CA2263102C - Compositions comprising microparticles of water-insoluble substances and method for preparing same - Google Patents
Compositions comprising microparticles of water-insoluble substances and method for preparing same Download PDFInfo
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- CA2263102C CA2263102C CA002263102A CA2263102A CA2263102C CA 2263102 C CA2263102 C CA 2263102C CA 002263102 A CA002263102 A CA 002263102A CA 2263102 A CA2263102 A CA 2263102A CA 2263102 C CA2263102 C CA 2263102C
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/5123—Organic compounds, e.g. fats, sugars
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5192—Processes
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S977/00—Nanotechnology
- Y10S977/70—Nanostructure
- Y10S977/827—Nanostructure formed from hybrid organic/inorganic semiconductor compositions
- Y10S977/828—Biological composition interconnected with inorganic material
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S977/00—Nanotechnology
- Y10S977/84—Manufacture, treatment, or detection of nanostructure
- Y10S977/882—Assembling of separate components, e.g. by attaching
- Y10S977/883—Fluidic self-assembly, FSA
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S977/00—Nanotechnology
- Y10S977/902—Specified use of nanostructure
- Y10S977/904—Specified use of nanostructure for medical, immunological, body treatment, or diagnosis
- Y10S977/906—Drug delivery
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S977/00—Nanotechnology
- Y10S977/902—Specified use of nanostructure
- Y10S977/904—Specified use of nanostructure for medical, immunological, body treatment, or diagnosis
- Y10S977/915—Therapeutic or pharmaceutical composition
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S977/00—Nanotechnology
- Y10S977/902—Specified use of nanostructure
- Y10S977/904—Specified use of nanostructure for medical, immunological, body treatment, or diagnosis
- Y10S977/931—Medical device coating
Abstract
Submicron size particles of pharmaceutical or other water-insoluble or poorly water-insoluble substances are prepared using a combination of one or more surface modifiers/surfactants such as polaxomers, poloxamines, polyoxyethylene sorbitan fatty acid esters and the like together with natural or synthetic phospholipids. Particles so produced have a volume weighted mean particle size at least one-half smaller than obtainable using a phospolipid alone. Compositions so prepared are resistant to particle size growth on storage.
Description
METHOD FOR PREPARTNG SAME
This invention relates to compositions and procedures that yield s sub-micron and micron stable particles of water-insoluble or poorly soluble drugs or other industrially useful insoluble compounds. The compositions of this invention include combinations of natural or synthetic phospholipds, and one or more non-ionic. anionic or cationic surfactants coated or adhered onto the surfaces of the water io insoluble-compound particles. The combination of phospholipids and surfactants allows the formation and stabilization of the sub-micron and micron size compound particles via hydrophilic, lipophilic and electrostatic interactions and therefore prevent these particles from aggregation or flocculation.
m BACKGROUND OF THE INVENTION
There is a critical need in the pharmaceutical and other biological based industries to formulate water-insoluble or poorly ao soluble substances into formulations for oral, injectable, inhalation and ophthalmic routes of delivery. Water insoluble compounds are those having poor solubility in water, that is < ~ mg!ml at physiological pH (6.~-7.4). Preferably their water solubility is <
1 mg/ml, more preferably < 0.1 mg/ml. It is desirable that the dnig is ~ stable in water as a dispersion; otherwise a lyophilized or spray-dried solid form may be desirable.
This invention relates to compositions and procedures that yield s sub-micron and micron stable particles of water-insoluble or poorly soluble drugs or other industrially useful insoluble compounds. The compositions of this invention include combinations of natural or synthetic phospholipds, and one or more non-ionic. anionic or cationic surfactants coated or adhered onto the surfaces of the water io insoluble-compound particles. The combination of phospholipids and surfactants allows the formation and stabilization of the sub-micron and micron size compound particles via hydrophilic, lipophilic and electrostatic interactions and therefore prevent these particles from aggregation or flocculation.
m BACKGROUND OF THE INVENTION
There is a critical need in the pharmaceutical and other biological based industries to formulate water-insoluble or poorly ao soluble substances into formulations for oral, injectable, inhalation and ophthalmic routes of delivery. Water insoluble compounds are those having poor solubility in water, that is < ~ mg!ml at physiological pH (6.~-7.4). Preferably their water solubility is <
1 mg/ml, more preferably < 0.1 mg/ml. It is desirable that the dnig is ~ stable in water as a dispersion; otherwise a lyophilized or spray-dried solid form may be desirable.
As used herein, "micro" refers to a particle having diameter of from nanometers to micrometers. Microparticles, as used herein. refer to solid particles of irregular, non-spherical or spherical shapes.
Formulations containing these microparticles provide some specific advantages over the unformulated non-micronized ding particles, which include improved oral bioavailability of drugs that are poorly absorbed from GI tract, development of injectable formulations that are currently available only in oral dosage form, less toxic injectable formulations that are currently prepared with organic solvents.
io sustained release of intramuscular injectable drugs that are cun-ently administered through daily injection or constant infusion, and preparation of inhaled, ophthalmic formulation of dings that otherwise could not be formulated for nasal or ocular use.
Current technology for delivering insoluble dings as described in US Patents x,091,188; x,091,187 and ~,7?~.442 focuses on (a) either coating small drug particles with natural or synthetic phospholipds or (b) dissolving the drug in a suitable lipophilic carrier and forming an emulsion stabilized with nahiral or semisynthetic 2o phospholipids. One of the disadvantages of these formulations is that certain drug particles in suspension tend to grow over tirne because of the dissolution and reprecipitation phenomenon known as the "Oswald ripening".
DESCRIPTION OF THE INVENTION
The present invention focuses on preparing submicron size particles using a combination of surface modifiers) with a phospholipid, and how the growth of particle size, and hence storage stability, is controlled by adding a combination of surface modifier{s) with a phospholipid to the formulation.
The use of a surface modifier or combination of surface s modifiers in addition to a phospholipid is characterized by its ability to result in volume weighted mean particle size values that al-e (i) at least ~0% and preferably about ~0-90% smaller than what can be achieved using phospholipid alone without the use of a surfactant with the same energy input, and (ii) provide compositions resistant to io particle size growth on storage. While resistance to particle size growth on storage was an objective of this invention we were surprised to observe a significant reduction in particle size with the addition of the surfactant. In order to achieve the advantages of the present invention it is necessary that the phospholipid and the m surfactant both be present at the time of particle size reduction or precipitation.
Although we do not wish to be bound by any particular theory.
it appears that these surface modifiers generally. that is phospholipids 2o and one or more surfactants, adsorb to the surfaces of dmg particles.
and (a) convert lipophilic to hydrophilic surfaces with increased steric hindrance; stability, and (b) possibly modify zeta potential of surfaces with more charge repulsion stabilization. The concentrations of surface modifiers used in the process described here are normally 25 above their critical micelle concentrations (CMC) and hence facilitate the formation of sub-micron particles by stabilizing the particles.
Formulations containing these microparticles provide some specific advantages over the unformulated non-micronized ding particles, which include improved oral bioavailability of drugs that are poorly absorbed from GI tract, development of injectable formulations that are currently available only in oral dosage form, less toxic injectable formulations that are currently prepared with organic solvents.
io sustained release of intramuscular injectable drugs that are cun-ently administered through daily injection or constant infusion, and preparation of inhaled, ophthalmic formulation of dings that otherwise could not be formulated for nasal or ocular use.
Current technology for delivering insoluble dings as described in US Patents x,091,188; x,091,187 and ~,7?~.442 focuses on (a) either coating small drug particles with natural or synthetic phospholipds or (b) dissolving the drug in a suitable lipophilic carrier and forming an emulsion stabilized with nahiral or semisynthetic 2o phospholipids. One of the disadvantages of these formulations is that certain drug particles in suspension tend to grow over tirne because of the dissolution and reprecipitation phenomenon known as the "Oswald ripening".
DESCRIPTION OF THE INVENTION
The present invention focuses on preparing submicron size particles using a combination of surface modifiers) with a phospholipid, and how the growth of particle size, and hence storage stability, is controlled by adding a combination of surface modifier{s) with a phospholipid to the formulation.
The use of a surface modifier or combination of surface s modifiers in addition to a phospholipid is characterized by its ability to result in volume weighted mean particle size values that al-e (i) at least ~0% and preferably about ~0-90% smaller than what can be achieved using phospholipid alone without the use of a surfactant with the same energy input, and (ii) provide compositions resistant to io particle size growth on storage. While resistance to particle size growth on storage was an objective of this invention we were surprised to observe a significant reduction in particle size with the addition of the surfactant. In order to achieve the advantages of the present invention it is necessary that the phospholipid and the m surfactant both be present at the time of particle size reduction or precipitation.
Although we do not wish to be bound by any particular theory.
it appears that these surface modifiers generally. that is phospholipids 2o and one or more surfactants, adsorb to the surfaces of dmg particles.
and (a) convert lipophilic to hydrophilic surfaces with increased steric hindrance; stability, and (b) possibly modify zeta potential of surfaces with more charge repulsion stabilization. The concentrations of surface modifiers used in the process described here are normally 25 above their critical micelle concentrations (CMC) and hence facilitate the formation of sub-micron particles by stabilizing the particles.
Phospholipid and surface modifiers) are adsorbed on to the surfaces of drug particles in sufficient quantity to retard ding particle growth, reduce drug average particle size from ~ to 100 p.m to sub-micron and micron size particles by one or combination of methods s known in the art, such as sonication, homogenization, milling.
microfluidization, precipitation or recrystallization or precipitation from supercritical fluid, and maintain sub-micron and micron size particles on subsequent storage as suspension or solid dosage form.
io The concentration of phospholipid or surface modifier in the suspension or solid dosage form can be present in the range of 0.1 to 50%, preferably 0.2 to 20%, and more preferably 0.~ to 10%.
The formulations prepared by this invention may be lyophilized m into powders, which can be resuspended or filled into capsules or converted into granules or tablets with the addition of binders and other excipients known in the art of tablet making.
By industrially useful insoluble or poorly soluble compounds 2o we include biologically useful compounds, imaging agents, pharmaceutically useful compounds and in particular dings for human and veterinary medicine. Water insoluble compounds are those having a poor solubility in water, that is less than ~ mg/ml at a physiological pH of 6.~ to 7.4, although the water solubility may be 2s less than 1 mg/ml and even less than 0.1 mg/ml.
Examples of some preferred water-insoluble dnzgs include immunosuppressive and immunoactive agents, antiviral and antifungal agents, antineoplastic agents, analgesic and anti-inflammatory agents, antibiotics, anti-epileptics. anesthetics.
hypnotics, sedatives, antipsychotic agents, neuroleptic agents, antidepressants, anxiolytics, anticonvulsant agents, antagonists, 5 neuron blocking agents, anticholinergic and cholinomimetic agents, antimuscarinic and muscarinic agents, antiadrenergic and antarrhvthmics, antihypertensive agents, antineoplastic agents.
hormones, and nutrients. A detailed description of these and other suitable drugs may be found in Renlingtoyl's pllClYlIICIG'C'ZLIIC'Cij SC'lL'ilC'C'.5', io 18th edition, 1990, Mack Publishing Co. Philadelphia, PA.
The phospholipid may be any natural or synthetic phospholipid, for example phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol, m phosphatidic acid, lysophospholipids, ega or soybean phospholipid or a combination thereof. The phospholipid may be salted or desalted.
hydrogenated or partially hydrogenated or natural semisynthetic or synthetic.
2o Examples of some suitable second surface modifiers include:
(a) natural surfactants such as casein. gelatin, tragacanth, waxes.
enteric resins, paraffin, acacia, gelatin. cholesterol esters and triglycerides, (b) nonionic surfactants such as polyoxyethylene faty alcohol ethers, sorbitan fatty acid esters, polyoxyethylene fatty acid zs esters, sorbitan esters, glycerol monostearate, polyethylene. glycols.
cetyl alcohol, cetostearyl alcohol, stearyl alcohol, poloxamers.
polaxamines, methyIcellulose, hydroxycellulose, hydroxy propylcellulose, hydroxy propylmethylcellulose, noncrystalline cellulose, polyvinyl alcohol, polyvinylpvrrolidone, and synthetic phospholipids, (c) anionic surfactants such as potassium laurate, triethanolamine stearate, sodium lauryl sulfate, alkyl polyoxyethylene sulfates, sodium alginate, dioctyl sodium sulfosuccinate, negatively s charged phospholipids (phosphatidyl glycerol, phosphatidyl inosite, phosphatidylserine, phosphatidic acid and their salts), and negatively charged glyceryl esters, sodium carboxymethylcellulose, and calcium carboxymethylcellulose, (d) cationic surfactants such as quaternary ammonium compounds, benzalkonium chloride, io cetyltrimethylammonium bromide, chitosans and lauryldimethylbenzylammonium chloride, (e) colloidal clays such as bentonite and veegum. A detailed description of these surfactants may be found in Remington's Pharmaceutical Sciences. and Theory and Practice of Industrial Pharmacy, Lachman et al_ 1986.
is More specifically, examples of suitable second surface modifiers include one or combination of the following: polaxomers, such as PLURONIC~ F-68, F108 and F127, which are block copolymers of ethylene oxide and propylene oxide available fromBASF, and 20 poloxamines, such as TETRONIC ~ 908 (T908), which is a tetrafunctional block copolymer derived from sequential addition of ethylene oxide and propylene oxide to ethylene-diamine available from BASF. TritonT~t X-?00, which is an alkyl aryl polyether sulfonate, available from Rohm and Haas.TwEEN~20, ~0, 60 and 80, 25 which are polyoxyethylene sorbitan fatty acid esters, available from ICI Speciality Chemicals, CarbowaxT~i 3 ~ ~0 and 93~, which are polyethylene glycols available from Union Carbide, hydroxy propylmethylcellulose, dimyristoyl phosphatidyl~lycerol sodium salt, sodium dodecylsulfate, sodium deoxycholate, and cetyltrimethylammonium bromide.
It is thought that some of the functions of the second surface modifier{s) as it relates to this invention are suppressing the process of Oswald Ripening and therefore maintaining the particle size.
increasing the storage stability, minimizing sedimentation. and decreasing the particle growth during lyophilization and reconstitution: adhere or coat firmly onto the surfaces of io water-insoluble drug particles and therefore modify the interfaces between the particles and the liquid in the resulting formulations:
increase the interface compatibility beriveen water-insoluble dnia particles and the liquid; and possibly to orient preferentially themselves with the hydrophilic portion sticking into the aqueous m solution and the lipophilic portion strongly adsorbed at the water-insoluble drug particle surfaces Considerable variations as to the identities and types of phospholipid and especially the surface active anent or agents should 2o be expected depending upon the drug or active agent selected as the surface properties of these small particles are different. The most advantageous surface active agent for the insoluble dmg will be apparent following empirical tests to identify the surfactant or surfactant system/combination resulting in the requisite particle size 25 and particle size stability on storage over time.
Various procedures can be used to produce these stable sub-micron and micron size particles including mixing the insoluble substance with phospholipid and precipitating from a dissolved mixture of the substance, phospholipid and surfactant using other surfactants followed by sonication, milling, homogenization, microfluidization, and antisolvent and solvent precipitation. l~Iannitol s and other agents may be added to adjust the final formulation to isotonicity as well as a stabilizing aid during drying.
Unless otherwise specified, all parts and percentages reported herein are weight per unit volume (w/v), in which the volume in the io denominator represents the total volume of the system. Diameters of dimensions are given in millimeters (mm = 10-' meters), micrometers (um = i 0-° meters), manometers (nm = 10-9 meters) or Angstrom units (= 0.1 nm). Volumes are given in liters (L), milliliters (mL = 10-' L) and microliters (pL = 10-~L). Dilutions are by volume. All m temperatures are reported in degrees Celsius. The compositions of the invention can comprise, consist essentially of or consist of the materials set forth and the process or method can comprise. consist essentially of or consist of the steps set forth with such materials.
2o The following examples further explain and illustrate the invention:
Example 1 25 Microparticle-cyclosporine, of an immunosuppressive drug.
was prepared as follows. The composition and concentration of excipients of the microparticle cyclosporine formulation are listed below:
microfluidization, precipitation or recrystallization or precipitation from supercritical fluid, and maintain sub-micron and micron size particles on subsequent storage as suspension or solid dosage form.
io The concentration of phospholipid or surface modifier in the suspension or solid dosage form can be present in the range of 0.1 to 50%, preferably 0.2 to 20%, and more preferably 0.~ to 10%.
The formulations prepared by this invention may be lyophilized m into powders, which can be resuspended or filled into capsules or converted into granules or tablets with the addition of binders and other excipients known in the art of tablet making.
By industrially useful insoluble or poorly soluble compounds 2o we include biologically useful compounds, imaging agents, pharmaceutically useful compounds and in particular dings for human and veterinary medicine. Water insoluble compounds are those having a poor solubility in water, that is less than ~ mg/ml at a physiological pH of 6.~ to 7.4, although the water solubility may be 2s less than 1 mg/ml and even less than 0.1 mg/ml.
Examples of some preferred water-insoluble dnzgs include immunosuppressive and immunoactive agents, antiviral and antifungal agents, antineoplastic agents, analgesic and anti-inflammatory agents, antibiotics, anti-epileptics. anesthetics.
hypnotics, sedatives, antipsychotic agents, neuroleptic agents, antidepressants, anxiolytics, anticonvulsant agents, antagonists, 5 neuron blocking agents, anticholinergic and cholinomimetic agents, antimuscarinic and muscarinic agents, antiadrenergic and antarrhvthmics, antihypertensive agents, antineoplastic agents.
hormones, and nutrients. A detailed description of these and other suitable drugs may be found in Renlingtoyl's pllClYlIICIG'C'ZLIIC'Cij SC'lL'ilC'C'.5', io 18th edition, 1990, Mack Publishing Co. Philadelphia, PA.
The phospholipid may be any natural or synthetic phospholipid, for example phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol, m phosphatidic acid, lysophospholipids, ega or soybean phospholipid or a combination thereof. The phospholipid may be salted or desalted.
hydrogenated or partially hydrogenated or natural semisynthetic or synthetic.
2o Examples of some suitable second surface modifiers include:
(a) natural surfactants such as casein. gelatin, tragacanth, waxes.
enteric resins, paraffin, acacia, gelatin. cholesterol esters and triglycerides, (b) nonionic surfactants such as polyoxyethylene faty alcohol ethers, sorbitan fatty acid esters, polyoxyethylene fatty acid zs esters, sorbitan esters, glycerol monostearate, polyethylene. glycols.
cetyl alcohol, cetostearyl alcohol, stearyl alcohol, poloxamers.
polaxamines, methyIcellulose, hydroxycellulose, hydroxy propylcellulose, hydroxy propylmethylcellulose, noncrystalline cellulose, polyvinyl alcohol, polyvinylpvrrolidone, and synthetic phospholipids, (c) anionic surfactants such as potassium laurate, triethanolamine stearate, sodium lauryl sulfate, alkyl polyoxyethylene sulfates, sodium alginate, dioctyl sodium sulfosuccinate, negatively s charged phospholipids (phosphatidyl glycerol, phosphatidyl inosite, phosphatidylserine, phosphatidic acid and their salts), and negatively charged glyceryl esters, sodium carboxymethylcellulose, and calcium carboxymethylcellulose, (d) cationic surfactants such as quaternary ammonium compounds, benzalkonium chloride, io cetyltrimethylammonium bromide, chitosans and lauryldimethylbenzylammonium chloride, (e) colloidal clays such as bentonite and veegum. A detailed description of these surfactants may be found in Remington's Pharmaceutical Sciences. and Theory and Practice of Industrial Pharmacy, Lachman et al_ 1986.
is More specifically, examples of suitable second surface modifiers include one or combination of the following: polaxomers, such as PLURONIC~ F-68, F108 and F127, which are block copolymers of ethylene oxide and propylene oxide available fromBASF, and 20 poloxamines, such as TETRONIC ~ 908 (T908), which is a tetrafunctional block copolymer derived from sequential addition of ethylene oxide and propylene oxide to ethylene-diamine available from BASF. TritonT~t X-?00, which is an alkyl aryl polyether sulfonate, available from Rohm and Haas.TwEEN~20, ~0, 60 and 80, 25 which are polyoxyethylene sorbitan fatty acid esters, available from ICI Speciality Chemicals, CarbowaxT~i 3 ~ ~0 and 93~, which are polyethylene glycols available from Union Carbide, hydroxy propylmethylcellulose, dimyristoyl phosphatidyl~lycerol sodium salt, sodium dodecylsulfate, sodium deoxycholate, and cetyltrimethylammonium bromide.
It is thought that some of the functions of the second surface modifier{s) as it relates to this invention are suppressing the process of Oswald Ripening and therefore maintaining the particle size.
increasing the storage stability, minimizing sedimentation. and decreasing the particle growth during lyophilization and reconstitution: adhere or coat firmly onto the surfaces of io water-insoluble drug particles and therefore modify the interfaces between the particles and the liquid in the resulting formulations:
increase the interface compatibility beriveen water-insoluble dnia particles and the liquid; and possibly to orient preferentially themselves with the hydrophilic portion sticking into the aqueous m solution and the lipophilic portion strongly adsorbed at the water-insoluble drug particle surfaces Considerable variations as to the identities and types of phospholipid and especially the surface active anent or agents should 2o be expected depending upon the drug or active agent selected as the surface properties of these small particles are different. The most advantageous surface active agent for the insoluble dmg will be apparent following empirical tests to identify the surfactant or surfactant system/combination resulting in the requisite particle size 25 and particle size stability on storage over time.
Various procedures can be used to produce these stable sub-micron and micron size particles including mixing the insoluble substance with phospholipid and precipitating from a dissolved mixture of the substance, phospholipid and surfactant using other surfactants followed by sonication, milling, homogenization, microfluidization, and antisolvent and solvent precipitation. l~Iannitol s and other agents may be added to adjust the final formulation to isotonicity as well as a stabilizing aid during drying.
Unless otherwise specified, all parts and percentages reported herein are weight per unit volume (w/v), in which the volume in the io denominator represents the total volume of the system. Diameters of dimensions are given in millimeters (mm = 10-' meters), micrometers (um = i 0-° meters), manometers (nm = 10-9 meters) or Angstrom units (= 0.1 nm). Volumes are given in liters (L), milliliters (mL = 10-' L) and microliters (pL = 10-~L). Dilutions are by volume. All m temperatures are reported in degrees Celsius. The compositions of the invention can comprise, consist essentially of or consist of the materials set forth and the process or method can comprise. consist essentially of or consist of the steps set forth with such materials.
2o The following examples further explain and illustrate the invention:
Example 1 25 Microparticle-cyclosporine, of an immunosuppressive drug.
was prepared as follows. The composition and concentration of excipients of the microparticle cyclosporine formulation are listed below:
Cyclosporine ~0 mg.~ml Egg Phosphatidylcholine 100 mg/ml Mannitol mg/ml TWEEN~ 80 10 mg/ml s Distilled Water qs to 100%
Total Volume 20 ml Cyclosporine with an average particle size from ~-100 Vim. and mannitol were purchased from Sigma, egg phosphatidylcholine was io produced by Pfanstiehl, TWEEN~ 80 was purchased from IC I.
The above components were placed in a 30 ml beaker and pre-mixed with a hand-held biohomoaenizer (Honeywell DR 4?00 model GP) for 1-~ min. During homogenization. dilute NaOH was is added to the pre-mix to adjust the pH from 3.1 to 7 ~- 0.~. The pre-mix was placed in a water jacketed vessel (~0 m1 capacit~~) through which thermostated water at =1°C was circulated to control the temperature of the formulation. The pre-mix was subjected to high shear energy of a probe sonicator (Fisher, model »0 Sonic 2o Dismembrator) with a 0.~ inch diameter probe. Sonic pulses of 10 seconds at 10-seconds intervals at a power setting of ~ were utilized.
During sonication the temperature of the formulation was 18 -~
3°C.
The pH during sonication was adjusted to 7 t 0.~ with dilute NaOH.
Total sonication time employed to prepare the microparticle 2s cyclosporine was usually 10.~ hours or less. The microparticle-cyclosporine formulation was placed in ?0 ml vials and stored at ~
and ?~ °C for further stability studies.
Particle size distribution of the suspension was analyzed with a NICOMP model 370 Particle Size Analyzer. This instmment utilizes photon correlation spectroscopy for particle sizing in the submicron region. A small volume of the suspension was diluted with water and s placed in the cell of the particle size analyzer. Particle size determination based on volume weighted and number weiehted particle size determination of the suspension, represented as a Craussian distribution by the NICONIP 370 software. yielded the mean particle size values, which are listed below in Table I.
io Table I: Volume-and Number-weighted Particle Size Stability of Microparticle-Cyclosporine is Storage Storage Storage at 4C at 2~C
Time Mean Particle Mean Particle Size (nm) Size (nm) Days Volume- Number- Volume- Number-Weighted Weighted Weighted Weighted ~ 1 358 76 4~ ~ 66 Approximately 20 ~tl of the freshly prepared suspension was placed on a clean slide, with a clean cover glass, and examined under 2s an Olympus BH2 microscope with 1000X magnification. An eye-piece equipped with a graticule was used to estimate the particle size. Most of the particles in the suspension were 0.3-0.~ um.
IZ
Furthermore. microscopic examination of the suspension confirmed non-a2glomerated or flocculated micron and sub-micron size drug particles exhibiting Brownian motion.
s Example 2 For purpose of comparison (not according to the invention) using only a phospholipid, microparticle-cvclosporine with lecithin alone (without the second surface modifier. TwEEN~ 8o) was also io prepared using the same procedure as Example 1. The suspension was stored in 20 ml glass vials for storage stability studies. The volume and number weighted mean particle size values of the suspension stored at 4 and ?~ °C are listed below-. The results in Table TI illustrate that the presence of lecithin alone (without the io presence of TWEEN~ 80) does not provide the particle side reduction and enhancement in storage stability as described in E~tample 1.
Table Ii: Volume-weighted Particle Size Stability of IVIicroparticle-Cyclosporine Storage Storage Stora~~e at 4C at 2~C
Time Mean Particle Mean Particle Size (nm) Size (nm) Days Volume- Number- Volume- Number-Weighted Weighted Weighted Weighted 0 704 ~ 91 704 91 2s 1 1472 X03 2230 7 Example 3 For purpose of comparison (not according to the invention) using only a surface modifier, microparticle-cyclosporine with TWEEN~
80 alone {without a phospholipid, egg phosphatidylcholine) was also s prepared using the same procedure as Example 1. The suspension was stored in 20 ml glass vials. The results in Table III illustrate that the presence of TWEEN~80 alone (without the presence of phospholipid does not provide particle size reduction as in Example I .
io Table III: Volume- and W tuber-weighted Particle Size Stability of iVticroparticle-Cyclosporine Mean Particle Size (nm) Day Volume-Weighted Number-Weighted i5 0 521 67 Example 4 The following microparticle-Docosanol formulations were prepared by the process of the invention with TWEEN~ 80, or TWEEN~ 20, 2o egg phosphatidylcholine, and/or PHOSPHOLIPON~ 90H as surface modifiers. Docosanol is available from Sigma. The formulations were prepared according to the procedures of Example 1. The compositions and concentration of excipients of the microparticle formulations are listed below.
il~Iicroparticle-Docosanol (Example :t.l, comparative) Docosanol 20 mg/ml Egg Phosphatidylcholine ~0 mglml s Mannitol » mg/ml Distilled Water qs to 100%
Total Volume 20 ml iVlicroparticle-Docosanol (EYample =1.2) io Docosanol ?0 mQ/ml Egg Phosphatidylcholine 50 mJmI
l~Iannitol mJml TWEEN~' 80 10 mgiml m Distilled Water qs to 100!
Total Volume ?0 ml lVlicroparticle-Docosanol (Example 4.3) Docosanol 20 mg/ml Egg Phosphatidylcholine ~0 mg,~ml I~Iannitol > j mglml TWEEN~ 20 10 mg/ml 2s Disrilled Water qs to 100%
Total Volume 20 ml lVIicroparticle-Docosanol (Example 4.4) Docosanol 20 mg/ml PHOSPHOLIPON ~ 90H 30 mg/ml s Mannitol 5~ mg/ml TWEEN~ 80 10 mglml Distilled Water qs to 100%
Total Volume 20 ml to IVIicroparticle-Docosanol (E~cample 4.5, Comparative) Docosanol ?0 maiml Mannitol 5 ~ m aim 1 TWEEN~ 80 10 m 2/m 1 is Distilled Water qs to 100%
Total Volume ?0 ml The mean volume-and number-weighted particle size values of the suspension were 286 nm, and 98 nm, respectively.
The volume weighted mean particle size values of the above suspension stored at 4°C are listed below in Tabie IV.
WO 98/07414 PCTlUS97/04695 Table IV: V olume-weighted and Number Weighted Particle Size Stability of Microparticle-Docosanol Stored at :I°C.
s Storage (Example (Example 4.1) 4.2) Time Mean Particle Mean Particle Size (nm) Size (nm) Days Volume- Number- Volume- Number-Weighted Weighted Weighted Weighted 3 0 ND ND 1 ~ 6 81 to Storage (Example (Example 4.3) 4.4) Time Mean Particle Mean Particle Size (nm) Size (nm) Days Volume- Number- Volume- Number-Weighted Weighted Weighted Weighted 0 129 61 90 3~
30 184 99 1?i 39 ND = Not Determined The above data illustrate the much smaller particles produced by the present invention with the presence of a surfactant in addition to the phospholipid and that these particles retain their particle size over time without significant increase in size.
Example 5 The following seven microparticle-RTP-4.0» ( an antiviral drug) formulations were prepared with combinations of TWEEN~ 80, TETRONIC~ 908, PLURONIC~ F-68, egg phosphatidylcholine, and/or PHOSPHOLIPON ~ 90H as surface modifiers. The details of the sonication method are similar to those discussed in Example 1. The compositions and concentration of excipients of the microparticle formulations are listed below:
io I~ticroparticle-RTP-4055 (Example 5.1, Comparative) RTP-4 0 > > j 0 m Jm 1 Egg Phosphatidyicholine 50 mg/ml m Distilled Water qs to 100°'0 Total Volume 2~ ml The mean volume weighted particle size of the suspension was 319 nm.
l~Iicroparticle-RTP-4055 (Example 5.2) RTP-40» >0 mgiml Egg Phosphatidylcholine 50 mg/mI
2s Mannitol 5~ mg/ml PLURONIC~ F-68 5 mglml Distilled Water qs to 100°io Total Volume 2~ ml The mean volume- and number-weighted particle size values of the suspension were 672 nm and 76 nm respectively.
s Nlicroparticle-RTP-4055 (Example 5.3) RTP-4055 50 m~ml Egg Phosphatidylcholine 50 mg/mI
I~Iannito 1 5 5 m Jm 1 io TETRONIC~ 908 5 m~/ml Distilled Water qs to 100%
Total Volume 2~ ml The mean volume- and number- weighted particle size values of the is suspension were 436 nm and 59 nm respectively.
Nlicroparticle-RTP-4055 (Example 5.:1, Comparative) RTP-4055 50 mg/ml 2o PHOSPHOLIPON ~ 90H 30 m~/ml Distilled Water qs to 100°ro Total Volume 2~ ml The mean volume- number- weighted particle size values of the 2s suspension were 1117 nm. and 108 nm respectively.
Ig iVticroparticle-RTP-x055 (Example 5.5) RTP-4.055 50 m~lml PHOSPHOLIPON ~' 90H 30 mg/ml Mannitol 55 mglml Dimyristoylphosphatidyl choline (DMPG) 3 mg/ml TWEEN~ 80 10 mg/ml Distilled Water qs to 100i io Total Volume ?~ ml The mean volume weighted particle size of the suspension was 236 nm. The particle size of the suspension stored at 4°C for 1 ~.veek and 1 month are 328 and 397 nm, respectively. which indicates the is stability of the suspension.
IVIicroparticie-RTP-4055 (EYampie 5.6) RTP-4055 50 mglml 2o PHOSPHOLIPON~ 90H 30 mg/ml Mannitol 5~ m~!ml TWEEN~ 80 1 Q ma/ml Distilled Water qs to 100%
Total Volume 25 ml The mean volume- and number- wei'hted particle size values of the suspension were 382 nm and 59 nm respectively. Within the error limits, there was no variation in the mean panicle size after one week of storage at 4 °C.
l~Iicroparticle-RTP-4055 (Example 5.7, Comparative) RTP-4055 50 mg/ml Mannitol 5 5 m a/m 1 TWEEN~ 80 10 m~%ml Distilled Water qs to 100'a io Total Volume ?5 ml The volume- and number-weighted mean particle size values of the suspension were 545 nm, and 75 nm, respectively within the error limits, there was no variation in the mean particle size after one week is of storage at 4°C.
Example 6 2o The following six microparticle-Piroxicam formulations were prepared with combination of TWEEN~ 80, TETRONIC~ 908, PLURONIC~ F-68, and/or egg phosphatidylcholine as surface modifiers. Piroxicam was received from Cipla. The details of the sonication method are similar to those discussed in example 1. The compositions and concentration a5 of excipients of the micraparticle formulations are listed below:
lVlicroparticle-Piroxicam (Example 6.1) Piroxicam 67 mg/ml Egg Phosphatidylcholine b7 mgJml s Mannitol 67 mg/ml TWEEN~ 80 5 mg/ml TETRONIC~ 908 5 mg/ml Distilled Water qs to 100% (wiv) Total Volume 1 ~ ml The mean volume- and number- weighted particle size values of the suspension were 674 nm and 72 nm respectively.
Nlicroparticle-Piroxicam (Example 6.2) Piroxicam 67 mg/ml Egg Phosphatidylcholine 67 mg/ml Mannitol 67 mg/ml TETRONIC~ 908 5 mg/ml 2o Distilled Water qs to 100% (w/v) Total Volume 15 ml The mean volume- and number- weighted particle size values 2s of the suspension were 45~ nm and 58 nm respectively.
ylicroparticle-Piroxicam (Example 6.3) Piroxicam 67 mg/ml Egg Phosphatidylcholine 67 mg/ml Mannitol 67 mJml PLURONIC~ F-68 5 mgJml Distilled Water qs to 100% (wiv) Total Volume 1 ~ ml io The mean volume- and number- weighted particle size values of the suspension were ~6~ nm and 68 nm respectively.
Nlicroparticle-Piroxicam {Example 6.=1) is Piroxicam 6 i maiml Egg Phosphatidylcholine 67 mg/ml Nlannitol 6 7 m ~/m TWEEN~' 80 ~ ma/ml Cetyltrimethylammonium 2o bromide 10 m~iml Distilled Water qs to 100°io (wlv) Total Volume 1 ~ ml zs The mean volume- and number- weizhted particle size values of the suspension were :~79 nm and 80 nm respectively.
Microparticle-Piroxicam (Example 6.5) Piroxicam 67 mg/ml Egg Phosphatidylcholine 67 mglml s Mannitol 67 mg/ml Cetyltrimethylammonium bromide 10 mg/mI
Distilled Water qs to 100°..% (wlv) io Total Volume 1 ~ ml The mean volume- and number- weighted particle size values of the suspension were 670 nm and 128 nm respectively.
m l4licroparticle-Piroxicam (Example 6.6, Comparative) Piroxicam 67 m~.~ml Mannitol 67 ma/ml TWEEN~ 80 ~ mg/ml 2o TETRONIC~' 908 S mg/mI
Distilled Water qs to 100~0 Total Volume 2~ ml The volume- and number- weighted particle size values of the zs suspension were 1184 nm and 38~ nm, respectively.
Total Volume 20 ml Cyclosporine with an average particle size from ~-100 Vim. and mannitol were purchased from Sigma, egg phosphatidylcholine was io produced by Pfanstiehl, TWEEN~ 80 was purchased from IC I.
The above components were placed in a 30 ml beaker and pre-mixed with a hand-held biohomoaenizer (Honeywell DR 4?00 model GP) for 1-~ min. During homogenization. dilute NaOH was is added to the pre-mix to adjust the pH from 3.1 to 7 ~- 0.~. The pre-mix was placed in a water jacketed vessel (~0 m1 capacit~~) through which thermostated water at =1°C was circulated to control the temperature of the formulation. The pre-mix was subjected to high shear energy of a probe sonicator (Fisher, model »0 Sonic 2o Dismembrator) with a 0.~ inch diameter probe. Sonic pulses of 10 seconds at 10-seconds intervals at a power setting of ~ were utilized.
During sonication the temperature of the formulation was 18 -~
3°C.
The pH during sonication was adjusted to 7 t 0.~ with dilute NaOH.
Total sonication time employed to prepare the microparticle 2s cyclosporine was usually 10.~ hours or less. The microparticle-cyclosporine formulation was placed in ?0 ml vials and stored at ~
and ?~ °C for further stability studies.
Particle size distribution of the suspension was analyzed with a NICOMP model 370 Particle Size Analyzer. This instmment utilizes photon correlation spectroscopy for particle sizing in the submicron region. A small volume of the suspension was diluted with water and s placed in the cell of the particle size analyzer. Particle size determination based on volume weighted and number weiehted particle size determination of the suspension, represented as a Craussian distribution by the NICONIP 370 software. yielded the mean particle size values, which are listed below in Table I.
io Table I: Volume-and Number-weighted Particle Size Stability of Microparticle-Cyclosporine is Storage Storage Storage at 4C at 2~C
Time Mean Particle Mean Particle Size (nm) Size (nm) Days Volume- Number- Volume- Number-Weighted Weighted Weighted Weighted ~ 1 358 76 4~ ~ 66 Approximately 20 ~tl of the freshly prepared suspension was placed on a clean slide, with a clean cover glass, and examined under 2s an Olympus BH2 microscope with 1000X magnification. An eye-piece equipped with a graticule was used to estimate the particle size. Most of the particles in the suspension were 0.3-0.~ um.
IZ
Furthermore. microscopic examination of the suspension confirmed non-a2glomerated or flocculated micron and sub-micron size drug particles exhibiting Brownian motion.
s Example 2 For purpose of comparison (not according to the invention) using only a phospholipid, microparticle-cvclosporine with lecithin alone (without the second surface modifier. TwEEN~ 8o) was also io prepared using the same procedure as Example 1. The suspension was stored in 20 ml glass vials for storage stability studies. The volume and number weighted mean particle size values of the suspension stored at 4 and ?~ °C are listed below-. The results in Table TI illustrate that the presence of lecithin alone (without the io presence of TWEEN~ 80) does not provide the particle side reduction and enhancement in storage stability as described in E~tample 1.
Table Ii: Volume-weighted Particle Size Stability of IVIicroparticle-Cyclosporine Storage Storage Stora~~e at 4C at 2~C
Time Mean Particle Mean Particle Size (nm) Size (nm) Days Volume- Number- Volume- Number-Weighted Weighted Weighted Weighted 0 704 ~ 91 704 91 2s 1 1472 X03 2230 7 Example 3 For purpose of comparison (not according to the invention) using only a surface modifier, microparticle-cyclosporine with TWEEN~
80 alone {without a phospholipid, egg phosphatidylcholine) was also s prepared using the same procedure as Example 1. The suspension was stored in 20 ml glass vials. The results in Table III illustrate that the presence of TWEEN~80 alone (without the presence of phospholipid does not provide particle size reduction as in Example I .
io Table III: Volume- and W tuber-weighted Particle Size Stability of iVticroparticle-Cyclosporine Mean Particle Size (nm) Day Volume-Weighted Number-Weighted i5 0 521 67 Example 4 The following microparticle-Docosanol formulations were prepared by the process of the invention with TWEEN~ 80, or TWEEN~ 20, 2o egg phosphatidylcholine, and/or PHOSPHOLIPON~ 90H as surface modifiers. Docosanol is available from Sigma. The formulations were prepared according to the procedures of Example 1. The compositions and concentration of excipients of the microparticle formulations are listed below.
il~Iicroparticle-Docosanol (Example :t.l, comparative) Docosanol 20 mg/ml Egg Phosphatidylcholine ~0 mglml s Mannitol » mg/ml Distilled Water qs to 100%
Total Volume 20 ml iVlicroparticle-Docosanol (EYample =1.2) io Docosanol ?0 mQ/ml Egg Phosphatidylcholine 50 mJmI
l~Iannitol mJml TWEEN~' 80 10 mgiml m Distilled Water qs to 100!
Total Volume ?0 ml lVlicroparticle-Docosanol (Example 4.3) Docosanol 20 mg/ml Egg Phosphatidylcholine ~0 mg,~ml I~Iannitol > j mglml TWEEN~ 20 10 mg/ml 2s Disrilled Water qs to 100%
Total Volume 20 ml lVIicroparticle-Docosanol (Example 4.4) Docosanol 20 mg/ml PHOSPHOLIPON ~ 90H 30 mg/ml s Mannitol 5~ mg/ml TWEEN~ 80 10 mglml Distilled Water qs to 100%
Total Volume 20 ml to IVIicroparticle-Docosanol (E~cample 4.5, Comparative) Docosanol ?0 maiml Mannitol 5 ~ m aim 1 TWEEN~ 80 10 m 2/m 1 is Distilled Water qs to 100%
Total Volume ?0 ml The mean volume-and number-weighted particle size values of the suspension were 286 nm, and 98 nm, respectively.
The volume weighted mean particle size values of the above suspension stored at 4°C are listed below in Tabie IV.
WO 98/07414 PCTlUS97/04695 Table IV: V olume-weighted and Number Weighted Particle Size Stability of Microparticle-Docosanol Stored at :I°C.
s Storage (Example (Example 4.1) 4.2) Time Mean Particle Mean Particle Size (nm) Size (nm) Days Volume- Number- Volume- Number-Weighted Weighted Weighted Weighted 3 0 ND ND 1 ~ 6 81 to Storage (Example (Example 4.3) 4.4) Time Mean Particle Mean Particle Size (nm) Size (nm) Days Volume- Number- Volume- Number-Weighted Weighted Weighted Weighted 0 129 61 90 3~
30 184 99 1?i 39 ND = Not Determined The above data illustrate the much smaller particles produced by the present invention with the presence of a surfactant in addition to the phospholipid and that these particles retain their particle size over time without significant increase in size.
Example 5 The following seven microparticle-RTP-4.0» ( an antiviral drug) formulations were prepared with combinations of TWEEN~ 80, TETRONIC~ 908, PLURONIC~ F-68, egg phosphatidylcholine, and/or PHOSPHOLIPON ~ 90H as surface modifiers. The details of the sonication method are similar to those discussed in Example 1. The compositions and concentration of excipients of the microparticle formulations are listed below:
io I~ticroparticle-RTP-4055 (Example 5.1, Comparative) RTP-4 0 > > j 0 m Jm 1 Egg Phosphatidyicholine 50 mg/ml m Distilled Water qs to 100°'0 Total Volume 2~ ml The mean volume weighted particle size of the suspension was 319 nm.
l~Iicroparticle-RTP-4055 (Example 5.2) RTP-40» >0 mgiml Egg Phosphatidylcholine 50 mg/mI
2s Mannitol 5~ mg/ml PLURONIC~ F-68 5 mglml Distilled Water qs to 100°io Total Volume 2~ ml The mean volume- and number-weighted particle size values of the suspension were 672 nm and 76 nm respectively.
s Nlicroparticle-RTP-4055 (Example 5.3) RTP-4055 50 m~ml Egg Phosphatidylcholine 50 mg/mI
I~Iannito 1 5 5 m Jm 1 io TETRONIC~ 908 5 m~/ml Distilled Water qs to 100%
Total Volume 2~ ml The mean volume- and number- weighted particle size values of the is suspension were 436 nm and 59 nm respectively.
Nlicroparticle-RTP-4055 (Example 5.:1, Comparative) RTP-4055 50 mg/ml 2o PHOSPHOLIPON ~ 90H 30 m~/ml Distilled Water qs to 100°ro Total Volume 2~ ml The mean volume- number- weighted particle size values of the 2s suspension were 1117 nm. and 108 nm respectively.
Ig iVticroparticle-RTP-x055 (Example 5.5) RTP-4.055 50 m~lml PHOSPHOLIPON ~' 90H 30 mg/ml Mannitol 55 mglml Dimyristoylphosphatidyl choline (DMPG) 3 mg/ml TWEEN~ 80 10 mg/ml Distilled Water qs to 100i io Total Volume ?~ ml The mean volume weighted particle size of the suspension was 236 nm. The particle size of the suspension stored at 4°C for 1 ~.veek and 1 month are 328 and 397 nm, respectively. which indicates the is stability of the suspension.
IVIicroparticie-RTP-4055 (EYampie 5.6) RTP-4055 50 mglml 2o PHOSPHOLIPON~ 90H 30 mg/ml Mannitol 5~ m~!ml TWEEN~ 80 1 Q ma/ml Distilled Water qs to 100%
Total Volume 25 ml The mean volume- and number- wei'hted particle size values of the suspension were 382 nm and 59 nm respectively. Within the error limits, there was no variation in the mean panicle size after one week of storage at 4 °C.
l~Iicroparticle-RTP-4055 (Example 5.7, Comparative) RTP-4055 50 mg/ml Mannitol 5 5 m a/m 1 TWEEN~ 80 10 m~%ml Distilled Water qs to 100'a io Total Volume ?5 ml The volume- and number-weighted mean particle size values of the suspension were 545 nm, and 75 nm, respectively within the error limits, there was no variation in the mean particle size after one week is of storage at 4°C.
Example 6 2o The following six microparticle-Piroxicam formulations were prepared with combination of TWEEN~ 80, TETRONIC~ 908, PLURONIC~ F-68, and/or egg phosphatidylcholine as surface modifiers. Piroxicam was received from Cipla. The details of the sonication method are similar to those discussed in example 1. The compositions and concentration a5 of excipients of the micraparticle formulations are listed below:
lVlicroparticle-Piroxicam (Example 6.1) Piroxicam 67 mg/ml Egg Phosphatidylcholine b7 mgJml s Mannitol 67 mg/ml TWEEN~ 80 5 mg/ml TETRONIC~ 908 5 mg/ml Distilled Water qs to 100% (wiv) Total Volume 1 ~ ml The mean volume- and number- weighted particle size values of the suspension were 674 nm and 72 nm respectively.
Nlicroparticle-Piroxicam (Example 6.2) Piroxicam 67 mg/ml Egg Phosphatidylcholine 67 mg/ml Mannitol 67 mg/ml TETRONIC~ 908 5 mg/ml 2o Distilled Water qs to 100% (w/v) Total Volume 15 ml The mean volume- and number- weighted particle size values 2s of the suspension were 45~ nm and 58 nm respectively.
ylicroparticle-Piroxicam (Example 6.3) Piroxicam 67 mg/ml Egg Phosphatidylcholine 67 mg/ml Mannitol 67 mJml PLURONIC~ F-68 5 mgJml Distilled Water qs to 100% (wiv) Total Volume 1 ~ ml io The mean volume- and number- weighted particle size values of the suspension were ~6~ nm and 68 nm respectively.
Nlicroparticle-Piroxicam {Example 6.=1) is Piroxicam 6 i maiml Egg Phosphatidylcholine 67 mg/ml Nlannitol 6 7 m ~/m TWEEN~' 80 ~ ma/ml Cetyltrimethylammonium 2o bromide 10 m~iml Distilled Water qs to 100°io (wlv) Total Volume 1 ~ ml zs The mean volume- and number- weizhted particle size values of the suspension were :~79 nm and 80 nm respectively.
Microparticle-Piroxicam (Example 6.5) Piroxicam 67 mg/ml Egg Phosphatidylcholine 67 mglml s Mannitol 67 mg/ml Cetyltrimethylammonium bromide 10 mg/mI
Distilled Water qs to 100°..% (wlv) io Total Volume 1 ~ ml The mean volume- and number- weighted particle size values of the suspension were 670 nm and 128 nm respectively.
m l4licroparticle-Piroxicam (Example 6.6, Comparative) Piroxicam 67 m~.~ml Mannitol 67 ma/ml TWEEN~ 80 ~ mg/ml 2o TETRONIC~' 908 S mg/mI
Distilled Water qs to 100~0 Total Volume 2~ ml The volume- and number- weighted particle size values of the zs suspension were 1184 nm and 38~ nm, respectively.
Claims (46)
1. A composition comprising microparticles comprising an industrially useful water-insoluble or poorly water soluble compound having surfaces to which a phospholipid and at least one surfactant are absorbed or adhered, said microparticles produced by applying to a mixture comprising particles of the compound, the phospholipid, and the surfactant, an energy input in an amount sufficient to produce microparticles whose volume-weighted mean particle size is at least 50% smaller than the volume-weighted mean particle size of particles of the compound produced (i) without the presence of the surfactant and (ii) by applying the same energy input.
2. The composition according to claim 1, which composition is a pharmaceutical composition.
3. The pharmaceutical composition according to claim 2, wherein the composition is formulated for oral, inhalation, ocular, nasal, or injectable administration.
4. The composition according to claim 2 or claim 3, wherein the composition is formulated in injectable form for intravenous, intra-arterial, intra-muscular, intradermal, subcutaneous, intra-articular, cerebrospinal, epidural, intracostal, intraperitoneal, intratumor, intrabladder, intra-lesion, or subconjunctival administration.
5. The composition according to any one of claims 1 to 4, wherein the composition is in the form of a dried suspension that can be resuspended in an aqueous or non-aqueous medium.
6. The composition according to any one of claims 1 to 5, wherein the composition is formulated as a suspension, spray-dried powder, lyophilized powder granule, or tablet.
7. The composition according to any one of claims 1 to 6, wherein the water-insoluble or poorly water-soluble compound is a biologically useful compound or an imaging agent.
8. The composition according to claim 7, wherein the biologically useful compound is selected from the group consisting of an immunosuppressive agent, an immunoactive agent, an antiviral agent, an antifungal agent, an antineoplastic agent, an analgesic agent, an anti-inflammatory agent, an antibiotic, an anti-epileptic agent, an anesthetic, a hypnotic, a sedative, an antipsychotic agent, a neuroleptic agent, an antidepressant, an anxiolytic, an anticonvulsant agent, an antagonist, a neuron blocking agent, an anticholinergic agent, a cholinomimetic agent, an antimuscarinic agent, a muscarinic agent, an antiadrenergic, an antiarrhythmic, an antihypertensive agent, a hormone, a nutrient, and combinations thereof.
9. The composition according to any one of claims 1 to 8, wherein the surfactant is a polyoxyethylene sorbitan fatty acid ester, a block copolymer of ethylene oxide and propylene oxide, a tetrafunctional block copolymer derived from sequential addition of ethylene oxide and propylene oxide to ethylenediamine, an alkyl aryl polyether sulfonate, polyethylene glycol, sodium dodecylsulfate, sodium deoxycholate, cetyltrimethylammonium bromide, or a combination thereof.
10. The composition according to any one of claims 1 to 9, wherein the surfactant is a cholesterol ester, a sorbitan fatty ester, a sorbitan ester, glycerol monostearate, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, a polyoxyethylene fatty acid ester, a polyvinyl alcohol, polyvinylpyrrolidone, potassium laurate, triethanolamine stearate, an alkyl polyoxyethylene sulfate, dioctyl sodium sulfosuccinate, a negatively charged glyceryl ester, a quaternary ammonium cationic surfactant, benzalkonium chloride, cetyltrimethylammonium bromide, a chitosan, lauryldimethylbenzylammonium chloride, or any combination thereof.
11. The composition according to any one of claims 1 to 10, wherein the phospholipid is of egg or plant origin, semisynthetic, or synthetic.
12. The composition according to any one of claims 1 to 11, wherein the phospholipid is partly or fully hydrogenated.
13. The composition according to any one of claims 1 to 12, wherein the phospholipid is in a desalted or salt form.
14. The composition according to any one of claims 1 to 13, wherein the phospholipid is a phosphatidylcholine, soybean phospholipid, dimyristoyl phosphatidylglycerol sodium salt, a phosphatidylethanolamine, a phosphatidylserine, a phosphatidic acid, a lysophospholipid, a phosphotidylinositol, or a combination thereof.
15. The composition according to any one of claims 1 to 14, wherein the composition comprises a combination of phospholipids.
16. The composition according to any one of claims 1 to 15, wherein the phospholipid is present in the range of 0.2% to 20%, w/v.
17. The composition according to claim 16, wherein the phospholipid is present in the range of 0.5% to 10%, w/v.
18. A process for preparing stable, sub-micron and micron sized microparticles of a water-insoluble or a poorly water soluble industrially useful compound having surfaces to which a phospholipid and at least one surfactant are absorbed or adhered, said process comprising: reducing the particle size of particles of the compound by sonication, homogenization, milling, microfluidization, precipitation, or recrystallization, in the presence of a phospholipid and a surfactant, which are present in a range of 0.1% to 50%, w/v.
19. A process for preparing microparticles of a water-insoluble or poorly water soluble industrially useful compound having surfaces to which a phospholipid and a surfactant are absorbed or adhered, said process comprising:
(a) mixing particles of a water-insoluble or poorly soluble industrially useful compound with a phospholipid and a surfactant, which are present a range of 0.1% to 50%, w/v; and (b) applying energy to the mixture in an amount sufficient to produce microparticles of the compound having a volume-weighted mean particle size that is at least 50% smaller than particles produced (i) without the presence of the surfactant and (ii) by applying the same energy input.
(a) mixing particles of a water-insoluble or poorly soluble industrially useful compound with a phospholipid and a surfactant, which are present a range of 0.1% to 50%, w/v; and (b) applying energy to the mixture in an amount sufficient to produce microparticles of the compound having a volume-weighted mean particle size that is at least 50% smaller than particles produced (i) without the presence of the surfactant and (ii) by applying the same energy input.
20. The process according to claim 18 or claim 19, wherein the phospholipid is of egg or plant origin, semisynthetic, or synthetic.
21. The process according to any one of claims 18 to 20, wherein the phospholipid is partly or fully hydrogenated.
22. The process according to any one of claims 18 to 21, wherein the phospholipid is in a desalted or salt form.
23. The process according to any one of claims 18 to 22, wherein the phospholipid is selected from the group consisting of a phosphatidylcholine, soybean phospholipid, dimyristoyl phosphatidylglycerol sodium salt, a phosphatidylethanolamine, a phosphatidylserine, a phosphatidic acid, a lysophospholipid, a phosphotidylinositol, and any combination thereof.
24. The process according to any one of claims 18 to 23, wherein the surfactant is a polyoxyethylene sorbitan fatty acid ester, a block copolymer of ethylene oxide and propylene oxide, a tetrafunctional block copolymer derived from sequential addition of ethylene oxide and propylene oxide to ethylenediamine, an alkyl aryl polyether sulfonate, polyethylene glycol, sodium dodecylsulfate, sodium deoxycholate, cetyltrimethylammonium bromide, or a combination of any thereof.
25. The process according to any one of claims 18 to 24, wherein the surfactant is a cholesterol ester, a sorbitan fatty ester, a sorbitan ester, glycerol monostearate, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, a polyoxyethylene fatty acid ester, a polyvinyl alcohol, polyvinylpyrrolidone, potassium laurate, triethanolamine stearate, an alkyl polyoxyethylene sulfate, dioctyl sodium sulfosuccinate, a negatively charged glyceryl ester, a quaternary ammonium cationic surfactant, a benzalkonium chloride, cetyltrimethylammonium bromide, a chitosan, lauryldimethylbenzylammonium chloride, or any combination thereof.
26. The process according to any one of claims 18 to 25, wherein the surfactant is present in a concentration above the critical micelle concentration.
27. The process according to any one of claims 18 to 26, wherein the compound is a biologically useful compound or an imaging agent.
28. The process according to claim 27, wherein the biologically useful compound is an immunosuppressive agent, an immunoactive agent, an antiviral agent, an antifungal agent, an antineoplastic agent, an analgesic agent, an anti-inflammatory agent, an antibiotic, an anti-epileptic agent, an anesthetic, a hypnotic, a sedative, an antipsychotic agent, a neuroleptic agent, an antidepressant, an anxiolytic, an anticonvulsant agent, an antagonist, a neuron blocking agent, an anticholinergic agent, a cholinomimetic agent, an antimuscannic agent, a muscarinic agent, an antiadrenergic, an antiarrhythmic, an antihypertensive agent, a hormone, a nutrient, or a combination of any thereof.
29. The process according to claim 28, wherein the biologically useful compound is an antifungal agent.
30. The process according to any one of claims 18 to 29, including the step of formulating the particles into a composition.
31. The process according to claim 18, comprising reducing the size of the particles of the compound by antisolvent-solvent precipitation.
32. The process according to claim 18, comprising reducing the size of particles of the compound by precipitation from supercritical fluids.
33. The process according to claim 18, comprising precipitation and microfluidization of the compound in the presence of phospholipid and surfactant.
34. The process according to claim 33, involving precipitating the particles of the compound in the presence of the phospholipid and the surfactant, followed by microfluidization of the precipitated particles, the phospholipid, and the surfactant.
35. The process according to any one of claims 18 to 34, wherein the phospholipid is present in the range of 0.2% to 20%, w/v.
36. The process according to claim 35, wherein the phospholipid is present in the range of 0.5% to 10%, w/v.
37. Solid microparticles of a water-insoluble or poorly water soluble compound having surfaces to which a phospholipid and at least one surfactant are absorbed or adhered, wherein the concentration of phospholipid or surfactant in the composition is in a range of 0.1% to 50%, w/v, said microparticles produced by applying to a mixture comprising particles of the compound, the phospholipid, and the surfactant an energy input in an amount sufficient to produce microparticles whose volume-weighted mean particle size is at least 50% smaller than the volume-weighted mean particle size of particles of the compound produced (i) without the surfactant and (ii) by applying the same energy input.
38. A composition comprising the microparticles according to claim 37.
39. The composition according to claim 38, wherein the microparticles are nonaggregated.
40. The composition according to claim 38 or claim 39, wherein the microparticles are nonflocculated.
41. The composition according to any one of claims 38 to 40, wherein the composition is a pharmaceutically acceptable composition and the water-insoluble or poorly water-soluble compound is an antifungal agent.
42. A composition comprising microparticles of an industrially useful water-insoluble or poorly water soluble compound having surfaces to which a surfactant and a phospholipid are adhered or absorbed, wherein the concentration of phospholipid or surfactant in the composition is in a range of 0.1% to 50%, w/v, said microparticles produced by applying to a mixture comprising particles of the compound, the phospholipid, and the surfactant, an energy input in an amount sufficient to produce microparticles whose volume-weighted mean particle size is at least 50% smaller than volume-weighted mean particle size of particles of the compound produced without the presence of the surfactant by applying the same energy input, wherein the surfactant is selected from the group consisting of a sorbitan ester, a sorbitan fatty ester, a polyoxyethylene sorbitan fatty acid ester, a block copolymer of ethylene oxide and propylene oxide, a tetrafunctional block copolymer derived from sequential addition of ethylene oxide and propylene oxide to ethylenediamine, an alkyl aryl polyether sulfonate, polyethylene glycol, sodium dodecylsulfate, sodium deoxycholate, a cholesterol ester, glycerol monostearate, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, a polyoxyethylene fatty acid ester, a polyvinyl alcohol, polyvinylpyrrolidone, potassium laurate, triethanolamine stearate, an alkyl polyoxyethylene sulfate, dioctyl sodium sulfosuccinate, a negatively charged glyceryl ester, a quaternary ammonium cationic surfactant, benzalkonium chloride, cetyltrimethylammonium bromide, a chitosan, lauryldimethylbenzylammonium chloride, and combinations thereof.
43. The composition according to claim 42, wherein the composition is a pharmaceutically acceptable composition and the water-insoluble or poorly water soluble compound is an immunosuppressive agent, an immunoactive agent, an antiviral agent, an antifungal agent, an antineoplastic agent, an analgesic agent, an antiinflammatory agent, an antibiotic, an anti-epileptic agent, an anesthetic, a hypnotic, a sedative, an antipsychotic agent, a neuroleptic agent, an antidepressant, an anxiolytic, an anticonvulsant agent, an antagonist, a neuron blocking agent, an anticholinergic agent, a cholinomimetic agent, an antimuscarinic agent, a muscarinic agent, an antiadrenergic, an antiarrhythmic, an antihypertensive agent, a hormone, a nutrient, or a combination thereof.
44. A process for preparing microparticles of a water-insoluble or poorly water soluble industrially useful compound having surfaces to which a phospholipid and a surfactant are adhered or absorbed, comprising:
(a) mixing particles of a water-insoluble or poorly soluble industrially useful compound with a phospholipid and a surfactant present in a concentration in a range of 0.1% to 50%, w/v; and (b) applying energy to the mixture in an amount sufficient to produce microparticles of the compound having a volume-weighted mean particle size that is at least 50% smaller than the volume-weighted mean particle size of particles produced without the presence of the surfactant by applying the same energy input, wherein the surfactant is selected from the group consisting of a sorbitan ester, a sorbitan fatty ester, a polyoxyethylene sorbitan fatty acid ester, a block copolymer of ethylene oxide and propylene oxide, a tetrafunctional block copolymer derived from sequential addition of ethylene oxide and propylene oxide to ethylenediamine, an alkyl aryl polyether sulfonate, polyethylene glycol, sodium dodecylsulfate, sodium deoxycholate, a cholesterol ester, glycerol monostearate, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, a polyoxyethylene fatty acid ester, a polyvinyl alcohol, polyvinylpyrrolidone, potassium laurate, triethanolamine stearate, an alkyl polyoxyethylene sulfate, dioctyl sodium sulfosuccinate, a negatively charged glyceryl ester, a quaternary ammonium cationic surfactant, benzalkonium chloride, cetyltrimethylammonium bromide, a chitosan, lauryldimethylbenzylammonium chloride, and combinations thereof.
(a) mixing particles of a water-insoluble or poorly soluble industrially useful compound with a phospholipid and a surfactant present in a concentration in a range of 0.1% to 50%, w/v; and (b) applying energy to the mixture in an amount sufficient to produce microparticles of the compound having a volume-weighted mean particle size that is at least 50% smaller than the volume-weighted mean particle size of particles produced without the presence of the surfactant by applying the same energy input, wherein the surfactant is selected from the group consisting of a sorbitan ester, a sorbitan fatty ester, a polyoxyethylene sorbitan fatty acid ester, a block copolymer of ethylene oxide and propylene oxide, a tetrafunctional block copolymer derived from sequential addition of ethylene oxide and propylene oxide to ethylenediamine, an alkyl aryl polyether sulfonate, polyethylene glycol, sodium dodecylsulfate, sodium deoxycholate, a cholesterol ester, glycerol monostearate, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, a polyoxyethylene fatty acid ester, a polyvinyl alcohol, polyvinylpyrrolidone, potassium laurate, triethanolamine stearate, an alkyl polyoxyethylene sulfate, dioctyl sodium sulfosuccinate, a negatively charged glyceryl ester, a quaternary ammonium cationic surfactant, benzalkonium chloride, cetyltrimethylammonium bromide, a chitosan, lauryldimethylbenzylammonium chloride, and combinations thereof.
45. The process according to claim 44, including reducing the particle size of particles of the compound by sonication, homogenization, milling, microfluidization, precipitation, or recrystallization, in the presence of the phospholipid and the surfactant.
46. The process according to claim 44, wherein the water-insoluble or poorly water soluble compound is an immunosuppressive agent, an immunoactive agent, an antiviral agent, an antifungal agent, an antineoplastic agent, an analgesic agent, an antiinflammatory agent, an antibiotic, an anti-epileptic agent, an anesthetic, a hypnotic, a sedative, an antipsychotic agent, a neuroleptic agent, an antidepressant, an anxiolytic, an anticonvulsant agent, an antagonist, a neuron blocking agent, an anticholinergic agent, a cholinomimetic agent, an antimuscarinic agent, a muscarinic agent, an antiadrenergic, an antiarrhythmic, an antihypertensive agent, a hormone, a nutrient, or a combination thereof.
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| US70148396A | 1996-08-22 | 1996-08-22 | |
| US08/701,483 | 1996-08-22 | ||
| PCT/US1997/004695 WO1998007414A1 (en) | 1996-08-22 | 1997-03-28 | Compositions comprising microparticles of water-insoluble substances and method for preparing same |
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| CA2263102A1 CA2263102A1 (en) | 1998-02-26 |
| CA2263102C true CA2263102C (en) | 2006-08-15 |
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| CA002263102A Expired - Fee Related CA2263102C (en) | 1996-08-22 | 1997-03-28 | Compositions comprising microparticles of water-insoluble substances and method for preparing same |
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| EP (1) | EP0925061B1 (en) |
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| RO (1) | RO120603B1 (en) |
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1997
- 1997-03-28 RU RU99105851/14A patent/RU2186562C2/en not_active IP Right Cessation
- 1997-03-28 CZ CZ0059699A patent/CZ299790B6/en not_active IP Right Cessation
- 1997-03-28 IL IL12863297A patent/IL128632A/en not_active IP Right Cessation
- 1997-03-28 CN CNB971973652A patent/CN1303985C/en not_active Expired - Fee Related
- 1997-03-28 EP EP97917593A patent/EP0925061B1/en not_active Expired - Lifetime
- 1997-03-28 NZ NZ333844A patent/NZ333844A/en not_active IP Right Cessation
- 1997-03-28 CA CA002263102A patent/CA2263102C/en not_active Expired - Fee Related
- 1997-03-28 PL PL331715A patent/PL192560B1/en unknown
- 1997-03-28 RO RO99-00195A patent/RO120603B1/en unknown
- 1997-03-28 ES ES97917593T patent/ES2252780T3/en not_active Expired - Lifetime
- 1997-03-28 AT AT97917593T patent/ATE314055T1/en not_active IP Right Cessation
- 1997-03-28 JP JP10510706A patent/JP2000516244A/en active Pending
- 1997-03-28 KR KR1019997001435A patent/KR100542816B1/en not_active IP Right Cessation
- 1997-03-28 DE DE69734988T patent/DE69734988T2/en not_active Expired - Lifetime
- 1997-03-28 AU AU25871/97A patent/AU719085B2/en not_active Ceased
- 1997-03-28 WO PCT/US1997/004695 patent/WO1998007414A1/en active IP Right Grant
- 1997-03-28 HU HU9903537A patent/HU226608B1/en not_active IP Right Cessation
- 1997-09-29 US US08/939,699 patent/US5922355A/en not_active Expired - Lifetime
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1998
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| WO1998007414A1 (en) | 1998-02-26 |
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| CN1228021A (en) | 1999-09-08 |
| AU2587197A (en) | 1998-03-06 |
| RO120603B1 (en) | 2006-05-30 |
| CN1303985C (en) | 2007-03-14 |
| NO325197B1 (en) | 2008-02-18 |
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| AU719085B2 (en) | 2000-05-04 |
| EP0925061A1 (en) | 1999-06-30 |
| KR100542816B1 (en) | 2006-01-11 |
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| CA2263102A1 (en) | 1998-02-26 |
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| EP0925061B1 (en) | 2005-12-28 |
| RU2186562C2 (en) | 2002-08-10 |
| JP2000516244A (en) | 2000-12-05 |
| US5922355A (en) | 1999-07-13 |
| PL192560B1 (en) | 2006-11-30 |
| ES2252780T3 (en) | 2006-05-16 |
| US6228399B1 (en) | 2001-05-08 |
| HU226608B1 (en) | 2009-04-28 |
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| ATE314055T1 (en) | 2006-01-15 |
| IL128632A (en) | 2003-03-12 |
| DE69734988T2 (en) | 2006-09-21 |
| HK1021140A1 (en) | 2000-06-02 |
| IL128632A0 (en) | 2000-01-31 |
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