WO1993018754A1 - Self-assembling diketopiperazine drug delivery system - Google Patents
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- WO1993018754A1 WO1993018754A1 PCT/US1993/002245 US9302245W WO9318754A1 WO 1993018754 A1 WO1993018754 A1 WO 1993018754A1 US 9302245 W US9302245 W US 9302245W WO 9318754 A1 WO9318754 A1 WO 9318754A1
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- microparticles
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- diketopiperazines
- biologically active
- diketopiperazine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
Definitions
- This invention is generally in the area of drug delivery systems and is particularly related to reversible microencapsulation of drugs by certain 2,5- diketo-derivatives of piperazine.
- the field of oral drug delivery covers a broad range of delivery systems ranging from simple mechanical carriers such as pressed tablets which transport compounds that can be safely and efficiently delivered through the stomach, to enteric coatings which delay the release of the encapsulated compound to later in the digestive process and lower in the gastrointestinal tract.
- enteric coatings have been used to encapsulate and protect the drug prior to reaching the small intestine. In some cases these are effective. However, there are drugs that are also unstable to the conditions present in the small intestine and therefore must be administered in much higher dosages if the drug is to be released in the small intestine for an effective amount to penetrate to the bloodstream. In these cases, it is necessary to have a mechanism whereby the coating is not only stable to the conditions present in the digestive tract, as well as to the conditions under which it is stored prior to administration to the patient, but which allows the encapsulated drug to pass into the bloodstream.
- the most desirable delivery system from a manufacturing standpoint is one that is self assembling from simple, chemically defined precursors, which are stable over the pH, temperature and solvent range of interest, yet resistant to rapid protease attack. Ideally, these precursors are economical and available, using available technology, in production volume.
- One of the best known self-assembling ' encapsulation systems is the amino acid polymer self- assembling microcapsules first pioneered by Dr. Sidney Fox (Molecular Evolution and the Origin of Life) . The initial experiments were with "proteinoids”, a "linear thermal condensation polymer of a mixture of naturally occurring amino acids", the same system subsequently patented by Steiner and Rosen for drug delivery.
- Drug delivery systems have been developed based on the formation of diketopiperazine microparticles.
- the microparticle is stable at low pH and disintegrates at a pH of about 6.5 or greater, and is particularly useful for oral drug delivery.
- the microparticles are formed in the presence of the drug to be delivered, for example, insulin or heparin.
- the diketopiperazine microparticles are preferably formed in the presence of the drug to be encapsulated by acidification of weakly alkaline solutions of a diketopiperazine derivative that contains one or more carboxylic acid groups.
- Figure 1 is a schematic of the synthesis of 2,5- diketo-3,6-di(4-succinylaminobutyl)piperazine.
- Figure 2a is a graph of the average percent reduction in blood glucose levels measured in mg/dl for four and five subjects, respectively, receiving 1 ml of encapsulated insulin/kg of body weight at various time intervals (hours) .
- Figures 2b is a graph of the average percent reduction in blood glucose measured in mg/dl over time (hours) , following administration of the microparticles not containing insulin.
- Figure 3a is a graph of the clotting time (seconds) as % of baseline over time (minutes) for plasma from animals which have received encapsulated heparin by oral gavage.
- Figure 3b is a graph of the clotting time (seconds) as % of baseline over time (minutes) for plasma from animals which have received microparticles not containing heparin by oral gavage.
- the present invention is a drug delivery system using diketopiperazines to form microparticles encapsulating a drug to be delivered.
- microparticles includes microcapsules having an outer shell surrounding a core material; microspheres containing drug dispersed throughout the sphere; and microparticles of irregular shape.
- the microparticles are microspheres of between 0.1 to ten microns in diameter.
- drug and “cargo” refer to the pharmacologically active agent incorporated into the microparticles.
- a clinically viable micro-encapsulation system should ideally be constructed from a chemically- defined synthetic subunit.
- the subunit should be of minimum complexity to permit toxicity and efficacy data to be derived to establish both safety and reproducible bioavailability with an acceptably narrow range of deviation from lot to lot (manufacturability) .
- the system should be self-assembling under closely controllable conditions, which conditions are benign to a range of potential drugs to be encapsulated. While the charge distribution, solubility and hydrophobicity of the cargo must clearly have some influence on assembly, a well- selected system should accept, with little modification, a range of drug cargoes. For specific cargoes, the material can optimized with minor structural manipulations.
- the basic building blocks of a self-assembling system should be nonlinear in structure and should be synthesized to provide a known non-stochastic starting structure. Furthermore, the pH-dependent assembly/disassembly range should be closely controlled and defined.
- Such rigid structures include amino acids and other components.
- planar rings provides excellent stiffness, reducing the degree of freedom and therefore the variability in performance.
- nucleic acids adenine and guanine are examples of the type of structures displaying significant stiffness, comprising six member rings that share an edge with five member rings. This rigidity and stability may account for their evolutionary selection as genetic code elements, imparting dimensional stability in bridging the double helix.
- an "end cap” on a polymer such as pyroglutamate increases the stability of the system by aiding in "surface tiling" to provide a net curvature to a cross-linked sheet.
- a preferred planar ring element that provides excellent rigidity and appropriate attachment sites for synthetic variation is diketopiperazine or one of its substitution derivatives, including diketomorpholines, diketodioxanes or others.
- a system based upon diketopiperazine structural elements forms microparticles with desirable size distributions and pH ranges as well as good cargo tolerance.
- a wide range of stable, reproducible characteristics can be generated with appropriate manipulations of the attachment sites, resulting in substantial yields and excellent reproducibility.
- Toxicity, size, pH range and cargo capacity should be stable, experimentally verifiable parameters of the system.
- the diketopiperazines or their substitution analogs are rigid planar hexagonal rings with opposing heteroatoms and unbonded electron pairs.
- One or both of the nitrogens can be replaced with oxygen to create the substitution analogs diketomorpholine and diketodioxane, respectively. Although it is possible to replace a nitrogen with a sulfur atom, this does not yield a stable structure.
- the general formula for diketopiperazine and its analogs is shown below.
- ring atoms X at positions 1 and 4 are either 0 or N; and at least one of the side-chain substituents R at positions 3 and 6 contains an ionizable group such as a carboxyl group if the composition is used for oral delivery and exhibits pH-dependent assembly- disassembly, one or both must be ionizable to control release conditions.
- diketopiperazines includes diketopiperazines and derivatives and modifications thereof falling within the scope of the above-general formula.
- Diketopiperazines can be formed by cyclodimerization of amino acid ester derivatives, as described by Katchalski, et al. , J. Amer. Chem. Soc. 68, 879-880 (1946), by cyclization of dipeptide ester derivatives, or by thermal dehydration of amino acid derivatives in high-boiling solvents, as described by Kopple, et al. , J. Orcr. Chem. 33(2), 862-864 (1968), the teachings of which are incorporated herein. 2,5- diketo-3,6-di(aminobutyl)piperazine (Katchalski et al.
- lysine anhydride was conveniently prepared via cyclodimerization of N-epsilon-Z-L-lysine in molten phenol, similar to the Kopple method in J. Org. Chem . , followed by removal of the blocking (Z)- groups with 4.3 M HBr in acetic acid.
- This route is preferred because it uses a commercially available starting material, it involves reaction conditions that are reported to preserve stereochemistry of the starting materials in the product and all steps can be easily scaled up for manufacture.
- 2,5-diketo-3,6-di(4- succinylaminobutyl)piperazine is shown schematically in Figure 1.
- 2,5-diketo-3,6-di(aminobutyl)piperazine is exhaustively succinylated with succinic anhydride in mildly alkaline aqueous solution to yield a product which is readily soluble in weakly alkaline aqueous solution, but which is quite insoluble in acidic aqueous solutions.
- concentrated solutions of the compound in weakly alkaline media are rapidly acidified under appropriate conditions, the material separates from the solution as microparticles.
- drug is encapsulated within microparticles by dissolving the diketopiperazine in bicarbonate or other basic solution, adding the drug in solution or suspension to be encapsulated, then solidifying the structure by adding acid, such as l M citric acid.
- the microparticles can be stored in the dried state and reconstituted for administration to a patient.
- the reconstituted microparticles maintain their stability in an acidic medium and open up as the medium approaches physiological pH in the range of 6.5.
- materials such as a cyclo-Lys(Z)-Lys(Z) synthetic intermediate treated with a limiting amount of HBr in acetic acid to remove one rather than both of the Z groups, are soluble in weakly acidic aqueous solutions and precipitate when the solution is made weakly alkaline with sodium bicarbonate, and could be used to form microparticles for drug delivery where it is desirable to achieve release under acidic conditions, for example, following phagocytosis and endocytosis into lysosomes.
- Another material that should exhibit this response to pH was obtained by heating diketopiperazine with succinic anhydride in refluxing toluene, which is expected to yield a diketopiperazine derivative N-succinylated at the 1 and 4 positions of the ring. Materials that can be encapsulated.
- biologically active agents having therapeutic, prophylactic or diagnostic activities can be delivered. These can be organic or inorganic compounds, proteins, or a wide variety of other compounds, including nutritional agents such as vitamins, minerals, amino acids and fats.
- the materials are biologically active agents that are to be released in the circulatory system after transport from the GI tract following oral delivery.
- proteins and peptides examples include proteins and peptides (wherein protein is defined as consisting of 100 amino acid residues or more and a peptide is less than 100 amino acid residues) , such as insulin and other hormones, .polysaccharides, such as heparin, nucleic acids (such as antisense) , lipids and lipopolysaccharides, and organic molecules having biological activity such as many of the antibiotics, anti-inflammatories, antivirals, vaso- and neuroactive . agents. Specific examples include hormones, anticoagulants, immunomodulating agents, cytotoxic agents, antibiotics, antivirals, antisense, antigens, and antibodies. In some instances, the proteins may be antibodies or antigens which otherwise would have to be administered by injection to elicit an appropriate response.
- these biological agents are unstable in gastric acid, diffuse slowly through gastrointestinal membranes, and/or are susceptible to enzymatic destruction in the gastrointestinal tract.
- the biological agents are encapsulated to protect them in the gastrointestinal tract prior to release in the blood stream.
- the protective material, the diketopiperazines are not biologically active and do not alter the pharmacologic properties of the therapeutic agents.
- the microparticles are acid stable and hence resist the acidic environment of the stomach. In addition they are resistant to enzymatic degradation in the stomach. They are believed to pass through the endothelium into the blood stream where they become soluble in the near neutral pH of the blood, liberating the pharmacologically active compound.
- agents include hormones, antigens, antibiotics, steroids, decongestants, neuroactive agents, and anesthetics or sedatives.
- the agents can be in various forms, such as uncharged molecules or . components of molecular complexes.
- salts of metals, amines or organic cations e.g., quaternary ammonium
- Simple derivatives of the drugs such as ethers, esters, and amides
- Radioisotopes and radiopaque agents include gallium, technetium, indium, strontium, iodine, barium, and- phosphorus.
- the microparticles can be administered in suspension or encapsulated in another material such as an enteric coating or stabilizing agent such as albumin or lactose. These materials and methods for use thereof are well known to those in the pharmaceutical industry.
- the pharmaceutical composition may consist only of the microparticles or may further include the encapsulated compound, or other compounds. For example, it may be desirable to administer a compound that is stable to passage through the stomach that is then rapidly absorbed in one dosage in the intestine, followed by the more controlled, delayed release of the same or a different compound from the microparticles, i.e., enterically protected basic stable, neutral, soluble microcapsules, if the compound can tolerate encapsulation.
- microparticles can be administered topically, locally or systemically by parenteral administration or enteral administration. Enteral Administration.
- Microparticles having biologically active agents are preferably administered orally. These microparticles, depending on the chemical nature and size, will either be absorbed to, or passed through, the epithelial lining of the gastrointestinal tract into the bloodstream or lymphatic system. Parenteral Administration.
- Microparticles of less than five microns readily pass through a needle for intravenous administration.
- Suitable pharmaceutical carriers for example, a phosphate buffered saline, are known and commercially available.
- Intravenous administration may be preferred for targeted delivery of incorporated compounds to phagocytic cells, for example, of antiparasitic or anti-HIV drugs, where the pathogenic agent is also selective for these cell types.
- Microcapsules should be stable at neutral pH and dissolve at low pH, the reverse of the oral system. Subcutaneous, Intramuscular and Intraperitoneal Administratio .
- Microparticles produced as described above are small enough to be injected through a standard gauge needle under the skin or into the peritoneum for subsequent release of incorporated drug. Adhesion of the microparticles to the peritoneum aids in localizing release of the incorporated drug. Microparticles can also be implanted or injected intramuscularly for immunization or other purposes where slower release into the bloodstream is desirable. Carriers such as phosphate buffer saline, or an adjuvant such as an oil, can be used as a carrier for the microparticles. Pharmaceutically acceptable carriers are known to those skilled in the art. Topical Administration.
- Microparticles are suspended in a suitable pharmaceutical carrier for administration using methods appropriate for the carrier and site of administration.
- a suitable pharmaceutical carrier for administration using methods appropriate for the carrier and site of administration.
- microparticles are administered to the eye in a buffered saline solution, approximately pH 7.4, or in an ointment such as mineral oil.
- the dosage will be dependent on the compound to be" released as well as the rate of release.
- the microparticles, or aggregations of microparticles into films, disks, or tablets, with incorporated compound can be administered to the skin in an ointment or cream.
- Suitable pharmaceutical carriers are known to those skilled in the art and commercially available.
- antibiotics or growth factors amino acids, peptides, or protein growth factors
- open wounds are of particular therapeutic importance in a variety of medical and surgical situations including, but not limited to, thermal burns, chemical burns, surgical wounds, diabetic ulcers and vascular insufficiency. Diagnostic Applications.
- microparticles containing radiopaque compounds, radioisotopes, or radiolucent compounds are particularly suited for use in diagnostic procedures.
- the microparticles can be administered parenterally or enterally.
- Microparticles that bind to mucosal membranes are particularly preferred for these applications, especially for imaging of the nasal and pharyngeal, gastrointestinal, and genito-urinary tracts.
- Intravenous administration of microparticles containing imaging agents are particularly useful for imaging liver, spleen or lung. Targeted Administration.
- Phagocytic cells within the Peyer's patches appear to selectively take up microparticles administered orally. Phagocytic cells of the reticuloendothelial system also take up microparticles when administered intravenously. Microparticles of less than five microns diameter can be injected without embolytic complications. Endocytosis of the microparticles by macrophages can be used to target the microparticles to the spleen, bone marrow, liver and lymph nodes.
- the charge or lipophilicity of the microparticle is used to change the properties of the protein carrier.
- the lipophilicity of the inner surface of the microcapsules can be modified by linking lipophilic groups to increase solubility of some drugs, thereby increasing drug cargo capacity.
- Other modifications can be made before or after formation of the microparticle, as long as the modification after formation does not have a detrimental effect on the incorporated compound.
- the microparticles are stored lyophilized or encapsulated in standard gel capsule materials, for subsequent oral administration.
- the dosage is determined by the amount of encapsulated drug, the rate of release within the gastrointestinal tract, and the pharmokinetics of the compound.
- the microparticles can also be administered by injection, either intravenous, intramuscular, or subcutaneous, topically, or by means of a transdermal patch where release is activated by contact with the low pH of the skin (reverse stability formulation) .
- Example l Preparation of diketopiperazine microparticles. c ⁇ clb-Lys(Z)-Lys(Z) (Cyclodimerization of N-epsilon-(Z)-L-lysine)
- N-epsilon-Z-L-lysine (Sigma Chemical Co, St. Louis, MO, 50 grams) was cyclized as follows. The compound was placed with 250 grams of crystalline phenol in a 500 mL resin reaction kettle under a gentle flow of nitrogen gas (prepurified grade) . The temperature of the reaction mixture was raised to 175°C (heating mantle) and held at that temperature under nitrogen for 18 hours. The reaction kettle was removed from the heating mantle and allowed to cool until the outside of the vessel was not warm to the touch and crystals were just beginning to form in the reaction mixture. The reaction mixture was then mixed with 1.5 L anhydrous ether with stirring to precipitate a fine, white powder.
- the material was dissolved in 50 mL of hot glacial acetic acid and the solution was filtered to remove a small amount of insoluble material. On cooling, a solid crystallized from the acetic acid solution. This material was collected by filtration, then suspended in 200 mL 1:1 water:methanol. The suspension was brought to gentle reflux, then allowed to stand at room temperature for 2 days. The purified product (JG48) was collected by filtration and air dried on the filter. This procedure yielded 3.7 grams of purified cyclo-Lys ( Z)-lys ( z) .
- the cyclo-Lys-Lys dihydrobromide from the preceding procedure was acylated into 2,5-diketo- ,6- di(4-aminobutyl)piperazine with succinic anhydride.
- succinic anhydride succinic anhydride.
- it was dissolved in 200 mL of solution made by saturating water with sodium bicarbonate at room temperature. This dissolution was done slowly so that carbon dioxide gas could escape without causing the mixture to foam out of the reaction vessel.
- the solution was filtered to remove a small amount of insoluble material and the filter was washed with an additional 50 mL of saturated sodium bicarbonate solution which was added to the filtrate.
- the solution was stirred with an efficient magnetic stirrer and with continuous monitoring of the pH using a glass electrode.
- the initial pH was 8.7.
- Succinic anhydride (30 grams) was added in ten portions. Each time the pH of the reaction mixture fell to 7.5, it was readjusted to 8.7 with 4 M NaOH.
- the pattern of adding succinic- anhydride and readjusting the pH was continued until all of the succinic anhydride was dissolved and the final pH stabilized (about half an hour after addition of the last portion of succinic anhydride) .
- citric acid (10 grams) was added to the reaction mixture, then the pH was slowly adjusted to 2.2 with concentrated HCl. (There is a vigorous evolution of carbon dioxide during this process, which is controlled by slow addition of the HCl) . At about pH 3-3.5, a solid product began to separate from the solution. At pH 2.2 the solution was filled with fine particles. The mixture was placed in the refrigerator overnight, then the product was collected by filtration, washed with water, and air dried on the filter. The yield was 11.7 grams of off-white powder (JG52) .
- Example 2 Suppression of blood glucose by oral administration of insulin.
- Porcine insulin (Sigma Chemical Co., St. Louis, MO, specific activity of approximately 26 U/mg) was encapsulated in 2,5-diketo-3,6-di(4- succinylaminobutyl)piperazine by dissolving the piperazine in a saturated sodium bicarbonate solution to form a 125 mg piperazine/mL solution, then mixing this solution with an equal volume of a 1 M citric acid solution containing the insulin to be incorporated in a concentration of 20 mg insulin/ml. This yields a suspension of approximately 67.5 mg microparticles/ml.
- mice received by oral gavage encapsulated insulin administered at a calculated dosage of between 1.25 and 2.0 mg insulin/kg of body weight.
- rats received an amorphous precipitate of the polymer and insuin prepared so that no insulin was encapsulated in spheres, but the concentration of insulin in the final solution was the same as that used in the original preparation.
- this suspension was administered by oral gavage to four control rats, at a dose of 1 ml of suspension/kg of body weight, no significant decrease in blood glucose was noted.
- subjects were administered insulin subcutaneously as both an aqueous solution and in the form of an amorphous precipitate to demonstrate the biological activity of the insulin itself.
- Blood glucose levels were measured on samples taken from the tail at various times after treatment and measured as mg of glucose/dl of blood using one drop of tail blood squeezed onto a Glucofilm strip.
- Figure 2a presents the average percent reduction in blood glucose levels measured in (mg/dl) for nine subjects receiving 1 ml of encapsulated insulin suspension at a concentration of 10 mg/kg of body weight at various time intervals.
- the encapsulated insulin produced a marked fall in blood glucose levels when administered orally.
- Oral administration of an amorphous precipitate- solution of the polymer with the same amount of insulin failed to produce a significant change in blood glucose levels, as shown by Figure 2b.
- the same solution injected subcutaneously produced a characteristic drop in blood glucose; as did an injection of pure insulin in an aqueous solution.
- the absence of a pharmacologic effect with oral administration of unencapsulated insulin is consistent with the findings of other studies in the literature done at higher doses in both animals and humans.
- Figure 2a demonstrates that blood glucose levels are returning to pre-administration values at 240 minutes.
- Example 3 Inhibition of clotting in blood by microencapsulated heparin.
- Heparin (Sigma Chemical Co., St. Louis, MO, specific activity approximately 26 U/mg) ) was encapsulated as described above by dissolving the disuccinyl derivative of 2,5-deketo-3,6-di(4- aminobutyl)piperazine in a saturated sodium bicarbonate solution to a concentration of 120 mg piperazine/mL of solution, then mixing this with an equal volume of 1 M citric acid containing 100 mg sodium heparin/mL citric acid.
- the final suspension contained 50 mg of heparin/ml of suspension. Of this, approximately 20% was encapsulated, yielding a theoretical maximum concentration of encapsulated heparin of 10 mg of heparin per ml of suspension.
- the solution containing encapsulated heparin was administrated to eight rats weighing approximately 250 grams, by oral gavage. The rats were fasted overnight prior to treatment. Each rat received l ml of suspension per kg of body weight. Additionally, a suspension of microcapsules formed in 1 M citric acid with no heparin present was administered to a group of four (4) control rats.
- Figure 3b shows the results of the control group. The results clearly indicate that the microparticles themselves do not appreciably effect clotting time.
Abstract
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Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE69301311T DE69301311T2 (en) | 1992-03-11 | 1993-03-11 | SELF-AGGLOMERATING DIKETOPIPERAZINE DRUG DELIVERY SYSTEM |
JP5516624A JP2617273B2 (en) | 1992-03-11 | 1993-03-11 | Self-assembling diketopiperazine drug delivery system |
AU38044/93A AU680408B2 (en) | 1992-03-11 | 1993-03-11 | Self-assembling diketopiperazine drug delivery system |
CA002131366A CA2131366C (en) | 1992-03-11 | 1993-03-11 | Self-assembling diketopiperazine drug delivery system |
EP93920574A EP0630236B1 (en) | 1992-03-11 | 1993-03-11 | Self-assembling diketopiperazine drug delivery system |
GR960401019T GR3019622T3 (en) | 1992-03-11 | 1996-04-10 | Self-assembling diketopiperazine drug delivery system. |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US849,186 | 1992-03-11 | ||
US07/849,186 US5352461A (en) | 1992-03-11 | 1992-03-11 | Self assembling diketopiperazine drug delivery system |
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WO1993018754A1 true WO1993018754A1 (en) | 1993-09-30 |
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PCT/US1993/002245 WO1993018754A1 (en) | 1992-03-11 | 1993-03-11 | Self-assembling diketopiperazine drug delivery system |
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US (2) | US5352461A (en) |
EP (1) | EP0630236B1 (en) |
JP (1) | JP2617273B2 (en) |
AT (1) | ATE132744T1 (en) |
AU (1) | AU680408B2 (en) |
CA (1) | CA2131366C (en) |
DE (1) | DE69301311T2 (en) |
DK (1) | DK0630236T3 (en) |
ES (1) | ES2089844T3 (en) |
GR (1) | GR3019622T3 (en) |
WO (1) | WO1993018754A1 (en) |
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US9393372B2 (en) | 2008-06-13 | 2016-07-19 | Mannkind Corporation | Dry powder drug delivery system |
US9512073B2 (en) | 2011-10-27 | 2016-12-06 | Massachusetts Institute Of Technology | Amino acid-, peptide-and polypeptide-lipids, isomers, compositions, and uses thereof |
US9522176B2 (en) | 2013-10-22 | 2016-12-20 | Shire Human Genetic Therapies, Inc. | MRNA therapy for phenylketonuria |
US9629804B2 (en) | 2013-10-22 | 2017-04-25 | Shire Human Genetic Therapies, Inc. | Lipid formulations for delivery of messenger RNA |
CN106659731A (en) * | 2014-05-30 | 2017-05-10 | 夏尔人类遗传性治疗公司 | Topical compositions and methods for treating wounds |
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 |
US9840479B2 (en) | 2014-07-02 | 2017-12-12 | Massachusetts Institute Of Technology | Polyamine-fatty acid derived lipidoids and uses thereof |
US9850269B2 (en) | 2014-04-25 | 2017-12-26 | Translate Bio, Inc. | Methods for purification of messenger RNA |
US9925144B2 (en) | 2013-07-18 | 2018-03-27 | Mannkind Corporation | Heat-stable dry powder pharmaceutical compositions and methods |
US9957499B2 (en) | 2013-03-14 | 2018-05-01 | Translate Bio, Inc. | Methods for purification of messenger RNA |
US9983108B2 (en) | 2009-03-11 | 2018-05-29 | Mannkind Corporation | Apparatus, system and method for measuring resistance of an inhaler |
US10138213B2 (en) | 2014-06-24 | 2018-11-27 | Translate Bio, Inc. | Stereochemically enriched compositions for delivery of nucleic acids |
US10159644B2 (en) | 2012-10-26 | 2018-12-25 | Mannkind Corporation | Inhalable vaccine compositions and methods |
US10201618B2 (en) | 2015-06-19 | 2019-02-12 | Massachusetts Institute Of Technology | Alkenyl substituted 2,5-piperazinediones, compositions, and uses thereof |
US10307464B2 (en) | 2014-03-28 | 2019-06-04 | Mannkind Corporation | Use of ultrarapid acting insulin |
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 |
US10576166B2 (en) | 2009-12-01 | 2020-03-03 | Translate Bio, Inc. | Liver specific delivery of messenger RNA |
US10625034B2 (en) | 2011-04-01 | 2020-04-21 | Mannkind Corporation | Blister package for pharmaceutical cartridges |
US10669383B2 (en) | 2006-10-31 | 2020-06-02 | Evonik Corporation | Spheronized polymer particles |
US11174500B2 (en) | 2018-08-24 | 2021-11-16 | Translate Bio, Inc. | Methods for purification of messenger RNA |
US11173190B2 (en) | 2017-05-16 | 2021-11-16 | Translate Bio, Inc. | Treatment of cystic fibrosis by delivery of codon-optimized mRNA encoding CFTR |
US11224642B2 (en) | 2013-10-22 | 2022-01-18 | Translate Bio, Inc. | MRNA therapy for argininosuccinate synthetase deficiency |
US11253605B2 (en) | 2017-02-27 | 2022-02-22 | Translate Bio, Inc. | Codon-optimized CFTR MRNA |
US11254936B2 (en) | 2012-06-08 | 2022-02-22 | Translate Bio, Inc. | Nuclease resistant polynucleotides and uses thereof |
US11446127B2 (en) | 2013-08-05 | 2022-09-20 | Mannkind Corporation | Insufflation apparatus and methods |
Families Citing this family (137)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6331318B1 (en) * | 1994-09-30 | 2001-12-18 | Emisphere Technologies Inc. | Carbon-substituted diketopiperazine delivery systems |
US5714167A (en) | 1992-06-15 | 1998-02-03 | Emisphere Technologies, Inc. | Active agent transport systems |
US6099856A (en) | 1992-06-15 | 2000-08-08 | Emisphere Technologies, Inc. | Active agent transport systems |
US5443841A (en) | 1992-06-15 | 1995-08-22 | Emisphere Technologies, Inc. | Proteinoid microspheres and methods for preparation and use thereof |
US6221367B1 (en) | 1992-06-15 | 2001-04-24 | Emisphere Technologies, Inc. | Active agent transport systems |
US5578323A (en) | 1992-06-15 | 1996-11-26 | Emisphere Technologies, Inc. | Proteinoid carriers and methods for preparation and use thereof |
US5693338A (en) * | 1994-09-29 | 1997-12-02 | Emisphere Technologies, Inc. | Diketopiperazine-based delivery systems |
US5352461A (en) * | 1992-03-11 | 1994-10-04 | Pharmaceutical Discovery Corporation | Self assembling diketopiperazine drug delivery system |
US6916489B2 (en) * | 1992-06-15 | 2005-07-12 | Emisphere Technologies, Inc. | Active agent transport systems |
US5811127A (en) | 1992-06-15 | 1998-09-22 | Emisphere Technologies, Inc. | Desferrioxamine oral delivery system |
US5792451A (en) | 1994-03-02 | 1998-08-11 | Emisphere Technologies, Inc. | Oral drug delivery compositions and methods |
US5401516A (en) | 1992-12-21 | 1995-03-28 | Emisphere Technologies, Inc. | Modified hydrolyzed vegetable protein microspheres and methods for preparation and use thereof |
US5709861A (en) | 1993-04-22 | 1998-01-20 | Emisphere Technologies, Inc. | Compositions for the delivery of antigens |
US6461643B2 (en) | 1993-04-22 | 2002-10-08 | Emisphere Technologies, Inc. | Oral drug delivery compositions and methods |
US5643957A (en) | 1993-04-22 | 1997-07-01 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
EP1025840B1 (en) | 1993-04-22 | 2005-06-29 | Emisphere Technologies, Inc. | Oral drug compositions |
US20010003001A1 (en) | 1993-04-22 | 2001-06-07 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
US5958457A (en) | 1993-04-22 | 1999-09-28 | Emisphere Technologies, Inc. | Compositions for the delivery of antigens |
US20010003739A1 (en) * | 1993-06-24 | 2001-06-14 | Astrazeneca Ab | Systemic administration of a therapeutic preparation |
US5830853A (en) | 1994-06-23 | 1998-11-03 | Astra Aktiebolag | Systemic administration of a therapeutic preparation |
US6794357B1 (en) * | 1993-06-24 | 2004-09-21 | Astrazeneca Ab | Compositions for inhalation |
US6632456B1 (en) | 1993-06-24 | 2003-10-14 | Astrazeneca Ab | Compositions for inhalation |
US5466259A (en) * | 1994-03-07 | 1995-11-14 | Durette; Jean-Francois | Orbital implant and method |
US6165976A (en) | 1994-06-23 | 2000-12-26 | Astra Aktiebolag | Therapeutic preparation for inhalation |
BR9510510A (en) | 1994-12-22 | 1998-07-07 | Astra Ab | Pharmaceutical aerosol formulation using it and processes for manufacturing it to treat a patient in need of therapy |
US6524557B1 (en) * | 1994-12-22 | 2003-02-25 | Astrazeneca Ab | Aerosol formulations of peptides and proteins |
US6001347A (en) | 1995-03-31 | 1999-12-14 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
US5965121A (en) | 1995-03-31 | 1999-10-12 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
US5989539A (en) | 1995-03-31 | 1999-11-23 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
US6090958A (en) | 1995-03-31 | 2000-07-18 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
US5650386A (en) | 1995-03-31 | 1997-07-22 | Emisphere Technologies, Inc. | Compositions for oral delivery of active agents |
US5866536A (en) | 1995-03-31 | 1999-02-02 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
BR9604880A (en) | 1995-03-31 | 1998-05-19 | Emisphere Tech Inc | Compound composition dosage unit form methods for administering a biologically active agent for preparing a composition for administering an active agent and for preparing a compound and pharmacological composition |
US5820881A (en) | 1995-04-28 | 1998-10-13 | Emisphere Technologies, Inc. | Microspheres of diamide-dicarboxylic acids |
US5750147A (en) | 1995-06-07 | 1998-05-12 | Emisphere Technologies, Inc. | Method of solubilizing and encapsulating itraconazole |
US5667806A (en) | 1995-06-07 | 1997-09-16 | Emisphere Technologies, Inc. | Spray drying method and apparatus |
US6051258A (en) | 1995-06-07 | 2000-04-18 | Emisphere Technologies, Inc. | Proteinoid emulsions and methods for preparation and use thereof |
GB2320248B (en) | 1995-09-11 | 1999-04-14 | Emisphere Tech Inc | Method for preparing omega-aminoalkanoic acid derivatives from cycloalkanones |
SI9720025A (en) | 1996-03-29 | 1999-08-31 | Emishphere Technologies, Inc. | Compounds and compositions for delivering active agents |
AU3828597A (en) | 1996-06-14 | 1998-01-07 | Emisphere Technologies, Inc. | Microencapsulated fragrances and method for preparation |
WO1998021951A1 (en) | 1996-11-18 | 1998-05-28 | Emisphere Technologies, Inc. | Methods and compositions for inducing oral tolerance in mammals |
US6313088B1 (en) | 1997-02-07 | 2001-11-06 | Emisphere Technologies, Inc. | 8-[(2-hydroxy-4-methoxy benzoyl) amino]-octanoic acid compositions for delivering active agents |
US6358504B1 (en) | 1997-02-07 | 2002-03-19 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
US6060513A (en) | 1997-02-07 | 2000-05-09 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
US5990166A (en) | 1997-02-07 | 1999-11-23 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
US5879681A (en) | 1997-02-07 | 1999-03-09 | Emisphere Technolgies Inc. | Compounds and compositions for delivering active agents |
US5804688A (en) | 1997-02-07 | 1998-09-08 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
US5939381A (en) | 1997-02-07 | 1999-08-17 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
US5876710A (en) | 1997-02-07 | 1999-03-02 | Emisphere Technologies Inc. | Compounds and compositions for delivering active agents |
US5863944A (en) | 1997-04-30 | 1999-01-26 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
US5962710A (en) | 1997-05-09 | 1999-10-05 | Emisphere Technologies, Inc. | Method of preparing salicyloylamino acids |
US5891237A (en) * | 1997-10-08 | 1999-04-06 | Millennium Inorganic Chemicals, Ltd. | Production of free flowing spheres using partially neutralized fatty acid |
WO2000006184A1 (en) | 1998-07-27 | 2000-02-10 | Emisphere Technologies, Inc. | Pulmonary delivery of active agents |
US6440929B1 (en) | 1998-07-27 | 2002-08-27 | Emisphere Technologies, Inc. | Pulmonary delivery of active agents |
US6991798B1 (en) | 1998-08-07 | 2006-01-31 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
JP4430235B2 (en) * | 1998-08-07 | 2010-03-10 | エミスフェアー・テクノロジーズ・インク | Compounds and compositions for delivery of active agents |
BR0008590A (en) * | 1999-01-08 | 2001-10-30 | Emisphere Tech Inc | Polymeric delivery agent, composition, unit dosage form, method for administering a biologically active agent to an animal requiring the agent, method for preparing a composition; it's composed |
EP1156812A4 (en) * | 1999-02-23 | 2004-09-29 | Isis Pharmaceuticals Inc | Multiparticulate formulation |
WO2000050386A1 (en) | 1999-02-26 | 2000-08-31 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
CA2369591C (en) * | 1999-04-05 | 2011-06-14 | Emisphere Technologies, Inc. | Disodium salts, monohydrate, and ethanol solvates |
AU2012201760B2 (en) * | 1999-06-29 | 2015-04-16 | Mannkind Corporation | Purification and stabilization of peptide and protein pharmaceutical agents |
US7129274B1 (en) | 1999-11-05 | 2006-10-31 | Emisphere Technologies Inc. | Phenoxy carboxylic acid compounds and compositions for delivering active agents |
US7279597B1 (en) | 1999-11-05 | 2007-10-09 | Emisphere Technologies, Inc. | Phenyl amine carboxylic acid compounds and compositions for delivering active agents |
ATE427743T1 (en) | 1999-11-15 | 2009-04-15 | Biocure Inc | POLYMERIC HOLLOW PARTICLES RESPONSIVE TO EXTRAORDINARY CONDITIONS |
AU2274201A (en) | 1999-12-16 | 2001-06-25 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
US7833549B2 (en) * | 2000-01-19 | 2010-11-16 | Mannkind Corporation | Dry powder formulations of antihistamine for nasal administration |
US6808707B2 (en) | 2000-02-04 | 2004-10-26 | Matrix Design | Wound healing compositions and methods using tropoelastin and lysyl oxidase |
DE10019879A1 (en) * | 2000-04-20 | 2001-10-25 | Degussa | Production of known and new 2,5-diketopiperazine derivatives useful for the synthesis of bioactive compounds, e.g. cyclo(Lys-Lys) |
US6537968B1 (en) * | 2000-07-24 | 2003-03-25 | Alphamed Pharmaceuticals Corp | Treatment of lupus erythematosus |
PT1311269E (en) * | 2000-08-04 | 2012-05-10 | Dmi Biosciences Inc | Method of using diketopiperazines and composition containing them |
WO2002062797A2 (en) * | 2000-12-29 | 2002-08-15 | Celltech R & D, Inc. | Pharmaceutical uses and synthesis of diketopiperazines |
US20030225300A1 (en) * | 2001-04-19 | 2003-12-04 | Emisphere Technologies Inc. | Compounds and compositions for delivering active agents |
US6991779B2 (en) * | 2002-01-18 | 2006-01-31 | Mannkind Corporation | Compositions for treatment or prevention of bioterrorism |
US7053034B2 (en) * | 2002-04-10 | 2006-05-30 | Salvona, Llc | Targeted controlled delivery compositions activated by changes in pH or salt concentration |
AU2003234240A1 (en) * | 2002-04-23 | 2003-11-10 | Teva Pharmaceutical Industries Ltd. | Pharmaceutical composition containing lamotrigine particles of defined morphology |
DE60326709D1 (en) * | 2002-04-29 | 2009-04-30 | Supernus Pharmaceuticals Inc | PHARMACEUTICAL FORMULATIONS WITH IMPROVED BIOAVAILABILITY |
US20080260838A1 (en) * | 2003-08-01 | 2008-10-23 | Mannkind Corporation | Glucagon-like peptide 1 (glp-1) pharmaceutical formulations |
US20040038865A1 (en) * | 2002-08-01 | 2004-02-26 | Mannkind Corporation | Cell transport compositions and uses thereof |
US20040224024A1 (en) * | 2003-04-23 | 2004-11-11 | Massachusetts Institute Of Technology | Controlled drug release formulations containing polyion complexes |
EP2537524B1 (en) * | 2003-05-15 | 2016-07-06 | Ampio Pharmaceuticals, Inc. | Treatment of T-cell mediated diseases |
KR20060054371A (en) * | 2003-07-31 | 2006-05-22 | 쓰리엠 이노베이티브 프로퍼티즈 컴파니 | Compositions for encapsulation and controlled release |
US7795007B2 (en) | 2003-09-23 | 2010-09-14 | Wisconsin Alumni Research Foundation | Detection of post-translationally modified peptides with liquid crystals |
US8133680B2 (en) * | 2003-09-23 | 2012-03-13 | Wisconsin Alumni Research Foundation | Using liquid crystals to detect affinity microcontact printed biomolecules |
US7338171B2 (en) * | 2003-10-27 | 2008-03-04 | Jen-Chuen Hsieh | Method and apparatus for visual drive control |
US20070027063A1 (en) * | 2004-01-12 | 2007-02-01 | Mannkind Corporation | Method of preserving the function of insulin-producing cells |
EP1708738B1 (en) * | 2004-01-12 | 2016-05-04 | MannKind Corporation | A method of reducing serum proinsulin levels in type 2 diabetics |
JP2005209106A (en) * | 2004-01-26 | 2005-08-04 | Nec Corp | Portable communication terminal, received e-mail management method, program and recording medium |
US20080248999A1 (en) * | 2007-04-04 | 2008-10-09 | Biodel Inc. | Amylin formulations |
US20080096800A1 (en) * | 2004-03-12 | 2008-04-24 | Biodel, Inc. | Rapid mucosal gel or film insulin compositions |
US20080085298A1 (en) * | 2004-03-12 | 2008-04-10 | Biodel, Inc. | Rapid Mucosal Gel or Film Insulin Compositions |
PT2319500E (en) * | 2004-03-12 | 2013-01-23 | Biodel Inc | Rapid acting drug delivery compositions |
EP1781254A2 (en) * | 2004-08-23 | 2007-05-09 | Mannkind Corporation | Pulmonary delivery of inhibitors of phosphodiesterase type 5 |
WO2006086107A2 (en) * | 2005-01-10 | 2006-08-17 | Mannkind Corporation | Methods and compositions for minimizing accrual of inhalable insulin in the lungs |
US20070004036A1 (en) * | 2005-07-01 | 2007-01-04 | Rodolfo Faudoa | Methods and compositions for keratinocyte culture |
US20070128685A1 (en) * | 2005-07-01 | 2007-06-07 | Rodolfo Faudoa | Methods and compositions for cell culture |
US20070003541A1 (en) * | 2005-07-01 | 2007-01-04 | Rodolfo Faudoa | Methods and compositions for therapeutics |
US7713929B2 (en) | 2006-04-12 | 2010-05-11 | Biodel Inc. | Rapid acting and long acting insulin combination formulations |
US8084420B2 (en) | 2005-09-29 | 2011-12-27 | Biodel Inc. | Rapid acting and long acting insulin combination formulations |
US20070086952A1 (en) * | 2005-09-29 | 2007-04-19 | Biodel, Inc. | Rapid Acting and Prolonged Acting Inhalable Insulin Preparations |
ATE465087T1 (en) | 2005-11-21 | 2010-05-15 | Mannkind Corp | DEVICE AND METHOD FOR POWDER DISPENSING AND MEASURING |
US7718609B2 (en) | 2006-04-12 | 2010-05-18 | Biodel Inc. | Rapid acting and long acting insulin combination formulations |
AU2007280995C1 (en) * | 2006-08-04 | 2013-05-23 | Manus Pharmaceuticals (Canada) Ltd. | Multifunctional bioactive compounds |
US8785396B2 (en) | 2007-10-24 | 2014-07-22 | Mannkind Corporation | Method and composition for treating migraines |
KR20100090692A (en) * | 2007-10-24 | 2010-08-16 | 맨카인드 코포레이션 | Delivery of active agents |
MX2010007342A (en) * | 2008-01-04 | 2010-08-26 | Biodel Inc | Insulin formulations for insulin release as a function of tissue glucose levels. |
EP2300011A4 (en) | 2008-05-27 | 2012-06-20 | Dmi Life Sciences Inc | Therapeutic methods and compounds |
BRPI0917568A2 (en) | 2008-08-05 | 2019-09-24 | Mannkind Corp | improved dust distributor modules and distributed dust assemblies |
TWI528982B (en) | 2009-03-04 | 2016-04-11 | 曼凱公司 | An improved dry powder drug delivery system |
CN104801215B (en) | 2009-11-02 | 2017-11-17 | 曼康公司 | The reactor of drug particles is produced with precipitation process |
MX357798B (en) | 2009-11-02 | 2018-07-25 | Mannkind Corp | Apparatus and method for cryogranulating a pharmaceutical composition. |
US9140651B2 (en) | 2010-05-07 | 2015-09-22 | Mannkind Corporation | Determining percent solids in suspension using raman spectroscopy |
WO2012033792A2 (en) | 2010-09-07 | 2012-03-15 | Dmi Acquisition Corp. | Treatment of diseases |
CN103200940A (en) | 2010-11-09 | 2013-07-10 | 曼金德公司 | Composition comprising a serotonin receptor agonist and a diketopiperazine for treating migraines |
KR20140027937A (en) | 2011-02-10 | 2014-03-07 | 맨카인드 코포레이션 | Formation of n-protected bis-3,6-(4-aminoalkyl)-2,5,diketopiperazine |
WO2012142320A2 (en) | 2011-04-12 | 2012-10-18 | Moerae Matrix Inc | Compositions and methods for preventing or treating diseases, conditions, or processes characterized by aberrant fibroblast proliferation and extracellular matrix deposition |
US9890200B2 (en) | 2011-04-12 | 2018-02-13 | Moerae Matrix, Inc. | Compositions and methods for preventing or treating diseases, conditions, or processes characterized by aberrant fibroblast proliferation and extracellular matrix deposition |
EP2717861A1 (en) * | 2011-06-06 | 2014-04-16 | Perosphere, Inc. | Bioadhesive drug delivery compositions |
US8980834B2 (en) | 2011-10-10 | 2015-03-17 | Ampio Pharmaceuticals, Inc. | Treatment of degenerative joint disease |
WO2013055749A1 (en) | 2011-10-10 | 2013-04-18 | Ampio Pharmaceuticals, Inc. | Implantable medical devices with increased immune tolerance, and methods for making and implanting |
BR112014008036A2 (en) | 2011-10-28 | 2017-04-11 | Ampio Pharmaceuticals Inc | rhinitis treatment |
WO2013114374A1 (en) | 2012-02-01 | 2013-08-08 | Protalix Ltd. | Dnase i polypeptides, polynucleotides encoding same, methods of producing dnase i and uses thereof in therapy |
JP6185489B2 (en) | 2012-02-09 | 2017-08-23 | ノーバス・インターナショナル・インコーポレイテッドNovus International,Inc. | Functional polymer composition |
WO2013162764A1 (en) | 2012-04-27 | 2013-10-31 | Mannkind Corp | Methods for the synthesis of ethylfumarates and their use as intermediates |
CA2878617A1 (en) | 2012-07-12 | 2014-01-16 | Houston Stephen Smith | Matrix and layer compositions for protection of bioactives |
SG10201707619RA (en) | 2013-03-15 | 2017-10-30 | Ampio Pharmaceuticals Inc | Compositions for the mobilization, homing, expansion and differentiation of stem cells and methods of using the same |
US10336788B2 (en) | 2014-04-17 | 2019-07-02 | Moerae Matrix, Inc. | Inhibition of cardiac fibrosis in myocardial infarction |
EP4066836A1 (en) | 2014-08-18 | 2022-10-05 | Ampio Pharmaceuticals, Inc. | Treatment of joint conditions |
WO2016057693A1 (en) | 2014-10-10 | 2016-04-14 | Alnylam Pharmaceuticals, Inc. | Methods and compositions for inhalation delivery of conjugated oligonucleotide |
CA2967621A1 (en) | 2014-11-17 | 2016-05-26 | Moerae Matrix, Inc. | Compositions and methods for preventing or treating diseases, conditions, or processes characterized by aberrant fibroblast proliferation and extracellular matrix deposition |
CA2978941A1 (en) | 2015-03-12 | 2016-09-15 | Moerae Matrix, Inc. | Use of mk2 inhibitor peptide-containing compositions for treating non-small cell lung cancer with same |
CN104961687B (en) * | 2015-06-03 | 2017-07-25 | 苏州维泰生物技术有限公司 | 1,2 diazine derivatives and its preparation, purposes |
WO2016209969A1 (en) | 2015-06-22 | 2016-12-29 | Ampio Pharmaceuticals, Inc. | Use of low molecular weight fractions of human serum albumin in treating diseases |
JP2019504684A (en) * | 2016-01-29 | 2019-02-21 | マンカインド コーポレイション | Dry powder inhaler |
TW201809049A (en) | 2016-03-31 | 2018-03-16 | 盧伯利索先進材料有限公司 | Biodegradable and/or bioabsorbable thermoplastic polyurethanes |
US10584306B2 (en) | 2017-08-11 | 2020-03-10 | Board Of Regents Of The University Of Oklahoma | Surfactant microemulsions |
US20200230066A1 (en) * | 2017-10-06 | 2020-07-23 | The Regents Of The University Of California | Self-Assembled Microcapsules for Optically Controlled Cargo Encapsulation and Release |
CA3102967A1 (en) * | 2018-06-07 | 2019-12-12 | Mannkind Corporation | Composition and method for inhalation |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1155036A (en) * | 1966-07-08 | 1969-06-11 | Ethan Allan Brown | Injectionable Substance |
GB1255805A (en) * | 1967-12-16 | 1971-12-01 | Albert Ag Chem Werke | Improvements in delayed release pharmaceutical preparations and stabilisation of vitamins |
FR2145555A1 (en) * | 1971-07-13 | 1973-02-23 | Beecham Group Ltd | |
EP0284039A2 (en) * | 1987-03-24 | 1988-09-28 | Chugai Seiyaku Kabushiki Kaisha | Slow-release pharmaceutical composition |
EP0350246A2 (en) * | 1988-07-05 | 1990-01-10 | Takeda Chemical Industries, Ltd. | Sustained release microcapsule for water soluble drug |
US4976968A (en) * | 1989-02-24 | 1990-12-11 | Clinical Technologies Associates, Inc. | Anhydrous delivery systems for pharmacological agents |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4400330A (en) * | 1982-07-29 | 1983-08-23 | Stauffer Chemical Company | Method for preparation of N-phosphonomethylglycine |
US4694082A (en) * | 1985-09-23 | 1987-09-15 | Monsanto Company | Compound 1,4-diisopropyl-2,5-diketopiperazine |
US4925673A (en) * | 1986-08-18 | 1990-05-15 | Clinical Technologies Associates, Inc. | Delivery systems for pharmacological agents encapsulated with proteinoids |
US5075109A (en) * | 1986-10-24 | 1991-12-24 | Southern Research Institute | Method of potentiating an immune response |
US4983402A (en) * | 1989-02-24 | 1991-01-08 | Clinical Technologies Associates, Inc. | Orally administerable ANF |
JP2571874B2 (en) * | 1989-11-06 | 1997-01-16 | アルカーメス コントロールド セラピューティクス,インコーポレイテッド | Protein microsphere composition |
US5352461A (en) * | 1992-03-11 | 1994-10-04 | Pharmaceutical Discovery Corporation | Self assembling diketopiperazine drug delivery system |
-
1992
- 1992-03-11 US US07/849,186 patent/US5352461A/en not_active Expired - Lifetime
-
1993
- 1993-03-11 EP EP93920574A patent/EP0630236B1/en not_active Expired - Lifetime
- 1993-03-11 AU AU38044/93A patent/AU680408B2/en not_active Expired
- 1993-03-11 JP JP5516624A patent/JP2617273B2/en not_active Expired - Lifetime
- 1993-03-11 DK DK93920574.6T patent/DK0630236T3/en active
- 1993-03-11 WO PCT/US1993/002245 patent/WO1993018754A1/en active IP Right Grant
- 1993-03-11 ES ES93920574T patent/ES2089844T3/en not_active Expired - Lifetime
- 1993-03-11 DE DE69301311T patent/DE69301311T2/en not_active Expired - Lifetime
- 1993-03-11 AT AT93920574T patent/ATE132744T1/en active
- 1993-03-11 CA CA002131366A patent/CA2131366C/en not_active Expired - Lifetime
-
1994
- 1994-09-01 US US08/299,842 patent/US5503852A/en not_active Expired - Lifetime
-
1996
- 1996-04-10 GR GR960401019T patent/GR3019622T3/en unknown
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1155036A (en) * | 1966-07-08 | 1969-06-11 | Ethan Allan Brown | Injectionable Substance |
GB1255805A (en) * | 1967-12-16 | 1971-12-01 | Albert Ag Chem Werke | Improvements in delayed release pharmaceutical preparations and stabilisation of vitamins |
FR2145555A1 (en) * | 1971-07-13 | 1973-02-23 | Beecham Group Ltd | |
EP0284039A2 (en) * | 1987-03-24 | 1988-09-28 | Chugai Seiyaku Kabushiki Kaisha | Slow-release pharmaceutical composition |
EP0350246A2 (en) * | 1988-07-05 | 1990-01-10 | Takeda Chemical Industries, Ltd. | Sustained release microcapsule for water soluble drug |
US4976968A (en) * | 1989-02-24 | 1990-12-11 | Clinical Technologies Associates, Inc. | Anhydrous delivery systems for pharmacological agents |
Non-Patent Citations (2)
Title |
---|
JOURN. AM. CHEM. SOC. vol. 68, May 1946, GASTON (US) pages 879 - 880 E. KATCHALSKI ET AL. 'synthesis of lysine anhydride' cited in the application * |
JOURN. ORG. CHEM. vol. 33, no. 2, February 1968, EASTON (US) pages 862 - 864 K.D. KOPPLE ET AL. 'a convenient synthesis of 2,5-piperazinediones' cited in the application * |
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Also Published As
Publication number | Publication date |
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DE69301311D1 (en) | 1996-02-22 |
ES2089844T3 (en) | 1996-10-01 |
GR3019622T3 (en) | 1996-07-31 |
US5352461A (en) | 1994-10-04 |
DE69301311T2 (en) | 1996-08-22 |
ATE132744T1 (en) | 1996-01-15 |
US5503852A (en) | 1996-04-02 |
CA2131366A1 (en) | 1993-09-30 |
EP0630236B1 (en) | 1996-01-10 |
EP0630236A1 (en) | 1994-12-28 |
DK0630236T3 (en) | 1996-06-03 |
JPH07506818A (en) | 1995-07-27 |
JP2617273B2 (en) | 1997-06-04 |
AU680408B2 (en) | 1997-07-31 |
AU3804493A (en) | 1993-10-21 |
CA2131366C (en) | 2003-09-23 |
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