active compound. One suitable pH-modified precipitation method is described in U.S. patent No. 5,665,331. The method comprises the following steps: the pharmaceutical agent and the crystal growth regulator (CGM) are dissolved in an alkaline solution, and the solution is then neutralized with an acid in the presence of a suitable surface-modifying surfactant to form a finely particulate dispersion of the pharmaceutical agent. The precipitation step may be followed by a diafiltration purification step of the dispersant, and then the dispersant concentration is adjusted to the desired level. This method reportedly results in microcrystalline particles having a Z-average diameter of less than 400nm as measured by photon correlation spectroscopy. Examples of other pH-altering precipitation methods are described in U.S. patent nos. 5,716,642; 5,662,883, respectively; 5,560,932, respectively; and 4,608,278.

Injection precipitation method

[0073] Another precipitation technique is injection precipitation. Suitable injection precipitation techniques are described in U.S. Pat. nos. 4,997,454 and 4,826,689. First, a suitable solid compound is dissolved in a suitable organic solvent to form a solvent mixture. Then, a precipitating non-solvent miscible with the organic solvent is added to the solvent mixture at an injection rate of about 0.01ml per minute to about 1000ml per minute per 50ml volume at between about-10 ℃ and about 100 ℃ to produce a suspension of precipitated non-aggregated solid particles of a compound having a substantially uniform average diameter of no more than 10 μm. Preferably, the solution is agitated (e.g., by stirring) and the solution is infused with a non-solvent that acts as a precipitant. The non-solvent may contain a surfactant to stabilize the particles against aggregation. The particles are then separated from the solvent. Depending on the solid compound and the desired particle size, the temperature, the ratio of non-solvent to solvent, the rate of injection, the rate of stirring and the volume, etc., can vary according to the invention. Particle size and non-solvent: the proportion of solvent volume is directly proportional to the injection temperature and inversely proportional to the injection rate and the agitation rate. The non-solvent used for precipitation may be aqueous or anhydrous, depending on the relative solubilities of the compound and the desired suspending vehicle.

Precipitation by temperature change

[0074] Another precipitation technique is temperature change precipitation. Temperature-shift precipitation techniques, also known as hot-melt techniques, are described in U.S. patent 5,188,837 to Domb. In one embodiment of the invention, lipid microvesicles (1 iposephene) are prepared as follows: (1) melting or dissolving a substance, such as a drug to be delivered in a melted carrier to form a liquid form of the substance to be delivered; (2) adding a phospholipid with an aqueous medium to the melted substance or carrier at a temperature higher than the melting temperature of the substance or carrier; (3) mixing the suspension at a temperature above the melting temperature of the support until a homogenous fine preparation is obtained; and then (4) rapidly cooling the preparation to room temperature or lower.

Solvent evaporation precipitation

[0075] Another precipitation technique is solvent evaporation precipitation. Solvent evaporation precipitation techniques are described in U.S. patent No. 4,973,465. The' 465 patent describes a method of making microcrystals comprising the steps of: (1) providing a solution of a pharmaceutical ingredient and a phospholipid dissolved in a common organic solvent or solvent combination, (2) evaporating the solvent and (3) suspending a film obtained by evaporating the solvent in an aqueous solution with vigorous stirring. The solvent may be removed by adding energy to the solution to evaporate a sufficient amount of the solvent to cause precipitation of the compound. The solvent may also be removed by other known techniques, such as applying a vacuum to the solution, or blowing nitrogen into the solution.

Reaction precipitation

[0076] Another precipitation technique is reactive precipitation. Reactive precipitation includes the step of dissolving a pharmaceutical compound in a suitable solvent to form a solution. The amount of compound added should be equal to or less than the saturation point of the compound in the solvent. The compounds are modified by reaction with a chemical agent or by corresponding addition of energy such as heat or UV light or similar modification, such that the modified compound has reduced solubility in the solvent and precipitates out of solution.

Compressed fluid precipitation

[0077] Another precipitation technique is compressed fluid precipitation. Suitable techniques for precipitation by compression of a fluid are described in U.S. patent No. 6,576,264. The method includes the step of dissolving a water-insoluble drug in a solvent to form a solution. The solution is then sprayed into a compressed fluid, which may be a gas, liquid, or supercritical fluid. Addition of a compressed fluid to a solute solution in a solvent causes the solute to reach or approach a supersaturated state and precipitate out as particles. In this case, the compressed fluid acts as an anti-solvent, which lowers the energy density of the solvent in which the drug is dissolved.

[0078] In addition, the drug may be dissolved in the compressed fluid and then ejected into the aqueous phase. The rapid expansion of the compressed fluid reduces the dissolving capacity of the fluid, causing the solute to precipitate out as particles in the aqueous phase. In this case, the compressed fluid acts as a solvent.

Other methods of particle preparation

[0079] In addition to methods such as nanosuspension preparation, the particles herein can also be prepared by mechanical milling of the active agent. Mechanical milling includes such techniques as jet milling, pearl milling, ball milling, hammer milling, fluid energy milling or wet milling techniques, such as those described in U.S. Pat. No. 5,145,684.

[0080] Another method of preparing the particles is by suspending the active agent. In this method, the activator particles are dispersed in an aqueous medium, and a pre-suspension is produced by directly adding the particles to the aqueous medium. The particles are typically coated with a surface modifier to inhibit aggregation of the particles. One or more other excipients may be added to the active agent or aqueous medium.

Nanoparticles for minimizing drug-drug interactions

[0081] Typically, the drug component in the form of nanoparticles will be captured by the immobilized macrophages within the RES or MPS, while the drug component in the form of a solution is absorbed and distributed systemically. More specifically, when administered parenterally, the drug components in nanoparticle form are generally not readily soluble in blood, are recognized as foreign, and need to be removed from the systemic circulation. Thus, the drug component in the form of nanoparticles is captured by the immobilized macrophages in the RES or MPS by phagocytosis. Entrapped within the immobilized macrophages, the drug component in the form of nanoparticles is solubilized therein, allowing it to migrate out of phagolysosomes and then into the extracellular environment.

[0082] Thus, phagocytosis and lysis of the immobilized macrophages cause the drug component in the form of nanoparticles to have a different metabolic timing from that of the drug component in the form of a solution. Thus, by administering the drug components in nanoparticle form (e.g., in nanosuspension form) and in solution form, the rate of dissolution and release of macrophages within the RES or MPS and, in effect, the drug-drug interactions between the drug components can be controlled so as to minimize the drug-drug interactions between the components.

[0083] Typically, the drug component in the form of nanoparticles comprises molecules that are aggregated into a crystal or amorphous state. Such aggregates must be broken down ("solubilized") within the MPS before the molecules can leave the extracellular environment. To enhance the likelihood of phagocytosis occurring, it is generally preferred that the nanoparticles in the nanosuspension have a crystalline form or character. In particular, the lattice-associated nanoparticles are more resistant to dissolution and therefore more resistant to systemic absorption and distribution than the amorphous nanoparticles or other materials. Amorphous nanoparticles are generally less resistant to dissolution. Thus, the amorphous form of the nanoparticles is often absorbed and distributed systemically. However, in some cases, amorphous nanoparticles may be taken up by RES or MPS. In some cases, the amorphous form of the nanoparticles may be reconstituted to become a crystalline form.

Microemulsion preparation

[0084] The drug component with the modified pharmacokinetic profile may also be provided in the form of a microemulsion. Microemulsions are modified vehicles for the delivery of pharmaceutical ingredients, typically consisting of water, oils and surfactants, which constitute a single optically isotropic and thermodynamically stable liquid solution. Microemulsion droplets range in size from about 10-100 nm. Microemulsions have the ability to solubilize water-soluble and oil-soluble compounds. Thus, for delivery, microemulsions may consist of oil droplets in an aqueous continuous medium, water in an oil continuous medium, or a bicontinuous structure known as cubosomes.

[0085] For oil-in-water microemulsions, the hydrophobic drug diffuses and releases more slowly than the water-soluble drug, and for oil-in-water microemulsions the opposite is true. Thus, in order to minimize drug-drug interactions, the absorption and distribution of the microemulsion may be modified by adjusting the oil/water partition.

[0086] Because of the presence of oil, microemulsions are readily insoluble in blood, are recognized as foreign, and need to be removed from the systemic circulation. Thus, microemulsions are captured by fixed macrophages in the RES or MPS by phagocytosis. The microemulsion is entrapped within immobilized macrophages, where it dissolves, allowing the drug components to migrate out of the phagolysosome and then into the extracellular environment.

[0087] The pharmacokinetic profile of the microemulsion form of the pharmaceutical component is altered from that of the non-microemulsion form of the component as a result of being captured by and exiting the MPS system. Thus, by formulating the components into microemulsions, thereby altering the pharmacokinetic profile of the drug components, drug-drug interactions can be reduced.

[0088] One suitable emulsion precipitation technique in preparing an emulsified formulation with an altered pharmacokinetic profile is described in co-pending and commonly assigned U.S. patent application publication No. 2005/0037083. In this method, the method comprises the steps of: (1) providing a multiphase system having an organic phase and an aqueous phase, the organic phase having a pharmaceutically effective compound therein; and (2) sonicating the system to evaporate a portion of the organic phase, resulting in precipitation of compounds in the aqueous phase, having an average effective particle size of no more than 2 μm. The step of providing a multi-phase system comprises the steps of: (1) mixing a water-immiscible solvent with a pharmaceutically effective compound to define an organic solution, (2) preparing a water-based solution having one or more surface active compounds, and (3) mixing the organic solution with an aqueous solution to form a multi-phase system. The step of mixing the organic and aqueous phases may be accomplished by using a piston-gap homogenizer, a colloid mill, a high speed stirring device, an extrusion device, a manual stirring or shaking device, a microfluidizer, or other device or technique for providing high shear conditions. The oil droplet size of the coarse emulsion in water is about no more than 1 μm in diameter. The coarse emulsion is sonicated to produce a microemulsion, and a submicron size suspension of particles is finally obtained.

[0089] Another method for preparing emulsions having submicron-sized particles is disclosed in co-pending and commonly assigned U.S. patent application publication No. 2003/0059472. The method comprises the following steps: (1) providing a raw dispersion of a multiphase system having an organic phase and an aqueous phase, the organic phase having a pharmaceutical compound therein; (2) providing energy to the raw dispersion to form a microdispersion; (3) freezing the microdispersion; and (4) lyophilizing the microdispersion to obtain submicron-sized particles of the pharmaceutical compound. The step of providing a multi-phase system comprises the steps of: (1) mixing a water-immiscible solvent with a pharmaceutically effective compound to provide an organic solution; (2) preparing a water-based solution having one or more surface active compounds; and (3) mixing the organic solution with the aqueous solution to form a multiphase system. The step of mixing the organic and aqueous phases may be accomplished by using a piston-gap homogenizer, a colloid mill, a high speed stirring device, an extrusion device, a manual stirring or shaking device, a microfluidizer, or other device or technique for providing high shear conditions.

[0090] Generally, a drug component in the form of a microemulsion has a faster dissolution rate than a drug component in the form of nanoparticles within the RES or MPS. The faster rate is because the drug component in the form of a microemulsion is engulfed by MPS, but the drug component molecules in the form of a microemulsion are not aggregated and thus are in a less soluble form. In contrast, a pharmaceutical component in the form of nanoparticles comprises molecules aggregated in a crystalline or amorphous state, which aggregation must be broken down ("dissolved") in the MPS before exiting to the extracellular environment. In further contrast, the drug components in the form of conventional solutions are rapidly distributed systemically. Thus, the rate of dissolution and release of drug components by macrophages within the RES or MPS and, in fact, the drug-drug interactions between drug components can be controlled by varying the delivery vehicle. For example, a drug component in the form of a microemulsion may be administered with another drug component in the form of nanoparticles, providing a drug combination with reduced drug-drug interactions. In addition, the drug microemulsion may be administered with another drug component in solution form in order to minimize drug-drug interactions between the components.

Emulsion formulation

[0091] The pharmaceutical composition with the altered pharmacokinetic profile may also be provided in the form of an emulsion. Emulsions include droplets of relatively large size compared to microemulsions. In contrast to spontaneously formed microemulsions, energy must be input to prepare the emulsion. Emulsion formation involves high pressure homogenization to create emulsion droplets (ranging in size from about 100nm to 10 μm) and new surfaces thereon. Depending on the surfactant, oil-water volume fraction, temperature, salt concentration, and the presence of co-surfactants and other co-solutes, the emulsion can be an oil-in-water or an oil-in-water. Multiple emulsions including water-in-oil-in-water or oil-in-water-in-oil can also be formed by a double homogenization step.

[0092] Due to the relatively large size of the oil droplets, oil-in-water emulsions have a large hydrophobic volume relative to the surface area of the oil-in-water. This relationship allows a large number of hydrophobic actives to be incorporated into the oil-in-water emulsifier. In addition, non-toxic surfactants such as phospholipids and other polar lipids can be used as stabilizers because of the small surface area and the relatively low amount of surfactant required to produce and stabilize the emulsion.

[0093] The emulsion droplets can be made less soluble in blood to allow time for them to be identified as foreign objects that need to be removed from the systemic circulation. For example, emulsions typically degrade 1 hour after injection. But can prepare emulsions that can be phagocytosed for longer durations of time. Thus, modified formulations of this emulsion are captured by fixed macrophages in the RES or MPS by phagocytosis. The emulsion is entrapped within the immobilized macrophages, where it dissolves, allowing the drug molecules to migrate out of the phagolysosome and then into the extracellular environment.

[0094] Thus, phagocytosis and lysis of the immobilized macrophages cause the emulsion to have a different metabolic timing from that of the drug component in the form of a solution. In another embodiment, drug-drug interactions may be reduced by controlling the emulsion components and the surface modifying agents thereon, incorporating them into the emulsion, thereby modifying the pharmacokinetic profile of the drug components.

[0095] Generally, a drug component in the form of an emulsion within the RES or MPS has a faster dissolution rate than a drug component in the form of nanoparticles. The faster rate is because the drug component in the emulsion is phagocytosed by MPS, but the drug component molecules in the emulsion are not in aggregated form. In contrast, a pharmaceutical component in the form of nanoparticles comprises molecules aggregated in a crystalline or amorphous state, which aggregation must be broken down before the molecules leave the extracellular environment. In further contrast, a pharmaceutical composition in solution form is absorbed and distributed systemically. Thus, the dissolution and release rate of the drug components by macrophages within the RES or MPS and, in fact, the drug-drug interactions between the drug components can be controlled by varying the delivery vehicle. For example, a drug component in the form of an emulsion may be administered with another drug component in the form of nanoparticles, providing a drug combination with reduced drug-drug interactions. In addition, the drug emulsion may be administered with another drug component in solution form in order to minimize drug-drug interactions between the components.

Micelle

[0096] The drug components with altered pharmacokinetic profiles may also be provided in micellar form. Micelles are modified carriers for the delivery of pharmaceutical ingredients, which comprise agglomerates of surfactant molecules. Micelle formation typically results from interactions between hydrophobic portions of the surfactant molecules. Interactions that resist micellar formation include electrostatic repulsion between charged head groups of ionic surfactants, repulsive-osmotic interactions between chain-like polar head groups, such as oligomeric chains, or steric interactions between bulky groups. To maintain a balance between resistance forces, micelle formation depends on the size of the hydrophobic groups, the nature of the polar head groups, the nature of the counterion (charged surfactant, salt concentration), pH, temperature and the presence of co-solutes. For example, an increase in the size of the hydrophobic domain results in an increase in hydrophobic interactions, thereby causing micellization.

[0097] Micelles form a very dynamic structure, so that the molecules therein generally remain in a non-aggregated state. Furthermore, in solution, the surfactant molecules are freely exchanged between the individual micelles. The solubility of hydrophobic drugs depends on the number of micelles and the degree of aggregation. Thus, larger micelles are generally more effective solubilizers of hydrophobic drugs than smaller micelles. Micelles comprising low molecular weight surfactants can rapidly disintegrate after parenteral administration. On the other hand, micelles comprising high molecular weight surfactants, higher concentrations of surfactants, and micelles formed in the form of block copolymers can be delayed in disintegration, allowing time for them to be recognized as foreign objects and thus phagocytosed.

[0098] Micelles can therefore be made insoluble in blood and identified as foreign objects that need to be removed from the systemic circulation. Thus, micelles are captured by fixed macrophages in RES or MPS by phagocytosis. The micelles are entrapped within the immobilized macrophages, where they lyse, allowing the drug components to migrate out of the phagolysosome and then into the extracellular environment. Thus, phagocytosis and lysis of micelles by immobilized macrophages results in micelles having a different metabolic timing from that of the drug component in solution. Thus, by controlling the structure of the micelle structure, thereby altering the pharmacokinetic profile of the micelle, drug-drug interactions can be reduced.

Liposomes

[0099] Drug components with altered pharmacokinetic profiles may also be provided in liposome form. Liposomes are modified carriers for the delivery of pharmaceutical ingredients, including aggregates of surfactant molecules and sometimes including, block polymers having one or more bilayer structures, usually including lipids. Liposomes have the ability to incorporate both water-soluble and oil-soluble substances.

[00100] Drug release in liposomes generally involves controlling the permeability of the lipid bilayer by (1) altering the composition of the lipid bilayer, (2) altering the pH, (3) removing the bilayer components, and (4) introducing complementary components. Nevertheless, liposomes remaining in the systemic circulation after initial administration are not readily absorbed and distributed.

[00101] More specifically, liposomes are not readily soluble in blood and are identified as foreign objects that need to be cleared from the systemic circulation. Thus, liposomes are captured by fixed macrophages in RES or MPS by phagocytosis. Liposomes are entrapped within immobilized macrophages, where they are solubilized, allowing the drug components to migrate out of the phagolysosome and then into the extracellular environment.

[00102] Thus, phagocytosis and lysis of the immobilized macrophages cause the liposomes to have a different metabolic timing from that of the drug component in solution. Thus, by controlling their composition, thereby altering the pharmacokinetic profile of the liposomes, drug-drug interactions can be reduced.

[00103] Generally, a drug component in the form of a liposome has a faster dissolution rate within the RES or MPS than a drug component in the form of nanoparticles, which are susceptible to phagocytosis. The faster rate is because the drug component is incorporated into the liposome in a molecularly dissolved state, whereas the drug component in nanoparticle form comprises the molecule in aggregated form, requiring an initial dissolution step in the MPS. In further contrast, the drug components in solution are prevented from phagocytosis and are distributed systemically. Thus, the pharmacokinetic profile of the drug components and, in fact, the drug-drug interactions between the drug components can be controlled by varying the delivery vehicle. For example, a drug component in the form of a liposome may be administered with a drug component in the form of nanoparticles, optionally in the form of micelle sizes, or optionally in the form of a solution, in order to minimize drug-drug interactions between the components.

Use of combination of multiple modified drug delivery vehicles

[00104] Pharmaceutical components with different modified drug delivery vehicles can be used to achieve minimization of drug-drug interactions between such components. In one aspect of the invention, a variety of drug delivery vehicles can be used to minimize drug-drug interactions between the various drug components. In this case, a first drug component is provided that has a particular pharmacokinetic profile based in part on its drug delivery state. For example, the first pharmaceutical component may be delivered in the form of nanoparticles, nanosuspensions, microemulsions, emulsions, micelles, or liposomes, among others. When the second pharmaceutical component is not in solution form, the first pharmaceutical component may also be delivered in solution form. A second drug component having another drug profile based in part on its drug delivery state is also provided. The second pharmaceutical component may be delivered in the form of nanoparticles, nanosuspensions, microemulsions, emulsions, micelles, or liposomes, among others. When the first pharmaceutical component is not in solution, the second pharmaceutical component can also be delivered in solution. The drug delivery vehicle is selected such that in the modified delivery state the first and second drug components do not significantly interact with each other, or at least that the interaction between their respective modes is significantly reduced relative to the unaltered formulation state of the combined components.

[00105] For example, typically nanosuspensions, microemulsions, emulsions, micelles and liposomes each have different dissolution and release rates within the macrophages of the RES or MPS. In a more specific example, the rate of dissolution of the liposomes is generally faster than that of nanosuspensions, which provides for a longer release time for the drug component in nanosuspensions. Thus, a pharmaceutical combination may be provided comprising at least one pharmaceutical component formulated in the form of a nanosuspension, said pharmaceutical component having a certain altered pharmacokinetic profile with a concentration that varies with time. A second pharmaceutical component formulated in the form of a liposome may also be provided, the second pharmaceutical component having a different altered pharmacokinetic profile with time-varying concentrations. When such a combination of drugs is administered to a mammal at about the same time or staggered times, or in the same or separate delivery compositions, the rate of dissolution of the liposomes in the MPS/RES is faster than the rate of dissolution of the nanosuspension. Thus, one or more drug components are formulated to have an altered pharmacokinetic profile, and the components are administered in such a manner so as to reduce drug-drug interactions that would otherwise occur if the administered composition had only an unaltered formulation state.

Example 1

[00106] Figure 3 illustrates that the altered pharmacokinetic profile results in a minimization of drug-drug interactions with itraconazole nanosuspensions. This curve plots the release of itraconazole, a nanosuspension, designated 10, compared to itraconazole for liquid injection, designated 12. The itraconazole formulation shown in fig. 3 is Sporanox ® brand intravenous solution manufactured by janssen pharmaceutical Products, l.p. The nano-suspension itraconazole component 10 and the liquid injection Sporanox ® itraconazole component 12 were both administered at10 mg/mL. The initial decline in the curve is consistent with the observed rapid removal of the liquid injectable Sporanox ® itraconazole component 12 from systemic circulation. The other data on the curves are consistent with the observed rapid removal of the nanosuspension itraconazole component 10 from the systemic circulation due to phagocytosis by RES or MPS.

[00107] Curve 10 of fig. 3 is also consistent with the observation that the nanosuspension itraconazole component 10 is captured and encapsulated by the RES or MPS immobilized macrophages, showing a decrease in nanosuspension concentration. The increase in nanosuspension concentration reported hereafter supports the conclusion that the nanosuspension itraconazole then dissolves there, allowing its migration out of phagolysosomes into the extracellular environment. The second slower decrease in nanosuspension concentration is consistent with the gradual metabolism of the nanosuspension. Overall, the data of fig. 3 support the conclusion that phagocytosis of nanosuspensions occurs. See "Long-Circulating and Target-Specific Nanoparticles: the Theory to Practice, "S.Moein Moghimi et al, pharmaceutical Reviews, Vol.53, No. 2(2001) and" Nanosuspensions in Drug Delivery, "Barrett E.Rabinow, Nature, Vol.3, (September 2004).

[00108]Itraconazole in the nanosuspension formulation was effective to cause a change in the pharmacokinetic profile of plasma concentrations over time, relative to the Sporanox ® itraconazole. For example, the peak plasma concentration level (C) of nanosuspension formulations compared to solution form_max) There is a drop. Furthermore, peak plasma concentration levels (C) were obtained over the same period for both formulations_max) Occur at different points in time. More specifically, Cmax of the nanosuspension plasma profile does not occur immediately after injection like the liquid injection form, but at a few smallThis occurs with the phagocytosis and release of nanoparticles from macrophages at the RES or MPS.

[00109] Accordingly, a pharmaceutical composition comprising itraconazole in the form of a nanosuspension having a certain modified release rate and modified pharmacokinetic profile may be provided. The pharmaceutical combination may also include another pharmaceutical component in liquid injectable form. Thus, by providing an itraconazole formulation in the form of a nanosuspension so as to modify the dissolution and release rate of the RES or MPS on such an itraconazole formulation, potential drug-drug interactions between the itraconazole formulation and another pharmaceutical component are minimized.

[00110] Equation 1 illustrates a mathematical expression of the drug metabolism-inhibiting factor (R).

R＝1+f_u*C_max，I，LKi equation 1

[00111] Drug metabolism inhibitor (R) means a drug that interferes with the first drug metabolism by co-administration, and a factor that requires an increase in drug concentration.

[00112]In equation 1, fu represents the unbound fraction of inhibitor drug in plasma, where the unbound drug is free to equilibrate, leaving the blood compartment and penetrating the membrane into the tissue. Ki represents the inhibition constant of the inhibitor for the drug whose concentration is affected. C_max，I，LLiver C representing post-administration inhibitor_max。C_max，I，LUsually by studying pharmacokinetics (C)_max，I，P) Plasma inhibitor C of (1)_maxMultiplied by the liver/plasma concentration ratio determined in the tissue distribution study.

[00113] Using midazolam as the second affected drug, an example of a drug inhibitory factor calculated comparing the Sporanox ® itraconazole component as a solution to the itraconazole nanosuspension formulation is given below.

[00114]For humans, the Sporanox ® itraconazole component as a solution has C_max，I，P3748 ng/ml. The liver/plasma concentration ratio (PL) was 3.5. Thus, C_max，I，L13118 ng/ml. For itraconazole, f of 200mg dose_u0.035. For midazolam, Ki is 0.275 μ M.

[00115]For dogs, the Sporanox ® itraconazole component as a solution has C_max，I，P3 μ g/ml. C in plasma Curve for Nanosuspension formulation of itraconazole Components_maxRather than occurring immediately after injection as a solution formulation, it occurs with its phagocytosis and release from liver macrophages after a few hours, as discussed in detail for fig. 3. Thus, for nanosuspension formulation C_max，I，P1 μ g/ml, which includes hydroxy-itraconazole metabolites other than itraconazole. In view of these values, Sporanox ® itraconazole has a plasma Cmax of 10.5 μ g/ml_max，I，LWhereas the nanosuspension formulation of itraconazole had a C of 1.085. mu.g/ml for both the starting compound and the metabolite_max，I，P. Thus, the drug metabolism inhibitor of Sporanox ® is (R) ═ 1+0.035(10.5/.275) ═ 2.35. The inhibition constant R of itraconazole nanosuspension formulations against midazolam is given by: r ═ 1+0.035(1.085/.275) ═ 1.14. From this mathematical expression, Sporanox will increase midazolam concentration by an effective factor (2.35) compared to the negligible increase (1.14) caused by nanosuspension formulations of itraconazole. Therefore, the concentration of itraconazole in the form of a nanosuspension may be increased to enhance efficacy, regardless of increased drug-drug interactions.

Example 2

[00116] This example illustrates the reduction in drug-drug interactions with itraconazole in modified drug delivery formulations. When administered in combination with various other drugs and not in accordance with the present invention, the Sporanox ® itraconazole increases the plasma concentration of certain drugs. These include antiarrhythmic agents (e.g., digoxin, dofetilide, quinidine, dosulpine), anticonvulsants (e.g., carbamazepine), antimycobacterial agents (e.g., rifabutin), antineoplastics (e.g., busulfan, docetaxel, vinca alkaloids), antipsychotics (e.g., pimozide), benzodiazepines (e.g., alprazolam, diazepam, midazolam, or triazobenzene), calcium channel blockers (e.g., dihydropyridines, veratridine), gastrointestinal motility agents (e.g., cisapride), HMG coa reductase inhibitors (e.g., atorvastatin, cerivastatin, rofecostine, simvastatin), immunosuppressive agents (e.g., cyclosporin, tacrolimus, sirolimus), oral hypoglycemic agents, protease inhibitors (indinavir, ritonavir, saquinavir), levomethadone (levomethadyl), ergot alkaloids, halofantrins, alfentanil, buspirone, methylprednisolone, budesonide, dextroamphetamine, trimetrexate, warfarin, cilostazol and cletripan. Side effects associated with this drug-drug interaction include, among other things, severe cardiovascular events, prolonged hypnotic and sedative effects, and cerebral ischemia. Thus, in accordance with the teachings of the present invention, the formulation of Sporanox ® itraconazole is modified in order to minimize drug-drug interactions with the above listed drugs.

[00117] More specifically, the pharmacokinetic profile of the Sporanox ® itraconazole and, in effect, the drug-drug interactions between the Sporanox ® itraconazole and the various aforementioned drugs were reduced using different modified carriers for delivery of itraconazole. In this example, itraconazole in the form of a nanosuspension was administered in combination with digoxin in order to reduce drug-drug interactions. Other co-administrations are with itraconazole nanosuspensions and various other drugs mentioned above.

[00118] For example, itraconazole in the form of nanoparticles, nanosuspensions, emulsions, micelles, and liposomes each have different dissolution and release rates within the RES or MPS. Thus, itraconazole is administered in any one of an emulsion, microemulsion, liposome or micelle, and is administered in combination with the above drug in order to reduce drug-drug interactions (e.g., in the form of a microemulsion, emulsion, liposome or micelle of digoxin + itraconazole).

Example 3

[00119] This example focuses on the reduction of the drug-drug interaction of the Sporanox ® itraconazole and the drug component in the modified drug delivery formulation. Certain drugs increase the plasma concentration of itraconazole when administered in combination without the present invention. These drugs include macrolide antibiotics (e.g., clarithromycin, erythromycin) and protease inhibitors (indinavir, ritonavir). Consistent with the teachings herein, the formulation of these drugs is modified to reduce drug-drug interactions with the Sporanox ® itraconazole. More specifically, the pharmacokinetic profile is altered by modifying the vehicle that delivers the drug as described above. In fact, the drug-drug interactions between the modified delivery form of Sporanox ® itraconazole and the various above-mentioned drugs were reduced.

[00120] Nanosuspensions of clarithromycin were administered in combination with Sporanox ® itraconazole (in solution form), reducing drug-drug interactions between them compared to clarithromycin in its unmodified delivery form. In addition, one of the above drugs in emulsion, micelle or liposome form is administered in combination with Sporanox ® itraconazole in order to reduce drug-drug interactions.

[00121] While the invention has been described with reference to certain illustrative aspects, it is to be understood that this description is not intended to be construed in a limiting sense. Moreover, various modifications and adaptations may be made to the illustrative embodiments, including various combinations of certain aspects thereof, including those combinations of features disclosed separately or claimed herein, without departing from the essential spirit, essential characteristics, and scope of the present invention. Furthermore, it should be understood that any such modifications and improvements will be recognized by those skilled in the art as being equivalent to one or more elements of the following claims, and shall be covered by such claims to the fullest extent permitted by law.

Claims (61)

1. A pharmaceutical composition for minimizing pharmacokinetic drug-drug interaction in a mammal, the pharmaceutical composition comprising:

a first pharmaceutical component having a specific pharmacokinetic profile in a mammal; and

a second pharmaceutical component formulated for parenteral administration, said second pharmaceutical component being formulated such that the pharmacokinetic profile of said second pharmaceutical component is altered from its unaltered pharmacokinetic profile, said unaltered profile significantly affecting said particular pharmacokinetic profile of the first pharmaceutical component, such that said altered pharmacokinetic profile of said second pharmaceutical component does not substantially affect the pharmacokinetic profile of said first pharmaceutical component.

2. The pharmaceutical composition for minimizing pharmacokinetic drug-drug interaction of claim 1, wherein the second pharmaceutical component is insoluble.

3. The pharmaceutical composition for minimizing pharmacokinetic drug-drug interaction of claim 2, wherein the second pharmaceutical component is administered with a drug delivery vehicle modification.

4. The pharmaceutical composition for minimizing pharmacokinetic drug-drug interaction of claim 3, wherein the drug delivery vehicle modification is selected from the group consisting of nanoparticles, salt formations, solid carrier systems, co-solvents/solubilizers, micelles, lipid vesicles, oil-water partitions, liposomes, microemulsions, emulsions, and complexes.

5. The pharmaceutical composition for minimizing pharmacokinetic drug-drug interaction of claim 1, wherein the second pharmaceutical component is phagocytosed within the MPS of the mammal.

6. The pharmaceutical composition for minimizing pharmacokinetic drug-drug interaction of claim 1, wherein the second pharmaceutical component is administered using a micellar drug delivery carrier modification, wherein the pharmacokinetic profile of the second pharmaceutical component is altered by its association with the micelle.

7. The pharmaceutical composition for minimizing pharmacokinetic drug-drug interaction of claim 1, wherein the second pharmaceutical component is administered with a microemulsion drug delivery vehicle modification, the microemulsion comprising an oil/water partition, wherein the pharmacokinetic profile of the second pharmaceutical component is altered by its preparation as a microemulsion with the oil/water partition.

8. The pharmaceutical composition for minimizing pharmacokinetic drug-drug interaction of claim 1, wherein the second pharmaceutical component is administered with an emulsion drug delivery vehicle modification, the emulsion comprising an oil/water partition, wherein the pharmacokinetic profile of the second pharmaceutical component is altered by its preparation as an emulsion.

9. The pharmaceutical composition for minimizing pharmacokinetic drug-drug interaction of claim 3, wherein the drug delivery carrier modification further comprises a surface modifier, and the pharmacokinetic profile of the second pharmaceutical component is altered by its binding to the surface modifier.

10. The pharmaceutical composition for minimizing pharmacokinetic drug-drug interaction of claim 3, wherein the drug delivery carrier modification is a nanosuspension of crystalline nanoparticles.

11. The pharmaceutical composition for minimizing pharmacokinetic drug-drug interaction of claim 3, wherein the drug delivery carrier modification is a nanosuspension of amorphous nanoparticles.

12. The pharmaceutical composition for minimizing pharmacokinetic drug-drug interaction of claim 10, wherein the second pharmaceutical component is itraconazole.

13. The pharmaceutical composition for minimizing pharmacokinetic drug-drug interaction of claim 1, wherein the pharmacokinetic profile of the first and second pharmaceutical components is detected by a change in plasma concentration over time; and the modified formulated second pharmaceutical component has a pharmacokinetic profile of plasma concentration over time that differs from the pharmacokinetic profile of the second pharmaceutical component in the unmodified formulated state over the same period of time when administered to a mammal, wherein the different plasma concentration changes minimize pharmacokinetic drug-drug interactions between the first and second pharmaceutical components when the first and second pharmaceutical components are present in the mammal at the same time.

14. The pharmaceutical composition for minimizing pharmacokinetic drug-drug interaction of claim 13, wherein the unaltered second pharmaceutical component has a peak plasma concentration at a time point within a period of time, and the altered second pharmaceutical component exhibits a peak plasma concentration at a different time point within the same period of time due to its modified formulation.

15. The pharmaceutical composition for minimizing pharmacokinetic drug-drug interaction of claim 13, wherein the unaltered second pharmaceutical component has a peak plasma concentration, and the altered second pharmaceutical component has a peak plasma concentration that is lower than the peak plasma concentration of the unaltered second pharmaceutical component.

16. The pharmaceutical composition for minimizing pharmacokinetic drug-drug interaction of claim 13, wherein the pharmacokinetic profile of the concentration of the second pharmaceutical component over time is associated with phagocytosis of the second pharmaceutical component by macrophages within the MPS upon administration to the mammal.

17. The pharmaceutical composition for minimizing pharmacokinetic drug-drug interaction of claim 13, wherein the first pharmaceutical component has a plasma concentration at any given time point and the plasma concentration of the second pharmaceutical component in the modified formulation is lower than in the unmodified formulation state, thereby reducing the total concentration of the pharmaceutical components at said given time point.

18. The pharmaceutical composition for minimizing pharmacokinetic drug-drug interaction of claim 13, wherein a given formulation of the second pharmaceutical component exhibits a given mean plasma concentration over a period of time when administered to a mammal at a selected dose, and wherein the modified second pharmaceutical component exhibits a lower mean plasma concentration over a longer period of time when administered to a mammal at the same selected dose.

19. A method for minimizing drug-drug interactions in a mammal, comprising:

administering a first pharmaceutical component having a specific pharmacokinetic profile in a mammal;

providing a second pharmaceutical component, the second component of a given formulation having a specific pharmacokinetic profile in the mammal, wherein the specific pharmacokinetic profile of the second pharmaceutical component of the given formulation significantly affects the pharmacokinetic profile of the first pharmaceutical component when the first and second pharmaceutical components are present in the mammal at the same time;

formulating the second pharmaceutical component into a modified formulation, wherein the modified formulation changes the specific pharmacokinetic profile of the second pharmaceutical component to an altered pharmacokinetic profile; and

parenterally administering to the mammal a modified formulation of a second pharmaceutical component, wherein when the first and second pharmaceutical components are present in the mammal at the same time, the altered pharmacokinetic profile of the second component has a significantly reduced effect on the pharmacokinetic profile of the first drug as compared to the effect of the second pharmaceutical component on a given formulation.

20. The method for minimizing drug-drug interactions in a mammal of claim 19, wherein the altered pharmacokinetic profile of the second component does not substantially affect the pharmacokinetic profile of the first pharmaceutical component.

21. The method for minimizing drug-drug interactions in a mammal of claim 19, wherein the second pharmaceutical component is insoluble.

22. The method for minimizing drug-drug interactions in a mammal of claim 20, wherein the formulation of the second pharmaceutical component is modified by a drug delivery vehicle modification.

23. The method for minimizing drug-drug interactions in a mammal of claim 22, wherein the drug delivery vehicle modification is selected from the group consisting of nanoparticles, salt formation, solid carrier systems, co-solvents/solubilizers, micelles, lipid vesicles, oil-water partitions, liposomes, microemulsions, emulsions, and complexes.

24. The method for minimizing drug-drug interactions in a mammal of claim 19, wherein the first pharmaceutical component has a specific pharmacokinetic profile when administered to the mammal as measured by changes in plasma concentration over time; and when the second pharmaceutical component of the modified formulation is administered to the mammal, the second pharmaceutical component of the modified formulation has a pharmacokinetic profile, as measured by the change in plasma concentration over time, which differs from the pharmacokinetic profile of the second pharmaceutical component of the unmodified formulation over the same period of time, wherein the different plasma concentration changes minimize pharmacokinetic drug-drug interactions between the first and second pharmaceutical components when the first and second pharmaceutical components are present in the mammal at the same time.

25. The method for minimizing drug-drug interactions in a mammal of claim 24, wherein the first drug component has a plasma concentration at any given time point and the second drug component in the modified formulation has a lower plasma concentration than in the unmodified formulation state, thereby reducing the total concentration of the drug components at said given time point.

26. The method for minimizing drug-drug interactions in a mammal of claim 25, wherein a given formulation of the second pharmaceutical component exhibits a given mean plasma concentration over a period of time when administered to the mammal at a selected dose, and wherein a modified second pharmaceutical component exhibits a lower mean plasma concentration over a longer period of time when administered at the same selected dose.

27. The method for minimizing drug-drug interactions in a mammal of claim 25, wherein the second pharmaceutical component in the unmodified formulation has a peak plasma concentration and the second pharmaceutical component in the modified formulation has a peak plasma concentration that is lower than the peak plasma concentration of the second pharmaceutical component in the unmodified formulation.

28. The method for minimizing drug-drug interactions in a mammal of claim 25, wherein the pharmacokinetic profile of the concentration of the second pharmaceutical component over time in the modified formulation correlates with phagocytosis of the second pharmaceutical component in the modified formulation by macrophages within the MPS upon administration to the mammal.

29. A method for minimizing drug-drug interactions in a mammal, comprising:

providing a first pharmaceutical component having a specific pharmacokinetic profile in a mammalian body;

providing a second pharmaceutical component, the second component of a given formulation having a specific pharmacokinetic profile in the mammal, wherein the specific pharmacokinetic profile of the second pharmaceutical component significantly affects the pharmacokinetic profile of the first pharmaceutical component when the first and second pharmaceutical components are present in the mammal at the same time;

formulating the second pharmaceutical component into a modified formulation, wherein the modified formulation changes the specific pharmacokinetic profile of the second pharmaceutical component to an altered pharmacokinetic profile;

parenterally administering the modified second pharmaceutical component to the mammal; and

a first pharmaceutical component administered to a mammal, wherein the pharmacokinetic profile of the modified formulation of the second pharmaceutical component substantially minimizes the effect on the pharmacokinetic profile of the first pharmaceutical component when both the first and second pharmaceutical components are present in the mammal.

30. The method for minimizing drug-drug interactions in a mammal of claim 29, wherein the altered pharmacokinetic profile of the second component does not substantially affect the pharmacokinetic profile of the first pharmaceutical component.

31. The method for minimizing drug-drug interactions in a mammal of claim 30, wherein the second pharmaceutical component is insoluble.

32. The method for minimizing drug-drug interactions in a mammal of claim 31, wherein the formulation of the second pharmaceutical component is modified by a drug delivery vehicle modification.

33. The method for minimizing drug-drug interactions in a mammal of claim 32, wherein the drug delivery vehicle modification is selected from the group consisting of nanoparticles, salt formation, solid carrier systems, co-solvents/solubilizers, micelles, lipid vesicles, oil-water partitions, liposomes, microemulsions, emulsions, and complexes.

34. The method for minimizing drug-drug interactions in a mammal of claim 30, wherein the second pharmaceutical component in the unmodified formulation has a specific pharmacokinetic profile when administered to the pharmaceutical mammal as measured by plasma concentration over time; and the second pharmaceutical component in the modified formulation has a different pharmacokinetic profile over the same period of time, as measured by the change in plasma concentration over time, than the second pharmaceutical component in the unmodified formulation when administered to a mammal, wherein the different change in plasma concentration minimizes pharmacokinetic drug-drug interactions between the first and second pharmaceutical components when the first and second pharmaceutical components are present simultaneously in the mammal.

35. The method for minimizing drug-drug interactions in a mammal of claim 34, wherein the second pharmaceutical component in the unmodified formulation has a peak plasma concentration at a time point in a time period and the second pharmaceutical component in the modified formulation has a peak plasma concentration occurring at a different time point in the same time period.

36. The method for minimizing drug-drug interactions in a mammal of claim 35, wherein the second pharmaceutical component in the unmodified formulation has a peak plasma concentration and the second pharmaceutical component in the modified formulation has a peak plasma concentration that is lower than the peak plasma concentration of the second pharmaceutical component in the unmodified formulation.

37. The method for minimizing drug-drug interactions in a mammal of claim 34, wherein the pharmacokinetic profile of the concentration of the second pharmaceutical component in the modified formulation as a function of time is correlated with phagocytosis by macrophages of MPS of the second pharmaceutical component in the modified formulation following administration to the mammal.

38. A pharmaceutical composition for minimizing pharmacokinetic drug-drug interaction in a mammal, the pharmaceutical composition comprising:

a first drug component metabolized by a particular drug-metabolic mechanism according to a particular metabolic time limit, and

a second pharmaceutical component phagocytosed in MPS, the second pharmaceutical component metabolized by a similar drug-metabolism mechanism as the first pharmaceutical component, wherein phagocytosis of the second pharmaceutical component results in a metabolic timing that is different from that of the first pharmaceutical component, the different metabolic timing minimizing pharmacokinetic drug-drug interactions between the first and second pharmaceutical components when the first and second pharmaceutical components are present concurrently in the mammal.

39. The pharmaceutical composition for minimizing pharmacokinetic drug-drug interaction of claim 38, wherein the second pharmaceutical component is insoluble.

40. The pharmaceutical composition for minimizing pharmacokinetic drug-drug interaction of claim 39, wherein the second pharmaceutical component is administered with a drug delivery vehicle modification.

41. The pharmaceutical composition for minimizing pharmacokinetic drug-drug interaction of claim 40, wherein the drug delivery carrier modification is selected from the group consisting of nanoparticles, salt formations, solid carrier systems, co-solvents/solubilizers, micelles, lipid vesicles, oil-water partitions, liposomes, microemulsions, emulsions, and complexes.

42. The pharmaceutical composition for minimizing pharmacokinetic drug-drug interaction of claim 38, wherein the drug-metabolic mechanism is interaction with a specific class of drug-metabolizing enzymes.

43. The pharmaceutical composition for minimizing pharmacokinetic drug-drug interaction of claim 38, wherein the second pharmaceutical component is administered with a microemulsion drug delivery vehicle modification, wherein the pharmacokinetic profile of the second pharmaceutical component is altered by its association with the microemulsion.

44. The pharmaceutical composition for minimizing pharmacokinetic drug-drug interaction of claim 38, wherein the second pharmaceutical component is administered using an emulsion drug delivery vehicle modification, wherein the pharmacokinetic profile of the second pharmaceutical component is altered by its association with the emulsion.

45. The pharmaceutical composition for minimizing pharmacokinetic drug-drug interaction of claim 40, wherein the drug delivery carrier modification further comprises a surface modifier, and the pharmacokinetic profile of the second pharmaceutical component is altered by its binding to the surface modifier.

46. The pharmaceutical composition for minimizing pharmacokinetic drug-drug interaction of claim 39, wherein the drug delivery carrier modification is a nanoparticle nanosuspension.

47. The pharmaceutical composition for minimizing pharmacokinetic drug-drug interaction of claim 37, wherein the second pharmaceutical component is itraconazole.

48. A method for minimizing drug-drug interactions in a mammal, comprising:

administering to a mammal a first pharmaceutical component that is metabolized by a specific drug-metabolic mechanism according to a specific metabolic timing;

providing a second pharmaceutical component that, when administered to a mammal, is metabolized in a given formulation by a drug-metabolizing mechanism similar to that of the first pharmaceutical component and according to a metabolizing timing similar to that of the first pharmaceutical component;

modifying the formulation of the second pharmaceutical component, wherein the modified formulation causes the second pharmaceutical component to be phagocytosed within the MPS when administered to the mammal; and

a modified formulation of a second pharmaceutical component for parenteral administration to a mammal, wherein phagocytosis of the modified formulation of the second pharmaceutical component results in a metabolic timing that is different from the metabolic timing of the second pharmaceutical component in an unmodified formulation state, the different metabolic timing minimizing pharmacokinetic drug-drug interactions between the first pharmaceutical component and the second pharmaceutical component when both are present in the mammal.

49. The method for minimizing drug-drug interactions in a mammal of claim 48, wherein the second pharmaceutical component is insoluble.

50. The method for minimizing drug-drug interactions in a mammal of claim 49, wherein the formulation of the second pharmaceutical component is modified by a drug delivery vehicle modification.

51. The method for minimizing drug-drug interactions in a mammal of claim 50, wherein the drug delivery vehicle modification is selected from the group consisting of nanoparticles, salt formation, solid carrier systems, co-solvents/solubilizers, micelles, lipid vesicles, oil-water partitions, liposomes, microemulsions, emulsions, and complexes.

52. A method for minimizing drug-drug interactions in a mammal, comprising:

providing a first pharmaceutical component that is metabolized by a specific drug-metabolism mechanism according to a specific metabolic timing;

providing a second pharmaceutical component that, when administered to a mammal, is metabolized in a given formulation by a drug-metabolizing mechanism similar to that of the first pharmaceutical component and according to a metabolizing timing similar to that of the first pharmaceutical component;

modifying the formulation of the second pharmaceutical component, wherein the modified formulation causes the second pharmaceutical component to be phagocytosed within the MPS when administered to the mammal;

modified formulations for parenteral administration of a second pharmaceutical component to a mammal; and

administering a first pharmaceutical component to a mammal, wherein phagocytosis of a modified formulation of the second pharmaceutical component results in a metabolic timing that is different from the metabolic timing of the second pharmaceutical component in an unmodified formulation state, said different metabolic timing minimizing pharmacokinetic drug-drug interactions between the first pharmaceutical component and the second pharmaceutical component when both are present in the mammal.

53. The method for minimizing drug-drug interactions in a mammal of claim 52, wherein the second pharmaceutical component is insoluble.

54. The method for minimizing drug-drug interactions in a mammal of claim 53, wherein the formulation of the second pharmaceutical component is modified by a drug delivery vehicle modification.

55. The method of claim 54 wherein the drug delivery vehicle modification is selected from the group consisting of nanoparticles, salt formation, solid carrier systems, co-solvents/solubilizers, micelles, lipid vesicles, oil-water partitions, liposomes, microemulsions, emulsions, and complexes.

56. A pharmaceutical composition for minimizing pharmacokinetic drug-drug interaction in a mammal, the pharmaceutical composition comprising:

a first pharmaceutical component selected from the group consisting of antiarrhythmics, anticonvulsants, antimycobacterial agents, antineoplastics, antipsychotics, benzodiazepines, calcium channel blockers, gastrointestinal motility agents, HMG coa reductase inhibitors, immunosuppressants, oral hypoglycemic agents, protease inhibitors, levomethadone, ergot alkaloids, fluroxyphenanthrol, alfentanil, buspirone, methylprednisolone, budesonide, dextroamphetamine, trimetrexate, warfarin, cilostazol and cletripan, wherein said first pharmaceutical component has a specific pharmacokinetic profile in a mammal; and

a second pharmaceutical component of itraconazole formulated for parenteral administration, said second pharmaceutical component of itraconazole being formulated such that the pharmacokinetic profile of said second pharmaceutical component of itraconazole is altered from its unaltered pharmacokinetic profile, which unaltered profile significantly affects said specific pharmacokinetic profile of the first pharmaceutical component, whereby said altered pharmacokinetic profile of said second pharmaceutical component of itraconazole does not substantially affect the pharmacokinetic profile of said first pharmaceutical component.

57. The pharmaceutical composition for minimizing drug-drug interactions in a mammal of claim 56, wherein said second pharmaceutical component of itraconazole is administered with a drug delivery vehicle modification.

58. The pharmaceutical composition for minimizing pharmacokinetic drug-drug interaction of claim 57, wherein the drug delivery carrier modification is selected from the group consisting of nanoparticles, salt formations, solid phase carrier systems, co-solvents/solubilizers, micelles, lipid vesicles, oil-water partitions, liposomes, microemulsions, emulsions, and complexes.

59. A pharmaceutical composition for minimizing pharmacokinetic drug-drug interaction in a mammal, the pharmaceutical composition comprising:

a first pharmaceutical component of itraconazole in the form of a solution, wherein the first pharmaceutical component of itraconazole has a specific pharmacokinetic profile in mammals; and

a second pharmaceutical component selected from the group consisting of a macrolide antibiotic and a protease inhibitor formulated for parenteral administration, said second pharmaceutical component formulated to alter the pharmacokinetic profile of said second pharmaceutical component from its unaltered pharmacokinetic profile, such unaltered profile significantly affecting said particular pharmacokinetic profile of the first pharmaceutical component of itraconazole, whereby said altered pharmacokinetic profile of said second pharmaceutical component does not substantially affect the pharmacokinetic profile of said first pharmaceutical component of itraconazole.

60. The pharmaceutical composition for minimizing drug-drug interactions in a mammal of claim 59, wherein the second pharmaceutical component is administered with a drug delivery vehicle modification.

61. The pharmaceutical composition for minimizing pharmacokinetic drug-drug interaction of claim 60, wherein the drug delivery carrier modification is selected from the group consisting of nanoparticles, salt formations, solid carrier systems, co-solvents/solubilizers, micelles, lipid vesicles, oil-water partitions, liposomes, microemulsions, emulsions, and complexes.