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    • 专利摘要:
    Particulate crystalline therapeutic substances are formulated with stabilizers to enhance contact between the crystalline therapeutic substances and the mucosal membranes to provide extended therapeutic effect.
    公开号:US20010006617A1
    申请号:US08/815,346
    申请日:1997-03-11
    公开日:2001-07-05
    发明作者:Gary G. Liversidge；W. Mark Eickhoff；Kathleen J. Illig；Pramod Sarpotdar；Stephen B. Ruddy
    申请人:Elan Pharma International Ltd；
    IPC主号:A61K49-049
    专利说明:
    [0001] This is a continuation-in-part of copending application Ser. No. 08/366,841, filed Dec. 30, 1994. [0001] BACKGROUND OF THE INVENTION
    [0002] 1. Field of the Invention [0002]
    [0003] This invention relates to improved formulations of poorly soluble crystalline therapeutic agents which are absorbed through mucous membranes. [0003]
    [0004] 2. Background of the Invention [0004]
    [0005] There is a constant need in the pharmaceutical industry for improved pharmaceutical formations which enhance the efficacy of poorly soluble therapeutic agents. There is especially a need for formulations that (1) enhance the adsorption of poorly soluble therapeutic agents across mucous membranes or (2) extend the period of time that poorly soluble therapeutic agents useful for treating of a site have contact with the mucosa of the site. [0005]
    [0006] Since most poorly soluble crystalline therapeutic agents do not inherently adhere to mucosal surfaces, there is a need to provide in such formulations, primary surface active stabilizers with appropriate mucoadhesive properties and secondary excipients that provide for an improvement in therapeutic efficacy as compared with existing products and formulations. Therefore, the physical-chemical properties of the therapeutic agents, and any desired surface active stabilizers and viscosity modifiers must be taken into consideration. [0006]
    [0007] The identification of surface active stabilizers for use with small particles of crystaline poorly soluble drugs, wherein the surface active stabilizer has bioadhesive or mucoadhesive properties to mucous membranes, in particular, to the entire GI tract, has not been reported to date. The development of appropriate surface active stabilizers that will enable mucous membranes to be utilized to enhance bioavailability represents a difficult technical problem. [0007]
    [0008] Bioadhesion is usually achieved by interaction of either a synthetic or natural polymeric substance with mucosal membranes. Such technology has been employed to enhance drug delivery by decreasing the transit time of a drug substance in the GI tract and hence promote an opportunity for enhanced absorption. Highly charged carboxylated polyanions are good candidates for use as bioadhesives in the GI tract. See, for example: Park, K. and Robinson, J. R., Bioadhesion: Polymers and Platforms for Oral-Controlled Drug Delivery; Method to Study Bioadhesion. Int. J. Pharm., 19, 107 (1984). The formation of a bioadhesive bond between a polymeric substance and the mucosal lining of the GI tract can be visualized as a two step process, i.e., initial contact between the two surfaces and the formation of secondary bonds due to non-covalent interactions. Bioadhesives specific for mucous membranes must interact with the mucus layer during attachment. Mucus, a general term for the heterogenous secretion found on the epithelial or endothelial surfaces of the mucous membranea, is made of the following components: glycoprotein macromolecules, inorganic salts, proteins, lipids and mucopolysaccharides. These glycoproteins typically consist of a protein core with carbohydrate side chains. This forms a network of mucus that is a continuous layer covering the muscous membrane. From a bioadhesive perspective, mucus consists of highly hydrated, crosslinked linear, flexible yet random coiled glycoprotein molecules with a net negative charge. Understanding the principles of bioadhesion is the basis for producing an improved formulation for poorly soluble therapeutic agent. Bioadhesion accounts for the interaction between a biological surface and a biomaterial substance. As noted previously, bioadhesive agents are usually polymeric substances that adhere to tissues by ionic or covalent bonds or by physical attachment. Several theories of bioadhesion have been published including electronic, adsorption, wetting, diffusion and fracture theories. Bioadhesives bind to membrane surfaces and are retained for variable periods of time. [0008]
    [0009] The primary difficulty with previously reported mucoadhesive stabilizers is that they do not interact effectively with both the particles of the therapeutic agent and mucous membrane uniformly so that, e.g., both the upper and lower GI tract can be used as sites to increase bioavailability. The stabilizers used for this purpose must be adsorb sufficiently to the different regions of the GI tract. In practice, stabilizers tend to be adsorbed at some biological surfaces differentially than at others due to a variety of complex reasons. There is a need for formulations of particles of therapeutic agents that are adsorbed sufficiently over the entire mucous membrane. [0009]
    [0010] It has now been discovered that particles of crystalline therapeutic agents modified by having a poloxamer absorbed on the surface thereof, can be adsorbed onto the mucosal surface, including the GI tract. [0010]
    [0011] In another embodiment the present invention relates to improved formulations of therapeutic agents, including gastrointestinal therapeutic agents, wherein the formulations provide prolonged local contact of the therapeutic agents with the mucosal layer, including the gastrointestinal tract. [0011] SUMMARY OF THE INVENTION
    [0012] In accordance with the present invention, there is provided a therapeutic composition comprising: [0012]
    [0013] from about 0.1% to about 45% w/v, and, preferably, from about 0.5% to about 15% w/v, of particles of a poorly water-soluble crystalline therapeutic agent having a weight average particle size of less than about 2,000 nm, more preferably, a weight average particle size of less than about 1,000 nm, and most preferably, a weight average particle size of less than about 400 nm; [0013]
    [0014] from about 0.1% to about 10% w/v, and preferably of from about 0.25% to about 5% w/v of a poloxamer; and [0014]
    [0015] water to make 100% w/v. [0015]
    [0016] These compositions can be administered by any route that will result in the therapeeutic agent having contact with a mucous membrane. These routes include oral, rectal, nasal, occular, inhalation and vaginal. Preferred is oral and rectal because the compositions of the present invention will enable the thereapeutic agent to be adsorded across the mucous mebrane of the entire GI tract resulting in greatly enhance adsorption. [0016]
    [0017] Secondary stabilizers may also be used in the therapeutic composition up to about 1% w/v, preferably up to about 0.2% w/v, and most preferably up to about 0.1% w/v. Secondary stabilizers include dioctylsulfosuccinate (DOSS) and sodium lauryl sulfate (SLS). [0017]
    [0018] Other ingredients customarily used in pharmaceutical formulations may also be included, such as flavorants, colorants and preservatives to provide pharmaceutically acceptable and palatable formulations. [0018]
    [0019] The poloxamers useful in the present invention have an average molecular weight of from about 1,000 to 15,000 daltons; preferred have an average molecular weight of about 5,000 to 15,000 daltons. [0019]
    [0020] Poloxamers are polyethylene-polypropylene glycol block polymers containing ethylene oxide (PEO) and propylene oxide (PPO) moles according to the formula[0020]
    [0021] Preferred are poloxamers wherein; [0021]
    [0022] a is 46 to 128; [0022]
    [0023] b is 16 to 67; and [0023]
    [0024] c is 46 to 128. [0024]
    [0025] More preferred are poloxamers wherein; [0025]
    [0026] a is 46, 52, 62, 75, 97, 98, 122 and 128; [0026]
    [0027] b is 16, 30, 35, 39, 47, 54 and 67; and [0027]
    [0028] c is 46, 52, 62, 75, 97, 98, 122 and 128. [0028]
    [0029] Table 1 shows the various poloxamers by manufacturer-designated number. [0029] TABLE 1 Molecular Weights of PoloxamersAv. Values Poloxamer No. Pluronic Av. Mol. Wt a b c 401 4,400  6 67  6 402 5,000 13 67 13 403 5,750 21 67 21 407 F127 12,000  98 67 98 331 3,800  7 54  7 333 4,950 20 54 20 334 5,850 31 54 31 335 6,000 38 54 38 338 F108 15,000  128  54 128  282 3,650 10 47 10 284 4,600 21 47 21 288 F98 13,500  122  47 122  231 2,750  6 39  6 234 4,200 22 39 22 235 4,600 27 39 27 237 F87 7,700 62 39 62 238 F88 10,800  97 39 97 212 2,750  8 35  8 215 4,150 24 35 24 217 F77 6,600 52 35 52 181 2,000  3 30  3 182 2,500  8 30  8 183 2,650 10 30 10 184 2,900 13 30 13 185 3,400 19 30 19 188 F68 8,350 75 30 75 122 1,630  5 21  5 123 1,850  7 21  7 124 2,200 11 21 11 101 1,100  2 16  2 105 1,900 11 16 11 108 F38 5,000 46 16 46
    [0030] Certain number of these poloxamers are also known as Pluronic, which is a brand name of BASF Corporation. [0030]
    [0031] Preferred poloxamers for use in the present invention are: [0031]
    [0032] Pluronic F127 [0032]
    [0033] Pluronic F108 [0033]
    [0034] Pluronic F98 [0034]
    [0035] Pluronic F87 [0035]
    [0036] Pluronic F88 [0036]
    [0037] Pluronic F77 [0037]
    [0038] Pluronic F68 and [0038]
    [0039] Pluronic F38. [0039] DETAILED DESCRIPTION OF THE INVENTION
    [0040] The present invention is based on the discovery that particulate crystalline materials can be rendered mucoadhesive or bioadhesive, especially in the gastrointestinal tract, when the particles of poorly soluble crystalline therapeutic agents have certain poloxamers adsorbed on their surface. [0040]
    [0041] The invention can be practiced with a wide variety of crystalline agents that are water-insoluble or poorly soluble in water. As used herein “poorly soluble” means that the agent has a solubility in aqueous medium of less than about 10 mg/ml, and preferably of less than about 1 mg/ml, must preferably less than 0.1 mg/ml. Examples of preferred crystalline agents follow. [0041]
    [0042] Therapeutic Agents [0042]
    [0043] Suitable therapeutic agents can be selected from a variety of known classes of drugs which are known to be absorbed across muscous membrances, including, for example, analgesics, anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, antibiotics (including penicillins), anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antifungal agents, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, immunosuppressants, antithyroid agents, antiviral agents, anxiolytic sedatives (hypnotics and neuroleptics), astringents, beta-adrenoceptor blocking agents, cardiac inotropic agents, contrast media, corticosteroids, cough suppressants (expectorants and mucolytics), diagnostic agents, diagnostic imaging agents, diuretics, dopaminergics (antiparkinsonian agents), haemostatics, immunological agents, lipid regulating agents, muscle relaxants, parasympathomimetics, parathyroid calcitonin and biphosphonates, protease inhibitors, prostaglandins, radio-pharmaceuticals, sex hormones (including steroids), anti-allergic agents, stimulants and anoretics, sympathomimetics, thyroid agents, vasodilators and xanthines. [0043]
    [0044] Especially preferred are those drugs that are absorbed in the GI tract, such drugs, include, for example, antacids, anti-inflammatory agents, antibiotics (including penicillins), antimycobacterial agents, antiviral agents, corticosteroids, parasympathomimetics, radio-pharmaceuticals, sympathomimetics, demulcents, emollients, gastrointestinal protectives and adsorbents, antifungals, H2-blocking agents, proton pump inhibitors, muscarinic antagonists, bismuth compounds, sucralfate, carbenoxolone, prostaglandins, digestants, bile acids, laxatives, antiparasitic agents, anthelmintics, antiprotozoal agents, antimicrobial agents, vitamins, immunologic agents, vaccines, anesthetics, lipid-regulating agents and bile acid sequestrants. [0044]
    [0045] A description of these classes of drugs and a listing of species within each class can be found in Martindale, The Extra Pharmacopoeia, Twenty-Ninth Edition, The Pharmaceutical Press, London, 1989, the disclosure of which is hereby incorporated by reference in its entirety. The drug substances are commercially available and/or can be prepared by techniques known in the art. [0045]
    [0046] Preferred therapeutic agents include those intended for oral administration and rectal administration. [0046]
    [0047] Method of Preparing the Particles of the Therapeutics Agents [0047]
    [0048] As used herein, particle size is determined on the basis of weight average particle size as measured by conventional particle size measuring techniques well known to those skilled in the art, such as sedimentation field flow fractionation, photon correlation spectroscopy, or disk centrifugation. In present invention, the weight average particle size of the crystals of therapeutic agent and surface modifier is less than about 2,000 nm, preferred is less than about 1,000 nm, and more preferred is less than about 400 nm. It is particularly preferred that the particles of the present invention have an effective particle size which is less than 2,000 nm, the preferred 1,000 nm or the more preferred 400 nm. By “effective particle size” is meant that at least 90% of the particles in the sample measured by the above-noted weight sizing techniques have a particle size less than the stated size. With reference to the effective particle size, it is more preferred that at least 95% and, even more preferably, at least 99% of the particles have a particle size less than the desired particle size. [0048]
    [0049] The particles of this invention can be prepared in a method comprising the steps of dispersing a therapeutic agent in a liquid dispersion medium and applying mechanical means in the presence of grinding media to reduce the particle size of the therapeutic agent to the desired effective average particle size. The particles are reduced in size in the presence of the poloxamer. Alternatively, the particles can be intimately mixed with a poloxamer after attrition. [0049]
    [0050] A general procedure for preparing the particles of this invention is set forth below. The therapeutic agent is obtained commercially and/or prepared by techniques known in the art in a conventional coarse form. It is preferred, but not essential, that the particle size of the coarse substance selected be less than about 100 microns as determined by sieve analysis. If the coarse particle size of the substance is greater than about 100 microns, then it is preferred that the particles of the substance be reduced in size to less than 100 microns using a conventional milling method such as airjet or fragmentation milling. [0050]
    [0051] The mechanical means applied to reduce the particle size of the substance conveniently can take the form of a dispersion mill. Suitable dispersion mills include a ball mill, an attritor mill, a vibratory mill, and media mills such as a sand mill and a bead mill. A media mill is preferred due to the relatively shorter milling time required to provide the intended result, i.e., the desired reduction in particle size. [0051]
    [0052] The grinding media for the particle size reduction step can be selected from rigid media preferably spherical or particulate in form having an average size less than about 3 mm and, more preferably, less than about 1 mm. Such media desirably can provide the particles of the invention with shorter processing times and impart less wear to the milling equipment. The selection of material for the grinding media is not believed to be critical. We have found that zirconium oxide, such as 95% ZrO stabilized with magnesia, zirconium silicate and glass grinding media provide particles having levels of contamination which are believed to be acceptable for the preparation of pharmaceutical compositions. However, other media, such as stainless steel, titania, alumina, and 95% ZrO stabilized with yttrium, are expected to be useful. Preferred media have a density greater than about 3 g/cm[0052] 3.
    [0053] The attrition time can vary widely and depends primarily upon the particular mechanical means and processing conditions selected. For ball mills, processing times of up to five days or longer may be required. On the other hand, processing times of less than 1 day (residence times of one minute up to several hours) have provided the desired results using a high shear media mill. [0053]
    [0054] The particles must be reduced in size at a temperature which does not significantly degrade the therapeutic agent. Processing temperatures of less than about 30°-40° C. are ordinarily preferred. If desired, the processing equipment can be cooled with conventional cooling equipment. The method is conveniently carried out under conditions of ambient temperature and at processing pressures which are safe and effective for the milling process. For example, ambient processing pressures are typical of ball mills, attritor mills and vibratory mills. Processing pressures up to about 20 psi (1.4 kg/cm[0054] 2) are typical of media milling.
    [0055] The particle size was determined during the milling process and again immediately before the suspensions were administered. Particle size was determined on the Coulter Model N4MD Submicron Particle Analyzer (Coulter Corp.; Miami Lakes, Fla.); and using the Microtrac Ultrafine Particle Analyzer (Leeds and Northrup Co.; St. Petersburg, Fla.). [0055]
    [0056] The following formulation examples will further illustrate the present invention. [0056] Example 1Paclitaxol 10 g Pluronic F108 5.0 g Benzoate Sodium 0.2 g Saccharin Sodium 0.1 g FD & C Red No. 40 0.03 g Water, qs 100 ml Example 2Naproxen 5.0 g Pluronic F68 3.0 g Benzoate Sodium 0.2 g Sorbate Potassium 0.15 g Saccharin Sodium 0.1 g FD & C Red No. 40 0.03 g Water, qs 100 ml Example 3Griseofulvin 5.0 g Pluronic F127 2.5 g Benzoate Sodium 0.2 g Saccharin Sodium 0.1 g FD & C Red No. 3 0.03 g Water, qs 100 ml Example 4Paclitaxol 0.5 g Sucrose 10 g Pluronic F87 .25 g Dioctylsulfosuccinate 0.1 g Methylparabens 0.2 g Propylparabens 0.07 g FD & C Yellow No. 5 0.03 g Water, qs 100 ml Example 5Phenytoin 5.0 g Pluronic F108 2.5 g Sorbitol 5 g Benzoate Sodium 0.2 g Water, qs 100 ml
    [0057] The following Table 2 is a listing of formulations comprised of particles of therapeutic agents produced by wet grinding in the presence of the poloxamer listed which resulted in the particles having the poloxamer absorbed on the surface thereof. The weight average particle size of the resulting particles is also provided [0057] TABLE 2 Particle Size Therapeutic Therapeutic % Weight Agent Agent % Poloxamer Poloxamer Average naproxen 5% F-68 3.0% 270 nm indomethacin 5% F-68 1%   228 nm indomethacin 5% F-68 2.5% 193 nm ibuprofen 3% F-68 2.0% 253 nm phenytoin 5% F-68 2.5% 385 nm phenytoin 5% F-108 2.5% 385 nm phenytoin 5% F-127 2.5% 431 nm griseofulvin 5% F-68 2.5% 617 nm griseofulvin 5% F-127 2.5% 617 nm amphotericin B 5% F-68 2.5% 426 nm amphotericin B 5% F-127 2.5% 510 nm methotrexate 5% F-68 2.5% 196 nm methotrexate 5% F-127 2.5% 248 nm beclomethasone 5% F-68 2.5% 221 nm dipropionate beclomethasone 5% F-127 2.5% 244 nm dipropionate cyclosporine 5% F-127  4.75% 262 nm cyclosporine 5% F-127 2.5% 245 nm cyclosporine 5% F-127 1.0% 240 nm cyclosporine 5% F-127 0.5% 242 nm camptothecin 2% F-68 2%   107 nm camptothecin 2% F-108 1%   111 nm busulfan 2% F-108 0.5% 387 nm piposulfan 2% F-108 0.5% 339 nm paclitaxol   0.5% F-68  0.13% 172 nm paclitaxol   0.5% F-68  0.25% 247 nm paclitaxol   0.5% F-87  0.25% 225 nm paclitaxol   0.5% F-108 0.2% 195 nm paclitaxol   0.5% F-108  0.13% 165 nm paclitaxol   0.5% F-108 0.5% 190 nm paclitaxol   0.5% F-108 0.4% 190 nm paclitaxol   0.5% F-108  0.25% 206 nm paclitaxol   0.5% F-108 0.3% 189 nm paclitaxol 1% F-108 0.5% 143 nm paclitaxol 2% F-108 1%   137 nm paclitaxol 5% F-108 5%   197 nm paclitaxol 5% F-108  1.25% 142 nm paclitaxol 5% F-108 2.5% 173 nm paclitaxol   2.3% F-108  1.15% 275 nm paclitaxol 6% F-108 3%   175 nm paclitaxol 10%  F-108 5%   169 nm
    [0058] Determining Mucoadhesion Efficacy in the GI Tract [0058]
    [0059] The amount and site of the mucoadhesion was determined by x-ray diagnostic imaging. The imaging was performed in anesthetized rats with the exception of G05-R1 samples which were imaged in fasted and anesthetized ferrets. Images were obtained using the Siemens C-Arm Siremobil 3U x-ray unit. The imaging dose was 10 ml/kg administered via gastric intubation to the anesthetized animal. X-rays were taken at 15, 30, 45 and 60 minutes and at 1, 2, 5 and 24 hours post-dose. A 10-15 ml volume of air was introduced to the animal at 30 minutes to produce a double contrast image. [0059]
    [0060] Images were evaluated by the criteria of: coating, homogeneity, rate of gastric emptying and the total transit time. These are considered to be a measure of the stability of the suspension during transit down the GI tract and the ability of the formulation to adhere to the lower gastrointestinal tract. Suspensions were rated excellent when there was a uniform coating with transradiation of long intestinal segments, sufficient radiodensity to delineate anatomical structure, rapid emptying and transit, and stability and homogeneity during GI transit. A plus sign (+) was assigned when imaging in the lower GI was exceptional, a minus sign (−) as given when it was not. The suspension of the imaging agent [WIN 8883, ethyl 3,5-bis(acetylamino)-2,4,6-triodobenzoate], milled in Pluronic F127, was considered to be excellent for both upper and lower GI imaging in both rats and ferrets. All other suspensions were compared with this formulation. [0060]
    [0061] The efficacy of the particulate formulations to image the GI tract is shown in Table 3. [0061] TABLE 3 Imaging Efficacy of Particulate Formulations Prepared with Pluronic F127 Aqueous Particle Imaging Solubility Days Milling Size Efficacy Code WIN No. (μg/ml) Milled Process(a) (nm)(b) Range(c) (d,e)GO5 8883 <5 1.8 P 186/ND Narrow ++++(*) GO5 R2 8883 <5 5   JM 135/ND 80-230 ++++(*)
    [0062] Efficacy of Particle Formulations Prepared with Alternate Stabilizers [0062]
    [0063] The imaging efficacy of suspension formulations with alternate stabilizers are shown in Table 4. DOSS is Diioctylsulfosuccinate and was used as a secondary stabilizer is some formulations. [0063]
    [0064] Excellent imaging was obtained from suspensions of WIN 8883 stabilized with Pluronic F77 with 0.1% DOSS added (G29) and with Pluronic F88 (GO4), however, these suspensions did not image the lower GI as effectively as GO5. [0064]
    [0065] Good imaging was obtained from suspensions of WIN 8883 stabilized with F88 with 0.1% DOSS (G27), and F87 (G26). Good upper GI imaging was obtained from suspensions of WIN 8883 stabilized with F98 (G14), F108 (G15) and F68 with 0.1% w/v DOSS (G23). Fair imaging was obtained from the WIN 8883 suspensions stabilized F87 with 1% w/v DOSS (G25). Poor imagining was obtained when no stabilizer was used (GO2) and the formulation with F77 alone (G28) gelled during milling and therefore was not imaged. [0065]
    [0066] DOSS was needed to stabilize the suspension prepared in 4% w/v Pluronic F77 (G29). The same formulation without DOSS could not be imaged due to gelling during the milling process. [0066]
    [0067] DOSS had variable effects when used in conjunction with other stabilizers. The suspension stabilized with F88 (GO4) was rated as excellent. When 0.1% w/v DOSS was used as a secondary stabilizer (G24), the imaging efficacy was rated only as good. A similar result was noted with suspensions stabilized with F87. The suspension without DOSS (G26) was rated higher in imaging efficacy than did the same suspension with 0.1% w/v DOSS (G25). Suspensions stabilized with 4% w/v tyloxapol plus 0.1% w/v DOSS (G27) or without DOSS (G20) were both rated good. Milling time, however, was reduced and overall particle size was smaller with the DOSS-added suspension. [0067] TABLE 4 Imaging Efficacy of Diagnostic Agents Prepared with Poloxamer and Alternative Stabilizers Particle Imaging Stabilizer Days Milling Size Efficacy I.D. (w/v) Milled Process (nm)(b) Range(c) (d,e,f)GO2 None 6 JM 1000/ND Broad + GO5 4% F127   1.8 P 186/ND Narrow ++++(*) G29 4% F77/0.1% 5 JM 146/187 66-243 ++++ DOSS EGO4 4% F88   1.8 P 183/ND Narrow ++++(−)G21 4% PVA 6 JM 204/199 134-405 +++(*) G26 4% F87 5 JM 155  55-265 +++ G20 4% Tyloxapol 6 JM 180/262 137-521 +++ G22(f) 2% HPMC 6 JM 334/700  350-2596 +++ G24 4% F88/0.1% 5 JM 160 146-265 +++ DOSS G27 4% 5 JM 140  66-315 +++ Tyloxapol/ 0.1% DOSS G23 5% F68/0.1% 4 JM 147/170 108-602 +++(−) DOSS GO3 4% Tween 80 6 JM 161/ND Narrow ++ G18(f) 1% DOSS 4 JM 119/130  85-247 ++ G19(f) 4% PVP 5 JM 673/823  620-1265 ++ G25 4% F87/0.1% 5 JM 150  66-243 ++ DOSS
    [0068] [0068] TABLE 5 Comparison of Efficacy Between Pluronic F88 and Pluronic F127 Milling Particle Imaging Days Process Size Efficacy I.D. WIN No Pluronic Milled (a) (nm)(b) Range(c) (d,e)GO5 8883 F127 1.8 P 186/ND Narrow ++++(*) GO4 8883 F88 1.8 P 183/ND Narrow ++++(−)
    [0069] Summarizing the above-described test results, many different stabilizers were examined using suspensions of WIN 8883, of these, Pluronic F127 was considered excellent for imaging both the upper and lower GI. A suspension stabilized with F88 was judged as excellent but for the upper GI only. [0069]
    [0070] These studies indicate the site at which certain mucoadhesive stabilizers accrete, thus the formulator can use these studies to determine which stabilizer to utilize with a particular therapeutic agent in order to have the particles accrete at the desired site. [0070]
    [0071] The invention being thus described, it will be obvious that the same may be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the invention, and all such modifications as would be obvious to one skilled in the art are intended to be included within the scope of the following claims. [0071]
    权利要求:
    Claims (7)
    [1" id="US-20010006617-A1-CLM-00001] 1. A therapeutic formulation comprising:
    a—of from about 0.1 to about 45% w/v of particles of an poorly water soluble crystalline therapeutic agent having an weight average particle size of less than about 2,000 nm;
    b—of from about 0.1 to about 10% w/v of a poloxamer, the poloxamer absorbed on the surface of the particle and having the formula
    (polyethylene oxide)a−(polypropylene oxide)b−(polyethylene oxide)c
    wherein
    a is 46 to 128;
    b is 16 to 67; and
    c is 46 to 128; and
    c—water to make 100% w/v.
    [2" id="US-20010006617-A1-CLM-00002] 2. A therapeutic formulation comprising:
    a—of from about 0.5% to about 15% w/v of particles of a poorly soluble therapeutic agent, the particles having a weight average particle size of less than about 1,000 nm;
    b—of from about 0.25% to about 5% w/v of a poloxamer, the poloxamer absorbed on the surface of the particle and having the formula
    (polyethylene oxide)a−(polypropylene oxide)b−(polyethylene oxide)c
    wherein
    a is 46, 52, 62, 75, 97, 98, 122 and 128;
    b is 16, 30, 35, 39, 47, 54 and 67; and
    c is 46, 52, 62, 75, 97, 98, 122 and 128; and
    c—water to make 100% w/v.
    [3" id="US-20010006617-A1-CLM-00003] 3. The particles of
    claim 1 wherein said drug substance is selected from analgesics, anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, antibiotics, anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antifungal agents, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, immunosuppressants, antithyroid agents, antiviral agents, anxiolytic sedatives, astringents, beta-adrenoceptor blocking agents, cardiac inotropic agents, contrast media, corticosteroids, cough suppressants, diagnostic agents, diagnostic imaging agents, diuretics, dopaminergics, haemostatics, immunological agents, lipid regulating agents, muscle relaxants, parasympathomimetics, parathyroid calcitonin, biphosphonates, protease inhibitors, prostaglandins, radio-pharmaceuticals, sex hormones, steroids, anti-allergic agents, stimulants, sympathomimetics, thyroid agents, vasodilators and xanthines.
    [4" id="US-20010006617-A1-CLM-00004] 4. The formulation of
    claim 1 further comprising up to 1% w/v of a secondary stabilizer selected from the group consisting of dioctylsulfosuccinate and sodium lauryl sulfate.
    [5" id="US-20010006617-A1-CLM-00005] 5. An orally/rectally administrable gastrointestinal therapeutic formulation comprising:
    a—of from about 0.1 to about 45% w/v of particles of an poorly water soluble crystalline therapeutic agent having an weight average particle size of less than about 2,000 nm;
    b—of from about 0.1 to about 10% w/v of a poloxamer, the poloxamer absorbed on the surface of the particle and having the formula
    (polyethylene oxide)a−(polypropylene oxide)b−(polyethylene oxide)c
    wherein
    a is 46 to 128;
    b is 16 to 67; and
    c is 46 to 128; and
    c—water to make 100% w/v.
    [6" id="US-20010006617-A1-CLM-00006] 6. The therapeutic formulation of
    claim 5 comprising:
    a—of from about 0.5% to about 15% w/v of particles of a poorly soluble therapeutic agent, the particles having a weight average particle size of less than about 1,000 nm;
    b—of from about 0.25% to about 5% w/v of a poloxamer, the poloxamer absorbed on the surface of the particle and having the formula
    (polyethylene oxide)a−(polypropylene oxide)b−(polyethylene oxide)c
    wherein
    a is 46, 52, 62, 75, 97, 98, 122 and 128;
    b is 16, 30, 35, 39, 47, 54 and 67; and
    c is 46, 52, 62, 75, 97, 98, 122 and 128; and
    c—water to make 100% w/v.
    [7" id="US-20010006617-A1-CLM-00007] 7. The therapeutic formulation of
    claim 5 wherein said drug is selected from the group consisting of: antacids, anti-inflammatory agents, antibiotics (including penicillins), antimycobacterial agents, antiviral agents, corticosteroids, parasympathomimetics, radio-pharmaceuticals, sympathomimetics, demulcents, emollients, gastrointestinal protectives and adsorbents, antifungals, H2-blocking agents, proton pump inhibitors, muscarinic antagonists, bismuth compounds, sucralfate, carbenoxolone, prostaglandins, digestants, bile acids, laxatives, antiparasitic agents, anthelmintics, antiprotozoal agents, antimicrobial agents, vitamins, immunologic agents, vaccines, anesthetics, lipid-regulating agents and bile acid sequestrants.
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US20050158299A1|2003-10-29|2005-07-21|Margolin Alexey L.|Non-pancreatic proteases for controlling plasma cholecystokininconcentration and for treating pain|
    EP1661558A1|2004-11-30|2006-05-31|Basf Aktiengesellschaft|Compositions based on micro-prilled poloxamer particles and methods for their manufacturing|
    US20070224279A1|2001-09-14|2007-09-27|Elan Pharma International Ltd.|Stabilization of chemical compounds using nanoparticulate formulations|US4107288A|1974-09-18|1978-08-15|Pharmaceutical Society Of Victoria|Injectable compositions, nanoparticles useful therein, and process of manufacturing same|
    EP0093757A1|1981-11-12|1983-11-16|Ulf SCHRÖDER|Intravascularly administrable, magnetically responsive nanosphere or nanoparticle, a process for the production thereof, and the use thereof|
    US5015452A|1986-11-17|1991-05-14|Clarkson University|Process for synthesis of uniform colloidal particles of rare earth oxides|
    FR2608988B1|1986-12-31|1991-01-11|Centre Nat Rech Scient|PROCESS FOR THE PREPARATION OF COLLOIDAL DISPERSIBLE SYSTEMS OF A SUBSTANCE, IN THE FORM OF NANOPARTICLES|
    US5145684A|1991-01-25|1992-09-08|Sterling Drug Inc.|Surface modified drug nanoparticles|
    AU642066B2|1991-01-25|1993-10-07|Nanosystems L.L.C.|X-ray contrast compositions useful in medical imaging|
    US5342605A|1992-05-01|1994-08-30|Sterling Winthrop Inc.|Polymeric X-ray compositions containing iodinated polymeric beads|
    US5318768A|1992-05-01|1994-06-07|Sterling Winthrop Inc.|Polymeric x-ray contrast compositions containing an organic crystalline x-ray contrast agent|
    US5346702A|1992-12-04|1994-09-13|Sterling Winthrop Inc.|Use of non-ionic cloud point modifiers to minimize nanoparticle aggregation during sterilization|
    US5298262A|1992-12-04|1994-03-29|Sterling Winthrop Inc.|Use of ionic cloud point modifiers to prevent particle aggregation during sterilization|
    US5340564A|1992-12-10|1994-08-23|Sterling Winthrop Inc.|Formulations comprising olin 10-G to prevent particle aggregation and increase stability|
    US5336507A|1992-12-11|1994-08-09|Sterling Winthrop Inc.|Use of charged phospholipids to reduce nanoparticle aggregation|
    US5326552A|1992-12-17|1994-07-05|Sterling Winthrop Inc.|Formulations for nanoparticulate x-ray blood pool contrast agents using high molecular weight nonionic surfactants|
    US5326553A|1993-02-02|1994-07-05|Sterling Winthrop Inc.|Compositions of iodophenoxy alkanes and iodophenyl ethers in film-forming materials for visualization of the gastrointestinal tract|
    US5310538A|1993-03-11|1994-05-10|Sterling Winthrop Inc.|Compositions of iodophenoxy alkylene ethers in film-forming materials for visualization of the gastrointestinal tract|
    US5312616A|1993-03-11|1994-05-17|Sterling Winthrop Inc.|Compositions of iodobenzoic acid derivatives in film-forming materials for visualization of the gastrointestinal tract|
    US5336484A|1993-03-31|1994-08-09|Sterling Winthrop Inc.|Compositions of iodophenyl esters and iodophenyl sulfonates in film-forming materials for visualization of the gastronintestinal tract|
    US5368837A|1994-04-14|1994-11-29|Sterling Winthrop Inc.|X-ray contrast compositions containing an organic crystalline X-ray contrast agent and a cellulose derivative|
    US5466440A|1994-12-30|1995-11-14|Eastman Kodak Company|Formulations of oral gastrointestinal diagnostic X-ray contrast agents in combination with pharmaceutically acceptable clays|CA2185653C|1994-03-16|2009-01-13|Kathleen M. Miller|Stabilization of peptides and proteins for radiopharmaceutical use|
    US20050004049A1|1997-03-11|2005-01-06|Elan Pharma International Limited|Novel griseofulvin compositions|
    AT274341T|1995-02-24|2004-09-15|Elan Pharma Int Ltd|AEROSOLS CONTAINING NANOPARTICLE DISPERSIONS|
    ES2112765B1|1995-08-02|1999-03-01|Cantabria Ind Farmaceutica Sa|PROCEDURE FOR OBTAINING RADIOLOGICAL CONTRAST FORMULATIONS, FOR GASTROINTESTINAL EXPLORATIONS FOR EXTEMPORARY AND DIRECT USE.|
    US5879715A|1997-09-02|1999-03-09|Ceramem Corporation|Process and system for production of inorganic nanoparticles|
    EE04144B1|1997-11-17|2003-10-15|Janssen Pharmaceutica N.V.|A pharmaceutical composition and its use|
    US20040141925A1|1998-11-12|2004-07-22|Elan Pharma International Ltd.|Novel triamcinolone compositions|
    US8293277B2|1998-10-01|2012-10-23|Alkermes Pharma Ireland Limited|Controlled-release nanoparticulate compositions|
    US8236352B2|1998-10-01|2012-08-07|Alkermes Pharma Ireland Limited|Glipizide compositions|
    US20080213378A1|1998-10-01|2008-09-04|Elan Pharma International, Ltd.|Nanoparticulate statin formulations and novel statin combinations|
    US20040115134A1|1999-06-22|2004-06-17|Elan Pharma International Ltd.|Novel nifedipine compositions|
    US20110064803A1|2005-05-10|2011-03-17|Elan Pharma International Limited.|Nanoparticulate and controlled release compositions comprising vitamin k2|
    US20090297602A1|1998-11-02|2009-12-03|Devane John G|Modified Release Loxoprofen Compositions|
    JP2009517485A|2005-06-08|2009-04-30|エラン・ファルマ・インターナショナル・リミテッド|Nanoparticulate and controlled release compositions containing cefditoren|
    RU2236847C2|1998-11-02|2004-09-27|Илан Корпорейшн, Плк.|Composition as multiple particles with modified release|
    US9616150B2|1999-10-29|2017-04-11|Children's Hospital Los Angeles|Bone hemostasis method and materials|
    KR20010045671A|1999-11-05|2001-06-05|강경석|Radiopaque Markers for Radiorogy Examinations|
    US7089934B2|2000-02-28|2006-08-15|Vectura Limited|Delivery of oral drugs|
    US7198795B2|2000-09-21|2007-04-03|Elan Pharma International Ltd.|In vitro methods for evaluating the in vivo effectiveness of dosage forms of microparticulate of nanoparticulate active agent compositions|
    US7998507B2|2000-09-21|2011-08-16|Elan Pharma International Ltd.|Nanoparticulate compositions of mitogen-activated proteinkinase inhibitors|
    US6375986B1|2000-09-21|2002-04-23|Elan Pharma International Ltd.|Solid dose nanoparticulate compositions comprising a synergistic combination of a polymeric surface stabilizer and dioctyl sodium sulfosuccinate|
    US20080241070A1|2000-09-21|2008-10-02|Elan Pharma International Ltd.|Fenofibrate dosage forms|
    US6969529B2|2000-09-21|2005-11-29|Elan Pharma International Ltd.|Nanoparticulate compositions comprising copolymers of vinyl pyrrolidone and vinyl acetate as surface stabilizers|
    US6623761B2|2000-12-22|2003-09-23|Hassan Emadeldin M.|Method of making nanoparticles of substantially water insoluble materials|
    US6976647B2|2001-06-05|2005-12-20|Elan Pharma International, Limited|System and method for milling materials|
    JP2005504266A|2001-06-22|2005-02-10|エランファーマインターナショナル，リミティド|High-throughput screening methods using small-scale mills or microfluidics|
    US7758890B2|2001-06-23|2010-07-20|Lyotropic Therapeutics, Inc.|Treatment using dantrolene|
    JP4464129B2|2001-09-19|2010-05-19|エランファーマインターナショナル，リミティド|Nanoparticulate insulin preparation|
    DE60222160T2|2001-10-12|2008-06-12|Elan Pharma International Ltd., Athlone|COMPOSITIONS COMPRISING PROPERTIES OF IMMEDIATE RELEASE AND CONTROLLED RELEASE|
    JP2005519657A|2001-11-07|2005-07-07|インコール ファーマシューティカル カンパニー|Method of blood vessel imaging using nanoparticulate contrast agent|
    US20030129242A1|2002-01-04|2003-07-10|Bosch H. William|Sterile filtered nanoparticulate formulations of budesonide and beclomethasone having tyloxapol as a surface stabilizer|
    WO2003066021A2|2002-02-04|2003-08-14|Elan Pharma International, Ltd.|Drug nanoparticles with lysozyme surface stabiliser|
    US20040101566A1|2002-02-04|2004-05-27|Elan Pharma International Limited|Novel benzoyl peroxide compositions|
    EP1487419A2|2002-03-20|2004-12-22|Elan Pharma International Limited|Fast dissolving dosage forms having reduced friability|
    JP4842514B2|2002-03-20|2011-12-21|エランファーマインターナショナル，リミティド|Nanoparticle composition of angiogenesis inhibitor|
    US20080220075A1|2002-03-20|2008-09-11|Elan Pharma International Ltd.|Nanoparticulate compositions of angiogenesis inhibitors|
    US20040076586A1|2002-03-28|2004-04-22|Reinhard Koening|Compositions and methods for delivering pharmaceutically active agents using nanoparticulates|
    US9101540B2|2002-04-12|2015-08-11|Alkermes Pharma Ireland Limited|Nanoparticulate megestrol formulations|
    US7101576B2|2002-04-12|2006-09-05|Elan Pharma International Limited|Nanoparticulate megestrol formulations|
    US20100226989A1|2002-04-12|2010-09-09|Elan Pharma International, Limited|Nanoparticulate megestrol formulations|
    ES2380318T3|2002-04-12|2012-05-10|Alkermes Pharma Ireland Limited|Megestrol nanoparticular formulations|
    US20040018242A1|2002-05-06|2004-01-29|Elan Pharma International Ltd.|Nanoparticulate nystatin formulations|
    US7276249B2|2002-05-24|2007-10-02|Elan Pharma International, Ltd.|Nanoparticulate fibrate formulations|
    US20030224058A1|2002-05-24|2003-12-04|Elan Pharma International, Ltd.|Nanoparticulate fibrate formulations|
    US20070264348A1|2002-05-24|2007-11-15|Elan Pharma International, Ltd.|Nanoparticulate fibrate formulations|
    WO2003103632A1|2002-06-10|2003-12-18|Elan Pharma International, Ltd.|Nanoparticulate polycosanol formulations and novel polycosanol combinations|
    EP2283864A1|2002-07-16|2011-02-16|Elan Pharma International Ltd.|Liquid dosage compositions fo stable nanoparticulate active agents|
    DK1553927T3|2002-09-11|2011-01-31|Elan Pharma Int Ltd|Gel-stabilized, nanoparticle active ingredient compositions|
    EP1556091A1|2002-10-04|2005-07-27|Elan Pharma International Limited|Gamma irradiation of solid nanoparticulate active agents|
    AT514418T|2002-11-12|2011-07-15|Elan Pharma Int Ltd|RAPIDLY CRACKING SOLID PHARMACEUTICAL FORMS WITH NON-BROKEN CONSISTENCY AND PULLULAN|
    US20040105889A1|2002-12-03|2004-06-03|Elan Pharma International Limited|Low viscosity liquid dosage forms|
    AU2003297151A1|2002-12-17|2004-07-22|Elan Pharma International Ltd.|Milling microgram quantities of nanoparticulate candidate compounds|
    WO2004078162A1|2003-01-31|2004-09-16|Elan Pharma International Ltd.|Nanoparticulate topiramate formulations|
    US20040208833A1|2003-02-04|2004-10-21|Elan Pharma International Ltd.|Novel fluticasone formulations|
    WO2004073654A2|2003-02-20|2004-09-02|Santarus, Inc.|A novel formulation, omeprazole antacid complex-immediate release for rapid and sustained supression of gastric acid|
    US20050220870A1|2003-02-20|2005-10-06|Bonnie Hepburn|Novel formulation, omeprazole antacid complex-immediate release for rapid and sustained suppression of gastric acid|
    US20100297252A1|2003-03-03|2010-11-25|Elan Pharma International Ltd.|Nanoparticulate meloxicam formulations|
    US8512727B2|2003-03-03|2013-08-20|Alkermes Pharma Ireland Limited|Nanoparticulate meloxicam formulations|
    WO2004098649A2|2003-05-06|2004-11-18|Philips Intellectual Property & Standards Gmbh|Apparatus and method for examining an object by means of elastically scattered x-ray radiation and contrast agent|
    EP1626742A1|2003-05-22|2006-02-22|Elan Pharma International Limited|Sterilization of dispersions of nanoparticulate active agents with gamma radiation|
    US8993599B2|2003-07-18|2015-03-31|Santarus, Inc.|Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them|
    JP2007501839A|2003-08-08|2007-02-01|エランファーマインターナショナルリミテッド|New metaxalone composition|
    US20050220881A1|2003-10-10|2005-10-06|Bvm Holding Co.|Pharmaceutical composition|
    WO2005044234A2|2003-11-05|2005-05-19|Elan Pharma International Ltd.|Nanoparticulate compositions having a peptide as a surface stabilizer|
    EP1718303A4|2004-02-10|2010-09-01|Santarus Inc|Combination of proton pump inhibitor, buffering agent, and nonsteroidal anti-inflammatory agent|
    CA2561700A1|2004-04-16|2005-12-15|Santarus, Inc.|Combination of proton pump inhibitor, buffering agent, and prokinetic agent|
    US8815916B2|2004-05-25|2014-08-26|Santarus, Inc.|Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them|
    US8906940B2|2004-05-25|2014-12-09|Santarus, Inc.|Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them|
    GB0414825D0|2004-07-02|2004-08-04|Biostatus Ltd|Gel formulations and uses thereof|
    JP5324098B2|2004-11-16|2013-10-23|アルケルメスファーマアイルランドリミテッド|Injectable nanoparticulate olanzapine formulation|
    UA89513C2|2004-12-03|2010-02-10|Элан Фарма Интернешнл Лтд.|Nanoparticulate raloxifene hydrochloride composition|
    BRPI0519088A2|2004-12-15|2008-12-23|Elan Pharma Int Ltd|nanoparticulate tacrolimus formulations|
    US20060159767A1|2004-12-22|2006-07-20|Elan Pharma International Limited|Nanoparticulate bicalutamide formulations|
    AU2006204083A1|2005-01-06|2006-07-13|Elan Pharma International Ltd.|Nanoparticulate candesartan formulations|
    BRPI0608087A2|2005-02-15|2009-11-10|Elan Pharma Int Ltd|injectable and aerosol formulations of nanoparticulate benzodiazepine|
    CA2598288A1|2005-03-03|2006-09-14|Elan Pharma International Limited|Nanoparticulate compositions of heterocyclic amide derivatives|
    WO2006099121A2|2005-03-10|2006-09-21|Elan Pharma International Limited|Formulations of a nanoparticulate finasteride, dutasteride and tamsulosin hydrochloride, and mixtures thereof|
    EA200701987A1|2005-03-16|2008-02-28|Элан Фарма Интернэшнл Лтд.|STRUCTURES OF NANODISPERSON ANTAGONIST LEUKOTRIEN RECEPTORS / CORTICOSTEROID|
    MX2007011495A|2005-03-17|2007-12-06|Elan Pharma Int Ltd|Nanoparticulate biphosphonate compositions.|
    CA2602341A1|2005-03-23|2006-09-28|Elan Pharma International Limited|Nanoparticulate corticosteroid and antihistamine formulations|
    AU2006235478B2|2005-04-12|2011-07-21|Elan Pharma International Limited|Nanoparticulate and controlled release compositions comprising cyclosporine|
    EP1871345B1|2005-04-12|2012-08-01|Elan Pharma International Limited|Nanoparticulate erlotinib formulations|
    US20060246141A1|2005-04-12|2006-11-02|Elan Pharma International, Limited|Nanoparticulate lipase inhibitor formulations|
    WO2007086914A2|2005-05-10|2007-08-02|Elan Pharma International, Limited|Nanoparticulate clopidogrel formulations|
    US20100028439A1|2005-05-23|2010-02-04|Elan Pharma International Limited|Nanoparticulate stabilized anti-hypertensive compositions|
    WO2006133045A1|2005-06-03|2006-12-14|Elan Pharma International, Limited|Nanoparticulate benidipine compositions|
    CA2610480A1|2005-06-03|2007-05-10|Scott Jenkins|Nanoparticulate acetaminophen formulations|
    AU2006255177A1|2005-06-03|2006-12-14|Elan Pharma International, Limited|Nanoparticulate imatinib mesylate formulations|
    US20070059371A1|2005-06-09|2007-03-15|Elan Pharma International, Limited|Nanoparticulate ebastine formulations|
    CA2611741A1|2005-06-13|2006-12-28|Elan Pharma International, Limited|Nanoparticulate clopidogrel and aspirin combination formulations|
    CA2612384A1|2005-06-15|2006-12-28|Elan Pharma International, Limited|Nanoparticulate azelnidipine formulations|
    US20070015719A1|2005-07-07|2007-01-18|Elan Pharma International Limited|Nanoparticulate clarithromycin formulations|
    US20070104792A1|2005-09-13|2007-05-10|Elan Pharma International, Limited|Nanoparticulate tadalafil formulations|
    WO2007035348A2|2005-09-15|2007-03-29|Elan Pharma International, Limited|Nanoparticulate aripiprazole formulations|
    AU2006318349B2|2005-11-28|2010-08-19|Marinus Pharmaceuticals|Ganaxolone formulations and methods for the making and use thereof|
    US8367112B2|2006-02-28|2013-02-05|Alkermes Pharma Ireland Limited|Nanoparticulate carverdilol formulations|
    EP2040675A1|2006-05-30|2009-04-01|Elan Pharma International Limited|Nanoparticulate posaconazole formulations|
    TW200820991A|2006-07-10|2008-05-16|Elan Pharma Int Ltd|Nanoparticulate sorafenib formulations|
    EP2043623A4|2006-07-12|2013-03-20|Elan Pharma Int Ltd|Nanoparticulate formulations of modafinil|
    AU2007325628A1|2006-11-28|2008-06-05|Marinus Pharmaceuticals|Nanoparticulate formulations and methods for the making and use thereof|
    GB0625322D0|2006-12-19|2007-01-24|Pharmakodex Ltd|Pharmaceutical compositions|
    EP2268265A2|2008-03-21|2011-01-05|Elan Pharma International Limited|Compositions for site-specific delivery of imatinib and methods of use|
    WO2010009075A1|2008-07-14|2010-01-21|The University Of North Carolina At Chapel Hill|Methods and compositions comprising crystalline nanoparticles of hydrophobic compounds|
    US20100081954A1|2008-09-30|2010-04-01|Searete Llc, A Limited Liability Corporation Of The State Of Delaware|Method, device, and system to control pH in pulmonary tissue of a subject|
    EP3045043B1|2009-02-26|2020-04-29|Relmada Therapeutics, Inc.|Extended release oral pharmaceutical compositions of 3-hydroxy-n-methylmorphinan and method of use|
    FR2945950A1|2009-05-27|2010-12-03|Elan Pharma Int Ltd|ANTICANCER NANOPARTICLE COMPOSITIONS AND METHODS FOR PREPARING THE SAME|
    EP3167875A1|2009-05-27|2017-05-17|Alkermes Pharma Ireland Limited|Reduction of flake-like aggregation in nanoparticulate meloxicam compositions|
    US8889193B2|2010-02-25|2014-11-18|The Johns Hopkins University|Sustained delivery of therapeutic agents to an eye compartment|
    WO2011146583A2|2010-05-19|2011-11-24|Elan Pharma International Limited|Nanoparticulate cinacalcet formulations|
    WO2012039979A2|2010-09-10|2012-03-29|The Johns Hopkins University|Rapid diffusion of large polymeric nanoparticles in the mammalian brain|
    EA030318B1|2012-03-16|2018-07-31|Дзе Джонс Хопкинс Юниверсити|Non-linear multiblock copolymer-drug conjugates for the delivery of active agents|
    CA2867381C|2012-03-16|2016-09-20|The Johns Hopkins University|Controlled release formulations for the delivery of hif-1 inhibitors|
    CA2871778A1|2012-05-03|2013-11-07|Kala Pharmaceuticals, Inc.|Pharmaceutical nanoparticles showing improved mucosal transport|
    US9827191B2|2012-05-03|2017-11-28|The Johns Hopkins University|Compositions and methods for ophthalmic and/or other applications|
    US20210386661A1|2012-05-03|2021-12-16|The Johns Hopkins University|Compositions and methods for ophthalmic and/or other applications|
    EP2844227B1|2012-05-03|2020-11-18|Kala Pharmaceuticals, Inc.|Pharmaceutical nanoparticles showing improved mucosal transport|
    US9889208B2|2012-05-04|2018-02-13|The Johns Hopkins University|Lipid-based drug carriers for rapid penetration through mucus linings|
    WO2014124006A1|2013-02-05|2014-08-14|The Johns Hopkins University|Nanoparticles for magnetic resonance imaging tracking and methods of making and using thereof|
    法律状态:
    1997-10-03| AS| Assignment|Owner name: NANOSYSTEMS L.L.C., PENNSYLVANIA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:LIVERSIDGE, GARY G.;EICKHOFF, W. MARK;ILLIG, KATHLEEN J.;AND OTHERS;REEL/FRAME:008777/0980;SIGNING DATES FROM 19970825 TO 19970917 |
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    优先权:
    申请号 | 申请日 | 专利标题
    US08/366,841|US5628981A|1994-12-30|1994-12-30|Formulations of oral gastrointestinal diagnostic x-ray contrast agents and oral gastrointestinal therapeutic agents|
    US08/815,346|US6432381B2|1994-12-30|1997-03-11|Methods for targeting drug delivery to the upper and/or lower gastrointestinal tract|US08/815,346| US6432381B2|1994-12-30|1997-03-11|Methods for targeting drug delivery to the upper and/or lower gastrointestinal tract|
    US10/175,851| US20030054045A1|1994-12-30|2002-06-21|Formulations for therapeutic agents absorbed through mucous membranes|
    US10/683,154| US20050004049A1|1997-03-11|2003-10-14|Novel griseofulvin compositions|
    US11/546,378| US20070098805A1|1997-03-11|2006-10-12|Methods of making and using novel griseofulvin compositions|
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