WO2002078675A2 - Particles for inhalation having sustained release properties - Google Patents
Particles for inhalation having sustained release properties Download PDFInfo
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- WO2002078675A2 WO2002078675A2 PCT/US2002/009697 US0209697W WO02078675A2 WO 2002078675 A2 WO2002078675 A2 WO 2002078675A2 US 0209697 W US0209697 W US 0209697W WO 02078675 A2 WO02078675 A2 WO 02078675A2
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- metal cation
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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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/28—Insulins
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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
-
- 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
- A61K9/1611—Inorganic compounds
Definitions
- Pulmonary delivery of bioactive agents provides an attractive alternative to, for example, oral, transdermal and parenteral administration. That is, pulmonary administration can typically be completed without the need for medical intervention (e.g., it can be self -administered), the pain often associated with injection therapy is avoided, and the amount of enzymatic and pH mediated degradation of the bioactive agent, frequently encountered with oral therapies, can be significantly reduced.
- the lungs provide a large mucosal surface for drug absorption and there is no first-pass liver effect of absorbed drugs. Further, it has been shown that high bioavailability of many molecules, for example, macromolecules, can be achieved via pulmonary delivery or inhalation.
- the deep lung, or alveoli is the primary target of inhaled bioactive agents, particularly for agents requiring systemic delivery.
- the release kinetics or release profile of a bioactive agent into the local and/or systemic circulation is a key consideration in most therapies, including those employing pulmonary delivery. That is, many illnesses or conditions require administration of a constant or sustained levels of a bioactive agent to provide an effective therapy. Typically, this can be accomplished through a multiple dosing regimen or by employing a system that releases the medicament in a sustained fashion.
- U.S. Patent No. 5,997,848 to Patton et al. describes the rapid absorption of insulin following administration of a dry powder formulation via pulmonary delivery. The peak insulin level was reached in about 30 minutes for primates and in about 20 minutes for human subjects. Further, Heinemann, Traut and Heise teach in Diabetic Medicine 14:63-72 (1997) that the onset of action, assessed by glucose infusion rate, in healthy volunteers after inhalation was rapid with the half-maximal action reached in about 30 minutes.
- This invention is based upon the unexpected discovery that complexation of a multivalent metal cation with a therapeutic, prophylactic or diagnostic agent carrying a negative, and therefore opposite charge to that ofthe cation, results in a sustained release profile ofthe agent upon pulmonary delivery.
- the invention generally relates to a method for pulmonary delivery of therapeutic, prophylactic and diagnostic agents to a patient wherein the agent is released in a sustained fashion, and to a composition comprising particles suitable for use in the method.
- the particles are in the form of dry powder.
- the invention relates to a method for the pulmonary delivery of a therapeutic, prophylactic or diagnostic agent comprising administering to the respiratory tract of a patient in need of treatment, prophylaxis or diagnosis an effective amount of particles comprising a multivalent metal cation which is complexed with a therapeutic, prophylactic or diagnostic agent or any combination thereof, a pharmaceutically acceptable carrier and optionally, a multivalent metal cation-containing component.
- the therapeutic, prophylactic or diagnostic agent has a charge which permits complexation with the cation upon association ofthe two.
- the total amount of multivalent metal cation present in the particles is more than 1% weight/weight ofthe total weight ofthe agent (% w/w). Release ofthe agent from the administered particles occurs in a sustained fashion.
- the complexation of the therapeutic, prophylactic or diagnostic agent and the oppositely charged multivalent metal cation can result from metal coordination, ionic complexation, salt bridges, hydrogen bonding or a combination thereof.
- the particles suitable for use in the method can comprise a therapeutic, prophylactic or diagnostic agent which is complexed with a multivalent metal cation.
- the agent possesses a charge which allows it to undergo complexation with the metal cation upon association of the two.
- the charge of the agent upon complexation with the multivalent metal cation, prior to administration is that which the agent possesses at pulmonary pH.
- the particles are in the form of a dry powder.
- the particles suitable for pulmonary delivery can comprise a therapeutic, prophylactic or diagnostic agent which possesses an overall net negative charge, and is complexed with a multivalent metal cation.
- the agent can be insulin and the multivalent metal cation can be zinc.
- the particles ofthe invention comprise more than one multivalent metal cation, more than one bioactive agent or both.
- the particles can further comprise a carboxylic acid which is distinct from the bioactive agent and metal cation.
- the carboxylic acid includes at least two carboxyl groups.
- Carboxylic acids include the salts thereof as well as combinations of two or more carboxylic acids and/or salts thereof.
- the carboxylic acid is a hydrophilic carboxylic acid or salt thereof.
- Citric acid and citrates such as, for example sodium citrate, are preferred. Combinations or mixtures of carboxylic acids and/or their salts also can be employed.
- the particles suitable for use in the invention can further comprise an amino acid.
- the amino acid is hydrophobic.
- the particles can be in the form of a dry powder suitable for inhalation.
- the particles can have a tap density of less than about 0.4 g/cm 3 , preferably less than about 0.1 g/cm 3 .
- the particles suitable for use in the invention can have a median geometric diameter of from about 5 micrometers to about 30 micrometers.
- the particles suitable for use in the invention have an aerodynamic diameter of from about 1 to about 5 microns.
- the invention has numerous advantages. For example, particles suitable for inhalation can be designed to possess a sustained release profile. This sustained released profile provides for prolonged residence ofthe administered bioactive agent in the lung and thereby, increases the amount of time in which therapeutic levels of the agent are present in the local environment or systemic circulation.
- the sustained release of agent provides a desirable alternative to injection therapy currently used for many therapeutic, diagnostic and prophylactic agent requiring sustained release of agent, such as insulin for the treatment of diabetes.
- the invention provides a method of delivery to the pulmonary system wherein the high initial release or burst of agent typically seen in inhalation therapy is reduced. Consequently, patient compliance and comfort can be increased by not only reducing frequency of dosing, but by providing a therapy which is more amenable and efficacious to patients.
- FIG. 1A is a graph of insulin concentration ( ⁇ U/mL) in rat plasma versus time post administration of insulin powder Formulations 1-4.
- FIG. IB is a graph of insulin concentration ( ⁇ U/mL) in rat plasma versus time post administration of insulin powder Formulations 5-9. A reduction in the initial release is seen with sustained release Formulations 5-9 ofthe invention.
- FIG. 2 is graph showing insulin concentration (uU/mL) in rat plasma versus time post administration of Formulation No. 1 and Humulin L.
- FIG. 3 is a graph of plasma insulin concentration (uU/mL) versus time post administration of Formulation No. 1 and the fast release Formulation No. 5.
- FIG. 4 is a graph of Cumulative % Recovery in vitro versus time for various formulations.
- Therapeutic, prophylactic or diagnostic agents can also be referred to herein as “bioactive agents”, “medicaments” or “drugs”.
- the invention relates to a method for the pulmonary delivery of therapeutic, prophylactic and diagnostic agents comprising administering to the respiratory tract of a patient in need of treatment, prophylaxis or diagnosis an effective amount of particles comprising a multivalent metal cation which is complexed with a therapeutic, prophylactic or diagnostic agent or any combination thereof having a charge which permits complexation with the cation upon association with the agent, a pharmaceutically acceptable carrier and optionally, a multivalent metal cation- containing component wherein the total amount of multivalent metal cation present in the particles is more than 1% weight/weight ofthe total weight ofthe agent (% w/w).
- the agent is released from the administered particles in a sustained fashion.
- the particles can be in the form of a dry powder.
- sustained release refers to a release of active agent in which the period of release of an effective level of agent is longer than that seen with the same bioactive agent which is not complexed with a multivalent metal cation, prior to administration.
- sustained release also refers to a reduction in the burst of agent typically seen in the first two hours following administration, and more preferably in the first hour, often referred to as the "initial burst".
- the sustained release is characterized by both the period of release being longer in addition to a decreased initial burst.
- a sustained release of insulin can be a release showing elevated serum levels of insulin at least 4 hours post administration, such as about 6 hours or more.
- Pulmonary delivery refers to delivery to the respiratory tract.
- the upper and lower airways are called the conducting airways.
- the terminal bronchioli then divide into respiratory bronchioli which then lead to the ultimate respiratory zone, namely, the alveoli, or deep lung.
- the deep lung, or alveoli are typically the desired target of inhaled therapeutic formulations for systemic drug delivery.
- Complexation ofthe multivalent metal cation with the therapeutic, prophylactic or diagnostic agent can result from metal coordination, ionic complexation, salt bridges, hydrogen bonding or a combination thereof.
- complexation ofthe therapeutic, prophylactic or diagnostic agent and the multivalent metal cation can be a result of ionic complexation or bonding.
- the particles suitable for use in the method can comprise a therapeutic, prophylactic or diagnostic agent which is complexed with a multivalent metal cation wherein the charge of the agent is such that it is able to undergo complexation with the cation upon association, prior to administration.
- the particles suitable for pulmonary delivery can comprise a therapeutic, prophylactic or diagnostic agent which possesses an overall net negative charge at the time of complexation with a multivalent metal cation.
- the agent can be insulin and the multivalent metal cation can be zinc.
- Pulmonary pH range refers to the pH range which can be encountered in the lung of a patient. Typically, in humans, this range of pH is from about 6.4 to about 7.0, such as from 6.4 to about 6.7. pH values ofthe airway lining fluid (ALF) have been reported in "Comparative Biology ofthe Normal Lung", CRC Press, (1991) by R.A. Parent and range from 6.44 to 6.74)
- Multivalent metal cation refers to metal cations which possess a valency of +2 or more.
- the multivalent metal cation can be chosen to have a charge opposite to that of the active agent when the multivalent metal cation and active agent are associated. Combinations of multivalent metal cation can be used.
- Suitable multivalent metal cations include, but are not limited to, biocompatible multivalent metal cations. It is understood that the multivalent metal cations suitable for complexation with an active agent of opposite charge can be any ofthe transition state metals of the periodic table, and the non-transition state metals, for example, calcium (Ca), zinc (Zn), cadmium (Cd), mercury (Hg), strontium (Sr), and barium (Ba). Divalent metal cations are preferred, such as, Zn(II), Ca(II), Cu(H), Mg(II), Ni(II), Co(II), Fe(II), Ag(II), Mn(II) or Cd(H).
- the complexation of the multivalent metal cation with the bioactive agent of opposite charge can be achieved by associating, for example, mixing the bioactive agent in a suitable aqueous solvent with at least one suitable metal cation component under pH conditions suitable for complexation ofthe metal cation and the bioactive agent.
- the metal cation-complexed active agent will be in the form of a precipitate.
- the precipitated metal cation-complexed active agent remains in the solid state throughout the process used to obtain the final particles for administration.
- the bioactive agent is complexed with ZnA Most preferably, the Zn +2 is complexed to insulin.
- Suitable pH conditions to obtain complexation of a metal cation with a bioactive agent can be determined based on the pKa ofthe bioactive agent. That is, the pH of the system wherein complexation takes place should be adjusted based on the pKa ofthe active agent in order to impart a negative charge on the active agent.
- Suitable pH conditions are typically achieved through use of an aqueous buffer system as the solvent (e.g., citrate, phosphate, acetate, etc.). Adjustment to the desired pFI can be achieved with addition of an acid or base as appropriate.
- Suitable solvents are those in which the bioactive agent and the metal cation component are each at least slightly soluble. For example, sodium citrate, acetate, and phosphate buffers.
- the agent may be mixed with the metal cation component in a buffer system wherein the protein has a negative charge.
- an aqueous buffer system e.g. citrate, phosphate, acetate, etc.
- an appropriate base solution e.g. 1 N NaOH
- the metal cation complexed bioactive agent is then mixed with a pharmaceutically acceptable carrier.
- the solution containing the precipitated metal cation complexed biologically active agent is mixed with a solution ofthe pharmaceutically acceptable carrier.
- Suitable pharmaceutically acceptable carriers and appropriate solvent systems for use with same are provided in detail below.
- the solvent is then removed from the resulting mixture. Solvent removal techniques include, for example, lyophilization, evaporation and spray drying. Spray drying ofthe resulting mixture is a preferred method of preparing the particles ofthe invention. Specific spray drying processes are discussed in detail below. It is preferred that the solid metal cation complexed biologically active agent remain in solid form throughout the processing ofthe final particles.
- the total amount of multivalent metal cation present in the particles of the invention is more than 1% by weight ofthe total weight of the active agent (% w/w), such as, about 2%, about 3%, about 4%, about 5% etc.
- the ratio of multivalent cation to active agent present in the particles ofthe invention can be more than 1% w/w and range from about 1.5% w/w to about 2% w/w, or from about 2% w/w to about 2.5% w/w, or from about 2.5% w/w to about 3% w/w etc
- the upper limit of cation present depends upon the tolerance ofthe formulation by the recipient.
- the formulation can have the multivalent metal cation present at about 50%, 100%, 150%, 200%), 250%) by weight ofthe total weight ofthe active agent.
- Total amount of multivalent metal cation refers to the entire concentration of multivalent metal cation within the particles.
- the total amount of multivalent metal cation includes both multivalent metal cation which is complexed with the biologically active agent, as well as any multivalent metal cation which is present but not complexed with the biologically active agent.
- the multivalent metal cation which is not associated with the active agent can be present, for example, as the metal cation of a metal cation-containing component, such as a multivalent metal cation-containing salt.
- Suitable multivalent metal cation-containing components include, but are not limited to, salts having the multivalent metal cations described above and a suitable pharmaceutically acceptable counterion.
- the counterion can be, for example, chloride, bromide, citrate, tartrate, lactate, methanesulfonate, acetate, sulfonate formate, maleate, fumarate, malate, succinate, malonate, sulfate, phosphate, hydrosulfate, pyruvate, mucate, benzoate, glucuronate, oxalate, ascorbate, the conjugate base of a fatty acid (e.g., oleate, laurate, myristate, stearate, arachidate, behenate, arachidonate) and combinations thereof.
- a fatty acid e.g., oleate, laurate, myristate, stearate, arachidate, behenate, arachidonate
- the particles ofthe invention comprise a pharmaceutically acceptable carrier.
- Suitable pharmaceutically acceptable carriers can be chosen, for example, based on achieving particles having the proper characteristics for inhalation to the area of the respiratory tract where delivery is desired and therapeutic action is achieved.
- the pharmaceutically acceptable carrier of the particles is a phospholipid .
- suitable phospholipids include, among others, phosphatidic acids, phosphatidylcholines, phosphatidylalkanolamines such as a phosphatidylethanolamines, phosphatidylglycerols, phosphatidylserines, phosphatidylinositols and combinations thereof.
- Specific examples of phospholipids include, l,2-diacyl-s «-glycero-3- phosphocholine and a l,2-diacyl-.s «-glycero-3-phosphoalkanolamine phospholipids.
- Suitable examples of l,2-diacyl-5 «-glycero-3-phosphocholine phospholipids include, but are not limited to, l,2-dipalmitoyl-s «-glycero-3-phosphocholine (DPPC), 1,2- distearoyl-5 «-glycero-3- phosphocholine (DSPC), l,2-dilaureoyl-i , ⁇ -3-glycero- phosphocholine (DLPC), l,2-dimyristoyl-5 «-glycero-3-phosphocholine (DMPC), 1 ,2-dioleoyl-SH-glycero-3-phosphocholine (DOPC).
- DPPC l,2-dipalmitoyl-s «-glycero-3-phosphocholine
- DSPC 1,2- distearoyl-5 «-glycero-3- phosphocholine
- DLPC ⁇ -3-glycero- phosphocholine
- DMPC l,2-dim
- Suitable examples of l,2-diacyl-.s «-glycero-3-phosphoalkanolarnine phospholipids include, but are not limited to, l,2-dipalmitoyl-SH-g ⁇ ycero-3- ethanolamine(DPPE), l,2-dimyristoyl-sn-glycero-3-phosphoethanolamine(DMPE), 1 ,2-distearoyl-5 «-glycero-3-phosphoethanolamine(DSPE), 1 ,2-dilauroyl-sn-glycero- 3-phosphoethanolamine (DLPE), and l,2-dioleoyl-_? «-glycero-3- phosphoethanolamine (DOPE).
- DPPE l,2-dipalmitoyl-SH-g ⁇ ycero-3- ethanolamine
- DMPE l,2-dimyristoyl-sn-glycero-3-phosphoethanolamine
- DSPE 1,2-distearoyl-5 «-glycero
- phospholipids suitable for use in the invention as a pharmaceutically acceptable carrier include l,2-diacyl-sn-grycero-3- alkylphosphocho lines and l,2-diacyl-sn-glycero-3-alkylphosphoalkanolamines.
- l,2-diacyl--M-g ⁇ ycero-3-alkylphosphocholine phospholipids include, but are not limited to, l,2-dipalmitoyl-.sn-glycero-3- ethylphosphocholine(DPePC), l,2-dimyristoyksn-glycero-3- ethylphosphocholine(DMePC), 1 ,2-distearoyl-s «-glycero-3- ethylphosphocholine(DSePC), 1 ,2-dilauroyl-sn-glycero-3-ethylphosphocholine (DLePC), and 1 ,2-dioleoyl- ⁇ n-glycero-3-ethylphosphocholine(DOePC).
- DPePC dipalmitoyl-.sn-glycero-3- ethylphosphocholine
- DMePC l,2-dimyristoyksn-glycer
- l,2-diacyl-.sn-glycero-3-alkylphosphoalkanolamines include, but are not limited to l,2-dipalmitoyl-s ⁇ -glycero-3- ethylethanolamine(DPePE), 1 ,2-dimyristoyl-sM-glycero-3- ethylphosphoethanolamine(DMePE), 1 ,2-distearoyl-.s «-glycero-3- ethylphosphoethanolamine(DSePE), 1 ,2-dilauroyl-s «-glycero-3- ethylphosphoethanolamine (DLePE), and l,2-dioleoyl-s «-glycero-3- ethylphosphoethanolamine (DOePE).
- DPePE dipalmitoyl-s ⁇ -glycero-3- ethylethanolamine
- DMePE 1,2-dimyristoyl-sM-glycero-3
- phospholipids are known to those skilled in the art and are described in U.S. Patent Application No. 09/752,109 entitled “Particles for Inlialation Having Sustained Release Properties” filed on December 29, 2000 and U.S. Patent Application No. 09/752,106 entitled “Particles for Inhalation Having Sustained release Poperties” filed on December 29, 2000 the contents of all of which are incorporated herein in their entirety.
- the phospholipids are endogenous to the lung.
- the phospholipid can be present in the particles in an amount ranging from about 0 to about 90 weight %. More commonly it can be present in the particles in an amount ranging from about 10 to about 60 weight %.
- the phospholipids or combinations thereof are selected to impart controlled release properties to the highly dispersible particles.
- the phase transition temperature of a specific phospholipid can be below, around or above the physiological body temperature of a patient. Prefereed phase transition temperatures range from 30°C to 50°C, (e.g., within + 10 degrees ofthe normal body temperature of patient).
- the particles can be tailored to have controlled release properties. For example, by administering particles which include a phospholipid or combination of phospholipids which have a phase transition temperature higher than the patient's body temperature, the release of active agent can be slowed down.
- the dry powder for use in the invention comprises a multivalent metal cation which is complexed with a therapeutic, prophylactic or diagnostic agent or any combination thereof having a charge which permits complexatin with the cation upon association with the agent and optionally, a multivalent metal cation-containing component wherein the total amount of multivalent metal catin present in the dry powder is more than 1% weight/weight ofthe total weight ofthe agent (%w/w).
- bioactive agents can also be referred to herein as "bioactive agents", “medicaments” or “drugs”. It is understood that one or more bioactive agents can be present in the particles ofthe invention. Hydrophilic as well as hydrophobic agents can be used. The agent must be capable of possessing a charge which allows it to undergo complexation with the metal cation.
- the amount of bioactive agent present in the particles ofthe invention can be from about 0.1 weight % to about 95 weight %. For example, from about 1 to about 50%, such as from about 5 to about 30%. Particles in which the drug is distributed throughout a particle are preferred. Suitable bioactive agents include agents which can act locally, systemically or a combination thereof.
- bioactive agent is an agent, or its pharmaceutically acceptable salt, which when released in vivo, possesses the desired biological activity, for example therapeutic, diagnostic and/or prophylactic properties in vivo.
- bioactive agent examples include, but are not limited to, proteins and peptides, polysaccharides and other sugars, lipids, and DNA and RNA nucleic acid sequences having therapeutic, prophylactic or diagnostic activities.
- Agents with a wide range of molecular weight can be used.
- the agents can have a variety of biological activities, such as vasoactive agents, neuroactive agents, hormones, anticoagulants, immunomodulating agents, cytotoxic agents, prophylactic agents, diagnostic agents, antibiotics, antivirals, antisense, antigens, antineoplastic agents and antibodies.
- Proteins include complete proteins, muteins and active fragments thereof, such as insulin, immunoglobulins, antibodies, cytokines (e.g., lymphokines, monokines, chemokines), interleukins, interferons ( ⁇ -IFN, ⁇ -LFN and ⁇ -LFN), erythropoietin, somatostatin, nucleases, tumor necrosis factor, colony stimulating factors, enzymes (e.g.
- superoxide dismutase, tissue plasminogen activator), tumor suppressors, blood proteins, hormones and hormone analogs e.g., growth hormone, such as human growth hormone (hGH), adrenocorticotropic hormone and luteinizing hormone releasing hormone (LHRH)
- vaccines e.g., tumoral, bacterial and viral antigens), antigens, blood coagulation factors; growth factors; granulocyte colony- stimulating factor ("G-CSF"
- peptides include parathyroid hormone-related peptide, protein inhibitors, protein antagonists, and protein agonists, calcitonin
- nucleic acids include, for example, antisense molecules, oligonucleotides, and ribozymes. Polysaccharides, such as heparin, can also be administered.
- Bioactive agents for local delivery within the lung include agents such as those for the treatment of asthma, chronic obstructive pulmonary disease (COPD), emphysema, or cystic fibrosis.
- COPD chronic obstructive pulmonary disease
- genes for the treatment of diseases such as cystic fibrosis can be administered, as can beta agonists, steroids, anticholinergics, and leukotriene modifiers for asthma.
- Nucleic acid sequences include genes, oligonucleotides, antisense molecules which can, for instance, bind to complementary DNA to inhibit transcription, and ribozymes.
- the particles can further comprise a carboxylic acid which is distinct from the metal cation complexed biologically active agent.
- the carboxylic acid includes at least two carboxyl groups.
- Carboxylic acids include the salts thereof as well as by combinations of two or more carboxylic acids and/or salts thereof.
- the carboxylic acid is a hydrophilic carboxylic acid or salt thereof.
- Suitable carboxylic acids include but are not limited to hydroxydicarboxyhc acids, hydroxytricarboxylic acids and the like. Citric acid and citrates, such as, for example sodium citrate, are preferred. Combinations or mixtures of carboxylic acids and/or their salts also can be employed.
- the carboxylic acid can be present in the particles in an amount ranging from about 0 to about 80% weight. Preferably, the carboxylic acid can be present in the particles in an amount of about 10 to about 20%.
- the particles suitable for use in the invention can further comprise an amino acid.
- the amino acid is hydrophobic.
- Suitable naturally occurring hydrophobic amino acids include but are not limited to, leucine, isoleucine, alanine, valine, phenylalanine, glycine and tryptophan. Combinations of hydrophobic amino acids can also be employed. Non-naturally occurring amino acids include, for example, beta-amino acids. Both D, L configurations and racemic mixtures of hydrophobic amino acids can be employed. Suitable hydrophobic amino acids can also include amino acid derivatives or analogs.
- an amino acid analog includes the D or L configuration of an amino acid having the following formula: -NH-CHR-CO-, wherein R is an aliphatic group, a substituted aliphatic group, a benzyl group, a substituted benzyl group, an aromatic group or a substituted aromatic group and wherein R does not correspond to the side chain of a naturally- occurring amino acid.
- aliphatic groups include straight chained, branched or cyclic C1-C8 hydrocarbons which are completely saturated, which contain one or two heteroatoms such as nitrogen, oxygen or sulfur and/or which contain one or more units of unsaturation.
- Aromatic or aryl groups include carbocyclic aromatic groups such as phenyl and naphthyl and heterocyclic aromatic groups such as imidazolyl, indolyl, thienyl, furanyl, pyridyl, pyranyl, oxazolyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl and acridintyl.
- Suitable substituents on an aliphatic, aromatic or benzyl group include -OH, halogen (-Br, -CI, -I and -F) -O(aliphatic, substituted aliphatic, benzyl, substituted benzyl, aryl or substituted aryl group), -CN, -NO 2 , -COOH, -NH 2 , -NH(aliphatic group, substituted aliphatic, benzyl, substituted benzyl, aryl or substituted aryl group), -N(aliphatic group, substituted aliphatic, benzyl, substituted benzyl, aryl or substituted aryl group) 2 , -COO(aliphatic group, substituted aliphatic, benzyl, substituted benzyl, aryl or substituted aryl group), -CONH 2 , -CONH(aliphatic, substituted aliphatic group, benzyl, substitute
- a substituted benzylic or aromatic group can also have an aliphatic or substituted aliphatic group as a substituent.
- a substituted aliphatic group can also have a benzyl, substituted benzyl, aryl or substituted aryl group as a substituent.
- a substituted aliphatic, substituted aromatic or substituted benzyl group can have one or more substituents. Modifying an amino acid substituent can increase, for example, the lipophilicity or hydrophobicity of natural amino acids which are hydrophilic.
- a number ofthe suitable amino acids, amino acid analogs and salts thereof can be obtained commercially. Others can be synthesized by methods known in the art.
- Hydrophobicity is generally defined with respect to the partition of an amino acid between a nonpolar solvent and water.
- Hydrophobic amino acids are those acids which show a preference for the nonpolar solvent.
- Relative hydrophobicity of amino acids can be expressed on a hydrophobicity scale on which glycine has the value 0.5. On such a scale, amino acids which have a preference for water have values below 0.5 and those that have a preference for nonpolar solvents have a value above 0.5.
- hydrophobic amino acid refers to an amino acid that, on the hydrophobicity scale has a value greater or equal to 0.5, in other words, has a tendency to partition in the nonpolar acid which is at least equal to that of glycine.
- amino acids which can be employed include, but are not limited to: glycine, proline, alanine, cysteine, methionine, valine, leucine, tyrosine, isoleucine, phenylalanine, tryptophan.
- Preferred hydrophobic amino acids include leucine, isoleucine, alanine, valine, phenylalanine, glycine and tryptophan.
- Combinations of hydrophobic amino acids can also be employed.
- combinations of hydrophobic and hydrophilic (preferentially partitioning in water) amino acids, where the overall combination is hydrophobic can also be employed.
- Combinations of one or more amino acids can also be employed.
- the amino acid can be present in the particles ofthe invention in an amount of from about 0% to about 60 weight %. Preferably, the amino acid can be present in the particles in an amount ranging from about 5 to about 30 weight %.
- the salt of a hydrophobic amino acid can be present in the particles of the invention in an amount of from about 0% to about 60 weight %. Preferably, the amino acid salt is present in the particles in an amount ranging from about 5 to about 30 weight %.
- the particles can also include other excipients such as, for example, buffer salts, dextran, polysaccharides, lactose, trehalose, cyclodextrins, proteins, polycationic complexing agents, peptides, polypeptides, fatty acids, fatty acid esters, inorganic compounds, phosphates. It is understood, however, that in certain embodiments, the particles are in the substantial absence ofthe polycationic complexing agent, protamine.
- excipients such as, for example, buffer salts, dextran, polysaccharides, lactose, trehalose, cyclodextrins, proteins, polycationic complexing agents, peptides, polypeptides, fatty acids, fatty acid esters, inorganic compounds, phosphates. It is understood, however, that in certain embodiments, the particles are in the substantial absence ofthe polycationic complexing agent, protamine.
- the particles can further comprise polymers.
- Biocompatible or biodegradable polymers are preferred. Such polymers are described, for example, in U.S. Patent No. 5,874,064, issued on February 23, 1999 to Edwards et al., the teachings of which are incorporated herein by reference in their entirety.
- the particles include a surfactant other than the phospholipids described above.
- surfactant refers to any agent which preferentially absorbs to an interface between two immiscible phases, such as the interface between water and an organic polymer solution, a water/air interface or organic solvent/air interface.
- Surfactants generally possess a hydrophilic moiety and a lipophilic moiety, such that, upon absorbing to particles, they tend to present moieties to the external environment that do not attract similarly-coated particles, thus reducing particle agglomeration.
- Surfactants may also promote absorption of a therapeutic or diagnostic agent and increase bioavailability ofthe agent.
- Suitable surfactants which can be employed in fabricating the particles ofthe invention include but are not limited to hexadecanol; fatty alcohols such as polyethylene glycol (PEG); polyoxyethylene-9-lauryl ether; a surface active fatty acid, such as palmitic acid or oleic acid; glycocholate; surfactin; a poloxamer; a sorbitan fatty acid ester such as sorbitan trioleate (Span 85); Tween 80 and tyloxapol.
- fatty alcohols such as polyethylene glycol (PEG); polyoxyethylene-9-lauryl ether
- a surface active fatty acid such as palmitic acid or oleic acid
- glycocholate glycocholate
- surfactin a poloxamer
- a sorbitan fatty acid ester such as sorbitan trioleate (Span 85); Tween 80 and tyloxapol.
- the surfactant can be present in the particles in an amount ranging from about 0 to about 5 weight %. Preferably, it can be present in the particles in an amount ranging from about 0.1 to about 1.0 weight %.
- the particles can be in the form of a dry powder suitable for inhalation.
- the particles can have a tap density of less than about 0.4 g/cm 3 .
- Particles which have a tap density of less than about 0.4 g/cm 3 are referred to herein as "aerodynamically light particles". More preferred are particles having a tap density less than about 0.1 g/cm 3 .
- Aerodynamically light particles have a preferred size, e.g., a volume median geometric diameter (VMGD) of at least about 5 microns ( ⁇ m).
- the VMGD is from about 5 ⁇ m to about 30 ⁇ m.
- the particles have a VMGD ranging from about 9 ⁇ m to about 30 ⁇ m.
- the particles have a median diameter, mass median diameter (MMD), a mass median envelope diameter (MMED) or a mass median geometric diameter (MMGD) of at least 5 ⁇ m, for example from about 5 ⁇ m to about 30 ⁇ m.
- Aerodynamically light particles preferably have "mass median aerodynamic diameter” (MMAD), also refened to herein as “aerodynamic diameter", between about 1 ⁇ m and about 5 ⁇ m.
- MMAD mass median aerodynamic diameter
- the MMAD is between about 1 ⁇ m and about 3 ⁇ m. In another embodiment, the MMAD is between about 3 ⁇ m and about 5 ⁇ m.
- the particles have an envelope mass density, also referred to herein as "mass density" of less than about 0.4 g/cm 3 .
- the envelope mass density of an isotropic particle is defined as the mass ofthe particle divided by the minimum sphere envelope volume within which it can be enclosed.
- Tap density can be measured by using instruments known to those skilled in the art such as the Dual Platform Microprocessor Controlled Tap Density Tester (Vankel, NC) or a GeoPycTM instrument (Micrometrics Instrument Corp., Norcross, GA 30093). Tap density is a standard measure of the envelope mass density.
- Tap density can be determined using the method of USP Bulk Density and Tapped Density, United States Pharmacopia convention, Rockville, MD, 10 th Supplement, 4950-4951, 1999.
- Features which can contribute to low tap density include irregular surface texture and porous structure.
- the diameter ofthe particles for example, their VMGD, can be measured using an electrical zone sensing instrument such as a Multisizer lie, (Coulter Electronic, Luton, Beds, England), or a laser diffraction instrument (for example Helos, manufactured by Sympatec, Princeton, NJ). Other instruments for measuring particle diameter are well known in the art.
- the diameter of particles in a sample will range depending upon factors such as particle composition and methods of synthesis.
- the distribution of size of particles in a sample can be selected to permit optimal deposition within targeted sites within the respiratory tract.
- aerodynamic diameter can be determined by employing a gravitational settling method, whereby the time for an ensemble of particles to settle a certain distance is used to determine the aerodynamic diameter ofthe particles.
- MMAD mass median aerodynamic diameter
- MSLI multi-stage liquid impinger
- the aerodynamic diameter, d 3ST can be calculated from the equation:
- d s is the geometric diameter, for example the MMGD and p is the powder density.
- Particles which have a tap density less than about 0.4 g/cm 3 , median diameters of at least about 5 ⁇ m, and an aerodynamic diameter of between about 1 ⁇ m and about 5 ⁇ m, preferably between about 1 ⁇ m and about 3 ⁇ m, are more capable of escaping inertial and gravitational deposition in the oropharyngeal region, and are targeted to the airways or the deep lung.
- the use of larger, more porous particles is advantageous since they are able to aerosolize more efficiently than smaller, denser aerosol particles such as those currently used for inhalation therapies.
- the larger aerodynamically light particles preferably having a VMGD of at least about 5 ⁇ m, also can potentially more successfully avoid phagocytic engulfrnent by alveolar macrophages and clearance from the lungs, due to size exclusion ofthe particles from the phagocytes' cytosolic space. Phagocytosis of particles by alveolar macrophages diminishes precipitously as particle diameter increases beyond about 3 ⁇ m. Kawaguchi, H., et al.,
- the particles may be fabricated with the appropriate material, surface roughness, diameter and tap density for localized delivery to selected regions ofthe respiratory tract such as the deep lung or upper or central airways.
- higher density or larger particles may be used for upper airway delivery, or a mixture of varying sized particles in a sample, provided with the same or different therapeutic agent may be administered to target different regions of the lung in one administration.
- Particles having an aerodynamic diameter ranging from about 3 to about 5 ⁇ m are preferred for delivery to the central and upper airways.
- Particles having an aerodynamic diameter ranging from about 1 to about 3 ⁇ m are preferred for delivery to the deep lung.
- Inertial impaction and gravitational settling of aerosols are predominant deposition mechanisms in the airways and acini ofthe lungs during normal breathing conditions. Edwards, D.A., J. Aerosol Sci, 26: 293-317 (1995). The importance of both deposition mechanisms increases in proportion to the mass of aerosols and not to particle (or envelope) volume. Since the site of aerosol deposition in the lungs is determined by the mass ofthe aerosol (at least for particles of mean aerodynamic diameter greater than approximately 1 ⁇ m), diminishing the tap density by increasing particle surface irregularities and particle porosity permits the delivery of larger particle envelope volumes into the lungs, all other physical parameters being equal.
- the low tap density particles have a small aerodynamic diameter in comparison to the actual envelope sphere diameter.
- the aerodynamic diameter, rf aer is related to the envelope sphere diameter, d (Gonda, I., "Physico-chemical principles in aerosol delivery,” in Topics in Pharmaceutical Sciences 1991 (eds. D.J.A. Crommelin and K.K. Midha), pp. 95-117, Stuttgart: Medpharm Scientific Publishers, 1992)), by the formula:
- d is always greater than 3 ⁇ m.
- p 0.1 g/cm 3
- the increased particle size diminishes interparticle adhesion forces.
- large particle size increases efficiency of aerosolization to the deep lung for particles of low envelope mass density, in addition to contributing to lower phagocytic losses.
- the aerodyanamic diameter can be calculated to provide for maximum deposition within the lungs, previously achieved by the use of very small particles of less than about five microns in diameter, preferably between about one and about three microns, which are then subject to phagocytosis. Selection of particles which have a larger diameter, but which are sufficiently light (hence the characterization "aerodynamically light"), results in an equivalent delivery to the lungs, but the larger size particles are not phagocytosed. Improved delivery can be obtained by using particles with a rough or uneven surface relative to those with a smooth surface.
- Suitable particles can be fabricated or separated, for example by filtration or centrifugation, to provide a particle sample with a preselected size distribution.
- greater than about 30%>, 50%, 70%, or 80% ofthe particles in a sample can have a diameter within a selected range of at least about 5 ⁇ m.
- the selected range within which a certain percentage ofthe particles must fall may be for example, between about 5 and about 30 ⁇ m, or optimally between about 5 and about 15 ⁇ m.
- at least a portion ofthe particles have a diameter between about 6 and about 11 ⁇ m.
- the particle sample also can be fabricated wherein at least about 90%, or optionally about 95 % or about 99%>, have a diameter within the selected range.
- Large diameter particles generally mean particles having a median geometric diameter of at least about 5 ⁇ m.
- the particles can be prepared by spray drying.
- a spray drying mixture also referred to herein as "feed solution” or “feed mixture” which includes the bioactive agent in association with a multivalent metal cation, for example, complexed, a pharmaceutically acceptable carrier and optionally a multivalent metal cation component are fed to a spray dryer.
- complexation ofthe multivalent metal cation with the bioactive agent of opposite charge can be achieved by mixing the bioactive agent in a suitable aqueous solvent with at least one suitable metal cation component under pH conditions suitable for forming a complex of metal cation and bioactive agent.
- the metal cation-complexed active agent will be in the form of a precipitate.
- the precipitated metal cation-complexed active agent remains in the solid state throughout the process used to obtain the final particles for administration.
- the bioactive agent is complexed with ZnA Most preferably, the Zn +2 is complexed to insulin.
- Suitable pH conditions to form a metal cation complexed bioactive agent can be determined based on the pKa ofthe bioactive agent. That is, the pH ofthe system wherein complexation takes place should be adjusted based on the pKa of the active agent in order to impart a negative charge on the active agent.
- Suitable pH conditions are typically achieved through use of an aqueous buffer system as the solvent (e.g., citrate, phosphate, acetate, etc.). Adjustment to the desired pH can be achieved with addition of an acid or base as appropriate.
- Suitable solvents are those in which the bioactive agent and the metal cation component are each at least slightly soluble. For example, sodium citrate, acetate, and phosphate buffer systems.
- Suitable organic solvents can be used to form a solution ofthe pharmaceutically acceptable carrier.
- an aqueous solvent can be used to solubilize the carrier or a combination of aqueous and organic solvent can be employed.
- Suitable organic solvents include, but are not limited to, alcohols for example, ethanol, methanol, propanol, isopropanol, butanols, and others.
- Other organic solvents include, but are not limited to, perfluorocarbons, dichloromethane, chloroform, ether, ethyl acetate, methyl tert-butyl ether and others.
- Aqueous solvents that can be present in the feed mixture include water and buffered solutions. Both organic and aqueous solvents can be present in the spray-drying mixture fed to the spray dryer.
- an ethanol water solvent is prefereed with the ethanof.water ratio ranging from about 50:50 to about 90:10.
- the mixture can have a neutral, acidic or alkaline pH.
- a pH buffer can be included. Preferably, the pH can range from about 3 to about 10.
- the total amount of solvent or solvents being employed in the mixture being spray dried generally is greater than 99 weight percent.
- the amount of solids (drug, charged lipid and other ingredients) present in the mixture being spray dried generally is less than about 1.0 weight percent.
- the amount of solids in the mixture being spray dried ranges from about 0.05%> to about 0.5% by weight.
- Suitable spray-drying techniques are described, for example, by K. Masters in "Spray Drying Handbook", John Wiley & Sons, New York, 1984. Generally, during spray-drying, heat from a hot gas such as heated air or nitrogen is used to evaporate the solvent from droplets formed by atomizing a continuous liquid feed. Other spray-drying techniques are well known to those skilled in the art. In a preferred embodiment, a rotary atomizer is employed. An example of a suitable spray dryer using rotary atomization includes the Mobile Minor spray dryer, manufactured by Niro, Inc., Denmark.
- the hot gas can be, for example, air, nitrogen or argon.
- the particles ofthe invention are obtained by spray drying using an inlet temperature between about 100° C and about 400° C and an outlet temperature between about 50°C and about 130°C.
- the spray dried particles can be fabricated with a rough surface texture to reduce particle agglomeration and improve flowability ofthe powder.
- the spray- dried particle can be fabricated with features which enhance aerosolization via dry powder inhaler devices, and lead to lower deposition in the mouth, throat and inhaler device.
- the particles of the invention can be employed in compositions suitable for drug delivery via the pulmonary system.
- such compositions can include the metal cation complexed biologically active agent and a pharmaceutically acceptable carrier for administration to a patient, preferably for administration via inhalation.
- the particles can be co-delivered with larger carrier particles, not including a therapeutic agent, the latter possessing mass median diameters for example in the range between about 50 ⁇ m and about 100 ⁇ m.
- the particles can be administered alone or in any appropriate pharmaceutically acceptable vehicle, such as a liquid, for example saline, or a powder, for administration to the respiratory system.
- Particles including a medicament are administered to the respiratory tract of a patient in need of treatment, prophylaxis or diagnosis.
- Administration of particles to the respiratory system can be by means such as known in the art.
- particles are delivered from an inhalation device.
- particles are administered via a dry powder inhaler (DPI).
- DPI dry powder inhaler
- MDI Metered-dose-inhalers
- instillation techniques also can be employed.
- the particles are administered as a dry powder via a dry powder inhaler.
- particles administered to the respiratory tract travel through the upper airways (oropharynx and larynx), the lower airways which include the trachea followed by bifurcations into the bronchi and bronchioli and through the terminal bronchioli which in turn divide into respiratory bronchioli leading then to the ultimate respiratory zone, the alveoli or the deep lung.
- the upper airways oropharynx and larynx
- the lower airways which include the trachea followed by bifurcations into the bronchi and bronchioli and through the terminal bronchioli which in turn divide into respiratory bronchioli leading then to the ultimate respiratory zone, the alveoli or the deep lung.
- most ofthe mass of particles deposits in the deep lung.
- delivery is primarily to the central airways. Delivery to the upper airways can also be obtained.
- delivery to the pulmonary system of particles is in a single, breath-actuated step, as described in U.S. Patent Application, High Efficient Delivery of a Large Therapeutic Mass Aerosol, Application No. 09/591,307, filed June 9, 2000, which is incorporated herein by reference in its entirety.
- at least 50% ofthe mass ofthe particles stored in the inhaler receptacle is delivered to a subject's respiratory system in a single, breath- activated step.
- at least 5 milligrams and preferably at least 10 milligrams of a medicament is delivered by administering, in a single breath, to a subject's respiratory tract particles enclosed in the receptacle. Amounts as high as 15, 20, 25, 30, 35, 40 and 50 milligrams can be delivered.
- the term "effective amount” means the amount needed to achieve the desired therapeutic or diagnostic effect or efficacy.
- the actual effective amounts of drug can vary according to the specific drug or combination thereof being utilized, the particular composition formulated, the mode of administration, and the age, weight, condition ofthe patient, and severity ofthe symptoms or condition being treated. Dosages for a particular patient can be determined by one of ordinary skill in the art using conventional considerations, (e.g. by means of an appropriate, conventional pharmacological protocol). For example, effective amounts of albuterol sulfate range from about 100 micrograms ( ⁇ g) to about 10 milligrams (mg).
- Aerosol dosage, formulations and delivery systems also may be selected for a particular therapeutic application, as described, for example, in Gonda, I. "Aerosols for delivery of therapeutic and diagnostic agents to the respiratory tract," in Critical Reviews in Therapeutic Drug Carrier Systems, 6: 273-313, 1990; and in Moren, "Aerosol dosage forms and formulations," in: Aerosols in Medicine. Principles, Diagnosis and Therapy, Moren, et al, Eds, Esevier, Amsterdam, 1985.
- Drug release rates can be described in terms of release constants.
- the first order release constant can be expressed using the following equations:
- M ( ⁇ ) is the total mass of drug in the drug delivery system, e.g. the dry powder
- M (t) is the amount of drug mass released from dry powders at time t.
- Equation (1) may be expressed either in amount (i.e., mass) of drug released or concentration of drug released in a specified volume of release medium.
- Equation (1) may be expressed as:
- C , ⁇ ) is the maximum theoretical concentration of drug in the release medium, and C (t) is the concentration of drug being released from dry powders to the release medium at time t.
- the release constants presented in Table 4 employ Equation (2).
- the term “a” or “an” refers to one or more.
- nominal dose refers to the total mass of bioactive agent which is present in the mass of particles targeted for administration and represents the maximum amount of bioactive agent available for administration.
- Humulin U (lOOU/ml) were all purchased from Eli Lilly and Co. (Indianapolis, IN). Recombinant human insulin was also purchased from Eli Lilly and Co. and was in solid form as crystals containing 1% Zn.
- Aerosizer/Aerodisperser (Amherst Process Instrument, Amherst, MA). Approximately 2 mg of powder formulation was introduced into the Aerodisperser and the aerodynamic size was determined by time of flight measurements.
- the volume median geometric diameter was measured using a RODOS dry powder disperser (Sympatec, Princeton, NJ) in conjunction with a HELOS laser diffractometer (Sympatec). Powder was introduced into the RODOS inlet and aerosolized by shear forces generated by a compressed air stream regulated at 2 bar. The aerosol cloud was subsequently drawn into the measuring zone ofthe HELOS, where it scattered light from a laser beam and produced a Fraunhofer diffraction pattern used to infer the particle size distribution and determine the median value. The volume median geometric diameter was also determined using a Coulter Multisizer II. Approximately 5-10 mg powder formulation was added to 50 mL isoton II solution until the coincidence of particles was between 5 and 8%.
- DPPC sodium hydroxide
- ethanol 1.0 N sodium hydroxide (NaOH) was then used to quickly adjust the solution to pH 6.7, resulting in precipitation of the zinc complexed insulin.
- a solution of DPPC in ethanol was prepared by dissolving 19.80 g of DPPC (Avati Polar Lipids, Alabaster, AL) in 23 L of 95% ethanol.
- the suspension of zinc complexed insulin was then added to the DPPC/ethanol solution.
- the final total solute concentration was 1.025 g/L comprising 0.60 g/L DPPC, 0.20 g/L leucine, 0.010 g/L recombinant insulin, 0.066 g/L ZnCl 2 , and 0.059 g/L sodium citrate.
- the final solute concentration was adjusted to 3.0 g/L by reducing the water and 95% ethanol to one third ofthe volumes described above.
- the suspension was then used to produce dry powders.
- a Nitro mobile model Spray Dryer (Niro, Inc., Columbus, MD) was used .
- Compressed air with variable pressure (1 to 5 bar) ran a rotary atomizer (2,000 to 30,000 rpm) located above the dryer.
- Liquid feed with varying rate (20 to 66 mL/min) was pumped continuously by an electronic metering pump (LMI, Model #A 151 - 192 s) to the atomizer. Both the inlet and outlet temperatures were measured.
- LMI electronic metering pump
- the inlet temperature was controlled manually; it could be varied between 100°C and 400°C and was established at 100, 110, 150, 175 or 200°C, with a limit of control of 5°C.
- the outlet temperature was determined by the inlet temperature and such factors as the gas and liquid feed rates (it varied between 50°C and 130°C).
- a container was tightly attached to the cyclone for collecting the powder product.
- the DPPC/citrate/insulin (60/10/30) spray drying solution was prepared by dissolving 600 mg DPPC in 600 mL of ethanol, dissolving 100 mg of sodium citrate and 300 mg of insulin (Eli Lilly and Co.) in 400 mL of water and then mixing the two solutions to yield one liter of cosolvent with a total solute concentration of 1 g/L (w/v). Higher solute concentrations of 3 g/L (w/v) were prepared by dissolving three times more of each solute in the same volumes of ethanol and water.
- % Represents amount % of each component in final dry formulation.
- the Cation/Insulin % (w/w) ratio can be determined as follows: Determine % of metal cation present in final formulation. Calculate ratio of % of metal cation/%) of Insulin in final formulation.
- the rate and extent of insulin absorption into the blood stream after pulmonary administration of dry powders containing insulin to rats was determined.
- a commercially available insulin formulation Humulin L, available from Eli Lilly and Co.
- the nominal insulin dose administered was 100 ⁇ g of insulin per rat.
- the total weight of powder administered per rat ranged from 0.33 mg to 2.0 mg, depending on the percent composition ofthe administered powder.
- mice Male Sprague Dawley Rats were obtained from Taconic Farms (Germantown, NY). At the time of use, the animals weighed between 291 and 467 g (mean weight was 373 g ⁇ 8.4 g (S.E.M.)). The animals were allowed free access to food and water.
- the powders were delivered to the lungs using an insufflator device used for administration of powders to rat lungs (PennCentury, Philadelphia, PA).
- the desired amount of powder was transferred into the sample chamber ofthe insufflator.
- the delivery tube ofthe insufflator was inserted through the mouth into the trachea and advanced until the tip of the tube was about a centimeter from the carina (first bifurcation).
- the volume of air used to deliver the powder from the insufflator sample chamber was 3 mL, delivered from a 10 mL syringe.
- the syringe was recharged and discharged two more times for a total of three discharges per powder dose.
- the injectable Humulin L was administered via subcutaneous injection, with an injection volume of 7.2 uL for a nominal dose of 25 ⁇ g of insulin.
- Catheters were placed in the jugular veins ofthe rats the day prior to dosing. At sampling time, blood samples were drawn from the catheters and immediately transferred to EDTA coated tubes. Sampling times generally were 0 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h after powder administration. In some cases, additional sampling time (5 min., 12 h) were included, and/or the 24 h time point omitted. Tubes were mixed and then centrifuged at room temperature for 5 minutes at 14,000 X g to separate the plasma from the cells. The plasma was placed into clean microfuge tubes and the samples were stored in the laboratory at 4°C if analysis was performed with 24 hours or a -75°C if analysis would occur later than 24 hours after collection.
- Table 3 shows plasma insulin levels obtained following administration by insufflation of certain formulation of Table 1 and subcutaneous injection of 25 ⁇ g nominal dose of Humulin L.
- the results for Formulations 1-4 are shown graphically in Figure 1 A ( ⁇ U/mL).
- the results for Formulations 5-9 are shown graphically in Figure IB ( ⁇ U/mL).
- the dispersion of dry powder in agarose was cooled in an ambient temperature dessicator box protected from light to allow gelling. Release studies were conducted on an orbital shaker at about 37°C. At predetermined time points, previous release medium (1.5 mL) was removed and fresh release medium (1.5 mL) was added to each vial. Typical time points for these studies were 5 minutes, 1, 2, 4, 6 and 24 hours.
- the release medium used consisted of 20 mM 4-(2- hydroxyethyl)-piperazine-l-ethanesulfonic acid (HEPES), 138 mM NaCl, 0.5%) Pluronic (Synperonic PE/F68; to prevent insulin filbrillation in the release medium); pH 7.4.
- a Pierce (Rockford, IL) protein assay kit See Anal Biochem, 150:76-85 (1985) using known concentrations of insulin standard was used to monitor insulin concentrations in the release medium.
- Table 4 summarizes the in vitro release data and first order release constants for powder formulations of Table 1 comprising insulin Humulin R, L and U.
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WO2021188620A1 (en) | 2020-03-17 | 2021-09-23 | Cocrystal Pharma Inc. | Peptidomimetic n5-methyl-n2-(nonanoyl-l-leucyl)-l-glutaminate derivatives, triazaspiro[4.14]nonadecane derivatives and similar compounds as inhibitors of norovirus and coronavirus replication |
AU2021254045A1 (en) | 2020-04-10 | 2022-10-13 | Cocrystal Pharma, Inc. | Inhibitors of norovirus and coronavirus replication |
TW202321196A (en) | 2021-08-03 | 2023-06-01 | 美商共結晶製藥公司 | Inhibitors for coronaviruses |
US20230303555A1 (en) | 2022-03-23 | 2023-09-28 | Rigel Pharmaceuticals, Inc. | Pyrimid-2-yl-pyrazole compounds as irak inhibitors |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5898028A (en) * | 1997-03-20 | 1999-04-27 | Novo Nordisk A/S | Method for producing powder formulation comprising an insulin |
Family Cites Families (148)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2533065A (en) | 1947-03-08 | 1950-12-05 | George V Taplin | Micropulverized therapeutic agents |
US2470296A (en) | 1948-04-30 | 1949-05-17 | Abbott Lab | Inhalator |
US3102077A (en) * | 1953-08-19 | 1963-08-27 | Christensen Henry Marinus | Preparation of insulin containing 2.75 to 8 percent zinc content |
US2992645A (en) | 1958-05-06 | 1961-07-18 | Benger Lab Ltd | Disperser for powders |
US3957965A (en) | 1967-08-08 | 1976-05-18 | Fisons Limited | Sodium chromoglycate inhalation medicament |
AU439432B2 (en) | 1968-11-28 | 1972-08-15 | Dulux Australia Ltd | Polymer and coating composition |
US4173488A (en) | 1968-12-23 | 1979-11-06 | Champion International Corporation | Oil-in-water emulsions containing hydropholeic starch |
US3781230A (en) | 1968-12-23 | 1973-12-25 | Champion Int Corp | Microcapsular opacifier system |
GB1410588A (en) | 1971-08-10 | 1975-10-22 | Fisons Ltd | Composition |
US4069819A (en) | 1973-04-13 | 1978-01-24 | Societa Farmaceutici S.P.A. | Inhalation device |
US4089800A (en) | 1975-04-04 | 1978-05-16 | Ppg Industries, Inc. | Method of preparing microcapsules |
US4161516A (en) | 1975-07-25 | 1979-07-17 | Fisons Limited | Composition for treating airway disease |
US4272398A (en) | 1978-08-17 | 1981-06-09 | The United States Of America As Represented By The Secretary Of Agriculture | Microencapsulation process |
US4743545A (en) | 1984-08-09 | 1988-05-10 | Torobin Leonard B | Hollow porous microspheres containing biocatalyst |
US4391909A (en) | 1979-03-28 | 1983-07-05 | Damon Corporation | Microcapsules containing viable tissue cells |
US4352883A (en) | 1979-03-28 | 1982-10-05 | Damon Corporation | Encapsulation of biological material |
DE3274065D1 (en) | 1981-07-08 | 1986-12-11 | Draco Ab | POWDER INHALATOR |
EP0072046B1 (en) | 1981-07-24 | 1986-01-15 | FISONS plc | Inhalation drugs, methods for their production and pharmaceutical formulations containing them |
US5260306A (en) | 1981-07-24 | 1993-11-09 | Fisons Plc | Inhalation pharmaceuticals |
DE3141641A1 (en) | 1981-10-16 | 1983-04-28 | Schering Ag, 1000 Berlin Und 4619 Bergkamen | ULTRASONIC CONTRAST AGENTS AND THEIR PRODUCTION |
US4459226A (en) | 1982-02-26 | 1984-07-10 | Eli Lilly And Company | Process for recovering insulin |
US4480041A (en) | 1982-07-09 | 1984-10-30 | Collaborative Research, Inc. | Use of phosphotriester intermediates for preparation of functionalized liposomes |
US4718433A (en) | 1983-01-27 | 1988-01-12 | Feinstein Steven B | Contrast agents for ultrasonic imaging |
US4572203A (en) | 1983-01-27 | 1986-02-25 | Feinstein Steven B | Contact agents for ultrasonic imaging |
ATE151286T1 (en) | 1983-11-14 | 1997-04-15 | Columbia Lab Inc | BIOADHESIVE AGENTS |
US4818542A (en) | 1983-11-14 | 1989-04-04 | The University Of Kentucky Research Foundation | Porous microspheres for drug delivery and methods for making same |
US4865789A (en) | 1983-11-14 | 1989-09-12 | Akzo Nv | Method for making porous structures |
CA1215922A (en) | 1984-05-25 | 1986-12-30 | Connaught Laboratories Limited | Microencapsulation of living tissue and cells |
US4679555A (en) | 1984-08-07 | 1987-07-14 | Key Pharmaceuticals, Inc. | Method and apparatus for intrapulmonary delivery of heparin |
US5340587A (en) | 1985-05-22 | 1994-08-23 | Liposome Technology, Inc. | Liposome/bronchodilator method & System |
WO1986006959A1 (en) | 1985-05-22 | 1986-12-04 | Liposome Technology, Inc. | Liposome inhalation method and system |
SE459005B (en) | 1985-07-12 | 1989-05-29 | Aake Rikard Lindahl | SET TO MANUFACTURE SPHERICAL POLYMER PARTICLES |
WO1987003197A1 (en) | 1985-11-29 | 1987-06-04 | Fisons Plc | Pharmaceutical composition including sodium cromoglycate |
GB8601100D0 (en) | 1986-01-17 | 1986-02-19 | Cosmas Damian Ltd | Drug delivery system |
US4741872A (en) | 1986-05-16 | 1988-05-03 | The University Of Kentucky Research Foundation | Preparation of biodegradable microspheres useful as carriers for macromolecules |
US5160745A (en) | 1986-05-16 | 1992-11-03 | The University Of Kentucky Research Foundation | Biodegradable microspheres as a carrier for macromolecules |
PT85521B (en) | 1986-08-11 | 1990-06-29 | Innovata Biomed Ltd | METHOD FOR PREPARING PHARMACEUTICAL COMPOSITIONS CONTAINING MICROCAPSULES |
GB8619519D0 (en) | 1986-08-11 | 1986-09-24 | Innovata Biomed Ltd | Inhalation preparation |
ATE76311T1 (en) | 1986-08-19 | 1992-06-15 | Genentech Inc | DEVICE AND DISPERSION FOR INTRAPULMONARY DELIVERY OF POLYPEPTIDE GROWTH SUBSTANCES AND CYTOKINES. |
PH23446A (en) | 1986-10-20 | 1989-08-07 | Novo Industri As | Peptide preparations |
US5075109A (en) | 1986-10-24 | 1991-12-24 | Southern Research Institute | Method of potentiating an immune response |
DE3637926C1 (en) | 1986-11-05 | 1987-11-26 | Schering Ag | Ultrasonic manometry in a liquid using microbubbles |
JPS63122620A (en) | 1986-11-12 | 1988-05-26 | Sanraku Inc | Polylactic acid microsphere and production thereof |
US4897256A (en) | 1986-11-25 | 1990-01-30 | Abbott Laboratories | LHRH analog formulations |
US4963297A (en) | 1987-12-22 | 1990-10-16 | The Liposome Company, Inc. | Spontaneous vesticulation of multilamellar liposomes |
US5204113A (en) | 1987-04-09 | 1993-04-20 | Fisons Plc | Pharmaceutical compositions containing pentamidine |
US4861627A (en) | 1987-05-01 | 1989-08-29 | Massachusetts Institute Of Technology | Preparation of multiwall polymeric microcapsules |
US5690954A (en) | 1987-05-22 | 1997-11-25 | Danbiosyst Uk Limited | Enhanced uptake drug delivery system having microspheres containing an active drug and a bioavailability improving material |
US5069936A (en) | 1987-06-25 | 1991-12-03 | Yen Richard C K | Manufacturing protein microspheres |
US4857311A (en) | 1987-07-31 | 1989-08-15 | Massachusetts Institute Of Technology | Polyanhydrides with improved hydrolytic degradation properties |
GB8723846D0 (en) | 1987-10-10 | 1987-11-11 | Danbiosyst Ltd | Bioadhesive microsphere drug delivery system |
US4855144A (en) | 1987-10-23 | 1989-08-08 | Advanced Polymer Systems | Synthetic melanin aggregates |
AU598958B2 (en) | 1987-11-12 | 1990-07-05 | Vestar, Inc. | Improved amphotericin b liposome preparation |
IE61591B1 (en) | 1987-12-29 | 1994-11-16 | Molecular Biosystems Inc | Concentrated stabilized microbubble-type ultrasonic imaging agent and method of production |
JP2670680B2 (en) | 1988-02-24 | 1997-10-29 | 株式会社ビーエムジー | Polylactic acid microspheres containing physiologically active substance and method for producing the same |
AU3073789A (en) | 1988-03-31 | 1989-10-05 | Abbott Laboratories | Drug delivery using pulmonary surfactant to facilitate absorption |
US5064650A (en) | 1988-04-19 | 1991-11-12 | Southwest Research Institute | Controlled-release salt sensitive capsule for oral use and adhesive system |
US4917119A (en) | 1988-11-30 | 1990-04-17 | R. J. Reynolds Tobacco Company | Drug delivery article |
GB8900267D0 (en) | 1989-01-06 | 1989-03-08 | Riker Laboratories Inc | Narcotic analgesic formulations and apparatus containing same |
IT1228459B (en) | 1989-02-23 | 1991-06-19 | Phidea S R L | INHALER WITH REGULAR AND COMPLETE EMPTYING OF THE CAPSULE. |
US4976968A (en) | 1989-02-24 | 1990-12-11 | Clinical Technologies Associates, Inc. | Anhydrous delivery systems for pharmacological agents |
DK0471036T4 (en) | 1989-05-04 | 2004-07-19 | Southern Res Inst | encapsulation |
US5176132A (en) | 1989-05-31 | 1993-01-05 | Fisons Plc | Medicament inhalation device and formulation |
US5174988A (en) | 1989-07-27 | 1992-12-29 | Scientific Development & Research, Inc. | Phospholipid delivery system |
IT1237118B (en) | 1989-10-27 | 1993-05-18 | Miat Spa | MULTI-DOSE INHALER FOR POWDER DRUGS. |
US5707644A (en) | 1989-11-04 | 1998-01-13 | Danbiosyst Uk Limited | Small particle compositions for intranasal drug delivery |
US5271961A (en) | 1989-11-06 | 1993-12-21 | Alkermes Controlled Therapeutics, Inc. | Method for producing protein microspheres |
US5580575A (en) | 1989-12-22 | 1996-12-03 | Imarx Pharmaceutical Corp. | Therapeutic drug delivery systems |
US5123414A (en) | 1989-12-22 | 1992-06-23 | Unger Evan C | Liposomes as contrast agents for ultrasonic imaging and methods for preparing the same |
US5334381A (en) | 1989-12-22 | 1994-08-02 | Unger Evan C | Liposomes as contrast agents for ultrasonic imaging and methods for preparing the same |
US5352435A (en) | 1989-12-22 | 1994-10-04 | Unger Evan C | Ionophore containing liposomes for ultrasound imaging |
AU636481B2 (en) | 1990-05-18 | 1993-04-29 | Bracco International B.V. | Polymeric gas or air filled microballoons usable as suspensions in liquid carriers for ultrasonic echography |
SE9002017D0 (en) | 1990-06-06 | 1990-06-06 | Kabivitrum Ab | PROCESS FOR MANUFACTURE OF MATRICES |
BR9106595A (en) | 1990-06-29 | 1993-04-20 | Fisons Plc | PRESSURIZED AEROSOL COMPOSITION |
US5614216A (en) | 1990-10-17 | 1997-03-25 | The Liposome Company, Inc. | Synthetic lung surfactant |
US5145684A (en) | 1991-01-25 | 1992-09-08 | Sterling Drug Inc. | Surface modified drug nanoparticles |
US5993805A (en) | 1991-04-10 | 1999-11-30 | Quadrant Healthcare (Uk) Limited | Spray-dried microparticles and their use as therapeutic vehicles |
GB9107628D0 (en) | 1991-04-10 | 1991-05-29 | Moonbrook Limited | Preparation of diagnostic agents |
US5874063A (en) | 1991-04-11 | 1999-02-23 | Astra Aktiebolag | Pharmaceutical formulation |
SE9302777D0 (en) | 1993-08-27 | 1993-08-27 | Astra Ab | Process for conditioning substances |
US5327883A (en) | 1991-05-20 | 1994-07-12 | Dura Pharmaceuticals, Inc. | Apparatus for aerosolizing powdered medicine and process and using |
DE69231992T2 (en) | 1991-06-10 | 2001-12-13 | Schering Corp | Chlorofluorocarbon free aerosol formulations |
AU659645B2 (en) | 1991-06-26 | 1995-05-25 | Inhale Therapeutic Systems | Storage of materials |
US5409688A (en) | 1991-09-17 | 1995-04-25 | Sonus Pharmaceuticals, Inc. | Gaseous ultrasound contrast media |
DK0617610T3 (en) | 1991-12-18 | 1997-10-06 | Minnesota Mining & Mfg | Suspension aerosol. |
US5169871A (en) | 1991-12-19 | 1992-12-08 | Hoechst Celanese Corp. | Highly porous compressible polymeric powders |
US6582728B1 (en) * | 1992-07-08 | 2003-06-24 | Inhale Therapeutic Systems, Inc. | Spray drying of macromolecules to produce inhaleable dry powders |
DK0679088T3 (en) | 1992-09-29 | 2002-10-28 | Inhale Therapeutic Syst | Pulmonary delivery of active fragments of parathyroid hormone |
US5698721A (en) | 1992-12-17 | 1997-12-16 | Megabios Corporation | Catonic amphiphiles |
GB9301629D0 (en) | 1993-01-27 | 1993-03-17 | Scotia Holdings Plc | Formulations containing unsaturated fatty acids |
US5970973A (en) | 1993-01-29 | 1999-10-26 | Aradigm Corporation | Method of delivering insulin lispro |
US5915378A (en) | 1993-01-29 | 1999-06-29 | Aradigm Corporation | Creating an aerosolized formulation of insulin |
US5888477A (en) | 1993-01-29 | 1999-03-30 | Aradigm Corporation | Use of monomeric insulin as a means for improving the bioavailability of inhaled insulin |
US5994314A (en) | 1993-04-07 | 1999-11-30 | Inhale Therapeutic Systems, Inc. | Compositions and methods for nucleic acid delivery to the lung |
US5456917A (en) | 1993-04-12 | 1995-10-10 | Cambridge Scientific, Inc. | Method for making a bioerodible material for the sustained release of a medicament and the material made from the method |
TW402506B (en) | 1993-06-24 | 2000-08-21 | Astra Ab | Therapeutic preparation for inhalation |
US5830853A (en) | 1994-06-23 | 1998-11-03 | Astra Aktiebolag | Systemic administration of a therapeutic preparation |
GB9313642D0 (en) | 1993-07-01 | 1993-08-18 | Glaxo Group Ltd | Method and apparatus for the formation of particles |
GB9313650D0 (en) | 1993-07-01 | 1993-08-18 | Glaxo Group Ltd | Method and apparatus for the formation of particles |
DE4323636A1 (en) | 1993-07-15 | 1995-01-19 | Hoechst Ag | Pharmaceutical preparations from coated, poorly water-soluble pharmaceutical substances for inhalation pharmaceutical forms and processes for their preparation |
US5534488A (en) | 1993-08-13 | 1996-07-09 | Eli Lilly And Company | Insulin formulation |
HU222355B1 (en) | 1993-10-01 | 2003-06-28 | Astra Aktiebolag | Process and apparatus for treatment of finely divided powdered medicament |
EP0655237A1 (en) | 1993-11-27 | 1995-05-31 | Hoechst Aktiengesellschaft | Medicinal aerosol formulation |
KR100419037B1 (en) | 1994-03-07 | 2004-06-12 | 넥타르 테라퓨틱스 | Methods of delivery of insulin through the lungs and their composition |
US6051256A (en) | 1994-03-07 | 2000-04-18 | Inhale Therapeutic Systems | Dispersible macromolecule compositions and methods for their preparation and use |
CA2190502A1 (en) | 1994-05-18 | 1995-11-23 | Robert M. Platz | Methods and compositions for the dry powder formulation of interferons |
US5474978A (en) | 1994-06-16 | 1995-12-12 | Eli Lilly And Company | Insulin analog formulations |
US5504188A (en) | 1994-06-16 | 1996-04-02 | Eli Lilly And Company | Preparation of stable zinc insulin analog crystals |
US5461031A (en) | 1994-06-16 | 1995-10-24 | Eli Lilly And Company | Monomeric insulin analog formulations |
GB9413202D0 (en) | 1994-06-30 | 1994-08-24 | Univ Bradford | Method and apparatus for the formation of particles |
US5547929A (en) | 1994-09-12 | 1996-08-20 | Eli Lilly And Company | Insulin analog formulations |
US5885613A (en) | 1994-09-30 | 1999-03-23 | The University Of British Columbia | Bilayer stabilizing components and their use in forming programmable fusogenic liposomes |
SA95160463B1 (en) | 1994-12-22 | 2005-10-04 | استرا أكتيبولاج | powders for inhalation |
GB9501841D0 (en) | 1995-01-31 | 1995-03-22 | Co Ordinated Drug Dev | Improvements in and relating to carrier particles for use in dry powder inhalers |
US5612053A (en) | 1995-04-07 | 1997-03-18 | Edward Mendell Co., Inc. | Controlled release insufflation carrier for medicaments |
US6309671B1 (en) | 1995-04-14 | 2001-10-30 | Inhale Therapeutic Systems | Stable glassy state powder formulations |
US5780014A (en) | 1995-04-14 | 1998-07-14 | Inhale Therapeutic Systems | Method and apparatus for pulmonary administration of dry powder alpha 1-antitrypsin |
US6258341B1 (en) | 1995-04-14 | 2001-07-10 | Inhale Therapeutic Systems, Inc. | Stable glassy state powder formulations |
US6019968A (en) | 1995-04-14 | 2000-02-01 | Inhale Therapeutic Systems, Inc. | Dispersible antibody compositions and methods for their preparation and use |
AU706195B2 (en) | 1995-04-14 | 1999-06-10 | Inhale Therapeutic Systems | Powdered pharmaceutical formulations having improved dispersibility |
US5654007A (en) | 1995-06-07 | 1997-08-05 | Inhale Therapeutic Systems | Methods and system for processing dispersible fine powders |
US5972331A (en) | 1995-12-22 | 1999-10-26 | Schering Corporation | Crystalline interferon alpha for pulmonary delivery and method for producing the same |
DK0877602T3 (en) | 1996-01-24 | 2002-05-06 | Byk Gulden Lomberg Chem Fab | Process for the preparation of powdered lung surfactant preparations |
US6254854B1 (en) | 1996-05-24 | 2001-07-03 | The Penn Research Foundation | Porous particles for deep lung delivery |
US20020052310A1 (en) | 1997-09-15 | 2002-05-02 | Massachusetts Institute Of Technology The Penn State Research Foundation | Particles for inhalation having sustained release properties |
US5874064A (en) | 1996-05-24 | 1999-02-23 | Massachusetts Institute Of Technology | Aerodynamically light particles for pulmonary drug delivery |
US6652837B1 (en) * | 1996-05-24 | 2003-11-25 | Massachusetts Institute Of Technology | Preparation of novel particles for inhalation |
US5855913A (en) | 1997-01-16 | 1999-01-05 | Massachusetts Instite Of Technology | Particles incorporating surfactants for pulmonary drug delivery |
USRE37053E1 (en) | 1996-05-24 | 2001-02-13 | Massachusetts Institute Of Technology | Particles incorporating surfactants for pulmonary drug delivery |
US5985309A (en) * | 1996-05-24 | 1999-11-16 | Massachusetts Institute Of Technology | Preparation of particles for inhalation |
US6103270A (en) | 1996-06-07 | 2000-08-15 | Inhale Therapeutic Systems | Methods and system for processing dispersible fine powders |
EP0971698A4 (en) | 1996-12-31 | 2006-07-26 | Nektar Therapeutics | Aerosolized hydrophobic drug |
US6043214A (en) * | 1997-03-20 | 2000-03-28 | Novo Nordisk A/S | Method for producing powder formulation comprising an insulin |
US7052678B2 (en) * | 1997-09-15 | 2006-05-30 | Massachusetts Institute Of Technology | Particles for inhalation having sustained release properties |
US6309623B1 (en) * | 1997-09-29 | 2001-10-30 | Inhale Therapeutic Systems, Inc. | Stabilized preparations for use in metered dose inhalers |
US6433040B1 (en) | 1997-09-29 | 2002-08-13 | Inhale Therapeutic Systems, Inc. | Stabilized bioactive preparations and methods of use |
DE69900746T2 (en) | 1998-01-30 | 2002-08-14 | Scios Inc | CONTROLLED ADMINISTRATION OF PEPTIDES OR PROTEINS |
EP1067839A1 (en) | 1998-04-08 | 2001-01-17 | Eli Lilly And Company | Pulmonary and nasal delivery of raloxifene |
US6284282B1 (en) * | 1998-04-29 | 2001-09-04 | Genentech, Inc. | Method of spray freeze drying proteins for pharmaceutical administration |
DE60036214T2 (en) | 1999-06-30 | 2008-05-21 | Nektar Therapeutics, San Carlos | METHOD AND SYSTEM FOR PRODUCING DRY POWDER BY SPRAY DRYING |
US6749835B1 (en) * | 1999-08-25 | 2004-06-15 | Advanced Inhalation Research, Inc. | Formulation for spray-drying large porous particles |
WO2001013891A2 (en) | 1999-08-25 | 2001-03-01 | Advanced Inhalation Research, Inc. | Modulation of release from dry powder formulations |
DK1223915T3 (en) | 1999-10-29 | 2006-03-06 | Nektar Therapeutics | Dry powder preparations with improved dispersivity |
WO2002009669A2 (en) | 2000-08-01 | 2002-02-07 | Inhale Therapeutic Systems, Inc. | Apparatus and process to produce particles having a narrow size distribution and particles made thereby |
EP1343372A2 (en) | 2000-12-21 | 2003-09-17 | Nektar Therapeutics | Pulmonary delivery of polyene antifungal agents |
ES2281458T3 (en) | 2000-12-21 | 2007-10-01 | Nektar Therapeutics | STABLE DUST COMPOSITIONS IN INTERLEUCINE RECEIVER STORAGE 4. |
CA2433335C (en) * | 2000-12-29 | 2010-04-20 | Advanced Inhalation Research, Inc. | Particles for inhalation having sustained release properties |
JP2004528339A (en) | 2001-04-26 | 2004-09-16 | ネクター セラピューティクス | Novel methods and compositions for delivering macromolecules to or through the respiratory tract |
-
2001
- 2001-03-30 US US09/822,716 patent/US7678364B2/en not_active Expired - Lifetime
-
2002
- 2002-03-27 WO PCT/US2002/009697 patent/WO2002078675A2/en not_active Application Discontinuation
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5898028A (en) * | 1997-03-20 | 1999-04-27 | Novo Nordisk A/S | Method for producing powder formulation comprising an insulin |
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US10945972B2 (en) | 2002-05-03 | 2021-03-16 | Nektar Therapeutics | Particulate materials |
WO2008013938A3 (en) * | 2006-07-27 | 2008-06-26 | Nektar Therapeutics | Aerosolizable formulation comprising insulin for pulmonary delivery |
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US10806770B2 (en) | 2014-10-31 | 2020-10-20 | Monash University | Powder formulation |
Also Published As
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US7678364B2 (en) | 2010-03-16 |
WO2002078675A3 (en) | 2002-11-28 |
US20020034477A1 (en) | 2002-03-21 |
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