IL143196A - Method of preparing stable suspensions of insoluble microparticles and suspensions prepared thereby - Google Patents
Method of preparing stable suspensions of insoluble microparticles and suspensions prepared therebyInfo
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- IL143196A IL143196A IL143196A IL14319601A IL143196A IL 143196 A IL143196 A IL 143196A IL 143196 A IL143196 A IL 143196A IL 14319601 A IL14319601 A IL 14319601A IL 143196 A IL143196 A IL 143196A
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Description
METHOD OF PREPARING STABLE SUSPENSIONS OF INSOLUBLE MICROP ARTICLES AND SUSPENSIONS PREPARED THEREBY This invention relates to procedures that yield sub-micron and micron-size stable particles of water-insoluble or poorly soluble drugs or other industrially useful insoluble compounds. This invention provides for the first time a reliable HLB-based selection criteria for selecting the type and amount of surface modifiers used to obtain sub-micron stable suspensions.
BACKGROUND OF THE INVENTION Various proposals have been made for preparing formulations of water-insoluble drugs in aqueous solutions using surface modifiers such as phospholipids alone or with one or more surfactants. However, no criteria are set out for selecting the characteristics and quantities U.S. 5, 145,684 describes a poorly soluble drug having a non-crosslinked surface modifier adsorbed on its surface. The amount of surface modifier is 0.1% - 90% by weight, and the resulting particle size is less than 400 nm. The use of cloud-point modifiers is described in US 5,298,262, 5,326,552, 5,336,507, 5,340,564 and 5,470,583 in which a poorly-soluble drug or diagnostic agent has adsorbed on its surface both a cloud-point modifier and a non-crosslinked ionic surfactant. The cloud point modifier is said to increase the cloud point of the surfactant such that the resulting nanoparticles are resistant to particle size growth upon heat sterilization at 12 C. These patents provide different examples of specific cloud point modifiers used in conjunction with different surfactants in which the cloud-point modifying surfactants are arbitrarily selected.
WO 98/07414 describes a poorly soluble drug having two surface modifiers adsorbed on its surface; the addition of the second surface modifier provides approximately a 50% reduction in particle size as compared to the use of only one modifier.
EP 0580690B1 describes solubilizing water-insoluble peptides by coating them with a charged phospholipid such that the weight ratio of drug to phospholipid is above a critical number. Poloxamer 188 is also used to prepare the drug particles at concentration from 0.01 % - 0.5%. A reduction in the magnitude of the zeta potential is observed as the poloxamer 88 concentration is increased. 143196/4 US 5,091,187 renders water-insoluble drugs injectable by formulating them as aqueous suspensions of phospholipid-coated microcrystals. The crystalline drug is reduced to 50nm - 10 μιτι by sonication or other processes inducing high shear in the presence of phospholipid. Phospholipid is described as the sole surface modifier.
US 5,858,410 solubilizes water-insoluble drugs by the addition of a surfactant (synthetic or natural) using a piston-gap homogenizer. The resulting particles are determined by photon correlation microscopy to be in the range of 10nm - 1 ,000 nm, with less than 0.1% of the population above 5 microns. Again, the surface modifiers are arbitrarily selected.
US Patent No. 5,100,591 is directed to a process for preparing lipid microparticles of a waitr-insoluble substance capable of interacting physiocochemically with phospholipids. The substance and phospholipid(s) are dissolved in an organic solvent and subsequently mixed with an aqueous solution to yield a precipitate, followed by the removal of the organic solvent to recover suspensions of microparticles. US Patent No. 5,100.591 does not relate to the determining of the hydrophile-lipophile balance of the suspension and does not provide criteria, for selecting a phospholipid.
DESCRIPTION OF THE INVENTION The composite suspensions prepared by this invention include, in addition to particles of a water-insoluble or poorly soluble drug or other industrially useful compound, natural or synthetic phospholipids or surfactant alone, or in combination with each other.
According to a first aspect of the invention there is provided a method of obtaining a stable system of micron or sub-micron sized microparticles of a water insoluble or poorly soluble drug of stable particle size in a stable suspension prepared in an aqueous medium the method consisting essentially of the steps of: (a) selecting a type and an amount of phospholipid surface modifiers; (b) selecting a type and an amount of surfactant surface modifier selected from the group consisting of casein, gelatin, tragacanth, waxes, paraffin, acacia and gelatin cholesterol esters; polyoxyethylene fatty alcohol ethers, sorbitan fatty acid esters, polyoxyethylene fatty acid esters, sorbitan esters, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, poloxamers, poloxamines, methylcellulose, hydroxycellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, noncrystalline cellulose; polyvinyl alcohol, polyvinylpyrrolidones; and bentonite, veegum and colloidal silica;.and (c) mixing the phospholipid and surfactant from (a) and (b), wherein the amount and type of phospholipid and surfactant selected relative to the amount of drug yields 143196/ 1 a system Hydrophile-Lipophile Balance (HLB) between 4 and 9, wherein the system HLB is defined by the formula: ^ (weight of surface modifier j) System HLB = · — x (HLB value of surface modifier jj) J (weight of drug) and wherein the system is stable if, placed in a vial and sealed, at least two of the following conditions are satisfied: (1) the volume weighted average particle size is less than 1.5 μπι at 4°C over a period of four weeks; (2) the volume weighted average particle size is less than 1.5 μπι at 25°C over a period of four weeks; (3) the volume weighted average particle size is less than 2.5 μπι at 40°C over a period of one week; (4) the volume weighted average particle size is less than 1.5 μπι following 7-day shaking, wherein the vial is laid on its side on a shaking table at ambient temperature, the shaking speed at 100 rpm to 110 rpm; or (5) the volume weighted average particle size is less than 1.5 μηι following 3 cycles of thermal cycling, wherein one cycle consists of storage at 4°C for 1 to 2 days and then at 40°C for 1 to 2 days.
The Hydrophile-Lipophile Balance (HLB) is a scale that balances between two opposing tendencies present in a surfactants: hydrophilic (that portion which has an affinity towards water) versus lipophilic (that portion which has an affinity towards oil). The more hydrophilic surfactants have high HLB numbers (in excess of 10), while surfactants with HLB numbers from 1-10 are considered to be lipophilic. Preferably the HLB value of the surface modifier or modifiers is between 5 and 35.
According to a second aspect of the invention there is provided a method for preparing a system comprising a stable micron or sub-micron size suspension of a water-insoluble or a poorly soluble drug compound suspended in an aqueous medium, wherein the aqueous medium includes surface modifiers selected from the group consisting of phospholipid surface modifiers and surfactant surface modifiers, consisting essentially of the steps of: selecting the phospholipid surface modifier and an amount of the phospholipid surface modifier, 2A 143196/ 1 selecting a surfactant surface modifier selected from the group consisting of casein, gelatin, tragacanth, waxes, paraffin, acacia and gelatin cholesterol esters; polyoxyethylene fatty alcohol ethers, sorbitan fatty acid esters, polyoxyethylene fatty acid esters, sorbitan esters, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, poloxamers, poloxamines, methylcellulose, hydroxycellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, noncrystalline cellulose; polyvinyl alcohol, polyvinylpyrrolidones; and bentonite, veegum and colloidal silica and an amount of the surfactant surface modifier, and mixing the phospholipid and surfactant, based on the formula: 2 (weight of surface modifier j) System HLB = · x (HLB value of surface modifier j) J (weight of drug) such that the system Hydrophile-Lipophile Balance (HLB) is between 4 and 9.
The water insoluble or poorly water soluble compound may be selected from various therapeutic agents, including an antifungal agent, immunosuppressive or 2B immunoactive agent, antiviral agent; antineoplastic agent, analgesic or antiinflammatory agent, antibiotic, antiepileptic, anesthetic, hypnotic, sedative, antipsychotic agent, neuroleptic agent, antidepressant, anxiolytic, anticonvulsant agent, antagonist, neuron blocking agent, anticholinergic or cholinomimetic agent, antimuscarinic or muscarinic agent, antiadrenergic, or an antarrhythmic, antihypertensive agent, hormone or a nutrient.
The surface modifiers employed usually fail into two general categories, phospholipids and surfactants. The phospholipid may be any naturally occurring phospholipid or mixtures of phospholipids, sometimes referred to herein as "commercial" phospholipids, such as egg or soybean phospholipid or a combination thereof. The phospholipid may be desalted, hydrogenated or partially hydrogenated or natural, semi-synthetic or synthetic. Examples of commercially available phospholipids include but are not limited to egg phospholipids P123 (Pfanstiehl), Lipoid E80 (Lipoid); and hydrogenated soy phospholipids Phospholipon 90H and 100H (Natterman) and 99% pure egg and soy phosphatidyl choline (Avanti Polar Lipids). The amount of phospholipid present in the composition ranges from 0.01% to ■ 50%, preferably from 0.05% to 20%.
The surfactant, sometimes referred to as a second surface modifier, includes: (a) natural surfactants such as casein, gelatin, tragacanth, waxes, enteric resins, paraffin, acacia, gelatin cholesterol esters and triglycerides (b) nonionic surfactants such as polyoxyethyiene fatty alcohol ethers, sorbitan fatty acid esters, polyoxyethylene fatty acid esters, sorbitan esters glycerol monostearate, polyethylene glycols, cetyl alcohol, cetostearyl alcohol, stearyi alcohol, poioxamers, poloxamines, methylcellulose, hydroxycelllulose, hydroxy propylcellulose, hydroxy propylmethylcellulose, noncrystalline cellulose; polyvinyl alcohol, polyvinylpyrrolidone, and synthetic phospholipids, and (c) colloidal clays such as bentonite, veegum and colloidal silica. A detailed description of these surfactants may be found in Remington's Pharmaceutical Sciences, and Theory of Practice of Industrial Pharmacy, Lachman et al 1986.
Specific examples of suitable second surface modifiers include the following: poioxamers, such as Pluronic™ F68, F 08, and F127, which are block copolymers of ethylene oxide and propylene oxide available from BASF, and poloxamines, such as 3 143196/2 Tetronic™ 908, which is a tetrafunctional block copolymer derived from sequential addition of ethylene oxide and propylene oxide to ethylene-diamine available from BASF, Triton™ X-l OO, which is an alkyl aryi polyether sulfonate, available from Rohm and Haas. Tween 20, 40, 60 and 80, which are polyoxyethyiene sorbitan fatty acid esters available from ICl Specialty Chemicals, Carbowax™ 3550 and 934, which are polyethylene glycols available from Union Carbide, hydroxy propylmethylcellulose and polyvinylpyrrolidone.
Preferably the surface modifier is a polyoxyethyiene sorbitan fatty acid ester, a block copolymer of ethylene oxide and propylene oxide, polyoxyethylerte stearate a tetrafunctional block copolymer derived from sequential addition of ethylene oxide and propylene oxide to ethylenediamine, an alkyl aryl polyether sulfonate, polyethylene glycol, hydroxy propylmethylcellulose, and polyvinylpyrrolidone.
The surfactant desirably is a polyoxyethyiene sorbitan fatty acid ester polyoxyethyiene stearate, a block copolymer of ethylene oxide, and propylene oxide, a tetra functional block copolymer derived from sequential addition of ethylene oxide and propylene oxide to ethylenediamine, an alkyl aryl polyether sulfonate, polyethylene glycol, hydroxy propylmethylcellulose, and polyvinylpyrrolidone.
The phospholipid may be desalted, hydrogenated or partially hydrogenated or natural, semisynthetic or synthetic and preferably is phosphatidylcholine, phosphatidylethanotamine, phosphatidylserine, phosphatidylinoistol, phosphatidylglycerol or phosphatide acid.
Passages in the description which fall outside the ambit of the claims are not part of the invention.
DESCRIPTION OF THE PREFERRED EMBODIMENTS To further illustrate and describe the selection process of the present invention the following experiments were carried out. In the examples that follow a premix was processed at a constant temperature and pressure by using high-pressure equipment that subjects the formulation to shear, cavitation, impact, and attrition, that is in either a.Microfluidizer or a homogenizes Details are given in the following table. 4 Total Passes Average Average Formulation at Operating Pressure Temperature type Processing Machine Pressure (kPsi) (C) Cyciosporine Avestin C-50 homogenizer 200 18 10 Ursodioi Avestin C-5 homogenizer 100 18 Ί Fenofibrate Microfiuidizer M110 EH 50 18 5 A "pass" is defined as one cycle of the formulation through the different elements of the processing machine. The "pass" or cycle for each machine is as follows: Avestin C-50 and C-5: Formulation is placed in inlet reservoir then passes to the homogenization valve, next a heat exchanger then back to the inlet reservoir. It is the homogenization valve that subjects the formulation to the forces of shear, cavitation, impact and attrition. M110 EH: The formulation is first put through 20 passes of the bypass loop, defined as follows: inlet reservoir to auxiliary processing module to heat exchanger then back to inlet reservoir. The resulting formulation is then put through the interaction chamber loop, defined as follows: inlet reservoir to auxiliary processing module to interaction chamber to heat exchanger then back to inlet reservoir. It is in the interaction chamber where the formulation is subject to the forces of shear, cavitation, impact and attrition. Followed by processing, each formulation was collected and placed in vials, capped with rubber stoppers and sealed with an aluminum cap, for stability testing! Acceptable particles are those microparticles falling within the range of 0.05 to 10 microns.
In the examples that follow the following materials are employed. 5 List of Abbreviations of Surface Modifiers Full Name Abbreviation Lipoid E-80 LipE80 Phospholipon 100H Ph 100H Myrj 52 Myrj 52 Tween 80 Tw 80 Pluronic F68 (also known as Poloxomer 188) PF68 Pluronic F108 (also known as Poloxomer 338) PF108 Pluronic F127 (also known as Poloxamer 407) PF127 Tetronic 908 T908 The five different tests were used to evaluate the stability of the formulations. 6 Stability Test Description 4°C Sample stored at 4°C (temperature controlled) 25°C Sample stored at 25°C (temperature controlled, 60% relative humidity) 40°C Sample stored at 40°C (temperature controlled) Shaking Sample laid down on its side on a shaking table at ambient room temperature. The shaking speed was at 100 rpm-110 rpm.
Thermal One cycle defined as follows: sample stored at 4°C for 1-2 days, then Cycling at 40°C for 1-2 days.
A formulation is regarded as being stable if at least two of the following conditions are satisfied: (1) The average particle size is less than 1.5 pm at 4°C over a period of four weeks. (2) The average particle size is less than 1.5 pm at 25°C over a period of four weeks. (3) The average particle size is less than 2.5 pm at 40°C over a period of one week. (4) The average particle size is less than 1.5 pm following 7-day shaking. (5) The average particle size is less than 1.5 pm following 3 cycles of thermal cycling.
Example A In this example the effect of system HLB on particle size and stability of cyclosporine microparticies were assessed. We found that when the combination of phospholipid plus one surface modifier are chosen such that the system HLB value is above 9, the resulting formulation is unstable. However, if a combination is chosen such that the resulting system HLB value is less than 9 (but greater than 0), the resulting formulation is sub-micron size and stable. The control experiment without surface modifier is included as a reference. 7 SUBSTITUTE SHEET RULE 26 Example B Next the effect of system HLB on particle size and stability of ursodiol microparticles was studied. These experiments, prepared in 50 gram batches with 5.5% w/w mannitol, illustrate that when the combination of phospholipid plus one or more surface modifiers are chosen such that the system HLB value is above 9 or less than 4, the resulting formulation is unstable. However, if a combination is chosen such that the system HLB value is between 4 and 9, the resulting formulation is sub-micron size and stable. The control experiment without surface modifiers is included as a reference. 9 TABLE 2.1 - URSODIOL 10% w/w + 2 Surface Modifiers Ursodiol 10% w/w + 3 Surface Modifiers * In absence of surface modifiers, mixing is quite difficult, excessive foam is generated, a Table 2.2. - Stability of IDD-P™ Ursodiol Ex 4C stability 22C stability 40C stability 7-day , 3-cycle Size Shaking Therm (micr) Days Size Days Size Days Size 3 0.99 28 1.03 28 1.05 7■ 1.07 1.05 1.07 . 5 . 0.99 28 1.02 28 1.03 7 1.06 1.04 1.09 .
Results for Tables 2.1 and 2.2 show the following important conclusions: Examples 1 ,2 and 3 in Table 2.1 illustrate the effect of increasing the phospholipid concentration from 0%, 2.4% w/w and 6% w/w such that the system HLB values are 0, 1.7, and 4.2 respectively. In case of example 1 where there are no surface modifiers, mixing of the drug and water is difficult, and the formulation cannot be homogenized. The formulation with the system HLB above 4 is sub-micron size and stable, whereas the others are not.
Examples 3 and 4 illustrate the effect of increasing the PF 68 concentration from 0% to 2%, at a fixed phospholipid concentration of 6%, such that the system HLB values are 4.2 and 10 respectively. The formulation with the system HLB between 4 - 9 is sub-micron size and stable, whereas the other formulation is not.
Examples 4 and 5 illustrate the effect of decreasing the phospholipid concentration from 6% to 3.8%, at a fixed PF 68 concentration of 2%, such that the system HLB values are 10 and 8.5 respectively. The formulation with the system HLB between 4 - 9 is sub-micron size and stable, whereas the other formulation is not.
Examples 6 and 7 illustrate the effect of the system HLB value outside the range of 3.9 - 9: particle size greater than 1 micron, and unstable formulations. In particular, example 5 has an system HLB of less than 3.9, whereas example 6 has an system HLB value of greater than 9.
Example C The example studies the effect of system HLB on fenofibrate particle size and stability. These experiments show that when the combination of phospholipid plus one 11 or more surface modifiers are chosen such that the system HLB value is less than 4, the resulting formulation is unstable. However, if a combination is chosen such that the resulting system HLB value is between 4 to 9, the resulting formulation is sub-micron size and stable. The control experiment of no surface modifier is included as a reference. 12 TABLE 3.1 -FENOFIBRATE 10% w/w (+ 5.5% w/w Mannitol) * In absence of surface modifiers, mixing is quite difficult, the drug floats on top of aqueous phas processed.
* *No Mannitol present The formulations given in Table 3.1 were prepared in 200 gram batches on the M1 10 EH at an operating pressure of 18,000 psi. Prior to homogenization, 1 N NaOH was added to adjust the pH in the range 6-8. Particle size is a volume-weighted average, measured on the Malvern Mastersizer.
Table 3.2 - Stability of Microparticles of Fenofibrate The above examples 2 and 4 in Table 3.1 illustrate the effect of increasing the PF 127 concentration from 0% to 1% w/w such that the system HLB vaiues are 2.1 and 5, respectively. The formulation with the system HLB above 4 is sub-micron size and stable, whereas the other formulation is not. Examples 3 and 4 illustrate the effect of changing the relative amounts of Lip E80 and PF 127 such that the total surface modifier concentration is 4% w/w. The formulation with a system HLB value > 4 (example 4) is stable, whereas the formulation with a system HLB value of < 4 (example 3) is not stable.
Examples 5 and 6 illustrate the effect of changing the relative amounts of Phospholipon 100H and PF 108; the formulation with a system HLB value > 4 (example 5) is stable, whereas the formulation with a system HLB value of < 4 (example 6) is not stable.
Examples 7 and 8 are stable, sub-micron size formulations with total surface modifier concentration of 2.5% w/w, such that the system HLB value of each formulation is between 4 and 9. In both formulations, different combinations of Lipoid E80 and PF 127 are used.
Examples 3 and 7 illustrate the effect of. increasing the PF 127 weight ratio relative to the drug from 0 to 1 , while maintaining the Lip E80 weight ratio at 4. The 14 system HLB values are 2.8 and 5.7, respectively. The formulation with the system HLB above 4 is sub-micron size and stable, whereas the other formulation is not stable.
EXAMPLE D The formulation of this example as set out in Table 4.1 was prepared as a 200 gram batch (120 passes at 22°C) on the M110EH at an operating pressure of 18 kpsi Particle size is a volume-weighted average, measured on the Malvern Mastersizer. 15 6 - After 4 wks at 25°, the particle size is 0.34 microns, identical to the starting size, hence the particles were stable.
The above example in Table 4.1 , with a system HLB within the ranage of 4-9, exhibits good stability at room temperature (four weeks at 25°C). The lyophiiized drug (with 5% w w PVP) reconstituted to 0.37 microns, almost identical to the starting size. In addition, this formulation showed significant bioavailability in Bioavailability in dogs was 27% and in rats gave 33%. 17
Claims (9)
1. A method of obtaining a stable system of micron or sub-micron sized microparticles of a water insoluble or poorly soluble drug of stable particle size in a stable suspension prepared in an aqueous medium the method consisting essentially of the steps of: (a) selecting a type and an amount of phospholipid surface modifiers; (b) selecting a type and an amount of surfactant surface modifier selected from the group consisting of casein, gelatin, tragacanth, waxes, paraffin, acacia and gelatin cholesterol esters; polyoxyethylene fatty alcohol ethers, sorbitan fatty acid esters, polyoxyethylene fatty acid esters, sorbitan esters, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, poloxamers, poloxamines, methylcellulose, hydroxycellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, noncrystalline cellulose; polyvinyl alcohol, polyvinylpyrrolidones; and bentonite, veegum and colloidal silica;_and (c) mixing the phospholipid and surfactant from (a) and (b), wherein the amount and type of phospholipid and surfactant selected relative to the amount of drug yields a system Hydrophile-Lipophile Balance (HLB) between 4 and 9, wherein the system HLB is defined by the formula: ^ (weight of surface modifier j) System HLB = x (HLB value of surface modifier j) (weight of drug) and wherein the system is stable if, placed in a vial and sealed, at least two of the following conditions are satisfied: (1) the volume weighted average particle size is less than 1.5 μιη at 4°C over a period of four weeks; (2) the volume weighted average particle size is less than 1.5 μπι at 25°C over a period of four weeks; (3) the volume weighted average particle size is less than 2.5 μπι at 40°C over a period of one week; (4) the volume weighted average particle size is less than 1.5 μη following 7-day shaking, wherein the vial is laid on its side on a shaking table at ambient temperature, the shaking speed at 100 rpm to 1 10 rpm; or 18 143196/4 (5) the volume weighted average particle size is less than 1.5 μιη following 3 cycles of thermal cycling, wherein one cycle consists of storage at 4°C for 1 to 2 days and then at 40°C for 1 to 2 days.
2. The method of claim 1 , wherein the HLB value of-the surfactant surface modifier is between 5 and 35.
3. The method of claim 1 , wherein the phospholipid surface modifier selected from the group consisting of egg phospholipid, soybean phospholipid, and combinations thereof.
4. The method of claim 1, wherein the phospholipid surface modifier is desalted, hydrogenated or partially hydrogenated.
5. The method of claim 1 , wherein the phospholipid surface modifier is selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol, phosphatidic acid, lysophospholipid, and combinations thereof.
6. The method of claim 1, wherein the surfactant surface modifier is selected from the group consisting of a polyoxyethylene sorbitan fatty acid ester, a block copolymer of ethylene oxide and propylene oxide, polyoxyethylene stearate, a tetrafunctional block copolymer derived from sequential addition of ethylene oxide and propylene oxide to ethyl enediamine, an alkyl aryl polyether sulfonate, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, and polyvinyl alcohol.
7. The method of claim 1 , wherein the water-insoluble or poorly water soluble drug is an antifungal agent, immunosuppressive agent, immunoactive agent, antiviral agent, antineoplastic agent, analgesic, anti-inflammatory agent, antibiotic, antiepileptic, anesthetic, hypnotic, sedative, antipsychotic agent, neuroleptic agent, antidepressant, anxiolytic, anticonvulsant agent, antagonist, neuron blocking agent, anticholinergic agent, cholinomimetic agent, antimuscarinic agent, muscarinic agent, antiadrenergic, antiarrhythmic, antihypertensive agent, hormone, or a nutrient.
8. A method for preparing a system comprising a stable micron or sub-micron size suspension of a water-insoluble or a poorly soluble drug compound suspended in an aqueous medium, wherein the aqueous medium includes surface modifiers selected from the group consisting of phospholipid surface modifiers and surfactant surface modifiers, consisting essentially of the steps of: 19 143196/2 selecting the phospholipid surface modifier and an amount of the phospholipid surface modifier, selecting a surfactant surface modifier selected from the group consisting of casein, gelatin, tragacanth, waxes, paraffin, acacia and gelatin cholesterol esters; polyoxyethylene fatty alcohol ethers, sorbitan fatty acid esters, polyoxyethylene fatty acid esters, sorbitan esters, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, poloxamers, poloxamines, methylcellulose, hydroxycellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, noncrystalline cellulose; polyvinyl alcohol, polyvinylpyrrolidones; and bentonite, veegum and colloidal silica and an amount of the surfactant surface modifier, and mixing the phospholipid and surfactant, based on the formula: (weight of surface modifier j) System HLB = x (HLB value of surface modifier j) (weight of drug) such that the system Hydrophile-Lipophile Balance (HLB) is between 4 and 9.
9. A method according to any of claims 1 -8 substantially as described herein. For the Applicant, JMB, Factor & Co. RTP 90258/1.7 20
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US10920398P | 1998-11-20 | 1998-11-20 | |
PCT/US1999/027435 WO2000030615A1 (en) | 1998-11-20 | 1999-11-19 | Method of preparing stable suspensions of insoluble microparticles |
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IL143196A true IL143196A (en) | 2012-01-31 |
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IL14319699A IL143196A0 (en) | 1998-11-20 | 1999-11-19 | Method of preparing stable suspensions of insoluble microparticles |
IL143196A IL143196A (en) | 1998-11-20 | 2001-05-17 | Method of preparing stable suspensions of insoluble microparticles and suspensions prepared thereby |
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IL14319699A IL143196A0 (en) | 1998-11-20 | 1999-11-19 | Method of preparing stable suspensions of insoluble microparticles |
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EP (1) | EP1133280A1 (en) |
JP (1) | JP5296954B2 (en) |
KR (1) | KR20010075713A (en) |
CN (1) | CN1213733C (en) |
AU (1) | AU767737B2 (en) |
CA (1) | CA2349202C (en) |
IL (2) | IL143196A0 (en) |
WO (1) | WO2000030615A1 (en) |
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EP1267946A4 (en) * | 2000-02-28 | 2008-07-02 | Genesegues Inc | Nanocapsule encapsulation system and method |
AR035642A1 (en) | 2000-05-26 | 2004-06-23 | Pharmacia Corp | USE OF A CELECOXIB COMPOSITION FOR QUICK PAIN RELIEF |
US9700866B2 (en) | 2000-12-22 | 2017-07-11 | Baxter International Inc. | Surfactant systems for delivery of organic compounds |
US8067032B2 (en) | 2000-12-22 | 2011-11-29 | Baxter International Inc. | Method for preparing submicron particles of antineoplastic agents |
FR2819720B1 (en) | 2001-01-22 | 2004-03-12 | Fournier Lab Sa | NEW FENOFIBRATE TABLETS |
GB0119480D0 (en) | 2001-08-09 | 2001-10-03 | Jagotec Ag | Novel compositions |
US20060003012A9 (en) | 2001-09-26 | 2006-01-05 | Sean Brynjelsen | Preparation of submicron solid particle suspensions by sonication of multiphase systems |
BR0212833A (en) | 2001-09-26 | 2004-10-13 | Baxter Int | Preparation of submicron sized nanoparticles by dispersion and solvent or liquid phase removal |
UY27939A1 (en) | 2002-08-21 | 2004-03-31 | Glaxo Group Ltd | COMPOUNDS |
US7828996B1 (en) | 2009-03-27 | 2010-11-09 | Abbott Cardiovascular Systems Inc. | Method for the manufacture of stable, nano-sized particles |
AU2012346594B2 (en) * | 2011-11-30 | 2017-12-21 | Agency For Science, Technology And Research | GM1 ganglioside to Annexin V microparticle polypeptide ratio for biological monitoring |
CN114367383B (en) * | 2022-01-13 | 2024-01-09 | 苏州丰倍生物科技股份有限公司 | Fatty acid ester nano suspension, preparation method and application thereof |
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FR2651680B1 (en) * | 1989-09-14 | 1991-12-27 | Medgenix Group Sa | NOVEL PROCESS FOR THE PREPARATION OF LIPID MICROPARTICLES. |
US5091187A (en) * | 1990-04-26 | 1992-02-25 | Haynes Duncan H | Phospholipid-coated microcrystals: injectable formulations of water-insoluble drugs |
DE69734988T2 (en) * | 1996-08-22 | 2006-09-21 | Jagotec Ag | PREPARATIONS CONTAINING MICROPARTICLES OF WATER-INSOLUBLE SUBSTANCES AND METHOD FOR THE PRODUCTION THEREOF |
WO1999049846A2 (en) * | 1998-03-30 | 1999-10-07 | Rtp Pharma Inc. | Compositions containing microparticles of water-insoluble substances and method for their preparation |
JP2002516267A (en) * | 1998-05-29 | 2002-06-04 | アールティーピー・ファーマ・インコーポレーテッド | Thermally protected particulate composition and its final steam sterilization |
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1999
- 1999-11-19 EP EP99960497A patent/EP1133280A1/en not_active Ceased
- 1999-11-19 IL IL14319699A patent/IL143196A0/en unknown
- 1999-11-19 WO PCT/US1999/027435 patent/WO2000030615A1/en not_active Application Discontinuation
- 1999-11-19 AU AU17374/00A patent/AU767737B2/en not_active Ceased
- 1999-11-19 CN CNB998156442A patent/CN1213733C/en not_active Expired - Fee Related
- 1999-11-19 JP JP2000583499A patent/JP5296954B2/en not_active Expired - Fee Related
- 1999-11-19 KR KR1020017006123A patent/KR20010075713A/en not_active Application Discontinuation
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KR20010075713A (en) | 2001-08-09 |
JP5296954B2 (en) | 2013-09-25 |
AU1737400A (en) | 2000-06-13 |
WO2000030615A1 (en) | 2000-06-02 |
CA2349202A1 (en) | 2000-06-02 |
IL143196A0 (en) | 2002-04-21 |
JP2002530320A (en) | 2002-09-17 |
EP1133280A1 (en) | 2001-09-19 |
AU767737B2 (en) | 2003-11-20 |
CN1337877A (en) | 2002-02-27 |
CN1213733C (en) | 2005-08-10 |
CA2349202C (en) | 2012-06-19 |
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