WO1996020734A2 - Oral gastrointestinal x-ray contrast agents in combination with pharmaceutically acceptable clays and surfactants - Google Patents
Oral gastrointestinal x-ray contrast agents in combination with pharmaceutically acceptable clays and surfactants Download PDFInfo
- Publication number
- WO1996020734A2 WO1996020734A2 PCT/US1995/016446 US9516446W WO9620734A2 WO 1996020734 A2 WO1996020734 A2 WO 1996020734A2 US 9516446 W US9516446 W US 9516446W WO 9620734 A2 WO9620734 A2 WO 9620734A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- win
- acetylamino
- bis
- triiodo
- barium
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
- A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
- A61K49/0409—Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is not a halogenated organic compound
- A61K49/0414—Particles, beads, capsules or spheres
- A61K49/0423—Nanoparticles, nanobeads, nanospheres, nanocapsules, i.e. having a size or diameter smaller than 1 micrometer
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
- A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
- A61K49/0438—Organic X-ray contrast-enhancing agent comprising an iodinated group or an iodine atom, e.g. iopamidol
Definitions
- This invention relates to x-ray diagnostic imaging contrast formulations for imaging the gastrointestinal (hereinafter sometimes referred to as GI) tract
- GI gastrointestinal
- the formulations described herein have enhanced utility as oral/rectal GI diagnostic contrast agents.
- Barium sulfate formulations to image the gastrointestinal tract of patients.
- Barium sulfate can be given either orally to visualize the stomach and upper GI tract or rectally to visualize the colon and lower GI tract.
- Barium sulfate is usually administered as a suspension that has limited stability even with the addition of stabilizers, it is often too opaque to visualize all segments of the GI tract it often forms clumps that yield resultant radiopaque areas on x-ray films and has poor patient acceptability characteristics.
- Barium sulfate also shows poor affinity for coating the GI mucosa and consequently the patient is often needed to be manipulated or even rotated to ensure that the barium sulfate suspension coats the gastric mucosa. Nevertheless, segments of the GI tract are often either obscured or are not adequately coated to be visualized. It is not uncommon for the patient to undergo repeated examininations to achieve satisfactory imaging results.
- barium sulfate The most serious failings of currently available formulations of barium sulfate are that they do not adequately coat the entire GI tract, requiring subsequent examination, and they pose safety concerns especially with patients that are suspected of having intestinal perforations or obstructions. Perforations of the upper GI tract or small bowel occurs with sufficient frequency that the risk of localized tissue injury is present. It is also not uncommon for orally administered barium sulfate to accumulate proximally to an obstruction in the bowel causing impaction that can lead to eventual perforation of the GI tract. In addition, aspiration of barium sulfate in the lungs may cause occlusion of the bronchioli and resultant pulmonary sequela.
- Aqueous barium sulfate formulations are less constipating than non-aqueous barium sulfate formulations, however, they are often hypertonic, and consequently are irritating to the gastric mucosa.
- Oil based emulsions of iodinated organic substances Another class of compounds that have been investigated for imaging the GI tract are oil based emulsions of iodinated organic substances. Emulsions that have particle sizes of ⁇ 0.3 microns have been reported to image the small intestines of dogs but 50-70% of the oil based emulsions are reported to be absorbed from the intestine. Oily emulsions also appear to coat to some extent both the upper and lower segments of the GI tract as compared with non-oil based contrast agents. Oily emulsions are not usually contraindicated for patients with intestinal perforations or with intestinal obstructions. The major problems associated with these oil based emulsions is their tendency to be absorbed from the GI tract and the inherent toxicity that may be associated with the absorption of these agents.
- Emulsions such as PANTOPAQUE adhere to the gastric mucosa, have low viscosity, low surface tension, are miscible with tissue fluids and exhibit good radiopacity.
- PANTOPAQUE i.e., ethyl iodophenylundecylate
- adhere to the gastric mucosa have low viscosity, low surface tension, are miscible with tissue fluids and exhibit good radiopacity.
- the emulsions of these organic iodinated substances suffer from their undesirable toxic effects.
- GI diagnostic x-ray contrast agents that enable the visualization of both the upper and lower GI tract following a single administration, that is safe and efficacious and is not contraindicated for GI tract perforations and/or obstructions.
- Such an agent should have excellent mucosal coating properties for both the upper and lower GI tract, i.e. it should have mucoadhesive or bioadhesive properties that enable the entire GI tract to be visualized.
- the object of the present invention is to provide a formulation that enhances the imaging of the GI tract that takes into consideration the physical-chemical properties of the imaging agents, surface stabilizers and viscosity modifiers.
- 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.
- safe and effective x-ray contrast agents for visualizing the GI tract it is important to identify mucosal adhesives that coat the GI surfaces and visualize diseased or abnormal tissues.
- 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 Debvery; Method to Study Bioadhesion. Int. J. Pharm., 19, 107 (1984).
- 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 the GI tract must interact with the mucus layer during attachment.
- Mucus a general term for the heterogenous secretion found on the epithelial surfaces of the GI tract, 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 GI tract. 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 formulating an oral contrast x-ray agent for GI tract visualization. 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.
- Crystalline x-ray contrast agents do not inherently adhere to the mucosal surfaces of the GI tract. It has now been discovered that crystalline x-ray contrast agents modified by the addition of surfactants, however, can be rendered so that they adsorb onto the GI mucosal surface. This is achieved by the use of mucoadhesive surfactants.
- the primary difficulty with previously reported mucoadhesive surfactants is that they do not interact effectively with both the particles and GI tract uniformly so that both the upper and lower GI tract can be visualized by a single agent during one examination.
- the surfactants used for this purpose must adsorb sufficiently to the different regions of the GI tract to enhance visualization by the contrast agent.
- crystalline x-ray contrast agents modified by the addition of mucoadhesive surfactants in combination with certain pharmaceutically acceptable clays further enhance the GI imaging characteristics of formulations and render the formulations more palatable to the patient and possess better suspension properties.
- a method for x-ray diagnostic imaging of the GI tract which comprises orally or rectally administering to the patient an effective amount contrast producing amount of the above-described x-ray contrast compositions.
- a method for diagnostic imaging of the GI tract for use in medical procedures in accordance with this invention comprises orally or rectally administering to the mammalian patient in need of x-ray examination, an effective contrast producing amount of a composition of the present invention. After administration, at least a portion of the GI tract containing the administered composition is exposed to x-rays to produce an x-ray image pattern corresponding to the presence of the contrast agent, then the x-ray image is visualized and interpreted using techniques known in the art
- an orally/rectally administrable gastrointestinal diagnostic x-ray contrast formulation comprising: of from about 4 to about 45% w/v, and preferably of from about 15 to about 25% w/v, of an essentially water insoluble or poorly water-soluble particulate radiopaque crystalline material having an effective average particle size of less than about 2,000 nm, more preferably an effective average particle size of less than about 1,000 nm, and most preferably an effective average particle size of less than about 400 nm; of from about 0.5 to about 10% w/v, and preferably of from about 2 to about 6% w/v of a bioadhesive or mucoadhesive surfactant stabilizer (hereinafter sometimes referred to as "primary stabilizer");
- primary stabilizer a bioadhesive or mucoadhesive surfactant stabilizer
- Secondary stabilizers may also be used in the x-ray contrast formulation 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).
- ingredients customarily used in oral pharmaceutical formulations may also be included, such as flavorants, colorants and preservatives to provide pharmaceutically acceptable and palatable formulations without such additional ingredients affecting the gastrointestinal imaging efficacy of the formulations.
- the paniculate radiopaque material used in the present invention include barium salts known for use in diagnostic imaging formulations.
- the surfactants found to have bioadhesive or mucoadhesive properties include:
- Poloxamers are polyethylene-polypropylene glycol block polymers containing ethylene oxide (PEO) and propylene oxide (PPO) moles according to the formula (PEO)a - (PPO)b - (PEO)c wherein
- a is 46, 52, 62, 75, 97, 98, 122 and 128;
- b is 16, 30, 35, 39, 47, 54 and 67;
- c is 46, 52, 62, 75, 97, 98, 122 and 128.
- Table 1 shows the various poloxamers by manufacturer-designated number.
- Preferred surfactants for use in the present invention are:
- 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).
- ingredients customarily used in oral pharmaceutical formulations may also be included, such as flavorants, colorants and preservatives to provide pharmaceutically acceptable and palatable formulations.
- the present invention is based on the discovery that particulate crystalbne materials can be rendered mucoadhesive or bioadhesive in the gastrointestinal tract when the paniculate crystalline material is combined with certain surface active agents in a suspension.
- the invention can be practiced with a wide variety of crystalline materials that are water-insoluble or poorly soluble in water.
- poorly soluble means that the material has a solubibty in aqueous medium of less than about 10 mg/ml, and preferably of less than about 1 mg/ml. Examples of preferred radiopaque crystalline materials follow.
- a preferred x-ray contrast agent utibzed in the present invention is barium sulfate which is a white, radiopaque, crystalline powder that is essentially insoluble in water. It is commercially available in the particle size range of 0.001 to 0.1 mm diameter. Smaller particle size may also be obtained with techniques known in the prior an such as described in U.S. Patent No.5,145,684 which is incorporated herein by reference, or analogously, as described herein with respect to other crystalline radiopaque compounds.
- barium hexaboride barium chromite, barium fluogallate, barium tri-ortho phosphate, barium metasibcate, barium titanate and barium zirconate.
- Preferred organic radiopaque crystalline compounds of the present invention include, but are not bmited to the following compounds.
- 1,3,5-Triethyl-2,4,6-triiodobenzene was prepared in 56% yield from triethylbenzene (5.0 g, 31.4 mmol), [bis(trifluoroacetoxy)iodo]benzene (21.2 g, 49.2 mmol), and iodine (12.5 g, 47.2 mmol) in 50 ml of CCI 4 . Recrystalhzation from cyclohexane gave 9.5 g of pure material.
- Title Compound: 1 H (300 MHz) and 13 C (75 MHz) NMR spectra were consistent with the desired product. Calculated for C 12 H 15 I 3 : C 26.69, H 2.80, 1 70.51 ; Found: C 26.84, H 2.54, 1 70.39.
- 6-Ethoxy-6-oxohexyl 3,5-bis(acetylamino)-2,4,6-triiodobenzoate (WIN 67722) was prepared as follows.
- the radiopaque particulates were prepared by milling the large radiopaque particles mixed with an appropriate surface active agent to obtain the desired particle size.
- the large radiopaque particulates may be comminuted to the desired particle size and subsequently intimately mixed with the appropriate surface active agent. The milling technique is described in U.S. Patent No.
- particle size refers to a number average particle size as measured by conventional particle size measuring techniques web known to those skilled in the art, such as sedimentation field flow fractionation, photon correlation spectroscopy, or disk centrifugation.
- an effective average particle size of less than about 400 nm for example, it is meant that at least 90% of the particles have a weight average particle size of less than about 400 nm when measured by the above-noted techniques.
- the effective average particle size it is preferred that at least 95% and, more preferably, at least 99% of the particles have a particle size less than the effective average, e.g., 400 nm. In particularly preferred embodiments, essentially all of the particles have a size less than 400 nm.
- the particles of this invention can be prepared in a method comprising the steps of dispersing a radiopaque substance in a liquid dispersion medium and applying mechanical means in the presence of grinding media to reduce the particle size of the radiopaque substance to an effective average particle size of less than about 400 nm.
- the particles are reduced in size in the presence of the surface active agent.
- the particles can be intimately mixed with a surface active agent after attrition.
- the radiopaque substance selected 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 radiopaque substance selected be less than about 100 mm as determined by sieve analysis. If the coarse particle size of the radiopaque substance is greater than about 100 mm, then it is preferred that the particles of the radiopaque substance be reduced in size to less than 100 mm using a conventional milling method such as airjet of fragmentation milling.
- the mechanical means applied to reduce the particle size of the radiopaque 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.
- 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.
- 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.
- 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 3 .
- 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.
- the particles must be reduced in size at a temperature which does not significantly degrade the radiopaque substance. 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 2 ) are typical of media milling.
- Particle size analysis was carried out using the Microtract Ultrafine Particle Analyzer. (Leeds and Northrup Co.; St. Russia, Florida) Nanosuspension particle size was determined during the milling process and again immediately before the nanosuspensions were administered to rodents. Particle size was determined on the Coulter Model N4MD Submicron Particle Analyzer. (Coulter Corp.; Miami Lakes, Florida).
- the natural, pharmaceutically acceptable clays incorporated in the present invention comprise aluminum silicates. They are used in purified form, suitable for administration to patients.
- the natural, pharmaceutically acceptable clays of the present invention generally referred to as smectities, consist of dioctohedral smectites and trioctahedral smectites.
- Dioctahedral smectites include:
- M + is Na, Ca or Mg.
- Trioctahedral smectites include: saponite, having the formula
- M + is Na, Ca or Mg.
- the clays are available from chemical suppliers, such as, for example, American Colloid Company, Arlington Heights, IL, under the tradenames:
- the contrast agent, the mucoadhesive surfactant and the pharmaceutically acceptable clay are formulated for administration using physiologically acceptable carriers or excipients in a manner within the skill of the art.
- the contrast agent with the addition of pharmaceutically acceptable aids and excipients may be suspended in an aqueous medium resulting in a suspension.
- X-ray diagnostic 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.
- 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 nanosuspension during transit down the GI tract and the ability of the formulation to image the lower gastrointestinal tract
- Nanosuspensions 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 nanosuspension of WIN 8883 milled in Pluronic F127 was considered to be excellent for both upper and lower GI imaging in both rats and ferrets. All other nanosuspensions were compared with this formulation.
- the various polymeric surfactants and additional excipients used to prepare nanosuspensions are listed in Table 2. Nanosuspensions of WIN 8883 were milled at 20% solids by volume in presence of 4% w/v solutions of stabilizers unless specified otherwise.
- Good imaging was obtained from nanosuspensions of WIN 8883 stabilized with polyvinyl alcohol (PVA) (G21), tyloxapol (G20), tyloxapol with 0.1% w/v DOSS (G37), hydroxypropyl methylcebulose (G22), F88 with 0.1 % DOSS (G27), and F87 (G26).
- Good upper GI imaging was obtained from nanosuspensions of WIN 8883 stabilized with F98 (G14), F108 (G15) and F68 with 0.1% w/v DOSS (G23).
- DOSS and HPMC were found to be fair in regard to their stabilizing effect on imaging efficacy. DOSS itself was found to be fair (G18) while HPMC was rated as good, even with particle sizes greater than 700 nm. DOSS was needed to stabilize the nanosuspension prepared in 4% w/v Pluronic F77 (G29). The same formulation without DOSS could not be imaged due to gelling during the milling process.
- DOSS had variable effects when used in conjunction with other stabilizers.
- the nanosuspension stabilized with F88 (GO4) was rated as excellent.
- 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 nanosuspensions 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).
- (f)G31 was imaged within 24 hours of milling.
- twenty different stabilizers were examined using nanosuspensions of WTN 8883, of these, Pluronic F127 was considered excellent for imaging both the upper and lower GI.
- a nanosuspension stabilized with F88 was judged as excellent but for the upper GI only.
- Twenty compounds gave acceptable results as oral GI x-ray imaging agents.
- Three compounds WIN 8883, WIN 68183 and WIN 68756) and one stabilizer, Pluronic F127, was recognized as an excellent oral GI x-ray imaging agent. When nanosuspensions of these same three compounds were stabilized with F88, only the WIN 8883 nanosuspension produced excellent imaging, and then only in the upper GI.
- the dosages of the contrast agent used according to the method of the present invention will vary according to the precise nature of the contrast agent used. Preferably, however, the dosage should be kept as low as is consistent with achieving contrast enhanced imaging. By employing as small amount of contrast agent as possible, toxicity potential is minimized.
- contrast agents of the present invention dosages will be in the range of from about 0.1 to about 16.0 g iodine/kg body weight, preferably in the range of from about 0.5 to about 6.0 g iodine/kg of body weight and most preferably, in the range of from about 1.2 to about 2.0 g iodine/kg body weight for regular x-ray visualization of the GI tract
- the contrast agents of the present invention will be in the range of from about 1 to about 600 mg iodine/kg body weight, preferably in the range of from about 20 to about 200 mg iodine/kg body weight, and most preferably in the range of from about 40 to about 80 mg iodine/kg body weight.
Abstract
Description
Claims
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP95943457A EP0800404A2 (en) | 1994-12-30 | 1995-12-04 | Oral gastrointestinal diagnostic x-ray contrast agents in combination with pharmaceutically acceptable clays and surfactants |
AU44717/96A AU4471796A (en) | 1994-12-30 | 1995-12-04 | Oral gastrointestinal diagnostic x-ray contrast agents in combination with pharmaceutically acceptable clays and surfactants |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/367,407 | 1994-12-30 | ||
US08/367,407 US5466440A (en) | 1994-12-30 | 1994-12-30 | Formulations of oral gastrointestinal diagnostic X-ray contrast agents in combination with pharmaceutically acceptable clays |
Publications (2)
Publication Number | Publication Date |
---|---|
WO1996020734A2 true WO1996020734A2 (en) | 1996-07-11 |
WO1996020734A3 WO1996020734A3 (en) | 1996-10-10 |
Family
ID=23447049
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1995/016446 WO1996020734A2 (en) | 1994-12-30 | 1995-12-04 | Oral gastrointestinal x-ray contrast agents in combination with pharmaceutically acceptable clays and surfactants |
Country Status (5)
Country | Link |
---|---|
US (1) | US5466440A (en) |
EP (1) | EP0800404A2 (en) |
AU (1) | AU4471796A (en) |
CA (1) | CA2206961A1 (en) |
WO (1) | WO1996020734A2 (en) |
Families Citing this family (87)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5628981A (en) * | 1994-12-30 | 1997-05-13 | Nano Systems L.L.C. | Formulations of oral gastrointestinal diagnostic x-ray contrast agents and oral gastrointestinal therapeutic agents |
CA2213638C (en) * | 1995-02-24 | 2004-05-04 | Nanosystems L.L.C. | Aerosols containing nanoparticle dispersions |
US20050004049A1 (en) * | 1997-03-11 | 2005-01-06 | Elan Pharma International Limited | Novel griseofulvin compositions |
UA72189C2 (en) | 1997-11-17 | 2005-02-15 | Янссен Фармацевтика Н.В. | Aqueous suspensions of 9-hydroxy-risperidone fatty acid esters provided in submicron form |
US6319513B1 (en) | 1998-08-24 | 2001-11-20 | The Procter & Gamble Company | Oral liquid mucoadhesive compounds |
CA2346001C (en) * | 1998-10-01 | 2003-12-30 | Elan Pharma International, Limited | Controlled release nanoparticulate compositions |
US8236352B2 (en) | 1998-10-01 | 2012-08-07 | Alkermes Pharma Ireland Limited | Glipizide compositions |
US20080213378A1 (en) * | 1998-10-01 | 2008-09-04 | Elan Pharma International, Ltd. | Nanoparticulate statin formulations and novel statin combinations |
US8293277B2 (en) * | 1998-10-01 | 2012-10-23 | Alkermes Pharma Ireland Limited | Controlled-release nanoparticulate compositions |
US20040013613A1 (en) * | 2001-05-18 | 2004-01-22 | Jain Rajeev A | Rapidly disintegrating solid oral dosage form |
US20070160675A1 (en) * | 1998-11-02 | 2007-07-12 | Elan Corporation, Plc | Nanoparticulate and controlled release compositions comprising a cephalosporin |
CN100444830C (en) | 1998-11-02 | 2008-12-24 | 伊兰公司,Plc | Multiparticulate modified release composition |
US6428814B1 (en) * | 1999-10-08 | 2002-08-06 | Elan Pharma International Ltd. | Bioadhesive nanoparticulate compositions having cationic surface stabilizers |
US6969529B2 (en) | 2000-09-21 | 2005-11-29 | Elan Pharma International Ltd. | Nanoparticulate compositions comprising copolymers of vinyl pyrrolidone and vinyl acetate as surface stabilizers |
US6375986B1 (en) | 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 |
US7521068B2 (en) * | 1998-11-12 | 2009-04-21 | Elan Pharma International Ltd. | Dry powder aerosols of nanoparticulate drugs |
US20090104273A1 (en) * | 1999-06-22 | 2009-04-23 | Elan Pharma International Ltd. | Novel nifedipine compositions |
US7591998B2 (en) * | 2000-03-07 | 2009-09-22 | Kevin Tait | Stool marker |
AUPQ605500A0 (en) * | 2000-03-07 | 2000-03-30 | Medefield Pty Ltd | Stool marker |
US7998507B2 (en) * | 2000-09-21 | 2011-08-16 | Elan Pharma International Ltd. | Nanoparticulate compositions of mitogen-activated protein (MAP) kinase inhibitors |
US20030224058A1 (en) * | 2002-05-24 | 2003-12-04 | Elan Pharma International, Ltd. | Nanoparticulate fibrate formulations |
US7198795B2 (en) * | 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 |
US7276249B2 (en) | 2002-05-24 | 2007-10-02 | Elan Pharma International, Ltd. | Nanoparticulate fibrate formulations |
US6976647B2 (en) | 2001-06-05 | 2005-12-20 | Elan Pharma International, Limited | System and method for milling materials |
DE60203506T2 (en) * | 2001-06-22 | 2006-02-16 | Marie Lindner | HIGH-BY-STEP SCREENING PROCEDURE USING LABORATORY MILLS OR MICROFLUIDICS |
DE60217367T2 (en) * | 2001-09-19 | 2007-10-18 | Elan Pharma International Ltd. | NANOPARTICLE COMPOSITIONS CONTAINING INSULIN |
US6908626B2 (en) * | 2001-10-12 | 2005-06-21 | Elan Pharma International Ltd. | Compositions having a combination of immediate release and controlled release characteristics |
US20030152519A1 (en) * | 2001-11-07 | 2003-08-14 | Reinhard Koenig | Methods for vascular imaging using nanoparticulate contrast agents |
US20030129242A1 (en) * | 2002-01-04 | 2003-07-10 | Bosch H. William | Sterile filtered nanoparticulate formulations of budesonide and beclomethasone having tyloxapol as a surface stabilizer |
WO2003066021A2 (en) | 2002-02-04 | 2003-08-14 | Elan Pharma International, Ltd. | Drug nanoparticles with lysozyme surface stabiliser |
CA2479735C (en) * | 2002-03-20 | 2011-05-17 | Elan Pharma International Ltd. | Fast dissolving dosage forms having reduced friability |
AU2003224808A1 (en) * | 2002-03-28 | 2003-10-13 | Imcor Pharmaceutical Company | Compositions and methods for delivering pharmaceutically active agents using nanoparticulates |
US7101576B2 (en) * | 2002-04-12 | 2006-09-05 | Elan Pharma International Limited | Nanoparticulate megestrol formulations |
US20040105889A1 (en) * | 2002-12-03 | 2004-06-03 | Elan Pharma International Limited | Low viscosity liquid dosage forms |
ES2380318T3 (en) | 2002-04-12 | 2012-05-10 | Alkermes Pharma Ireland Limited | Megestrol nanoparticular formulations |
US9101540B2 (en) * | 2002-04-12 | 2015-08-11 | Alkermes Pharma Ireland Limited | Nanoparticulate megestrol formulations |
US20100226989A1 (en) * | 2002-04-12 | 2010-09-09 | Elan Pharma International, Limited | Nanoparticulate megestrol formulations |
ATE419835T1 (en) * | 2002-05-06 | 2009-01-15 | Elan Pharma Int Ltd | NYSTATIN NANOPARTICLE COMPOSITIONS |
JP4533134B2 (en) * | 2002-06-10 | 2010-09-01 | エラン ファーマ インターナショナル,リミティド | Nanoparticulate policosanol formulations and novel policosanol combinations |
US20040258757A1 (en) * | 2002-07-16 | 2004-12-23 | Elan Pharma International, Ltd. | Liquid dosage compositions of stable nanoparticulate active agents |
ES2355723T3 (en) * | 2002-09-11 | 2011-03-30 | Elan Pharma International Limited | COMPOSITIONS OF ACTIVE AGENT IN GAN STABILIZED NANOPARTICLES. |
WO2004032980A1 (en) * | 2002-10-04 | 2004-04-22 | Elan Pharma International Limited | Gamma irradiation of solid nanoparticulate active agents |
JP4776233B2 (en) * | 2002-11-12 | 2011-09-21 | エラン ファーマ インターナショナル,リミティド | Fast disintegrating solid formulation that is resistant to abrasion and contains pullulan |
US20040173696A1 (en) * | 2002-12-17 | 2004-09-09 | Elan Pharma International Ltd. | Milling microgram quantities of nanoparticulate candidate compounds |
WO2004078162A1 (en) * | 2003-01-31 | 2004-09-16 | Elan Pharma International Ltd. | Nanoparticulate topiramate formulations |
US20040208833A1 (en) * | 2003-02-04 | 2004-10-21 | Elan Pharma International Ltd. | Novel fluticasone formulations |
US20100297252A1 (en) * | 2003-03-03 | 2010-11-25 | Elan Pharma International Ltd. | Nanoparticulate meloxicam formulations |
US8512727B2 (en) | 2003-03-03 | 2013-08-20 | Alkermes Pharma Ireland Limited | Nanoparticulate meloxicam formulations |
WO2004105809A1 (en) * | 2003-05-22 | 2004-12-09 | Elan Pharma International Ltd. | Sterilization of dispersions of nanoparticulate active agents with gamma radiation |
JP2007501839A (en) * | 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 |
CA2791779A1 (en) * | 2003-10-28 | 2005-05-12 | Taro Pharmaceuticals U.S.A., Inc. | Spill resistant formulations containing clays |
JP4787165B2 (en) * | 2003-11-05 | 2011-10-05 | エラン ファーマ インターナショナル,リミティド | Nanoparticle compositions having peptides as surface stabilizers |
BRPI0518187A (en) * | 2004-11-16 | 2008-11-04 | Elan Pharma Int Ltd | injectable nanoparticulate olanzapine formulations |
US20090155331A1 (en) * | 2005-11-16 | 2009-06-18 | Elan Pharma International Limited | Injectable nanoparticulate olanzapine formulations |
UA89513C2 (en) * | 2004-12-03 | 2010-02-10 | Элан Фарма Интернешнл Лтд. | Nanoparticulate raloxifene hydrochloride composition |
AU2005316473B2 (en) * | 2004-12-15 | 2011-07-14 | Elan Pharma International Ltd. | Nanoparticulate tacrolimus formulations |
US20060159767A1 (en) * | 2004-12-22 | 2006-07-20 | Elan Pharma International Limited | Nanoparticulate bicalutamide formulations |
US20060165806A1 (en) * | 2005-01-06 | 2006-07-27 | Elan Pharma International Limited | Nanoparticulate candesartan formulations |
ATE412691T1 (en) | 2005-01-13 | 2008-11-15 | Cinv Ag | COMPOSITE MATERIALS CONTAINING CARBON NANOPARTICLES |
MX2007009915A (en) | 2005-02-15 | 2007-11-06 | Elan Pharma Int Ltd | Aerosol and injectable formulations of nanoparticulate benzodiazepine. |
US20060204588A1 (en) * | 2005-03-10 | 2006-09-14 | Elan Pharma International Limited | Formulations of a nanoparticulate finasteride, dutasteride or tamsulosin hydrochloride, and mixtures thereof |
BRPI0606283A2 (en) * | 2005-03-16 | 2009-06-09 | Elan Pharma Int Ltd | nanoparticulate leukotriene receptor antagonist / corticosteroid formulations |
WO2006102117A1 (en) * | 2005-03-17 | 2006-09-28 | Elan Pharma International Limited | Nanoparticulate biphosphonate compositions |
MX2007011772A (en) * | 2005-03-23 | 2007-12-05 | Elan Pharma Int Ltd | Nanoparticulate corticosteroid and antihistamine formulations. |
WO2006110809A2 (en) * | 2005-04-12 | 2006-10-19 | Elan Pharma International, Limited | Nanoparticulate lipase inhibitor formulations |
WO2006110811A1 (en) * | 2005-04-12 | 2006-10-19 | Elan Pharma International Limited | Nanoparticulate quinazoline derivative formulations |
WO2006110802A1 (en) * | 2005-04-12 | 2006-10-19 | Elan Pharma International Limited | Nanoparticulate and controlled release compositions comprising cyclosporine |
US20110064803A1 (en) * | 2005-05-10 | 2011-03-17 | Elan Pharma International Limited. | Nanoparticulate and controlled release compositions comprising vitamin k2 |
AU2006336417A1 (en) * | 2005-05-10 | 2007-08-02 | Elan Pharma International, Limited | Nanoparticulate clopidogrel formulations |
KR20080017065A (en) * | 2005-06-03 | 2008-02-25 | 엘란 파마 인터내셔널 리미티드 | Nanoparticulate acetaminophen formulations |
CN101232870A (en) * | 2005-06-03 | 2008-07-30 | 伊兰制药国际有限公司 | Nanoparticulate imatinib mesylate formulations |
CA2612994A1 (en) | 2005-06-08 | 2006-12-08 | Elan Pharma International Limited | Nanoparticulate and controlled release compositions comprising cefditoren |
WO2006135689A2 (en) * | 2005-06-09 | 2006-12-21 | Elan Pharma International, Limited | Nanoparticulate ebastine formulations |
WO2006138421A2 (en) * | 2005-06-15 | 2006-12-28 | Elan Pharma International Limited | Nanoparticulate azelnidipine formulations |
WO2007045616A1 (en) * | 2005-10-18 | 2007-04-26 | Cinvention Ag | Thermoset particles and methods for production thereof |
US8367112B2 (en) * | 2006-02-28 | 2013-02-05 | Alkermes Pharma Ireland Limited | Nanoparticulate carverdilol formulations |
BRPI0806916A2 (en) * | 2007-01-19 | 2014-04-29 | Cinv Ag | NON-DEGRADABLE POROUS IMPLANT MADE BY DUST |
US20080206862A1 (en) * | 2007-02-28 | 2008-08-28 | Cinvention Ag | High surface cultivation system bag |
WO2008104588A1 (en) * | 2007-02-28 | 2008-09-04 | Cinvention Ag | High surface cultivation system |
US20090238867A1 (en) * | 2007-12-13 | 2009-09-24 | Scott Jenkins | Nanoparticulate Anidulafungin Compositions and Methods for Making the Same |
KR20110007095A (en) * | 2008-03-21 | 2011-01-21 | 엘란 파마 인터내셔널 리미티드 | Compositions for site-specific delivery of imatinib and methods of use |
US20090311335A1 (en) * | 2008-06-12 | 2009-12-17 | Scott Jenkins | Combination of a triptan and an nsaid |
US20120065221A1 (en) | 2009-02-26 | 2012-03-15 | Theraquest Biosciences, Inc. | Extended Release Oral Pharmaceutical Compositions of 3-Hydroxy-N-Methylmorphinan and Method of Use |
US20100316725A1 (en) | 2009-05-27 | 2010-12-16 | Elan Pharma International Ltd. | Reduction of flake-like aggregation in nanoparticulate active agent compositions |
FR2945950A1 (en) | 2009-05-27 | 2010-12-03 | Elan Pharma Int Ltd | ANTICANCER NANOPARTICLE COMPOSITIONS AND METHODS FOR PREPARING THE SAME |
CN102497857A (en) | 2009-06-19 | 2012-06-13 | 纳米模型匈牙利有限公司 | Nanostructured sildenafil base, its pharmaceutically acceptable salts and co-crystals, compositions of them, process for the preparation thereof and pharmaceutical compositions containing them |
CN107709344B (en) | 2015-05-01 | 2022-07-15 | 共晶制药股份有限公司 | Nucleoside analogues for the treatment of flaviviridae and cancer |
Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5318767A (en) * | 1991-01-25 | 1994-06-07 | Sterling Winthrop Inc. | X-ray contrast compositions useful in medical imaging |
EP0602700A2 (en) * | 1992-12-17 | 1994-06-22 | NanoSystems L.L.C. | Novel formulations for nanoparticulate X-ray blood pool contrast agents using high molecular weight surfactants |
EP0605024A2 (en) * | 1992-12-16 | 1994-07-06 | NanoSystems L.L.C. | Use of purified surface modifiers to prevent particle aggregation during sterilization |
US5360604A (en) * | 1994-04-14 | 1994-11-01 | Sterling Winthrop Inc. | X-ray contrast compositions containing an organic crystalline X-ray contrast agent in combination with pharmaceutically acceptable clays |
US5424056A (en) * | 1993-03-01 | 1995-06-13 | Sterling Wintrhop Inc. | X-ray contrast compositions containing iodoaniline derivatives and pharmaceutically acceptable clays |
WO1995028969A1 (en) * | 1994-04-21 | 1995-11-02 | Nycomed Imaging As | X-ray contrast compositions containing pharmaceutically acceptable clays |
US5472683A (en) * | 1995-03-09 | 1995-12-05 | Eastman Kodak Company | Nanoparticulate diagnostic mixed carbamic anhydrides as X-ray contrast agents for blood pool and lymphatic system imaging |
US5484585A (en) * | 1993-03-11 | 1996-01-16 | Sterling-Winthrop Inc. | Compositions of iodobenzoic acid derivatives and pharmaceutically acceptable clays for visualization of the gastrointestinal tract |
US5500204A (en) * | 1995-02-10 | 1996-03-19 | Eastman Kodak Company | Nanoparticulate diagnostic dimers as x-ray contrast agents for blood pool and lymphatic system imaging |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4107288A (en) * | 1974-09-18 | 1978-08-15 | Pharmaceutical Society Of Victoria | Injectable compositions, nanoparticles useful therein, and process of manufacturing same |
EP0093757A1 (en) * | 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 (en) * | 1986-11-17 | 1991-05-14 | Clarkson University | Process for synthesis of uniform colloidal particles of rare earth oxides |
FR2608988B1 (en) * | 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 |
US4927624A (en) * | 1987-11-19 | 1990-05-22 | The University Of Rochester | Clay magnetic resonance contrast agents for gastrointestinal comsumption or introduction |
US5145684A (en) * | 1991-01-25 | 1992-09-08 | Sterling Drug Inc. | Surface modified drug nanoparticles |
US5107842A (en) * | 1991-02-22 | 1992-04-28 | Molecular Biosystems, Inc. | Method of ultrasound imaging of the gastrointestinal tract |
US5352434A (en) * | 1992-05-01 | 1994-10-04 | Sterling Winthrop Inc. | X-ray contrast compositions containing a barium salt and film-forming materials |
US5424142A (en) * | 1993-05-20 | 1995-06-13 | E-Z-Em, Inc. | Negative contrast agents for magnetic resonance imaging comprising barium sulfate and a clay |
-
1994
- 1994-12-30 US US08/367,407 patent/US5466440A/en not_active Expired - Lifetime
-
1995
- 1995-12-04 CA CA002206961A patent/CA2206961A1/en not_active Abandoned
- 1995-12-04 WO PCT/US1995/016446 patent/WO1996020734A2/en not_active Application Discontinuation
- 1995-12-04 EP EP95943457A patent/EP0800404A2/en not_active Withdrawn
- 1995-12-04 AU AU44717/96A patent/AU4471796A/en not_active Abandoned
Patent Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5318767A (en) * | 1991-01-25 | 1994-06-07 | Sterling Winthrop Inc. | X-ray contrast compositions useful in medical imaging |
EP0605024A2 (en) * | 1992-12-16 | 1994-07-06 | NanoSystems L.L.C. | Use of purified surface modifiers to prevent particle aggregation during sterilization |
EP0602700A2 (en) * | 1992-12-17 | 1994-06-22 | NanoSystems L.L.C. | Novel formulations for nanoparticulate X-ray blood pool contrast agents using high molecular weight surfactants |
US5447710A (en) * | 1992-12-17 | 1995-09-05 | Eastman Kodak Company | Method of making nanoparticulate X-ray blood pool contrast agents using high molecular weight nonionic surfactants |
US5424056A (en) * | 1993-03-01 | 1995-06-13 | Sterling Wintrhop Inc. | X-ray contrast compositions containing iodoaniline derivatives and pharmaceutically acceptable clays |
US5484585A (en) * | 1993-03-11 | 1996-01-16 | Sterling-Winthrop Inc. | Compositions of iodobenzoic acid derivatives and pharmaceutically acceptable clays for visualization of the gastrointestinal tract |
US5360604A (en) * | 1994-04-14 | 1994-11-01 | Sterling Winthrop Inc. | X-ray contrast compositions containing an organic crystalline X-ray contrast agent in combination with pharmaceutically acceptable clays |
WO1995028969A1 (en) * | 1994-04-21 | 1995-11-02 | Nycomed Imaging As | X-ray contrast compositions containing pharmaceutically acceptable clays |
US5500204A (en) * | 1995-02-10 | 1996-03-19 | Eastman Kodak Company | Nanoparticulate diagnostic dimers as x-ray contrast agents for blood pool and lymphatic system imaging |
US5472683A (en) * | 1995-03-09 | 1995-12-05 | Eastman Kodak Company | Nanoparticulate diagnostic mixed carbamic anhydrides as X-ray contrast agents for blood pool and lymphatic system imaging |
Non-Patent Citations (1)
Title |
---|
M.E. WOLFF, (EDITOR): "Burger's medicinal chemistry, fourth edition, Part III" 1979 , JOHN WILEY & SONS, NEW YORK, US XP002005069 see page 1140 - page 1203 * |
Also Published As
Publication number | Publication date |
---|---|
CA2206961A1 (en) | 1996-07-11 |
EP0800404A2 (en) | 1997-10-15 |
WO1996020734A3 (en) | 1996-10-10 |
AU4471796A (en) | 1996-07-24 |
US5466440A (en) | 1995-11-14 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US5466440A (en) | Formulations of oral gastrointestinal diagnostic X-ray contrast agents in combination with pharmaceutically acceptable clays | |
US5628981A (en) | Formulations of oral gastrointestinal diagnostic x-ray contrast agents and oral gastrointestinal therapeutic agents | |
US5580579A (en) | Site-specific adhesion within the GI tract using nanoparticles stabilized by high molecular weight, linear poly (ethylene oxide) polymers | |
US5593657A (en) | Barium salt formulations stabilized by non-ionic and anionic stabilizers | |
US5585108A (en) | Formulations of oral gastrointestinal therapeutic agents in combination with pharmaceutically acceptable clays | |
US5565188A (en) | Polyalkylene block copolymers as surface modifiers for nanoparticles | |
KR100320390B1 (en) | How to use tyloxapol as a microparticle stabilizer and dispersant | |
US5587143A (en) | Butylene oxide-ethylene oxide block copolymer surfactants as stabilizer coatings for nanoparticle compositions | |
US8097282B2 (en) | Methods of administering liquid droplet aerosols of nanoparticulate drugs | |
JPH04317053A (en) | X-ray contrast composition useful for forming medical image | |
NZ248727A (en) | Nanoparticles with x-ray contrast agent with high molecular weight surfactant adsorbed on the surface | |
US5368837A (en) | X-ray contrast compositions containing an organic crystalline X-ray contrast agent and a cellulose derivative | |
US5360604A (en) | X-ray contrast compositions containing an organic crystalline X-ray contrast agent in combination with pharmaceutically acceptable clays | |
CA2247041A1 (en) | Contrast medium | |
JPH09512029A (en) | X-ray contrast composition containing a pharmacologically acceptable clay | |
CA2193503C (en) | Butylene oxide-ethylene oxide block copolymer surfactants as stabilizer coatings for nanocrystal formulation | |
MXPA96004899A (en) | Compositions of contrast for x-rays containing clays pharmaceutically accepted |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A2 Designated state(s): AL AM AU BB BG BR BY CA CN CZ EE FI GE HU IS JP KG KP KR KZ LK LR LS LT LV MD MG MK MN MX NO NZ PL RO RU SG SI SK TJ TM TT UA US UZ VN |
|
AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): KE LS MW SD SZ UG AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG |
|
WD | Withdrawal of designations after international publication |
Free format text: US |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
ENP | Entry into the national phase |
Ref document number: 2206961 Country of ref document: CA Ref country code: CA Ref document number: 2206961 Kind code of ref document: A Format of ref document f/p: F |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1995943457 Country of ref document: EP |
|
WWP | Wipo information: published in national office |
Ref document number: 1995943457 Country of ref document: EP |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 1995943457 Country of ref document: EP |