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WO1997004747A1 - Systemes d'administration de medicaments pour medicaments macromoleculaires - Google Patents

Systemes d'administration de medicaments pour medicaments macromoleculaires Download PDF

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Publication number
WO1997004747A1
WO1997004747A1 PCT/US1996/012203 US9612203W WO9704747A1 WO 1997004747 A1 WO1997004747 A1 WO 1997004747A1 US 9612203 W US9612203 W US 9612203W WO 9704747 A1 WO9704747 A1 WO 9704747A1
Authority
WO
WIPO (PCT)
Prior art keywords
controlled release
pharmaceutical formulation
release pharmaceutical
poly
acid
Prior art date
Application number
PCT/US1996/012203
Other languages
English (en)
Inventor
James M. Dunn
Original Assignee
Dunn James M
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dunn James M filed Critical Dunn James M
Publication of WO1997004747A1 publication Critical patent/WO1997004747A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
    • A61K9/5153—Polyesters, e.g. poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin

Definitions

  • the present invention relates to improved pharmaceutical formulations for administration of macromolecules or drugs that are not bioavailable using standard pharmaceutical methods. More specifically, the invention relates to pharmaceutical formulations of controlled release rate dosages of the drugs that may be administered orally, parenterally, or by inhalation.
  • Oral delivery of drugs or long acting parenteral dosage forms of drugs is preferred by the patient and physician because of compliance and the inherent beneficial effect of constant pharmacodynamic action.
  • a drug to be absorbed by the intestine it must first become soluble in the aqueous media of the gut. Products that are rapidly dissolved in water are usually rapidly absorbed into the body.
  • these drugs when given parenterally may have short half lives or may not have effective injection delivery systems. This problem arises from the fact that the drugs are destroyed before being absorbed or they are of such a size and nature that the body cannot absorb the medication. Similarly, their injectable forms have short durations of action, requiring frequent injections, making the products unsuitable for use in the non hospitalized patient.
  • the driving force for passive drug diffusion is the difference between the concentration gradient of the diffusing drug in the intestinal tract and the concentration gradient on the other side of the plasma membrane.
  • the rate of drug penetration-diffusion corresponds to the concentration gradient as is characterized by
  • the present invention obviates the problems of solvation as well as the need for classic abso ⁇ tion for delivery of those drugs where the molecular size is too large to be absorbed when the product is formulated and administered, or because of the deleterious effects of gastrointestinal enzymes, and other factors.
  • the invention is directed to pharmaceutical formulations for effective controlled release of many drugs not now orally or parenterally available. These formulations, properly adjusted, also may be administered by inhalation and achieve the same kinetic characteristics.
  • the pharmaceutical formulations of this invention are made by entrapping the drug of choice in either an organic or water phase biodegradable hydrogel polymer system to produce nanoparticles.
  • the advantage of the nanoparticle system is that its absorption by the body is by the lymphatic or lacteal system. Because of the resistant hydrogel coating it is not affected by the enzymes or degradative influences present in the gastrointestinal tract. Using bioadhesive hydrogel polymers ensures a more prolonged duration of time in which the nanoparticles are in contact with the intestinal mucosa, obfuscating the deleterious action of heightened gastrointestinal peristalsis. All of these compounds work in harmony to produce viable products that have demonstrated favorable and reproducible effects in animals.
  • the invention thus describes simple and predictable methods for the preparation of oral, parenteral, or inhalation dosage forms of a drug or drugs entrapped in biodegradable hydrogel polymers.
  • the following combinations may be used to formulate a controlled release pharmaceutical product:
  • a controlled release pharmaceutical formulation with a biologically active molecule which is encapsulated with a cyclodextrin, entrapped with liposomes and formed into nanoparticles then with water-soluble hydrogel polymers, and then coated with one or more bioadhesive adjuvants.
  • the sphere size in the nanoparticle will typically be in the range of 500 to 1500 nm, so that the drug(s) so entrapped may be administered orally, parenterally, or by inhalation.
  • the exact diameter of the nanoparticles is not critical, provided that is sufficiently small for cell diffusion by the lymphatic or lacteal system.
  • the rate of active drug release from the entrapped spheres is dependent upon the basic kinetics of the drug administered, the amount of hydrogel polymer, the cyclodextrin used, the phospholipid coating and, in the case of parenteral administration, the method of administration, the area of deposition, and the vascularity of the body region.
  • inhalation dosing it is not necessary to use the bioadhesive adjuvants, although the adjuvants may be included in these formulations.
  • Heparin is a well-established drug that is a complex polysaccharide that is highly charged (electronegative). It has a molecular weight of 20,000-60,000 daltons, which are covalently attached to a core protein found in most secretory cells. Heparin is a multifaceted drug with primary actions as an anticoagulant. When venous or arterial thrombi occur and the patient survives, heparin is given at doses of 10,000-20,000 units every 4-6 hours to maintain blood levels at 0.5-1.5 anti-factor Xa units/mL, which should prevent further thromboembolic phenomena. After this, the heparin dose is usually maintained at 10,000 units every 4-6 hours to prevent further thromboembolic events.
  • heparin has the ability to bind to the arterial wall following angioplasty and ameliorate the proliferation of smooth muscle cells and ameliorate the restenosis that so often occurs with this procedure. Also, heparin is used as a preventive agent for those patients that are at close risk of stroke or heart attack as well as the patients recovering from a heart attack.
  • Heparin also has a clearing effect in the blood by activating lipoprotein lipase on the cell surface. This action clears hyperlipoproteinmia and lowers the low density lipoprotein. In animals, it has reversed the athrogenic deposits on the arterial walls, which is a phenomenon of arteriosclerosis in humans.
  • Insulin is a polypeptide with two peptide chains linked by a disulfide bridge.
  • the A chain of insulin contains 21 amino acids and the B peptide chain contains 30 amino acids. This structural integrity is important for its biologic activity. If the amino acid sequences are disrupted or the disulfide bridge broken, the hormone becomes inactivated.
  • biodegradable polymers poly (lactic acid), poly (glycolic acid), (poly (e-caprolactone), poly (p-hydrohybutyrate), poly (b-hydroxyvalerate).
  • methacrylate polymers can be used specifically in water soluble systems. These include, but are not limited to acrylic acid, methacrylacetic cyanoethyl methocrylitic aminoakyl methacrylate copolymers, ethoxyethyl methacrylate copolymers, polymethacrylic acid, methacrylate acid alkylamide copolymer, polymethacrylic acid, polyacrylic acid, methacryic acid alkylamide copolymer, polymethacrylic acid (anhydride), and polymethyl methacrylate.
  • the advantage of the acrylate series is that when properly compounded they are water soluble or can be supplied as a 30% aqueous solution with varying degrees of solubility.
  • polymers known to the art can be used in either the water or organic phase, if properly prepared.
  • An example of this is alginic acid in intimate admixture with the drug, then cross-linking the alginic acid with a known inorganic element such as zinc, magnesium, calcium, or sodium salts.
  • pectin, zein, and guar gum can be used and cross-linked with a metallic ion.
  • Ethyl cellulose can also be used as a polymer to entrap the molecule and can be used in an aqueous or organic solvent system.
  • Cyclodextrins are a new class of compounds derived from corn. They are cyclic, non-reducing oligosaccharides built up from six, seven, and eight glucopyranose rings known respectively as alpha, beta, and gamma cyclodextrins. In addition, hydroxypropyl and other groups have been and are added to the molecule giving each series its own specific characteristics and pharmacological behavior. These molecules have a unique shape as shown in Figure 1.
  • the cyclodextrins act as a biodegradable trapping agent, inco ⁇ orating the active medication into its core and forming a unique molecular inclusion complex. These complexes provide an anchoring compound with the formation of covalent bonds. This guest-host complex protects the active drug, while not forming tight chemical bonds.
  • Cyclodextrins can be used to entrap the drug, providing a guest-host interaction.
  • Cyclodextrins are usually used in amounts that range from 0.25%-2% W/W, depending upon the bioactive molecule and the degree of protection required. The type of cyclodextrins used will again depend upon the molecule and the degree of protection required. These parameters can easily be determined by routine experimentation by one of skill in the art.
  • Liposomes were first characterized in 1965. They are single or combinations of lipids formed into spherical shapes with drugs or other active medicaments. Lipids or liposomes, primarily phospholipids, are, in general, readily absorbed intact by the intestinal cells, degraded as they pass through the interstitial space and slowly reconstituted by the body where they are then excreted by active transport in the ileum and colon in a newly reconfigured formulation. About 30-40% of the fecal dry weight is fat or lipid. Most importantly, essentially all the fat or lipids ingested are absorbed directly into the portal blood and lymphatic system or by transcell migration. Liposomes, like their parent lipids, can enter the system in a number of ways:
  • Intermembrane transfer which occurs when liposomes are in close contact with the cell they are exchanged with certain lipids in the cell wall, where they are transported intact into the cell.
  • Fusion which occurs when there is a close approach of the lipids in the cell wall and those of the liposomal lipids. Fusion results in complete mixing of the plasma membrane and release of the liposomal contents into the cytoplasm of the cell.
  • liposomes have been used for some drug delivery, there are problems with manufacturing, stability, and assurance of release. Their advantage is that drugs encapsulated into a lipid sphere can carry an electrostatic charge, allowing them to interact with cells of the opposite charge. By such a process of fusion and constant release, they efficiently can deliver the active drug moiety to the body.
  • the preferred agents are cholesterol, lecithin, glycerol monostearate, phospholipon 90H (Natterman) maleated soybean oil, sphingomylein, phosphatidyl entanolamine, dipamitoyl phoisphophatidykaline, phophosinositol, phophatidic acid, triglycerides. Since lipids tend to undergo oxidative degeneration, alpha tocopherol is usually added as an ancillary agent along with other antioxidants when the drug and or the liposomes.
  • the preferred bioadhesive adjuvant(s) that is added only to the total formulation are hydroxypropyl methyl cellulose, methyl cellulose, pectin, guar gum, xantham gums, gum acacia, gum dragon, hydroxypropyl alginate, sodium carboxymethyl cellulose, carbomer 934-P, acrylic acid derivatives and those of similar pharmaceutical characteristics and behavior.
  • These adjuvants are pharmacopeial items and are blended in with the nanoparticle granulate at the final stage of production.
  • the preferred dose is a single or combination of these adjuvants at a 50/50 W/W ratio and a percentage weight of the total granulate of 0.1-3% preferably in the range of 0.3-1.5% and most preferably 0.2-1.2 weight percentage.
  • the invention describes the formulation of a range of products with a variety of process steps and combinations. Embodiments in addition to those illustrated will be readily understood by those skilled in the art.
  • the present invention includes within its scope novel processes and products derived from the invention whether as individual features or in combination with each other to produce novel combinations.
  • the invention is illustrated further by the following examples, which are not to be taken as limiting in any way.
  • gastrointestinal absorption of oral formulations of water soluble dyes entrapped into nanoparticles, prepared according to the present invention, were studied by light microscopy.
  • Nanoparticles containing fluorescent stains were prepared and administered orally with concomitant bioadhesive adjuvants, as a single dose to anesthetized rabbits, via a gastric tube.
  • the rabbits were sacrificed 7 and 14 days after oral administration of the manufactured spheres. Both ultraviolet light microscopy and direct vision revealed dye-containing spheres widely distributed throughout the animal's bodies.
  • the yield was 742 mg out of a theoretical yield of 1,400 mg.
  • the resultant powder/granulate was weighed and titrated against protamine in normal saline to ensure that heparin was in fact entrapped in the spheres. To do this, the beads were suspended in normal saline and agitated by vortex. Protamine was then added to the solution and no precipitate was observed. The nanoparticles were assayed before l o degradation and found to have 0.75 U/ mg of heparin.
  • Electron microscopy demonstrated an average diameter of 850 nm, with a range of 650 to 1250 nm.
  • nanoparticles were coated with bioadhesive adjuvant. Nanoparticles were coated by dispersion in 20-mL of an aqueous
  • Vancomycin hydrochloride (3,000 mg) was added to 300 mL of KH2PO4 at pH 6.8
  • Heparin nanoparticles prepared according to Example 1, were orally administered to rabbits in an animal study. These preliminary results showed that heparin, a large molecular weight drug, can be formulated for oral absorption in a controlled, sustained-release fashion.
  • the rabbits were sedated with xyalazine for administration of the drugs and control.
  • a soft #10 rubber French catheter was then placed into the animals' stomach and the material was delivered by pressure to simulate a controlled oral administration.
  • the tube was rinsed with deionized water to make sure all the particles were expelled from the tube into the rabbits' stomach. In all, this process was repeated five times over a six month period with three different animals treated each time, for a total of 15 animals.
  • the animals were housed and fed rabbit chow and were given water ad lib. Blood samples were taken from the marginal ear vein at the following times, 6 hours post dose, 24, 48, 96, 120 and 144 hours after drug administration. The blood samples were placed in a citrate Eppendorf test tube immediately after blood was obtained and spun down using 3,000 Xg for 23 minutes. All samples were then assayed for antifactor Xa by Dr. Richard Malar at the University Of Colorado-Veterans Administration Hospital coagulation lab. The test was blinded as to the specimen, its timing and the specific animal. Following the centrifugation, the plasma was removed and frozen immediately at -20"C until assay.
  • thromboplastin 100 mL/mouse
  • a blood clotting activating agent a blood clotting activating agent
  • the model measures the level of protection given by the various drugs.
  • the intravenous injection of thromboplastin with the dose of 100 ⁇ L/mice (0.2 ng) provokes a thromboembolism involving 80% mortality in 24 hours.
  • the intravenous heparin standard protects 50% of animals treated when administered in the range of 0.09 mg/kg.
  • the heparin nanoparticles were given by oral route in suspension in a carboxymethyl cellulose solution (0.06%) in doses of 50, 150, and 300 mg/kg.
  • heparin nanoparticles In addition to the three dosage levels of the heparin nanoparticles tested, a blank and two heparin standards were run.
  • the blank was the bioadhesive adjuvant, carboxymethyl cellulose, at 0.6%.
  • the first heparin standard was intravenous heparin at 0.3 mg/kg.
  • the second heparin standard was 85 mg/kg administered orally.
  • the fluid was then placed on a preheated stirring plate and at very low temperature ⁇ 40°C and stirred 1700 Rpm's for 30 minutes. After stirring was complete, the fluid was placed into a modified Pyrex® dish and allowed to air dry for 24 hours. At the end of this time there was a very fine granulated powder that was removed by a sharp razor blade edge and weighed. The theoretical yield was 2.80 grams, while the actual yield was 2.75 grams.

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Abstract

La présente invention permet d'administrer de grosses macromolécules par voie orale, par voie parentérale ou par inhalation. Des médicaments biologiquement actifs sont emprisonnés dans des polymères sous forme d'hydrogel biodégradable dans des systèmes organiques ou à phase aqueuse. Grâce à des cyclodextrines, les molécules sensibles peuvent être protégées au cours de la phase de production de granulations de nanoparticules.
PCT/US1996/012203 1995-07-27 1996-07-25 Systemes d'administration de medicaments pour medicaments macromoleculaires WO1997004747A1 (fr)

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US50824795A 1995-07-27 1995-07-27
US08/508,247 1995-07-27

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Cited By (63)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6524595B1 (en) * 2000-05-12 2003-02-25 Coletica Cyclodextrins preferentially substituted on their primary face by acid or amine functions
WO2003053470A2 (fr) * 2001-12-21 2003-07-03 Universiteit Gent Systemes de distribution d'agents biologiques par impulsions bases sur des solutions ou des hydrogels polymeriques degradables
EP1385530A1 (fr) * 2001-05-09 2004-02-04 Mediplex Corporation Formulation de derives d'heparine amphiphiles servant a ameliorer l'absorption par les muqueuses
US6740643B2 (en) * 1999-01-21 2004-05-25 Mirus Corporation Compositions and methods for drug delivery using amphiphile binding molecules
US6875448B1 (en) * 1999-09-03 2005-04-05 Chugai Seiyaku Kabushiki Kaisha Method of intracellular sustained-release of drug and preparations
WO2005110374A1 (fr) * 2004-04-30 2005-11-24 Allergan, Inc. Systemes de distribution de medicaments intraoculaires contenant un agent therapeutique, une cyclodextrine et un composant polymere
EP1696961A1 (fr) * 2003-12-24 2006-09-06 Samyang Corporation Compositions a nanoparticules de medicaments solubles dans l'eau administrees par voie orale et methodes de preparation
WO2006128937A2 (fr) 2005-06-02 2006-12-07 Universidade De Santiago De Compostela Nanoparticules qui contiennent du chitosane et de la cyclodextrine
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EP1774971A1 (fr) * 2005-10-14 2007-04-18 Advanced in Vitro Cell Technologies, S.L. Nanoparticules comprenant de chitosane et d'héparine
EP1808438A3 (fr) * 1999-06-29 2008-12-24 MannKind Corporation Purification et stabilisation de peptide et protéines dans des agents pharmaceutiques
WO2011015634A2 (fr) 2009-08-05 2011-02-10 Pieris Ag Formulations à libération contrôlée de mutéines de la lipocaline
EP2316490A2 (fr) 2000-10-31 2011-05-04 PR Pharmaceuticals, Inc. Methodes et compositions pour améliorer l'administration de molécules bioactives
WO2012050359A2 (fr) * 2010-10-14 2012-04-19 (주)아모레퍼시픽 Particule d'hydrogel revêtue d'un lipide et sa méthode de fabrication
WO2013134349A1 (fr) 2012-03-06 2013-09-12 Clemson University Systèmes d'administration pour améliorer l'efficacité d'un médicament
US8629151B2 (en) 2009-05-27 2014-01-14 Selecta Biosciences, Inc. Immunomodulatory agent-polymeric compounds
US8628801B2 (en) 2004-04-29 2014-01-14 Universidad De Navarra Pegylated nanoparticles
US8871269B2 (en) 2003-07-15 2014-10-28 Evonik Corporation Method for the preparation of controlled release formulations
US8895067B2 (en) 2004-04-29 2014-11-25 Universidad De Navarra Immune response stimulating composition comprising nanoparticles based on a methyl vinyl ether-maleic acid copolymer
US8900636B2 (en) 2003-07-23 2014-12-02 Evonik Corporation Controlled release compositions
US8906381B2 (en) 2008-10-12 2014-12-09 Massachusetts Institute Of Technology Immunonanotherapeutics that provide IGG humoral response without T-cell antigen
US8916196B2 (en) 2003-04-10 2014-12-23 Evonik Corporation Method for the production of emulsion-based microparticles
CN104257633A (zh) * 2014-08-27 2015-01-07 珠海健帆生物科技股份有限公司 抗凝缓释胶囊及其制备方法、功能性抗凝缓释器
US8932595B2 (en) 2008-10-12 2015-01-13 Massachusetts Institute Of Technology Nicotine immunonanotherapeutics
US9006175B2 (en) 1999-06-29 2015-04-14 Mannkind Corporation Potentiation of glucose elimination
US9066978B2 (en) 2010-05-26 2015-06-30 Selecta Biosciences, Inc. Dose selection of adjuvanted synthetic nanocarriers
US9080014B2 (en) 2006-05-15 2015-07-14 Massachusetts Institute Of Technology Polymers for functional particles
KR101550941B1 (ko) 2010-10-14 2015-09-07 (주)아모레퍼시픽 리피드가 코팅된 하이드로겔 입자 및 이의 제조방법
US9192675B2 (en) 2008-06-13 2015-11-24 Mankind Corporation Dry powder inhaler and system for drug delivery
US9217129B2 (en) 2007-02-09 2015-12-22 Massachusetts Institute Of Technology Oscillating cell culture bioreactor
US9220687B2 (en) 2008-12-29 2015-12-29 Mannkind Corporation Substituted diketopiperazine analogs for use as drug delivery agents
US9233072B2 (en) 2008-10-12 2016-01-12 Massachusetts Institute Of Technology Adjuvant incorporation in immunonanotherapeutics
US9233159B2 (en) 2011-10-24 2016-01-12 Mannkind Corporation Methods and compositions for treating pain
US9241903B2 (en) 2006-02-22 2016-01-26 Mannkind Corporation Method for improving the pharmaceutic properties of microparticles comprising diketopiperazine and an active agent
US9267937B2 (en) 2005-12-15 2016-02-23 Massachusetts Institute Of Technology System for screening particles
US9283193B2 (en) 2005-09-14 2016-03-15 Mannkind Corporation Method of drug formulation based on increasing the affinity of crystalline microparticle surfaces for active agents
US9308280B2 (en) 2008-10-12 2016-04-12 Massachusetts Institute Of Technology Targeting of antigen presenting cells with immunonanotherapeutics
US9333179B2 (en) 2007-04-04 2016-05-10 Massachusetts Institute Of Technology Amphiphilic compound assisted nanoparticles for targeted delivery
US9346766B2 (en) 2004-08-20 2016-05-24 Mannkind Corporation Catalysis of diketopiperazine synthesis
US9364619B2 (en) 2008-06-20 2016-06-14 Mannkind Corporation Interactive apparatus and method for real-time profiling of inhalation efforts
US9364436B2 (en) 2011-06-17 2016-06-14 Mannkind Corporation High capacity diketopiperazine microparticles and methods
US9381477B2 (en) 2006-06-23 2016-07-05 Massachusetts Institute Of Technology Microfluidic synthesis of organic nanoparticles
US9474717B2 (en) 2007-10-12 2016-10-25 Massachusetts Institute Of Technology Vaccine nanotechnology
US9492400B2 (en) 2004-11-04 2016-11-15 Massachusetts Institute Of Technology Coated controlled release polymer particles as efficient oral delivery vehicles for biopharmaceuticals
US9630930B2 (en) 2009-06-12 2017-04-25 Mannkind Corporation Diketopiperazine microparticles with defined specific surface areas
US9662461B2 (en) 2008-06-13 2017-05-30 Mannkind Corporation Dry powder drug delivery system and methods
US9675674B2 (en) 2004-08-23 2017-06-13 Mannkind Corporation Diketopiperazine salts for drug delivery and related methods
US9700690B2 (en) 2002-03-20 2017-07-11 Mannkind Corporation Inhalation apparatus
US9706944B2 (en) 2009-11-03 2017-07-18 Mannkind Corporation Apparatus and method for simulating inhalation efforts
US9802012B2 (en) 2012-07-12 2017-10-31 Mannkind Corporation Dry powder drug delivery system and methods
US9925144B2 (en) 2013-07-18 2018-03-27 Mannkind Corporation Heat-stable dry powder pharmaceutical compositions and methods
US9943571B2 (en) 2008-08-11 2018-04-17 Mannkind Corporation Use of ultrarapid acting insulin
US9983108B2 (en) 2009-03-11 2018-05-29 Mannkind Corporation Apparatus, system and method for measuring resistance of an inhaler
US10159644B2 (en) 2012-10-26 2018-12-25 Mannkind Corporation Inhalable vaccine compositions and methods
US10307464B2 (en) 2014-03-28 2019-06-04 Mannkind Corporation Use of ultrarapid acting insulin
US10342938B2 (en) 2008-06-13 2019-07-09 Mannkind Corporation Dry powder drug delivery system
US10421729B2 (en) 2013-03-15 2019-09-24 Mannkind Corporation Microcrystalline diketopiperazine compositions and methods
US10561806B2 (en) 2014-10-02 2020-02-18 Mannkind Corporation Mouthpiece cover for an inhaler
US10625034B2 (en) 2011-04-01 2020-04-21 Mannkind Corporation Blister package for pharmaceutical cartridges
US10933129B2 (en) 2011-07-29 2021-03-02 Selecta Biosciences, Inc. Methods for administering synthetic nanocarriers that generate humoral and cytotoxic T lymphocyte responses
CN114432243A (zh) * 2022-01-20 2022-05-06 华南师范大学 一种响应pH和葡萄糖的纳米载体及其应用
US11446127B2 (en) 2013-08-05 2022-09-20 Mannkind Corporation Insufflation apparatus and methods
US20230165795A1 (en) * 2018-03-20 2023-06-01 Universiteit Twente Liposomes for targeting tumor-associated macrophages

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5346702A (en) * 1992-12-04 1994-09-13 Sterling Winthrop Inc. Use of non-ionic cloud point modifiers to minimize nanoparticle aggregation during sterilization
US5417982A (en) * 1994-02-17 1995-05-23 Modi; Pankaj Controlled release of drugs or hormones in biodegradable polymer microspheres
US5510118A (en) * 1995-02-14 1996-04-23 Nanosystems Llc Process for preparing therapeutic compositions containing nanoparticles

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5346702A (en) * 1992-12-04 1994-09-13 Sterling Winthrop Inc. Use of non-ionic cloud point modifiers to minimize nanoparticle aggregation during sterilization
US5417982A (en) * 1994-02-17 1995-05-23 Modi; Pankaj Controlled release of drugs or hormones in biodegradable polymer microspheres
US5510118A (en) * 1995-02-14 1996-04-23 Nanosystems Llc Process for preparing therapeutic compositions containing nanoparticles

Cited By (105)

* Cited by examiner, † Cited by third party
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US6740643B2 (en) * 1999-01-21 2004-05-25 Mirus Corporation Compositions and methods for drug delivery using amphiphile binding molecules
US9801925B2 (en) 1999-06-29 2017-10-31 Mannkind Corporation Potentiation of glucose elimination
US7943178B2 (en) 1999-06-29 2011-05-17 Mannkind Corporation Methods and compositions for delivering peptides
US8389470B2 (en) 1999-06-29 2013-03-05 Mannkind Corporation Methods and compositions for delivering peptides
US9006175B2 (en) 1999-06-29 2015-04-14 Mannkind Corporation Potentiation of glucose elimination
US7648960B2 (en) 1999-06-29 2010-01-19 Mannkind Corporation Method for delivery of monomeric or dimeric insulin complexed to diketopiperazine microparticles
EP1808438A3 (fr) * 1999-06-29 2008-12-24 MannKind Corporation Purification et stabilisation de peptide et protéines dans des agents pharmaceutiques
US6875448B1 (en) * 1999-09-03 2005-04-05 Chugai Seiyaku Kabushiki Kaisha Method of intracellular sustained-release of drug and preparations
US6524595B1 (en) * 2000-05-12 2003-02-25 Coletica Cyclodextrins preferentially substituted on their primary face by acid or amine functions
EP2316490A2 (fr) 2000-10-31 2011-05-04 PR Pharmaceuticals, Inc. Methodes et compositions pour améliorer l'administration de molécules bioactives
EP1385530A4 (fr) * 2001-05-09 2005-11-09 Mediplex Corp Formulation de derives d'heparine amphiphiles servant a ameliorer l'absorption par les muqueuses
EP1385530A1 (fr) * 2001-05-09 2004-02-04 Mediplex Corporation Formulation de derives d'heparine amphiphiles servant a ameliorer l'absorption par les muqueuses
WO2003053470A2 (fr) * 2001-12-21 2003-07-03 Universiteit Gent Systemes de distribution d'agents biologiques par impulsions bases sur des solutions ou des hydrogels polymeriques degradables
WO2003053470A3 (fr) * 2001-12-21 2004-03-18 Univ Gent Systemes de distribution d'agents biologiques par impulsions bases sur des solutions ou des hydrogels polymeriques degradables
US9700690B2 (en) 2002-03-20 2017-07-11 Mannkind Corporation Inhalation apparatus
US8916196B2 (en) 2003-04-10 2014-12-23 Evonik Corporation Method for the production of emulsion-based microparticles
US10272044B2 (en) 2003-04-10 2019-04-30 Evonik Corporation Method for the production of emulsion-based microparticles
US8871269B2 (en) 2003-07-15 2014-10-28 Evonik Corporation Method for the preparation of controlled release formulations
US8900636B2 (en) 2003-07-23 2014-12-02 Evonik Corporation Controlled release compositions
EP1696961A1 (fr) * 2003-12-24 2006-09-06 Samyang Corporation Compositions a nanoparticules de medicaments solubles dans l'eau administrees par voie orale et methodes de preparation
EP1696961A4 (fr) * 2003-12-24 2010-09-01 Samyang Corp Compositions a nanoparticules de medicaments solubles dans l'eau administrees par voie orale et methodes de preparation
US8628801B2 (en) 2004-04-29 2014-01-14 Universidad De Navarra Pegylated nanoparticles
US8895067B2 (en) 2004-04-29 2014-11-25 Universidad De Navarra Immune response stimulating composition comprising nanoparticles based on a methyl vinyl ether-maleic acid copolymer
WO2005110374A1 (fr) * 2004-04-30 2005-11-24 Allergan, Inc. Systemes de distribution de medicaments intraoculaires contenant un agent therapeutique, une cyclodextrine et un composant polymere
US9796688B2 (en) 2004-08-20 2017-10-24 Mannkind Corporation Catalysis of diketopiperazine synthesis
US9346766B2 (en) 2004-08-20 2016-05-24 Mannkind Corporation Catalysis of diketopiperazine synthesis
US9675674B2 (en) 2004-08-23 2017-06-13 Mannkind Corporation Diketopiperazine salts for drug delivery and related methods
US10130685B2 (en) 2004-08-23 2018-11-20 Mannkind Corporation Diketopiperazine salts for drug delivery and related methods
KR100690318B1 (ko) 2004-09-25 2007-03-09 경북대학교 산학협력단 수용성 고분자 나노 하이드로겔의 제조방법
US9492400B2 (en) 2004-11-04 2016-11-15 Massachusetts Institute Of Technology Coated controlled release polymer particles as efficient oral delivery vehicles for biopharmaceuticals
WO2006128937A2 (fr) 2005-06-02 2006-12-07 Universidade De Santiago De Compostela Nanoparticules qui contiennent du chitosane et de la cyclodextrine
US10143655B2 (en) 2005-09-14 2018-12-04 Mannkind Corporation Method of drug formulation
US9717689B2 (en) 2005-09-14 2017-08-01 Mannkind Corporation Method of drug formulation based on increasing the affinity of crystalline microparticle surfaces for active agents
US9283193B2 (en) 2005-09-14 2016-03-15 Mannkind Corporation Method of drug formulation based on increasing the affinity of crystalline microparticle surfaces for active agents
US9446001B2 (en) 2005-09-14 2016-09-20 Mannkind Corporation Increasing drug affinity for crystalline microparticle surfaces
WO2007042572A1 (fr) * 2005-10-14 2007-04-19 Advanced In Vitro Cell Technologies, S.L. Nanoparticules de chitosane et d'heparine
AU2006301162B2 (en) * 2005-10-14 2012-04-05 Advancell Advanced In Vitro Cell Technologies, S.A. Chitosan and heparin nanoparticles
EP1774971A1 (fr) * 2005-10-14 2007-04-18 Advanced in Vitro Cell Technologies, S.L. Nanoparticules comprenant de chitosane et d'héparine
US9267937B2 (en) 2005-12-15 2016-02-23 Massachusetts Institute Of Technology System for screening particles
US9241903B2 (en) 2006-02-22 2016-01-26 Mannkind Corporation Method for improving the pharmaceutic properties of microparticles comprising diketopiperazine and an active agent
US10130581B2 (en) 2006-02-22 2018-11-20 Mannkind Corporation Method for improving the pharmaceutic properties of microparticles comprising diketopiperazine and an active agent
US9080014B2 (en) 2006-05-15 2015-07-14 Massachusetts Institute Of Technology Polymers for functional particles
US9688812B2 (en) 2006-05-15 2017-06-27 Massachusetts Institute Of Technology Polymers for functional particles
US9381477B2 (en) 2006-06-23 2016-07-05 Massachusetts Institute Of Technology Microfluidic synthesis of organic nanoparticles
US9217129B2 (en) 2007-02-09 2015-12-22 Massachusetts Institute Of Technology Oscillating cell culture bioreactor
US9333179B2 (en) 2007-04-04 2016-05-10 Massachusetts Institute Of Technology Amphiphilic compound assisted nanoparticles for targeted delivery
US9539210B2 (en) 2007-10-12 2017-01-10 Massachusetts Institute Of Technology Vaccine nanotechnology
US9474717B2 (en) 2007-10-12 2016-10-25 Massachusetts Institute Of Technology Vaccine nanotechnology
US9526702B2 (en) 2007-10-12 2016-12-27 Massachusetts Institute Of Technology Vaccine nanotechnology
US11547667B2 (en) 2007-10-12 2023-01-10 Massachusetts Institute Of Technology Vaccine nanotechnology
US10736848B2 (en) 2007-10-12 2020-08-11 Massachusetts Institute Of Technology Vaccine nanotechnology
US10201672B2 (en) 2008-06-13 2019-02-12 Mannkind Corporation Dry powder inhaler and system for drug delivery
US9511198B2 (en) 2008-06-13 2016-12-06 Mannkind Corporation Dry powder inhaler and system for drug delivery
US10751488B2 (en) 2008-06-13 2020-08-25 Mannkind Corporation Dry powder inhaler and system for drug delivery
US9339615B2 (en) 2008-06-13 2016-05-17 Mannkind Corporation Dry powder inhaler and system for drug delivery
US10342938B2 (en) 2008-06-13 2019-07-09 Mannkind Corporation Dry powder drug delivery system
US9446133B2 (en) 2008-06-13 2016-09-20 Mannkind Corporation Dry powder inhaler and system for drug delivery
US9662461B2 (en) 2008-06-13 2017-05-30 Mannkind Corporation Dry powder drug delivery system and methods
US9192675B2 (en) 2008-06-13 2015-11-24 Mankind Corporation Dry powder inhaler and system for drug delivery
US9364619B2 (en) 2008-06-20 2016-06-14 Mannkind Corporation Interactive apparatus and method for real-time profiling of inhalation efforts
US10675421B2 (en) 2008-06-20 2020-06-09 Mannkind Corporation Interactive apparatus and method for real-time profiling of inhalation efforts
US9943571B2 (en) 2008-08-11 2018-04-17 Mannkind Corporation Use of ultrarapid acting insulin
US9233072B2 (en) 2008-10-12 2016-01-12 Massachusetts Institute Of Technology Adjuvant incorporation in immunonanotherapeutics
US8932595B2 (en) 2008-10-12 2015-01-13 Massachusetts Institute Of Technology Nicotine immunonanotherapeutics
US9308280B2 (en) 2008-10-12 2016-04-12 Massachusetts Institute Of Technology Targeting of antigen presenting cells with immunonanotherapeutics
US8906381B2 (en) 2008-10-12 2014-12-09 Massachusetts Institute Of Technology Immunonanotherapeutics that provide IGG humoral response without T-cell antigen
US9439859B2 (en) 2008-10-12 2016-09-13 Massachusetts Institute Of Technology Adjuvant incorporation in immunoanotherapeutics
US9220687B2 (en) 2008-12-29 2015-12-29 Mannkind Corporation Substituted diketopiperazine analogs for use as drug delivery agents
US10172850B2 (en) 2008-12-29 2019-01-08 Mannkind Corporation Substituted diketopiperazine analogs for use as drug delivery agents
US9655850B2 (en) 2008-12-29 2017-05-23 Mannkind Corporation Substituted diketopiperazine analogs for use as drug delivery agents
US9983108B2 (en) 2009-03-11 2018-05-29 Mannkind Corporation Apparatus, system and method for measuring resistance of an inhaler
US8629151B2 (en) 2009-05-27 2014-01-14 Selecta Biosciences, Inc. Immunomodulatory agent-polymeric compounds
US9884112B2 (en) 2009-05-27 2018-02-06 Selecta Biosciences, Inc. Immunomodulatory agent-polymeric compounds
US9006254B2 (en) 2009-05-27 2015-04-14 Selecta Biosciences, Inc. Immunomodulatory agent-polymeric compounds
US9630930B2 (en) 2009-06-12 2017-04-25 Mannkind Corporation Diketopiperazine microparticles with defined specific surface areas
EP2550958A1 (fr) 2009-08-05 2013-01-30 Pieris AG Formulations à libération contrôlée de mutéines de la lipocaline
WO2011015634A2 (fr) 2009-08-05 2011-02-10 Pieris Ag Formulations à libération contrôlée de mutéines de la lipocaline
US9706944B2 (en) 2009-11-03 2017-07-18 Mannkind Corporation Apparatus and method for simulating inhalation efforts
US9764031B2 (en) 2010-05-26 2017-09-19 Selecta Biosciences, Inc. Dose selection of adjuvanted synthetic nanocarriers
US9066978B2 (en) 2010-05-26 2015-06-30 Selecta Biosciences, Inc. Dose selection of adjuvanted synthetic nanocarriers
US9849089B2 (en) 2010-10-14 2017-12-26 Amorepacific Corporation Hydrogel particle coated with lipid and method for manufacturing same
WO2012050359A2 (fr) * 2010-10-14 2012-04-19 (주)아모레퍼시픽 Particule d'hydrogel revêtue d'un lipide et sa méthode de fabrication
WO2012050359A3 (fr) * 2010-10-14 2012-07-05 (주)아모레퍼시픽 Particule d'hydrogel revêtue d'un lipide et sa méthode de fabrication
KR101550941B1 (ko) 2010-10-14 2015-09-07 (주)아모레퍼시픽 리피드가 코팅된 하이드로겔 입자 및 이의 제조방법
CN103167868A (zh) * 2010-10-14 2013-06-19 株式会社爱茉莉太平洋 包覆有脂质的水凝胶粒子及其制备方法
US10625034B2 (en) 2011-04-01 2020-04-21 Mannkind Corporation Blister package for pharmaceutical cartridges
US9364436B2 (en) 2011-06-17 2016-06-14 Mannkind Corporation High capacity diketopiperazine microparticles and methods
US10130709B2 (en) 2011-06-17 2018-11-20 Mannkind Corporation High capacity diketopiperazine microparticles and methods
US10933129B2 (en) 2011-07-29 2021-03-02 Selecta Biosciences, Inc. Methods for administering synthetic nanocarriers that generate humoral and cytotoxic T lymphocyte responses
US9233159B2 (en) 2011-10-24 2016-01-12 Mannkind Corporation Methods and compositions for treating pain
US10258664B2 (en) 2011-10-24 2019-04-16 Mannkind Corporation Methods and compositions for treating pain
US9610351B2 (en) 2011-10-24 2017-04-04 Mannkind Corporation Methods and compositions for treating pain
WO2013134349A1 (fr) 2012-03-06 2013-09-12 Clemson University Systèmes d'administration pour améliorer l'efficacité d'un médicament
US9802012B2 (en) 2012-07-12 2017-10-31 Mannkind Corporation Dry powder drug delivery system and methods
US10159644B2 (en) 2012-10-26 2018-12-25 Mannkind Corporation Inhalable vaccine compositions and methods
US10421729B2 (en) 2013-03-15 2019-09-24 Mannkind Corporation Microcrystalline diketopiperazine compositions and methods
US9925144B2 (en) 2013-07-18 2018-03-27 Mannkind Corporation Heat-stable dry powder pharmaceutical compositions and methods
US11446127B2 (en) 2013-08-05 2022-09-20 Mannkind Corporation Insufflation apparatus and methods
US10307464B2 (en) 2014-03-28 2019-06-04 Mannkind Corporation Use of ultrarapid acting insulin
CN104257633A (zh) * 2014-08-27 2015-01-07 珠海健帆生物科技股份有限公司 抗凝缓释胶囊及其制备方法、功能性抗凝缓释器
US10561806B2 (en) 2014-10-02 2020-02-18 Mannkind Corporation Mouthpiece cover for an inhaler
US20230165795A1 (en) * 2018-03-20 2023-06-01 Universiteit Twente Liposomes for targeting tumor-associated macrophages
US12156938B2 (en) * 2018-03-20 2024-12-03 Universiteit Twente Liposomes for targeting tumor-associated macrophages
CN114432243A (zh) * 2022-01-20 2022-05-06 华南师范大学 一种响应pH和葡萄糖的纳米载体及其应用
CN114432243B (zh) * 2022-01-20 2023-08-29 华南师范大学 一种响应pH和葡萄糖的纳米载体及其应用

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