US20020192164A1 - Methods and compositions for the pulmonary delivery insulin - Google Patents

Methods and compositions for the pulmonary delivery insulin Download PDF

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US20020192164A1
US20020192164A1 US10141044 US14104402A US2002192164A1 US 20020192164 A1 US20020192164 A1 US 20020192164A1 US 10141044 US10141044 US 10141044 US 14104402 A US14104402 A US 14104402A US 2002192164 A1 US2002192164 A1 US 2002192164A1
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insulin
method
dry powder
aerosol
powder
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John Patton
Linda Foster
Robert Platz
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Novartis Pharma AG
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Patton John S.
Foster Linda S.
Platz Robert M.
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/007Pulmonary tract; Aromatherapy
    • A61K9/0073Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075Sprays 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22Hormones
    • A61K38/28Insulins
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1617Organic compounds, e.g. phospholipids, fats
    • A61K9/1623Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12Carboxylic acids; Salts or anhydrides thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183Amino acids, e.g. glycine, EDTA or aspartame
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1617Organic compounds, e.g. phospholipids, fats
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S514/00Drug, bio-affecting and body treating compositions
    • Y10S514/866Diabetes

Abstract

Systemic delivery of insulin to a mammalian host is accomplished by inhalation of a dry powder of insulin. It has been found that dry insulin powders are rapidly absorbed through the alveolar regions of the lungs.

Description

  • This application is a continuation-in-part of application Ser. No. 08/207,472, filed on Mar. 7, 1994, the full disclosure of which is incorporated herein by reference.[0001]
  • BACKGROUND OF THE INVENTION
  • 1. Field of the Invention [0002]
  • The present invention relates generally to methods and compositions for the respiratory delivery of insulin to diabetic patients. More particularly, the present invention relates to the pulmonary delivery of dry powder insulin preparations for rapid systemic absorption through the lungs. [0003]
  • Insulin is a 50 amino acid polypeptide hormone having a molecular weight of about 6,000 which is produced in the pancreatic β-cells of normal (non-diabetic) individuals. Insulin is necessary for regulating carbohydrate metabolism by reducing blood glucose levels, and a systemic deficiency causes diabetes. Survival of diabetic patients depends on the frequent and long-term administration of insulin to maintain acceptable blood glucose levels. [0004]
  • Insulin is most commonly administered by subcutaneous injection, typically into the abdomen or upper thighs. In order to maintain acceptable blood glucose levels, it is often necessary to inject insulin at least once or twice per day, with supplemental injections of rapid-acting insulin being administered when necessary. Aggressive treatment of diabetes can require even more frequent injections, where the patient closely monitors blood glucose levels using home diagnostic kits. The present invention is particularly concerned with the administration of rapid acting insulins which are able to provide serum insulin peaks within one hour and glucose troughs within 90 minutes. [0005]
  • The administration of insulin by injection is undesirable in a number of respects. First, many patients find it difficult and burdensome to inject themselves as frequently as necessary to maintain acceptable blood glucose levels. Such reluctance can lead to non-compliance, which in the most serious cases can be life-threatening. Moreover, systemic absorption of insulin from subcutaneous injection is relatively slow, frequently requiring from 45 to 90 minutes, even when fast-acting insulin formulations are employed. Thus, it has long been a goal to provide alternative insulin formulations and routes of administration which avoid the need for self-injection and which can provide rapid systemic availability of the insulin. [0006]
  • A variety of such alternative insulin administration roots have been proposed, including intranasal, intrarectal, and intravaginal. [0007]
  • While these techniques avoid the discomfort and poor compliance associated with subcutaneous injection, they each suffer from their own limitations. Intrarectal and intravaginal are inconvenient, uncomfortable, and the latter is not available to the entire population of diabetics. Intranasal delivery would be convenient and probably less objectionable than injection, but requires the use of potentially toxic “penetration enhancers” to effect passage of insulin across the nasal mucosa, which is characterized by a thick epithelial layer which is resistant to the passage of macromolecules of particular interest to the present invention is pulmonary insulin delivery where a patient inhales an insulin formulation and systemic absorption occurs through the thin layer of epithelial cells in the alveolar regions of the lung. Such pulmonary insulin delivery appears to provide more rapid systemic availability than does subcutaneous injection and avoids the use of a needle. Pulmonary insulin delivery, however, has yet to achieve widespread acceptance. Heretofore, pulmonary delivery has been most often accomplished through nebulization of liquid insulin formulations, requiring the use of cumbersome liquid nebulizers. Moreover, the aerosols formed by such nebulizers have a very low insulin concentration, necessitating a large number of inhalations to provide an adequate dosage. Insulin concentration is limited due to the low solubility of insulin in suitable aqueous solutions. In some cases[0008] 1 as many as 80 or more breaths may be required to achieve an adequate dosage, resulting in an administration time from 10 to 20 minutes, or more.
  • It would be desirable to provide improved methods and compositions for the pulmonary delivery of insulin. It would be particularly desirable if such methods and compositions were sufficiently convenient to permit self-administration even away from home and were able to deliver a desired total dosage with a relatively low number of breaths, preferably fewer than ten. Such methods and compositions should also provide for rapid systemic absorption of the insulin, preferably reaching a serum peak within 45 minutes or less and a resulting glucose trough within about one hour or less. Such rapid acting formulations will preferably be suitable for use in aggressive treatment protocols where injection of intermediate and long-acting insulin can be reduced or eliminated. The compositions of the present invention should also be stable, preferably consisting of a concentrated dry powder formulation. [0009]
  • 2. Description of the Background Art [0010]
  • The respiratory delivery of aerosolized aqueous insulin solutions is described in a number of references, beginning with Gansslen (1925) [0011] Klin. Wochenschr. 4:71 and including Laube et al. (1993) TAMA 269:2106-21-9; Elliott et al. (1987) Aust. Paediatr. J. 23:293-297; Wigley et al. (1971) Diabetes 20:552-556. Corthorpe et al. (1992) Pharm Res 9:764-768; Govinda (1959) Indian J. Physiol. Pharmacol. 3:161-167; Hastings et al. (1992) J. Appl. Physiol. 73:1310-1316; Liu et al. (1993) JAMA 269:2106-2109; Nagano et al. (1985) Jikeikai Med. J. 32:503-506; Sakr (1992) Int. J. Phar. 86:1-7; and Yoshida et al. (1987) Clin. Res. 35:160-166. Pulmonary delivery of dry powder medicaments, such as insulin, in a large particle carrier vehicle is described in U.S. Pat. No. 5,254,330. A metered dose inhaler (MDI) for delivering crystalline insulin suspended in a propellant is described in Lee and Sciara (1976) J. Pharm. Sci. 65:567-572. A MDI for delivering insulin into a spacer for regulating inhalation flow rate is described in U.S. Pat. No. 5,320,094. The intrabronchial administration of recombinant insulin is briefly described in Schlüter et al. (Abstract) (1984) Diabetes 33:75A and Köhler et al. (1987) Atemw. Lungenkrkh. 13:230-232. Intranasal and respiratory delivery of a variety of polypeptides, including insulin, in the presence of an enhancer, are described in U.S. Pat. No. 5,011,678 and Nagai et al. (1984) J. Contr. Rel. 1:15-22. Intranasal delivery of insulin in the presence of enhancers and/or contained in controlled release formulations are described in U.S. Pat. Nos. 5,204,108; 4,294,829; and 4,153,689; PCT Applications WO 93/02712, WO 91/02545, WO 90/09780, and WO 88/04556; British Patent 1,527,605; Rydén and Edman (1992) Int. J. Pharm. 83:1-10; and Björk and Edman (1988) Int. J. Pharrm. 47:233-238. The preparation and stability of amorphous insulin were described by Rigsbee and Pikal at the American Association of Pharmaceutical Sciences (AAPS), Nov. 14-18, 1993, Lake Buena Vista, Fla. Methods for spray drying polypeptide, polynucleotide and other labile drugs in a carrier which forms an amorphous structure which stabilize the drug are described in European patent application 520 748.
  • SUMMARY OF THE INVENTION
  • According to the present invention, methods and compositions for the aerosolization and systemic delivery of insulin to a mammalian host, particularly a human patient suffering from diabetes, provide for rapid absorption into blood circulation while avoiding subcutaneous injection. In particular, the methods of the present invention rely on pulmonary delivery of insulin in the form of a dry powder. Surprisingly, it has been found that inhaled dry insulin powders are deposited in the alveolar regions of the lung and rapidly absorbed through the epithelial cells of the alveolar region into blood circulation. Thus, pulmonary delivery of insulin powders can be an effective alternative to administration by subcutaneous injection. [0012]
  • In a first aspect of the present invention, insulin is provided as a dry powder, usually but not necessarily in a substantially amorphous state, and dispersed in an air or other physiologically acceptable gas stream to form an aerosol. The aerosol is captured in a chamber having a mouthpiece, where it is available for a subsequent inhalation by a patient. Optionally, the dry powder insulin is combined with a pharmaceutically acceptable dry powder carrier, as described in more detail below. The insulin powder preferably comprises particles having a diameter less then 10 μm, more preferably less than 7.5 μm, and most preferably below 5 μm, usually being in the range from 0.1 μm to 5 μm. Surprisingly, it has been found that the dry powder insulin compositions of the present invention are absorbed in the lung without the use of penetration enhancers such as those required for absorption through the nasal mucosa and upper respiratory tract. [0013]
  • In a second aspect, the present invention provides insulin compositions consisting essentially of dry powder insulin having an average particle size below 10 μm which may be combined with dry powder pharmaceutical carriers. The insulin composition is preferably free from penetration enhancers and comprises particles having a diameter less than 10 μm, preferably less than 7.5 μm, and most preferably below 5 μm, usually being in the range from 0.1 μm to 5 μm. Usually, the insulin dry powder will have from 5% to 99% by weight insulin in the composition, more usually from 15% to 80%, in a suitable pharmaceutical carrier, usually a carbohydrate, an organic salt, an amino acid, peptide, or protein, as described in more detail hereinafter. [0014]
  • In a third aspect of the present invention, insulin dry powders are prepared by dissolving insulin in an aqueous buffer to form a solution and spray drying the solution to produce substantially amorphous particles having a particle size less than 10 μm, preferably less than 7.5 μm, and most preferably below 5 μm, usually being in the range from 0.1 μm to 5 μm. Optionally, the pharmaceutical carrier is also dissolved in the buffer, to form a homogeneous solution, wherein spray drying of the solution produces individual particles comprising insulin, carrier buffer, and any other components which were present in the solution. Preferably the carrier is a carbohydrate, organic salt, amino acid, peptide, or protein which produces a substantially amorphous structure upon spray drying. The amorphous carrier may be either glassy or rubbery and enhances stability of the insulin during storage. Advantageously, such stabilized formulations are also able to effectively deliver insulin to the blood stream upon inhalation to the alveolar regions of the lungs. [0015]
  • A further understanding of the nature and advantages of the invention will become apparent by reference to the remaining portions of the specification and drawings.[0016]
  • BRIEF DESCRIPTION OF THE DRAWINGS
  • FIG. 1 is a schematic illustration of a system for aerosolizing a dose of insulin according to the method of the present invention. [0017]
  • FIG. 2 is a schematic illustration of a patient inhaling an aerosolized dose of insulin from the system of FIG. 1. [0018]
  • FIGS. 3A and 3B are graphs illustrating the absorption of recombinant human insulin in rats and resulting glucose response following aerosolization of three different Do4 dry powder formulations. Each point represents the mean value from three different rats. At zero time, the dry powder aerosol generator was turned on. Aerosolization was complete at 5 min, 14 min and 20 min for the 87% insulin/citrate, 20% insulin-mannitol/citrate and 20% insulin-raffinose/citrate powders, respectively. Animals were fasted overnight. [0019]
  • FIGS. 4A and 4B are graphs illustrating mean serum time-concentration insulin and glucose profiles, respectively comparing aerosol and subcutaneous administrations in cynomolgus monkeys. The mean value for three monkeys is reported for the aerosol group, and the mean value for four monkeys is reported for the subcutaneous group. [0020]
  • FIG. 5A is a graph illustrating the mean insulin concentration over time for subcutaneous injection (∘) and for inhalation of three puffs () in humans. [0021]
  • FIG. 5B shows the mean glucose concentration corresponding to the insulin concentrations of FIG. 5A. [0022]
  • FIG. 6A is a graph illustrating serum insulin concentration over time as a result of subcutaneous injection (∘) and three puffs of aerosol administration () in humans. [0023]
  • FIG. 6B is a graph illustrating the serum glucose levels corresponding to the insulin levels in FIG. 6A. [0024]
  • FIGS. 7A and 7B provide a comparison of the intersubject variability of serum insulin ([0025] 7A) and glucose levels (7B) for subcutaneous administration (∘) and aerosol administration ().
  • FIGS. 8A, 8B, and SC show rpHPLC chromatograms of a human insulin. [0026]
  • FIG. 8A is a chromatograph of an insulin standard stressed in 10 mM HCl at 25° C., showing human insulin eluting at 23.87 minutes desamido insulin eluting at 30.47 minutes. [0027]
  • FIG. 8B shows a similar chromatogram of a human a insulin standard. FIG. 8C shows a similar chromatogram of reconstituted, spray-dried insulin formulation prepared according to the present invention. [0028]
  • FIG. 9 shows an ultraviolet spectra of an insulin formulation before and after spray drying. No light scattering was observed in the visible spectrum, indicating ill that insulin did not aggregate during the spray drying process.[0029]
  • DETAILED DESCRIPTION OF SPECIFIC EMBODIMENTS
  • According to the present invention, insulin is provided as a dry power. By “dry powder” it is meant that the moisture content of the powder is below about 10% by weight, usually below about 5% by weight, and preferably being below about 3% by weight. By “powder,” it is meant that the insulin comprises free flowing particulates having a size selected to permit penetration into the alveoli of the lungs, preferably being less than 10 μm in diameter, preferably less than 7.5 μm, and most preferably less than 5 μm, and usually being in the range from 0.1 μm to 5 μm in diameter. [0030]
  • The present invention is based at least in part on the unexpected observation that dry powder insulins are readily and rapidly absorbed through the lungs of a host. It was surprising that dry powder insulins could reach the alveolar region of the lungs, as water-soluble drugs such as insulin particles are known to be hygroscopic. See, e.g. Byron, ed., [0031] Respiratory Drug Delivery, CRC Press, Boca Raton (1990), p. 150. Thus, it would have been expected that as the particles passed through the airways of the lung (which has a relative humidity in excess of 99% at 37° C.), the individual particles would have a tendency to absorb water and grow to an effective particle size larger than the 10 μm upper limit of the present invention. If a substantial fraction of the insulin particles were larger than the target size range, it would be expected that the particles would deposit within the central airways of the lungs rather than the alveolar region, thus limiting delivery and subsequent systemic absorption. Moreover, the fluid layer over the epithelial cells of the lungs is very thin, usually a fraction of the diameter of the insulin powders being delivered. Thus, it was unpredictable prior to the present invention whether the dry insulin particles would dissolve upon deposition within the alveolar regions of the lungs. Surprisingly, the dry insulin powders are apparently able to both penetrate into the alveolar regions of the lungs and dissolve once they have deposited within the alveolar region of the lung. The dissolved insulin is then able to cross the epithelial cells into circulation.
  • It is presently believed that the effective absorption of insulin results from a rapid dissolution in the ultrathin (<0.1 μm) fluid layer of the alveolar lining. The particles of the present invention thus have a mean size which is from 10 to 50 times larger than the lung fluid layer, making it unexpected that the particles are dissolved and the insulin systemically absorbed in a rapid manner. Indeed, as shown in the Experimental section hereinafter, the dry insulin formulations of the present invention can provide even more rapid serum insulin peaks and glucose troughs than afforded by subcutaneous injection, which is presently the most common form of administration. An understanding of the precise mechanism, however, is not necessary for practicing the present invention as described herein. [0032]
  • Preferred compositions according to the present invention will be substantially free from penetration enhancers. “Penetration enhancers” are surface active compounds which promote penetration of insulin (or other drugs) through a mucosal membrane or lining and are proposed for use in intranasal, intrarectal, and intravaginal drug formulations. Exemplary penetration enhancers include bile salts, e.g., taurocholate, glycocholate, and deoxycholate; fusidates, e.g., taurodehydrofusidate; and biocompatible detergents, e.g., Tweens, Laureth-9, and the like. The use of penetration enhancers in formulations for the lungs, however, is generally undesirable because the epithelial blood barrier in the lung can be adversely affected by such surface active compounds. Surprisingly, it has been found that the dry powder insulin compositions of the present invention are readily absorbed in the lungs without the need to employ penetration enhancers. [0033]
  • Insulin dry powders suitable for use in the present invention include amorphous insulins, crystalline insulins, and mixtures of both amorphous and crystalline insulins. Dry powder insulins are preferably prepared by spray drying under conditions which result in a substantially amorphous powder having a particle size within the above-stated range. Alternatively, amorphous insulins could be prepared by lyophilization (freeze-drying), vacuum drying, or evaporative drying of a suitable insulin solution under conditions to produce the amorphous structure. The amorphous insulin so produced can then be ground or milled to produce particles within the desired size range. Crystalline dry powder insulins may be formed by grinding or jet milling of bulk crystalline insulin. The preferred method for forming insulin powders comprising particulates in the desired size range is spray drying, where pure, bulk insulin (usually in a crystalline form) is first dissolved in a physiologically acceptable aqueous buffer, typically a citrate buffer having a pH in the range from about 2 to 9. The insulin is dissolved at a concentration from 0.01% by weight to 1% by weight, usually from 0.1% to 0.2%. The solutions may then be spray dried in conventional spray drying equipment from commercial suppliers, such as Buchi, Niro, and the like, resulting in a substantially amorphous particulate product. [0034]
  • The dry insulin powders may consist essentially of insulin particles within the requisite size range and be substantially free from any other biologically active components, pharmaceutical carriers, and the like. Such “neat” formulations may include minor components, such as preservatives, present in low amounts, typically below 10% by weight and usually below 5% by weight. Using such neat formulations, the number of inhalations required for even high dosages can be substantially reduced, often to only a single breath. [0035]
  • The insulin powders of the present invention may optionally be combined with pharmaceutical carriers or excipients which are suitable for respiratory and pulmonary administration. Such carriers may serve simply as bulking agents when it is desired to reduce the insulin concentration in the powder which is being delivered to a patient, but may also serve to enhance the stability of the insulin compositions and to improve the dispersability of the powder within a powder dispersion device in order to provide more efficient and reproducible delivery of the insulin and to improve handling characteristics of the insulin such as flowability and consistency to facilitate manufacturing and powder filling. [0036]
  • Suitable carrier materials may be in the form of an amorphous powder, a crystalline powder, or a combination of amorphous and crystalline powders. Suitable materials include carbohydrates, e.g., monosaccharides such as fructose, galactose, glucose, D-mannose, sorbose, and the like; disaccharides, such as lactose, trehalose, cellobiose, and the like; cyclodextrins, such as 2-hydroxypropyl-β-cyclodextrin; and polysaccharides, such as raffinose, maltodextrins, dextrans, and the like; (b) amino acids, such as glycine, arginine, aspartic acid, glutamic acid, cysteine, lysine, and the like; (c) organic salts prepared from organic acids and bases, such as sodium citrate, sodium ascorbate, magnesium gluconate, sodium gluconate, tromethamine hydrochloride, and the like; (d) peptides and proteins, such as aspartame, human serum albumin, gelatin, and the like; (e) alditols, such as mannitol, xylitol, and the like. A preferred group of carriers includes lactose, trehalose, raffinose, maltodextrins, glycine, sodium citrate, tromethamine hydrochloride, human serum albumin, and mannitol. [0037]
  • Such carrier materials may be combined with the insulin prior to spray drying, i.e., by adding the carrier material to the buffer solution which is prepared for spray drying. In that way, the carrier material will be formed simultaneously with and as part of the insulin particles. Typically, when the carrier is formed by spray drying together with the insulin, the insulin will be present in each individual particle at a weight percent in the range from 5% to 95%, preferably from 20% to 80%. The remainder of the particle will primarily be carrier material (typically being from 5% to 95%, usually being from 20% to 80% by weight), but will also include buffer(s) and may include other components as described above. The presence of carrier material in the particles which are delivered to the alveolar region of the lung (i.e., those in the requisite size range below 10 μm) has been found not to significantly interfere with systemic absorption of insulin. [0038]
  • Alternatively, the carriers may be separately prepared in a dry powder form and combined with the dry powder insulin by blending. The separately prepared powder carriers will usually be crystalline (to avoid water absorption), but might in some cases be amorphous or mixtures of crystalline and amorphous. The size of the carrier particles may be selected to improve the flowability of the insulin powder, typically being in the range from 25 μm to 100 μm. Carrier particles in this size range will generally not penetrate into the alveolar region of the lung and will often separate from the insulin in the delivery device prior to inhalation. Thus, the particles which penetrate into the alveolar region of the lung will consist essentially of insulin and buffer. A preferred carrier material is crystalline mannitol having a size in the above-stated range. [0039]
  • The dry insulin powders of the present inventions may also be combined with other active components. For example, it may be desirable to combine small amounts of amylin or active amylin analogues in the insulin powders to improve the treatment of diabetes. Amylinis a hormone which is secreted with insulin from the pancreatic β-cells in normal (non-diabetic) individuals. It is believed that amylin modulates insulin activity in vivo, and it has been proposed that simultaneous administration of amylin with insulin could improve blood glucose control. Combining dry powder amylin with insulin in the compositions of the present invention will provide a particularly convenient product for achieving such simultaneous administration. Amylin may be combined with insulin at from 0.1% by weight to 10% by weight (based on the total weight of insulin in a dose), preferably from 0.5% by weight to 2.5% by weight. Amylin is available from commercial suppliers, such as Amylin Corporation, San Diego, Calif., and can be readily formulated in the compositions of the present invention. For example, amylin may be dissolved in aqueous or other suitable solutions together with the insulin, and optionally carriers, and the solution spray dried to produce the powder product. [0040]
  • The dry powder insulin compositions of the present invention are preferably aerosolized by dispersion in a flowing air or other physiologically acceptable gas stream in a conventional manner. One system suitable for such dispersion is described in copending application Ser. No. 07/910,048, which has been published as WO 93/00951, the full disclosures of which are incorporated herein by reference. Referring to FIG. 1 herein, dry, free-flowing insulin powder is introduced into a high velocity air or gas stream, and the resulting dispersion introduced into a holding chamber 10. The holding chamber [0041] 10 includes a mouthpiece 12 at an end opposite to the entry point of the air powder dispersion. The volume of the chamber 10 is sufficiently large to capture a desired dose and may optionally have baffles and/or one-way valves for promoting containment. After a dose of the insulin powder has been captured in chamber 10, a patient P (FIG. 2) inhales on the mouthpiece 12 to draw the aerosolized dispersion into his lungs. As the patient P inhales, make-up air is introduced through a tangentially oriented air inlet port 14, whereby the air flows in a generally vortical pattern to sweep the aerosolized insulin from the chamber into the patient's lungs. The volume of the chamber and the aerosolized dose are such that a patient is able to completely inhale the entire aerosolized insulin dose followed by sufficient air to ensure that the insulin reaches the lower alveolar regions of the lung.
  • Such aerosolized insulin powders are particularly useful in place of subcutaneous injections of rapid acting insulin in the treatment of diabetes and related insulin-deficiencies. Surprisingly, it has been found that the aerosol administration of dry powder insulin results in significantly more rapid insulin absorption and glucose response than is achieved by subcutaneous injection. Thus, the methods and compositions of the present invention will be particularly valuable in treatment protocols where a patient monitors blood glucose levels frequently and administers insulin as needed to maintain a target serum concentration, but will also be useful whenever systemic insulin administration is required. The patient can achieve a desired dosage by inhaling an appropriate amount of insulin, as just described. The efficiency of systemic insulin delivery via the method as just described will typically be in the range from about 15% to 30%, with individual dosages (on a per inhalation basis), typically being in the range from about 0.5 mg to 10 mg. Usually, the total dosage of insulin desired during a single respiratory administration will be in the range from about 0.5 mg to 15 mg. Thus, the desired dosage may be effective by the patient taking from 1 breath to 4 breaths. [0042]
  • The following examples are offered by way of illustration, not by way of limitation. [0043]
  • Experimental
  • Materials and Methods [0044]
  • Materials [0045]
  • Crystalline human zinc insulin, 26.3 Units/mg, (Lilly Lot #784KK2) was obtained from Eli Lilly and Company, Indianapolis, Ind. and found to be >99% pure as measured by rpHPLC. USP mannitol was obtained from Roquette Corporation (Gurnee, Ill.). Raffinose was purchased from Pfanstiehl Laboratories (Waukegan, Ill.). Sodium citrate dihydrate, USP, ACS and citric acid monohydrate USP were obtained from J. T. Baker (Phillipsburg, N.J.). [0046]
  • Powder Production [0047]
  • Insulin powders were made by dissolving bulk crystalline insulin in sodium citrate buffer containing excipient (mannitol, or raffinose, or none) to give final solids concentration of 7.5 mg/ml and a pH of 6.7±0.3. The spray dryer was operated with an inlet temperature between 110° C. to 120° C. and a liquid feed rate of 5 ml/min, resulting in an outlet temperature between 70° C. and 80° C. The solutions were then filtered through a 0.22 μm filter and spray dried in a Buchi Spray Dryer to form a fine white amorphous powder. The resulting powders were stored in tightly capped containers in a dry environment (<10% RH). [0048]
  • Powder Analyses [0049]
  • The particle size distribution of the powders was measured by liquid centrifugal sedimentation in a Horiba CAPA-700 Particle Size Analyzer following dispersion of the powders in Sedisperse A-11 (Micromeritics, Norcross, Ga.). The moisture content of the powders was measured by the Karl Fischer technique using a Mitsubishi CA-06 Moisture Meter. [0050]
  • The integrity of insulin before and after powder processing was measured against a reference standard of human insulin by redissolving weighed portions of powder in distilled water and comparing the redissolved solution with the original solution put into the spray dryer. Retention time and peak area by rpHPLC were used to determine whether the insulin molecule had been chemically modified or degraded in process. UV absorbance was used to determine insulin concentration (at 278 nm) and presence or absence of insoluble aggregates (at 400 nm). In addition, the pHs of the starting and reconstituted solutions were measured. The amorphous nature of the insulin powder was confirmed by polarizing light microscopy. [0051]
  • Rat Aerosol Exposures [0052]
  • Rat experiments were conducted in an aerosol exposure room. Female rats (280-300 gm) were fasted overnight. Animals (21-24/experiment) were placed in Plexiglas tubes and mounted into a 48 port, nose-only aerosol exposure chamber (In-Tox Products, Albuquerque, N. Mex.). Airflow to the breathing zone was maintained at 7.2-9.8 liters/minute and removed by vacuum so that there was a slight negative pressure (−1.5 cm H[0053] 2O) in the chamber as measured by a magnahelic gauge. Aerosol exposure times were between 5-20 minutes depending on how much powder was fed into the chamber. Powders were fed by hand into a small Venturi nozzle which dispersed the powder particles to form a fine aerosol cloud. The Venturi nozzle was operated at a pressure in excess of 15 psig, and the air flow was set at 7.2 l/min to 9.8 l/min. The Venturi nozzle was fitted into the bottom of a clear Plexiglas dispersion chamber (750 ml) which passed the aerosol directly into a nose-only exposure chamber.
  • Rat Aerosol Chamber Calibration [0054]
  • The concentration of the powder at the breathing zone was measured by taking multiple, timed filter samples at the breathing zone with In-Tox filter holders at a vacuum flow of 2 liters/min. The chamber was calibrated both with and without animals. Powder mass was determined gravimetrically. The particle size of the powders at the breathing zone was measured with cascade impactor (In Tox Products) placed at a breathing hole and operated at a flow of 2 liters/min. Powder mass on each stage was determined gravimetrically. [0055]
  • Each powder test utilized 21-24 rats and the aerosol exposures lasted 5-20 minutes. Three rats were killed at 0 time and then at −7, 15, 30, 60, 90, 120, 180, and 240 minutes after the termination of the aerosol exposure. Animals were anesthetized, their abdomens opened, and a large blood sample was drawn from the ventral aorta. The animals were then killed by cervical dislocation. [0056]
  • Blood was allowed to clot at room temperature for 30 minutes and then centrifuged for 20 minutes at 3500 rpm in serum separator tubes. Serum was either analyzed immediately or frozen at −80° C. until analysis. As soon as possible (0-7 min) after the termination of the aerosol dosing, 3 rats were killed, their blood drawn and their lungs lavaged with six 5 ml rinses of phosphate buffered saline (PBS). The amount of insulin in the final pooled lavage sample was used as the aerosol dose for the rat in calculations of bioavailability. [0057]
  • Primate Exposure System [0058]
  • Young, wild-captured, male cynomolgus monkeys strain [0059] Macaca fascicularis (2-5 kg) (Charles River Primates, Inc.) were used for the primate aerosol studies (3-4 animals/group). The animals were either subcutaneously injected with Humulin (Eli Lilly, Indianapolis, Ind.) or exposed to a powder aerosol of insulin. Each animal was placed in a head-only exposure unit to provide a fresh supply of the test atmosphere at an adequate flow rate (7 L/min) to provide minimum oxygen requirements of the animal. The animals were restrained in a chair-like apparatus which placed them in an upright sitting position. The hoods were clear allowing the animals complete visualization of their environment. An indwelling catheter was placed in the leg so that blood samples could be taken at any time. The monkeys were fully awake during the whole procedure and appeared to be calm. Primate blood was treated the same as rat (see above).
  • The primate aerosol exposure system included a breath monitor that allowed quantification of the amount of air inhaled by each monkey. This value, coupled with measurements of the concentration of insulin in the inspired air allowed the calculation of exactly how much insulin was inhaled by each animal. [0060]
  • Human Trials [0061]
  • Insulin was administered to 24 normal human subjects subcutaneously as well as by inhalation of aerosolized dry insulin powders. Each subcutaneous injection consisted of 10.4U of Humulin R, 100 U/ml (Eli Lilly, Indianapolis, Ind.). The dry insulin powders were amorphous and prepared by spray drying as described above with 20% by weight mannitol excipient. Doses (5 mg) of the insulin dry powder were dispersed in a high-velocity air stream to produce a fine aerosol that was captured in a chamber. Each subject inhaled the aerosol powder by taking a slow, deep breath of each aerosol bolus or “puff.” Powder was administered in three puffs (for a dosage of 31.9U). Serum insulin and glucose levels were determined over time, as described below. [0062]
  • Serum Assays [0063]
  • Serum insulin levels in rats, primates, and humans were determined using Coat-A-Count radio immunoassay kits for human insulin (Diagnostic Products Corporation, Los Angeles, Calif.). Standard curves were run with every batch of samples. The sensitivity of the assay was approximately 43 pg/ml. The within assay variability (%CV) is <5%. Glucose assays were performed by California Veterinary Diagnostics, Inc. in West Sacramento, Calif. using the Glucose/HK Reagent System Pack for the Boehringer Mannheim/Hitachi 747 Analyzer. The within assay variability (%CV) is <3%. [0064]
  • In the rate experiments, relative bioavailabilities of the aerosol were calculated by comparing the dose adjusted, immunoreactive insulin (IRI) area under the curve (AUC) of the concentration-time profile with that obtained from subcutaneous injection. In rats the total lavaged insulin mass was used as the aerosol dose. Some insulin is absorbed before the lungs can be lavaged so the dose estimated by this technique is probably a slight underestimate of the total deposited dose. No corrections for this presumed loss were made. [0065]
  • In the monkey experiments, relative bioavailabilities were calculated similar to the rats above except that instead of using lavaged lung insulin as the aerosol dose, the total amount of insulin inhaled was used. In the rats, only material deposited in the lungs, not insulin deposited in the nasal passages and throat, was included in the dose estimate. In the monkeys, all insulin that entered the animals was included in the dose estimate. [0066]
  • Results of Insulin Absorption in Rats [0067]
  • All of the insulin powders used in the animal studies had particle sizes (mass median diameters) ranging between 1-3 μm and moisture contents <3%. The insulin purity of the powders as measured by rpHPLC was >97%. Representative chromatographs of the 20% insulin formulation are shown in FIG. 8C. The powders yielded a clear solution upon reconstitution with pure water with an ultraviolet absorbance value <0.01 at 400 nm and a pH of 6.7±0.3. Representative ultraviolet (UV) spectra for the 20% insulin formulation are shown in FIG. 9. [0068]
  • The following three insulin powder formulations were tested in rats as aerosols in the In-Tox 48 port, exposure chamber. [0069]
  • 1. 87.9% insulin; 11.5% sodium citrate; 0.6% citric acid. [0070]
  • 2. 20% insulin; 66% mannitol: 12.4% sodium citrate: 0.6% citric acid. [0071]
  • 3. 20% insulin; 66% raffinose; 12.4% sodium citrate: 0.6% citric acid. [0072]
  • Table 1 lists the key measurements in the three different rat exposure studies including characterizations of the aerosol at the breathing zone and chamber operating conditions. A fraction of the powder fed into the venturi nozzle reached the breathing zones of the rats (34%-67%) because of losses in the walls due to impaction and incomplete dispersion of the powder during powder feed. The particle size of the aerosol at the breathing zone, however, was ideal for pulmonary deposition (1.3-1.9 μm) and was somewhat smaller than the original formulation particle size (2.0-2.8 μm) due to selective loss of the larger particles in the animal exposure chamber. [0073]
    TABLE 1
    Rat Aerosol Exposure Measurements
    20% Insulin 20% Insulin
    88% Insulin Mannitol Raffinose
    Chamber Flow Rate 7.2 L/min 9.6 L/min 9.8 L/min
    Powder Mass Median 2.2 μm 2.8 μm 2.0 μm
    Diameter (MMD)
    Powder Fed into Chamber 70 mgs 255 mgs    260 mgs 
    Powder Feed Time  5 min 14 min  20 min
    Powder at Breathing Zone 40 mgs 171 mgs    88 mgs
    Insulin at Breathing Zone 35 mgs 34 mgs   18 mgs
    % Total Powder at Breathing Zone 57% 67% 34%
    Mass Median Aerodynamic 1.1 mg/L 1.3 mg/L 0.45 mg/L
    Diameter (MAD)
    Particle Size at Breathing Zone 1.4 μm 1.9 μm 1.3 μm
    Insulin Recovered in Lavage 30.7 ± 5.2 μg 12.7 ± 6.9 μg 31.6 ± 12.9 μg
    Serum Insulin AUC (ng min/ml) 104 201 150
  • Table 2 shows the rat serum insulin and glucose results from the three aerosol and one SC study. FIGS. 3A and 3B show the serum immunoreactive insulin (IRI) concentration-time profiles and the serum glucose concentration-time profiles for the three formulations administered by aerosol. Table 3 presents the insulin t[0074] max, and the glucose tmin from the different studies as well as the relative bioavailability of the aerosol compared to SC injection.
    TABLE 2
    Serum Insulin and Glucose Results in Rats
    Serum Insulin Serum Glucose
    Time (pg/ml ± l S.D.) (mg/dl ± l S.D.)
    Formulation Route (min) n = 3rats/timept n = 3rats/timept
    88% Insulin Aerosol 0 230 ± 184 106 ± 12 
    (Aerosol exposure Aerosol 12 1020 ± 312  114 ± 10 
    completed at minute 5) Aerosol 21 165 ± 768 81 ± 10
    Av. Dose = 31 μg/rat Aerosol 36 876 ± 764 66 ± 7 
    Aerosol 66 684 ± 416 62 ± 15
    Aerosol 96 568 ± 128 65 ± 10
    Aerosol 126 564 ± 260 73 ± 11
    Aerosol 186 712 ± 140 93 ± 5 
    20% Insulin-Mannitol Aerosol 0 476 ± 56  165 ± 18 
    (Aerosol exposure Aerosol 22 1476 ± 428  117 ± 15 
    completed at minute 14) Aerosol 35 2480 ± 892  101 ± 19 
    Av. Dose = 13 μg/rat Aerosol 57 1204 ± 64  64 ± 13
    Aerosol 87 1084 ± 396  63 ± 17
    Aerosol 117 664 ± 180 105 ± 38 
    Aerosol 147 1228 ± 416  108 ± 22 
    Aerosol 207 676 ± 100 119 ± 33 
    20% Insulin-Raffinose Aerosol 0 426 ± 97  157 ± 37 
    (Aerosol exposure Aerosol 27 2948 ± 2816 139 ± 46 
    completed at minute 20) Aerosol 42 1504 ± 592  181 ± 11 
    Av. Dose = 32 μg/rat Aerosol 57 1272 ± 496  124 ± 45 
    Aerosol 87 852 ± 164 128 ± 17 
    Aerosol 117 604 ± 156 124 ± 9 
    Aerosol 147 532 ± 172 172 ± 12 
    Aerosol 207 556 ± 100 218 ± 34 
    20% Insulin-Mannitol Subcutan 0 360 ± 140 107 ± 5 
    Dose = 30 μg Subcutan 15 14200 ± 3160  53 ± 2 
    Insulin/rat
    Subcutan 30 10160 ± 720  24 ± 5 
    Subcutan 60 11000 ± 1080  28 ± 6 
    Subcutan 90 2440 ± 1160 25 ± 7 
    Subcutan 120 3520 ± 840  49 ± 3 
    Subcutan 180 1280 ± 800  40 ± 17
    Subcutan 240 400 ± 260 77 ± 34
  • [0075]
    TABLE 3
    A Comparison of Aerosol and Subcutaneous (SC)
    Insulin in Animals
    Rat Rat Monkey
    Rat Aerosol Aerosol Aerosol
    Rat Aerosol 20% Insulin 20% Insulin Monkey 20% Insulin
    SC 88% Insulin Mannitol Raffinose SC Mannitol
    Insulin Max*  15 min 16 min 21 min 17 min  15 min 30 min
    Glucose Min.*  30 min 31 min 43 min 37 min  45 min 45 min
    Glucose Drop  77% 42% 62% 21%  45% 73%
    Rel Bicavail. 100% 10%** 44%** 14%** 100% 12%***
  • All three formulations provided rapid absorbing insulin to the rats systemic circulation (FIGS. 3A and 3B). The bioavailability and glucose response were higher for the 20% insulin/mannitol powder (Table 3), although without performing many replicate experiments, it is uncertain if the difference was significant. [0076]
  • Primate Results [0077]
  • A dose identical to what was used in the human trial (0.2 U/kg, ˜27 μg/monkey) was injected into four monkeys to provide the SC data with which to compare the aerosol results (FIGS. 4A and 4B). Table 4 shows the monkey aerosol exposure data. Table 5 shows the mean serum insulins and glucoses for the aerosol exposure and the subcutaneous study. The aerosol dose yielded a robust insulin and glucose response (high dose). FIG. 4 shows a comparison of the mean serum insulin profiles from the two aerosol and one SC study. From the AUCs of these profiles the relative bioavailability of the aerosol insulin was calculated to be 12%. [0078]
    TABLE 4
    Monkey Aerosol Exposure Data
    Est. Est.
    Grav. Avg Inhaled Inhaled Est.
    filter Aerosol Inhaled Aerosol Insulin Body Insulin AUC
    Mass Conc. Volume Mass Mass Wt. Dose (ng min/
    Animal ID (mg) (μg/L) (L) (μg) (μg) (Kg) (μg/kg) ml)
    #1, 23-46 1.07 178 8.96 1597 320 3.92 81.5 347
    #2, 23-48 1.01 168 19.98 3363 673 3.81 176.6 1196
    #3, 122-55 0.97 162 14.68 2373 475 4.1 115.7 739
    489 ± 178
  • Human Results [0079]
  • The comparative results between respiratory delivery and subcutaneous injection are set forth in Table 5 below. Respiratory aerosol delivery resulted in more rapid absorption (peak at 20 minutes) than injection (peak at 60 minutes) with a more rapid glucose response (trough at 60 minutes) than with injection (trough at 90 minutes). Reproducibility was as good if not better with aerosol than with injection in both insulin and glucose response. Injection doses were carefully adjusted for weight, aerosol doses were not. Biological activity of aerosol insulin, based on glucose response, relative to injection was 28-36%. Bioavailability of aerosol insulin, based on area-under-the-insulin curve, relative to injection was 22.8% for the 3 puff group. [0080]
    TABLE 5
    Serum Insulin and Glucose Results in Humans
    INSULIN
    Relative
    Increase Bio-
    Dose/ in Serum availability
    Injection Dose in Insulin Time of Based on
    Subject #s or Blister Subject* μU/ml Maximum Insulin AUC
    1-24 10.4 U 10.4 U 5.8-20.9 60 min 100.0%
    (SC
    Injection)
    7-24 76.0 U 31.9 U 6.1-28.5 20 min  22.8%
    (3 puffs)
    GLUCOSE
    Drop Relative
    in Mean Bioactivity
    Serum Based on
    Glucose mg/dl Time of Glucose
    Subject #s mg/dl drop Minimum % SC Drop
    1-24 93.6-64.9 28.7 90 min  100%  100%
    (SC
    Injection)
    7-24 91.8-67.6 24.2 60 min 84.3% 27.4%
    (3 puffs)
  • The results of the human trials are further presented in FIGS. [0081] 5A-5B. FIG. 5A shows mean serum insulin over time for subcutaneous injection (∘), inhalation (3 puffs, ). Mean serum glucose levels are similarly presented in FIG. 5B. Insulin peaks and glucose troughs are shown in FIGS. 6A and 6B, respectively, while intersubject variability in serum insulin and glucose are presented in FIGS. 7A and 7B, respectively.
  • In addition, the shallow inspirations (tidal breathing) of the monkeys during the aerosol exposures do not represent the optimal breathing maneuver for deep lung deposition. A higher bioavailability was observed in humans (Table 5), as expected, when the optimum breathing maneuver was used and the aerosol bolus was taken by oral inhalation rather than by nasal inhalation. [0082]
  • Although the foregoing invention has been described in some detail by way of illustration and example, for purposes of clarity of understanding, it will be obvious that certain changes and modifications may be practiced within the scope of the appended claims. [0083]

Claims (25)

    What is claimed is:
  1. 1. A method for aerosolizing a dose of insulin, said method comprising:
    providing insulin as a dry powder;
    dispersing an amount of the dry powder in a gas stream to form an aerosol; and
    capturing the aerosol in a chamber having a mouthpiece for subsequent inhalation by a patient.
  2. 2. A method as in claim 1, wherein the insulin is substantially free from penetration enhancers.
  3. 3. A method as in claim 1, wherein the insulin is present in a dry powder carrier at a weight concentration in the range from about 5% to 99%.
  4. 4. A method as in claim 3, wherein the powder carrier comprises a carbohydrate, organic salt, amino acid, peptide, or protein.
  5. 5. A method as in claim 1, wherein the insulin dry powder comprises particles having an average size below 10 μm.
  6. 6. A method as in claim 1, wherein the dry powder comprises individual particles including both insulin and a carrier material.
  7. 7. A method a in claim 6, wherein the insulin is present in the individual particles at from 5% to 99% by weight.
  8. 8. An improved method for the respiratory delivery of insulin, wherein the improvement comprises delivering the insulin as a dry powder.
  9. 9. An improved method as in claim 8, wherein the insulin is substantially free from penetration enhancers.
  10. 10. An improved method as in claim 8, wherein the insulin is present in a dry powder carrier at a weight concentration in the range from about 10% to 99%.
  11. 11. An improved method as in claim 10, wherein the powder carrier comprises a carbohydrate, organic salt, amino acid, peptide, or protein.
  12. 12. An improved method as in claim 8, wherein the insulin dry powder comprises particles having an average size below 10 μm.
  13. 13. An improved method as in claim 8, wherein the dry powder comprises individual particles including both insulin and a carrier material.
  14. 14. An improved method as in claim 13, wherein the insulin is present in the individual particles at from 5% to 99% by weight.
  15. 15. A method for preparing a stable, dry powder insulin composition, said method comprising:
    dissolving insulin in an aqueous buffer to form a solution; and
    spray drying the solution to produce substantially amorphous particles having an average size below 10 μm.
  16. 16. A method as in claim 15, wherein the insulin is dissolved in a aqueous buffer together with a pharmaceutical carrier, wherein a dry powder having insulin present in individual particles at from 5% to 99% by weight is produced upon spray drying.
  17. 17. A method as in claim 16, wherein the pharmaceutical carrier is a carbohydrate, organic salt, amino acid, peptide, or protein which produces a powder upon spray drying.
  18. 18. A method as in claim 17, wherein the carbohydrate is selected from the group consisting of mannitol, raffinose, lactose, malto dextrin and trehalose.
  19. 19. A method as in claim 17, wherein the organic salt is selected from the group consisting of sodium citrate, sodium acetate, and sodium ascorbate.
  20. 20. An insulin composition for pulmonary delivery, said composition comprising individual particles which include insulin present at from 5% to 99% by weight in a pharmaceutical carrier material and have a size below 10 μm.
  21. 21. An insulin composition as in claim 20, wherein the composition is substantially free from penetration enhancers.
  22. 22. An insulin composition as in claim 20, wherein the pharmaceutical carrier material comprises a carbohydrate selected from the group consisting of mannitol, raffinose, lactose, malto dextrin, and trehalose.
  23. 23. An insulin composition as in claim 20, wherein the pharmaceutical carrier material comprises an organic salt selected from the group consisting of sodium citrate, sodium gluconate, and sodium ascorbate.
  24. 24. An insulin composition produced by the method of claim 15.
  25. 25. An insulin composition consisting essentially of dry powder insulin having an average particle size below 10 μm.
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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050276846A1 (en) * 1994-12-02 2005-12-15 Roser Bruce J Solid dose delivery vehicle and methods of making same
EP2060268A1 (en) * 2007-11-15 2009-05-20 Novo Nordisk A/S Pharmaceutical compositions for pulmonary or nasal delivery of peptides
US8168223B1 (en) 1997-09-29 2012-05-01 Novartis Pharma Ag Engineered particles and methods of use
US8246934B2 (en) 1997-09-29 2012-08-21 Novartis Ag Respiratory dispersion for metered dose inhalers comprising perforated microstructures
US8404217B2 (en) 2000-05-10 2013-03-26 Novartis Ag Formulation for pulmonary administration of antifungal agents, and associated methods of manufacture and use
US8709484B2 (en) 2000-05-10 2014-04-29 Novartis Ag Phospholipid-based powders for drug delivery
US8715623B2 (en) 2001-12-19 2014-05-06 Novartis Ag Pulmonary delivery of aminoglycoside
US8877162B2 (en) 2000-05-10 2014-11-04 Novartis Ag Stable metal ion-lipid powdered pharmaceutical compositions for drug delivery

Families Citing this family (251)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6673335B1 (en) * 1992-07-08 2004-01-06 Nektar Therapeutics Compositions and methods for the pulmonary delivery of aerosolized medicaments
US6582728B1 (en) * 1992-07-08 2003-06-24 Inhale Therapeutic Systems, Inc. Spray drying of macromolecules to produce inhaleable dry powders
US6258341B1 (en) * 1995-04-14 2001-07-10 Inhale Therapeutic Systems, Inc. Stable glassy state powder formulations
US6309671B1 (en) * 1995-04-14 2001-10-30 Inhale Therapeutic Systems Stable glassy state powder formulations
US6051256A (en) * 1994-03-07 2000-04-18 Inhale Therapeutic Systems Dispersible macromolecule compositions and methods for their preparation and use
DE69332105T2 (en) * 1992-09-29 2003-03-06 Inhale Therapeutic Systems San Pulmonary delivery of active fragments of parathyroid hormone
US7448375B2 (en) * 1993-01-29 2008-11-11 Aradigm Corporation Method of treating diabetes mellitus in a patient
US6024090A (en) * 1993-01-29 2000-02-15 Aradigm Corporation Method of treating a diabetic patient by aerosolized administration of insulin lispro
US6632456B1 (en) 1993-06-24 2003-10-14 Astrazeneca Ab Compositions for inhalation
US20010003739A1 (en) * 1993-06-24 2001-06-14 Astrazeneca Ab Systemic administration of a therapeutic preparation
US6165976A (en) 1994-06-23 2000-12-26 Astra Aktiebolag Therapeutic preparation for inhalation
RU2148398C1 (en) * 1993-06-24 2000-05-10 Астра Актиеболаг Therapeutic preparation and method for making inhalations
US6794357B1 (en) 1993-06-24 2004-09-21 Astrazeneca Ab Compositions for inhalation
US5830853A (en) 1994-06-23 1998-11-03 Astra Aktiebolag Systemic administration of a therapeutic preparation
EP1462096B1 (en) * 1994-03-07 2008-12-10 Nektar Therapeutics Methods and compositions for pulmonary delivery of insulin
US20030113273A1 (en) * 1996-06-17 2003-06-19 Patton John S. Methods and compositions for pulmonary delivery of insulin
CA2190502A1 (en) * 1994-05-18 1995-11-23 Robert M. Platz Methods and compositions for the dry powder formulation of interferons
US20030035778A1 (en) * 1997-07-14 2003-02-20 Robert Platz Methods and compositions for the dry powder formulation of interferon
US6586006B2 (en) 1994-08-04 2003-07-01 Elan Drug Delivery Limited Solid delivery systems for controlled release of molecules incorporated therein and methods of making same
US5863563A (en) * 1994-10-20 1999-01-26 Alphagene Inc. Treatment of pulmonary conditions associated with insufficient secretion of surfactant
US6524557B1 (en) 1994-12-22 2003-02-25 Astrazeneca Ab Aerosol formulations of peptides and proteins
CA2206782C (en) 1994-12-22 2007-04-03 Astra Aktiebolag Aerosol drug formulations
CN1170527C (en) 1994-12-22 2004-10-13 阿斯特拉公司 Therapeutic perparation for inhalation containing parathyroid hormone, PTH
US6428771B1 (en) 1995-05-15 2002-08-06 Pharmaceutical Discovery Corporation Method for drug delivery to the pulmonary system
GB9515182D0 (en) 1995-07-24 1995-09-20 Co Ordinated Drug Dev Improvements in and relating to powders for use in dry powder inhalers
DE19539574A1 (en) 1995-10-25 1997-04-30 Boehringer Mannheim Gmbh Preparations and processes for stabilizing biological materials by means of drying processes without freezing
WO1997026863A1 (en) 1996-01-24 1997-07-31 Byk Gulden Lomberg Chemische Fabrik Gmbh Process for the production of powdered pulmonary surfactant preparations
DE69728857T3 (en) 1996-02-09 2010-02-18 Quadrant Drug Delivery Ltd., Ruddington Solid pharmaceutical containing trehalose
US5874064A (en) * 1996-05-24 1999-02-23 Massachusetts Institute Of Technology Aerodynamically light particles for pulmonary drug 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
US5985309A (en) * 1996-05-24 1999-11-16 Massachusetts Institute Of Technology Preparation of particles for inhalation
US6254854B1 (en) 1996-05-24 2001-07-03 The Penn Research Foundation Porous particles for deep lung delivery
US6503480B1 (en) 1997-05-23 2003-01-07 Massachusetts Institute Of Technology Aerodynamically light particles for pulmonary drug delivery
US7052678B2 (en) 1997-09-15 2006-05-30 Massachusetts Institute Of Technology Particles for inhalation having sustained release properties
USRE37053E1 (en) 1996-05-24 2001-02-13 Massachusetts Institute Of Technology Particles incorporating surfactants for pulmonary drug delivery
CA2267063A1 (en) * 1996-10-01 1998-04-09 Amrad Operations Pty. Ltd. A method and compositions for treatment of insulin-dependant diabetes mellitus
US20030203036A1 (en) 2000-03-17 2003-10-30 Gordon Marc S. Systems and processes for spray drying hydrophobic drugs with hydrophilic excipients
US6001336A (en) * 1996-12-31 1999-12-14 Inhale Therapeutic Systems Processes for spray drying aqueous suspensions of hydrophobic drugs and compositions thereof
US5855913A (en) * 1997-01-16 1999-01-05 Massachusetts Instite Of Technology Particles incorporating surfactants for pulmonary drug delivery
RU2198181C2 (en) * 1997-03-20 2003-02-10 Ново Нордиск А/С Zinc-free insulin crystal for application in pulmonary compositions
US6310038B1 (en) 1997-03-20 2001-10-30 Novo Nordisk A/S Pulmonary insulin crystals
US5898028A (en) * 1997-03-20 1999-04-27 Novo Nordisk A/S Method for producing powder formulation comprising an insulin
DK0901786T3 (en) 1997-08-11 2007-10-08 Pfizer Prod Inc Solid pharmaceutical dispersions possess increased bioavailability
US6309623B1 (en) * 1997-09-29 2001-10-30 Inhale Therapeutic Systems, Inc. Stabilized preparations for use in metered dose inhalers
CA2308136A1 (en) * 1997-10-31 1999-05-14 Ronald Keith Wolff Method for administering acylated insulin
EP2311436A1 (en) 1998-04-27 2011-04-20 Altus Pharmaceuticals Inc. Stabilized protein crystals, formulations containing them and methods of making them
GB9814172D0 (en) * 1998-06-30 1998-08-26 Andaris Ltd Formulation for inhalation
US6451349B1 (en) * 1998-08-19 2002-09-17 Quadrant Healthcare (Uk) Limited Spray-drying process for the preparation of microparticles
US7678364B2 (en) 1999-08-25 2010-03-16 Alkermes, Inc. Particles for inhalation having sustained release properties
CA2346791C (en) 1998-10-09 2007-12-11 Inhale Therapeutic Systems, Inc. Flow resistance modulated aerosolized active agent delivery
US20060171899A1 (en) * 1998-12-10 2006-08-03 Akwete Adjei Water-stabilized aerosol formulation system and method of making
US7087215B2 (en) * 1998-12-21 2006-08-08 Generex Pharmaceuticals Incorporated Methods of administering and enhancing absorption of pharmaceutical agents
WO2000047203A9 (en) * 1999-02-12 2001-09-07 Mqs Inc Formulation and system for intra-oral delivery of pharmaceutical agents
CA2367131C (en) * 1999-04-05 2007-07-03 Solomon S. Steiner Methods for fine powder formation
US7001892B1 (en) 1999-06-11 2006-02-21 Purdue Research Foundation Pharmaceutical materials and methods for their preparation and use
US9006175B2 (en) * 1999-06-29 2015-04-14 Mannkind Corporation Potentiation of glucose elimination
US6444226B1 (en) 1999-06-29 2002-09-03 Pharmaceutical Discovery Corporation Purification and stabilization of peptide and protein pharmaceutical agents
GB9916316D0 (en) * 1999-07-12 1999-09-15 Quadrant Holdings Cambridge Dry powder compositions
JP2003510024A (en) * 1999-08-09 2003-03-18 インサイト・ゲノミックス・インコーポレイテッド Proteases and protease inhibitors
US7252840B1 (en) 1999-08-25 2007-08-07 Advanced Inhalation Research, Inc. Use of simple amino acids to form porous particles
US6749835B1 (en) * 1999-08-25 2004-06-15 Advanced Inhalation Research, Inc. Formulation for spray-drying large porous particles
US6586008B1 (en) * 1999-08-25 2003-07-01 Advanced Inhalation Research, Inc. Use of simple amino acids to form porous particles during spray drying
CA2384650A1 (en) * 1999-09-10 2001-03-15 Incyte Genomics, Inc. Apoptosis proteins
US6761909B1 (en) * 1999-12-21 2004-07-13 Rxkinetix, Inc. Particulate insulin-containing products and method of manufacture
WO2001045731A9 (en) * 1999-12-21 2002-05-30 Rxkinetix Inc Particulate drug-containing products and method of manufacture
JP2003519175A (en) * 1999-12-30 2003-06-17 カイロン コーポレイション The method for pulmonary delivery of interleukin-2
FI20002217A (en) * 1999-12-30 2001-07-01 Orion Yhtymae Oyj to inhalation
ES2327606T3 (en) 2000-01-10 2009-11-02 Maxygen Holdings Ltd GCSF conjugates.
JP2003524646A (en) * 2000-01-25 2003-08-19 エアロファーム テクノロジー インコーポレイテッド Pharmaceutical aerosol formulation
US6540982B1 (en) * 2000-01-25 2003-04-01 Aeropharm Technology Incorporated Medical aerosol formulation
US6540983B1 (en) * 2000-01-25 2003-04-01 Aeropharm Technology Incorporated Medical aerosol formulation
US6585957B1 (en) 2000-01-25 2003-07-01 Aeropharm Technology Incorporated Medicinal aerosol formulation
US6596261B1 (en) * 2000-01-25 2003-07-22 Aeropharm Technology Incorporated Method of administering a medicinal aerosol formulation
EP1259611A2 (en) * 2000-03-03 2002-11-27 Incyte Genomics, Inc. G-protein coupled receptors
JP4711520B2 (en) * 2000-03-21 2011-06-29 日本ケミカルリサーチ株式会社 Physiologically active peptide-containing powder
US8048451B2 (en) 2000-11-30 2011-11-01 Vectura Limited Pharmaceutical compositions for inhalation
US6447750B1 (en) * 2000-05-01 2002-09-10 Aeropharm Technology Incorporated Medicinal aerosol formulation
GB0010709D0 (en) * 2000-05-03 2000-06-28 Vectura Ltd Powders for use a in dry powder inhaler
GB0011807D0 (en) * 2000-05-16 2000-07-05 Quadrant Holdings Cambridge Formulation for inhalation
US7905230B2 (en) 2001-05-09 2011-03-15 Novartis Ag Metered dose inhaler with lockout
US6858199B1 (en) * 2000-06-09 2005-02-22 Advanced Inhalation Research, Inc. High efficient delivery of a large therapeutic mass aerosol
CA2412484A1 (en) 2000-06-16 2001-12-27 Incyte Genomics, Inc. G-protein coupled receptors
US20050164275A1 (en) * 2002-10-18 2005-07-28 Incyte Corporation Phosphodiesterases
US7575761B2 (en) * 2000-06-30 2009-08-18 Novartis Pharma Ag Spray drying process control of drying kinetics
US20020106368A1 (en) * 2000-07-28 2002-08-08 Adrian Bot Novel methods and compositions to upregulate, redirect or limit immune responses to peptides, proteins and other bioactive compounds and vectors expressing the same
WO2002009669A3 (en) * 2000-08-01 2002-05-30 Inhale Therapeutic Syst Apparatus and process to produce particles having a narrow size distribution and particles made thereby
US6613308B2 (en) 2000-09-19 2003-09-02 Advanced Inhalation Research, Inc. Pulmonary delivery in treating disorders of the central nervous system
US7608704B2 (en) 2000-11-08 2009-10-27 Incyte Corporation Secreted proteins
CN100400031C (en) * 2000-11-29 2008-07-09 伊藤火腿株式会社 Powdery preparations and proecss for producing the same
EP2168571A3 (en) * 2000-11-30 2011-11-16 Vectura Limited Particles for use in a Pharmaceutical Composition
US20020106331A1 (en) * 2000-12-08 2002-08-08 Joan Rosell Use of electrolytes (ions in solution) to suppress charging of inhalation aerosols
US20020141946A1 (en) * 2000-12-29 2002-10-03 Advanced Inhalation Research, Inc. Particles for inhalation having rapid release properties
WO2002053190A3 (en) * 2000-12-29 2003-03-27 Advanced Inhalation Res Inc Particles for inhalation having sustained release properties
EP1797902A3 (en) * 2000-12-29 2007-10-03 Advanced Inhalation Research, Inc. Particles for inhalation having sustained release properties
CA2469846A1 (en) 2001-02-27 2002-09-26 Maxygen Aps New interferon beta-like molecules
US9657294B2 (en) 2002-02-20 2017-05-23 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA)
US9181551B2 (en) 2002-02-20 2015-11-10 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA)
US9994853B2 (en) 2001-05-18 2018-06-12 Sirna Therapeutics, Inc. Chemically modified multifunctional short interfering nucleic acid molecules that mediate RNA interference
US6828297B2 (en) * 2001-06-04 2004-12-07 Nobex Corporation Mixtures of insulin drug-oligomer conjugates comprising polyalkylene glycol, uses thereof, and methods of making same
WO2003000326A1 (en) 2001-06-20 2003-01-03 Nektar Therapeutics Powder aerosolization apparatus and method
EP1270012A1 (en) * 2001-06-21 2003-01-02 Pfizer Products Inc. Use of pulmonary administration of insulin for treatment of diabetes
DE60217367D1 (en) * 2001-09-19 2007-02-15 Elan Pharma Int Ltd Nanoparticle compositions containing insulin
WO2003026559A3 (en) 2001-09-28 2003-11-06 Kurve Technology Inc Nasal nebulizer
EP1446104B2 (en) 2001-11-01 2011-08-03 Novartis AG Spray drying methods
WO2003043574A3 (en) 2001-11-19 2004-03-04 Becton Dickinson Co Pharmaceutical compositions in particulate form
US7182961B2 (en) 2001-11-20 2007-02-27 Advanced Inhalation Research, Inc. Particulate compositions for pulmonary delivery
JP2005514188A (en) 2001-12-07 2005-05-19 エイフェル テクノロジーズ リミテッド The synthesis of small particles
JP4739672B2 (en) 2001-12-21 2011-08-03 ネクター セラピューティクス Capsule package having a moisture barrier
WO2003070902A3 (en) * 2002-02-20 2006-03-02 Mariah R Baughn Receptors and membrane-associated proteins
US7754242B2 (en) * 2002-03-20 2010-07-13 Alkermes, Inc. Inhalable sustained therapeutic formulations
EP1487411A4 (en) 2002-03-20 2011-03-09 Alkermes Inc Inhalable sustained therapeutic formulations
US7008644B2 (en) * 2002-03-20 2006-03-07 Advanced Inhalation Research, Inc. Method and apparatus for producing dry particles
WO2003079993A3 (en) * 2002-03-20 2004-03-04 Advanced Inhalation Res Inc hGH (HUMAN GROWTH HORMONE) FORMULATIONS FOR PULMONARY ADMINISTRATION
CA2478980C (en) 2002-03-20 2008-07-15 Advanced Inhalation Research, Inc. Pulmonary delivery for levodopa
EP1894591B1 (en) 2002-03-20 2013-06-26 MannKind Corporation Cartridge for an inhalation apparatus
US20050163725A1 (en) * 2002-03-20 2005-07-28 Blizzard Charles D. Method for administration of growth hormone via pulmonary delivery
GB0208742D0 (en) 2002-04-17 2002-05-29 Bradford Particle Design Ltd Particulate materials
DE60302454T2 (en) 2002-04-19 2006-08-17 Yissum Research Development Company Of The Hebrew University Of Jerusalem Beta-agonist-compounds having nitric oxide donators-groups and reactive oxygen species-catcher groups and their use in the treatment of respiratory disorders
WO2003090717A1 (en) * 2002-04-23 2003-11-06 Nanotherapeutics, Inc Process of forming and modifying particles and compositions produced thereby
US9339459B2 (en) 2003-04-24 2016-05-17 Nektar Therapeutics Particulate materials
GB0216562D0 (en) 2002-04-25 2002-08-28 Bradford Particle Design Ltd Particulate materials
WO2003099359A1 (en) * 2002-05-09 2003-12-04 Kurve Technology, Inc. Particle dispersion chamber for nasal nebulizer
US6941980B2 (en) 2002-06-27 2005-09-13 Nektar Therapeutics Apparatus and method for filling a receptacle with powder
EP1531794B1 (en) 2002-06-28 2017-05-10 Civitas Therapeutics, Inc. Inhalable epinephrine
US20070276126A1 (en) * 2002-08-13 2007-11-29 Incyte Corporation Cell adhesion and extracellular matrix proteins
US20070219353A1 (en) * 2002-09-03 2007-09-20 Incyte Corporation Immune Response Associated Proteins
WO2004033636A3 (en) * 2002-10-04 2005-08-11 Mariah R Baughn Protein modification and maintenance molecules
US20070009886A1 (en) * 2002-11-12 2007-01-11 Incyte Corporation Carbohydrate-associated proteins
WO2004044165A3 (en) * 2002-11-13 2005-02-24 Incyte Corp Lipid-associated proteins
US20040105818A1 (en) 2002-11-26 2004-06-03 Alexza Molecular Delivery Corporation Diuretic aerosols and methods of making and using them
WO2004048550A3 (en) * 2002-11-26 2005-10-20 Incyte Corp Immune response associated proteins
US7516741B2 (en) 2002-12-06 2009-04-14 Novartis Ag Aerosolization apparatus with feedback mechanism
WO2004054606A1 (en) * 2002-12-13 2004-07-01 Pfizer Products Inc. Method of decreasing hepatic glucose output in diabetic patients
US20050236296A1 (en) * 2002-12-30 2005-10-27 Nektar Therapeutics (Formerly Inhale Therapeutic Systems, Inc.) Carry case for aerosolization apparatus
EP1578536B1 (en) 2002-12-30 2017-02-08 Novartis AG Prefilming atomizer
US7669596B2 (en) 2002-12-31 2010-03-02 Novartis Pharma Ag Aerosolization apparatus with rotating capsule
CA2520032C (en) 2003-04-09 2012-10-16 Nektar Therapeutics Aerosolization apparatus with air inlet shield
US8869794B1 (en) 2003-04-09 2014-10-28 Novartis Pharma Ag Aerosolization apparatus with capsule puncturing member
WO2004098539A3 (en) 2003-04-30 2007-01-04 Incyte Corp Kinases and phosphatases
US7683029B2 (en) * 2003-05-07 2010-03-23 Philip Morris Usa Inc. Liquid aerosol formulations containing insulin and aerosol generating devices and methods for generating aerosolized insulin
WO2004103364A3 (en) * 2003-05-16 2005-03-17 Arriva Pharmaceuticals Inc Treatment of respiratory disease by inhalation of synthetic matrix metalloprotease inhibitors
US7338171B2 (en) * 2003-10-27 2008-03-04 Jen-Chuen Hsieh Method and apparatus for visual drive control
KR100985126B1 (en) * 2004-01-12 2010-10-05 맨카인드 코포레이션 A method of reducing serum proinsulin levels in type 2 diabetics
US20050191360A1 (en) * 2004-02-10 2005-09-01 Advanced Inhalation Research, Inc. Particles for inhalation having rapid release properties
US20080090753A1 (en) * 2004-03-12 2008-04-17 Biodel, Inc. Rapid Acting Injectable Insulin Compositions
EP2106790B1 (en) * 2004-03-12 2012-10-24 Biodel, Inc. Rapid acting drug delivery compositions
WO2005092301A1 (en) 2004-03-26 2005-10-06 Universita' Degli Studi Di Parma Insulin highly respirable microparticles
US20060039985A1 (en) * 2004-04-27 2006-02-23 Bennett David B Methotrexate compositions
CN1997355A (en) * 2004-05-07 2007-07-11 哈佛学院校长同事会 Pulmonary malarial vaccine
US7481219B2 (en) * 2004-06-18 2009-01-27 Mergenet Medical, Inc. Medicine delivery interface system
CA2567785A1 (en) 2004-06-21 2006-01-05 Nektar Therapeutics Composition comprising amphotericin b methods and systems
US8513204B2 (en) 2004-06-21 2013-08-20 Novartis Ag Compositions comprising amphotericin B, mehods and systems
DK2626368T3 (en) 2004-07-19 2017-02-27 Biocon Ltd Insulin-oligomer conjugates, formulations and uses thereof
US7709639B2 (en) 2004-08-20 2010-05-04 Mannkind Corporation Catalysis of diketopiperazine synthesis
JP4990142B2 (en) 2004-08-23 2012-08-01 マンカインド コーポレイション Diketopiperazine salts for drug delivery, diketomorpholine salt or diketodioxanes salt,
US7115561B2 (en) * 2004-09-22 2006-10-03 Patterson James A Medicament composition and method of administration
WO2006033604A1 (en) * 2004-09-24 2006-03-30 Mederio Ag A metered medication dose
EP1809252A2 (en) 2004-10-29 2007-07-25 Presidents and Fellows of Harvard College Particles for treatment of pulmonary infection
US20060115468A1 (en) * 2004-11-26 2006-06-01 Kara Morrison Dietary supplement for treating and preventing gastrointestinal disorders
JP4744533B2 (en) 2004-12-30 2011-08-10 ドゥビエル カンパニー リミテッド Spray drying polymer collectin genus protein and a method of manufacturing the same
US20080206342A1 (en) * 2005-01-10 2008-08-28 Rosemary Kovelesky Compositions and Methods For Increasing the Bioavailability of Pulmonarily Administered Insulin
CN100431634C (en) * 2005-04-04 2008-11-12 陈庆堂;陈 欣 Dry powder aerosolizing inhalator
CN101203604A (en) * 2005-05-04 2008-06-18 伊卢米根生物科学公司 Oas1 gene mutation
US20070083677A1 (en) 2005-05-18 2007-04-12 Nektar Therapeutics Valves, devices, and methods for endobronchial therapy
US20070031342A1 (en) * 2005-06-22 2007-02-08 Nektar Therapeutics Sustained release microparticles for pulmonary delivery
EP1922150A1 (en) * 2005-07-07 2008-05-21 Nanotherapeutics, Inc. Process for milling and preparing powders and compositions produced thereby
KR20120060245A (en) 2005-09-14 2012-06-11 맨카인드 코포레이션 Method of drug formulation based on increasing the affinity of crystalline microparticle surfaces for active agents
US8084420B2 (en) 2005-09-29 2011-12-27 Biodel Inc. Rapid acting and long acting insulin combination formulations
WO2007041481A1 (en) * 2005-09-29 2007-04-12 Biodel, Inc. Rapid acting and prolonged acting insulin preparations
WO2007121256A3 (en) 2006-04-12 2008-07-10 Biodel Inc Rapid acting and long acting insulin combination formulations
US20070123449A1 (en) * 2005-11-01 2007-05-31 Advanced Inhalation Research, Inc. High load particles for inhalation having rapid release properties
GB0524194D0 (en) * 2005-11-28 2006-01-04 Univ Aston Respirable powders
US8058236B2 (en) * 2005-12-15 2011-11-15 Development Center For Biotechnology Aqueous inhalation pharmaceutical composition
WO2007102946A3 (en) 2006-01-23 2007-12-06 Amgen Inc Crystalline polypeptides
CA2643464A1 (en) 2006-02-22 2007-08-30 Mannkind Corporation A method for improving the pharmaceutic properties of microparticles comprising diketopiperazine and an active agent
EP1991532B1 (en) 2006-02-24 2017-01-11 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the jak pathway
US7713929B2 (en) 2006-04-12 2010-05-11 Biodel Inc. Rapid acting and long acting insulin combination formulations
US20080170996A1 (en) * 2006-07-28 2008-07-17 The Board Of Regents Of The University Of Texas System Compositions and Methods for Stimulation of Lung Innate Immunity
CN101573133B (en) 2006-07-31 2014-08-27 诺沃-诺迪斯克有限公司 PEGylated, extended insulins
GB0616299D0 (en) * 2006-08-16 2006-09-27 Cambridge Consultants Drug Capsules for dry power inhalers
US20080063722A1 (en) * 2006-09-08 2008-03-13 Advanced Inhalation Research, Inc. Composition of a Spray-Dried Powder for Pulmonary Delivery of a Long Acting Neuraminidase Inhibitor (LANI)
WO2008034881A1 (en) 2006-09-22 2008-03-27 Novo Nordisk A/S Protease resistant insulin analogues
KR20160106200A (en) 2007-02-11 2016-09-09 맵 파마슈티컬스, 인코포레이티드 Method of therapeutic administration of dhe to enable rapid relief of migraine while minimizing side effect profile
WO2008124522A3 (en) * 2007-04-04 2008-12-11 Biodel Inc Amylin formulations
WO2008132224A3 (en) 2007-04-30 2009-03-19 Novo Nordisk As Method for drying a protein composition, a dried protein composition and a pharmaceutical composition comprising the dried protein
WO2008137747A1 (en) 2007-05-02 2008-11-13 The Regents Of The University Of Michigan Nanoemulsion therapeutic compositions and methods of using the same
WO2009050738A3 (en) * 2007-10-16 2009-06-11 Biocon Ltd An orally administerable solid pharmaceutical composition and a process thereof
US8785396B2 (en) 2007-10-24 2014-07-22 Mannkind Corporation Method and composition for treating migraines
EP2207584A2 (en) * 2007-10-25 2010-07-21 Novartis Ag Powder conditioning of unit dose drug packages
EP2234644B1 (en) * 2008-01-04 2013-07-31 Biodel, Inc. Insulin formulations for insulin release as a function of tissue glucose levels
JP5762001B2 (en) 2008-03-14 2015-08-12 ノボ・ノルデイスク・エー/エス Protease stabilized insulin analogue
RU2571857C2 (en) 2008-03-18 2015-12-20 Ново Нордиск А/С Acylated insulin analogues stabilised with respect to proteases
US8485180B2 (en) * 2008-06-13 2013-07-16 Mannkind Corporation Dry powder drug delivery system
KR101629154B1 (en) 2008-06-13 2016-06-21 맨카인드 코포레이션 A dry powder inhaler and system for drug delivery
EP2403490A2 (en) 2009-03-04 2012-01-11 MannKind Corporation An improved dry powder drug delivery system
EP2609954A3 (en) 2008-06-20 2018-01-10 MannKind Corporation An interactive apparatus and method for real-time profiling of inhalation efforts
EP2328608A2 (en) 2008-08-11 2011-06-08 MannKind Corporation Use of ultrarapid acting insulin
US20110105383A1 (en) * 2008-09-10 2011-05-05 Magnus Hook Methods and compositions for stimulation of mammalian innate immune resistance to pathogens
EP2341942A1 (en) 2008-09-19 2011-07-13 Nektar Therapeutics Polymer conjugates of therapeutic peptides
JP5722782B2 (en) * 2008-09-26 2015-05-27 ナノバイオ コーポレーション Nanoemulsion therapeutic compositions and methods of use thereof
JP5731981B2 (en) 2008-10-17 2015-06-10 サノフィ−アベンティス・ドイチュラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング The combination of insulin and glp-1 agonist
EP3101031A1 (en) 2008-11-10 2016-12-07 Alexion Pharmaceuticals, Inc. Methods and compositions for treating complement-associated disorders
CA2743904A1 (en) 2008-11-17 2010-05-20 The Regents Of The University Of Michigan Cancer vaccine compositions and methods of using the same
US8314106B2 (en) 2008-12-29 2012-11-20 Mannkind Corporation Substituted diketopiperazine analogs for use as drug delivery agents
WO2010082543A1 (en) 2009-01-19 2010-07-22 三菱瓦斯化学株式会社 Method for injecting drug into living body by electrospraying and device therefor
JP5341532B2 (en) 2009-01-19 2013-11-13 第一電子工業株式会社 Electrical connector using a pair of incorrect fitting prevention key and the key of
CA2749217C (en) 2009-01-23 2017-03-21 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the jak pathway
CA2750711C (en) 2009-01-26 2015-07-07 Teva Pharmaceutical Industries Ltd. Processes for coating a carrier with microparticles
US9060927B2 (en) * 2009-03-03 2015-06-23 Biodel Inc. Insulin formulations for rapid uptake
WO2010102065A1 (en) 2009-03-05 2010-09-10 Bend Research, Inc. Pharmaceutical compositions of dextran polymer derivatives
DK2405963T3 (en) 2009-03-11 2013-12-16 Mannkind Corp An apparatus, system and method for measuring resistance in an inhaler
CA2835771C (en) 2009-03-18 2017-01-24 Incarda Therapeutics, Inc. Unit doses, aerosols, kits, and methods for treating heart conditions by pulmonary administration
KR101730351B1 (en) 2009-03-25 2017-04-28 보드 오브 리전츠, 더 유니버시티 오브 텍사스 시스템 Compositions for stimulation of mammalian innate immune resistance to pathogens
EP2411137B1 (en) 2009-03-27 2016-09-07 Bend Research, Inc. Spray-drying process
WO2010135459A3 (en) * 2009-05-19 2011-04-07 Mount Sinai School Of Medicine Of New York University Brain delivery of insulin to treat systemic inflammation
CA2764759A1 (en) 2009-06-09 2010-12-16 Defyrus, Inc. Administration of interferon for prophylaxis against or treatment of pathogenic infection
US8551528B2 (en) 2009-06-12 2013-10-08 Mannkind Corporation Diketopiperazine microparticles with defined specific surface areas
KR20120105405A (en) 2009-06-23 2012-09-25 알렉시온 파마슈티칼스, 인코포레이티드 Bispecific antibodies that bind to complement proteins
GB0918450D0 (en) 2009-10-21 2009-12-09 Innovata Ltd Composition
EP2496295A1 (en) 2009-11-03 2012-09-12 MannKind Corporation An apparatus and method for simulating inhalation efforts
KR20170100037A (en) 2009-11-13 2017-09-01 사노피-아벤티스 도이칠란트 게엠베하 Pharmaceutical composition comprising a glp-1 agonist and methionine
US8950394B2 (en) 2010-01-12 2015-02-10 Dance Biopharm Inc. Preservative-free single dose inhaler systems
WO2011092690A1 (en) 2010-01-26 2011-08-04 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd Compositions and methods for prevention and treatment of pulmonary hypertension
DK2563813T3 (en) 2010-04-30 2015-11-30 Alexion Pharma Inc Anti-c5a antibodies and methods of use of antibodies
EP2387989B1 (en) 2010-05-19 2014-07-16 Sanofi Long - acting formulations of insulins
US20130059916A1 (en) 2010-05-26 2013-03-07 Stephane Rocchi Biguanide compounds and its use for treating cancer
EP2582421A1 (en) 2010-06-21 2013-04-24 MannKind Corporation Dry powder drug delivery system and methods
JP6199186B2 (en) 2010-08-30 2017-09-20 サノフィ−アベンティス・ドイチュラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング Using ave0010 for the manufacture of a medicament for the treatment of type 2 diabetes
EP2611530A2 (en) 2010-09-03 2013-07-10 Bend Research, Inc. Spray-drying apparatus and methods of using the same
US8815294B2 (en) 2010-09-03 2014-08-26 Bend Research, Inc. Pharmaceutical compositions of dextran polymer derivatives and a carrier material
WO2012031129A3 (en) 2010-09-03 2012-04-26 Bend Research, Inc. Spray-drying apparatus and methods of using the same
US9248584B2 (en) 2010-09-24 2016-02-02 Bend Research, Inc. High-temperature spray drying process and apparatus
WO2012058210A1 (en) 2010-10-29 2012-05-03 Merck Sharp & Dohme Corp. RNA INTERFERENCE MEDIATED INHIBITION OF GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACIDS (siNA)
US9060938B2 (en) 2011-05-10 2015-06-23 Bend Research, Inc. Pharmaceutical compositions of active agents and cationic dextran polymer derivatives
US9821032B2 (en) 2011-05-13 2017-11-21 Sanofi-Aventis Deutschland Gmbh Pharmaceutical combination for improving glycemic control as add-on therapy to basal insulin
CA2754237A1 (en) 2011-05-27 2012-11-27 The Regents Of The University Of California Cyanoquinoline compounds having activity in correcting mutant-cftr processing and increasing ion transport and uses thereof
WO2012174472A1 (en) 2011-06-17 2012-12-20 Mannkind Corporation High capacity diketopiperazine microparticles
EP2750699B1 (en) 2011-08-29 2015-07-22 Sanofi-Aventis Deutschland GmbH Pharmaceutical combination for use in glycemic control in diabetes type 2 patients
WO2013030409A1 (en) 2011-09-01 2013-03-07 Sanofi-Aventis Deutschland Gmbh Pharmaceutical composition for use in the treatment of a neurodegenerative disease
CN103945859A (en) 2011-10-24 2014-07-23 曼金德公司 Methods and compositions for treating pain
CA2858247A1 (en) 2011-12-16 2013-06-20 Novartis Ag Aerosolization apparatus for inhalation profile-independent drug delivery
KR20140108516A (en) 2011-12-30 2014-09-11 그리폴스, 에스.에이. Alpha1-proteinase inhibitor for delaying the onset or progression of pulmonary exacerbations
US9770192B2 (en) * 2012-03-19 2017-09-26 Richard C. Fuisz Method and system to amplify and measure breath analytes
EP2828241A4 (en) 2012-03-23 2016-06-29 Oxigene Inc Compositions and methods for inhibition of cathepsins
US9481721B2 (en) 2012-04-11 2016-11-01 Novo Nordisk A/S Insulin formulations
EP2872205B1 (en) 2012-07-12 2017-02-08 MannKind Corporation Dry powder drug delivery systems
US20140179597A1 (en) * 2012-11-16 2014-06-26 Steven Lehrer Method for the treatment and prevention of Alzheimer's disease and central nervous system dysfunction
CA2918369A1 (en) 2013-07-18 2015-01-22 Mannkind Corporation Heat-stable dry powder pharmaceutical compositions and methods
EP3055325B1 (en) 2013-10-07 2018-01-03 Novo Nordisk A/S Novel derivative of an insulin analogue
KR20170125420A (en) 2014-03-07 2017-11-14 알렉시온 파마슈티칼스, 인코포레이티드 Anti-c5 antibodies having improved pharmacokinetics
CN107206058A (en) 2014-12-12 2017-09-26 赛诺菲-安万特德国有限公司 Insulin glargine/lixisenatide fixed ratio formulation

Citations (96)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US558085A (en) * 1896-04-14 And william c
US2598525A (en) * 1950-04-08 1952-05-27 E & J Mfg Co Automatic positive pressure breathing machine
US3202731A (en) * 1960-04-07 1965-08-24 Philips Corp Method of forming free flowing particles, containing a biologically valuable substance
US3300474A (en) * 1964-02-12 1967-01-24 Pharmacia Ab Sucrose ether copolymerizates
US3314803A (en) * 1966-01-26 1967-04-18 Gen Foods Corp Mannitol fixed flavor and method of making same
US3362405A (en) * 1964-04-06 1968-01-09 Hamilton O. Hazel Method and apparatus for admixing gas with solid particles
US3425600A (en) * 1966-08-11 1969-02-04 Abplanalp Robert H Pressurized powder dispensing device
US3554768A (en) * 1967-08-01 1971-01-12 Gen Foods Corp Carbohydrate fixed acetaldehyde
US3666496A (en) * 1969-09-03 1972-05-30 Firmenich Inc Water soluble,powdered,terpene-containing flavors
US3674901A (en) * 1966-07-26 1972-07-04 Nat Patent Dev Corp Surgical sutures
US3937668A (en) * 1970-07-15 1976-02-10 Ilse Zolle Method for incorporating substances into protein microspheres
US3964483A (en) * 1975-01-13 1976-06-22 Syntex Puerto Rico, Inc. Inhalation device
US3971852A (en) * 1973-06-12 1976-07-27 Polak's Frutal Works, Inc. Process of encapsulating an oil and product produced thereby
US4036223A (en) * 1975-01-29 1977-07-19 Obert Jean Claude Apparatus for generating aerosols of solid particles
US4069819A (en) * 1973-04-13 1978-01-24 Societa Farmaceutici S.P.A. Inhalation device
US4098273A (en) * 1975-01-13 1978-07-04 Syntex Puerto Rico, Inc. Inhalation device
US4109019A (en) * 1975-11-18 1978-08-22 William Percy Moore Process for improved ruminant feed supplements
US4153689A (en) * 1975-06-13 1979-05-08 Takeda Chemical Industries, Ltd. Stable insulin preparation for nasal administration
US4206200A (en) * 1977-10-27 1980-06-03 Behringwerke Aktiengesellschaft Stabilizer for polysaccharides
US4211769A (en) * 1977-08-24 1980-07-08 Takeda Chemical Industries, Ltd. Preparations for vaginal administration
US4249526A (en) * 1978-05-03 1981-02-10 Fisons Limited Inhalation device
US4253468A (en) * 1978-08-14 1981-03-03 Steven Lehmbeck Nebulizer attachment
US4338931A (en) * 1979-04-27 1982-07-13 Claudio Cavazza Device for the quick inhalation of drugs in powder form by humans suffering from asthma
US4446862A (en) * 1979-10-30 1984-05-08 Baum Eric A Breath actuated devices for administering powdered medicaments
US4452239A (en) * 1980-03-25 1984-06-05 Hilal Malem Medical nebulizing apparatus
US4503035A (en) * 1978-11-24 1985-03-05 Hoffmann-La Roche Inc. Protein purification process and product
US4533552A (en) * 1982-03-09 1985-08-06 Nippon Shinyaku Co., Ltd. Stabilization of azulene derivatives
US4534343A (en) * 1984-01-27 1985-08-13 Trutek Research, Inc. Metered dose inhaler
US4590206A (en) * 1981-07-24 1986-05-20 Fisons Plc Inhalation pharmaceuticals
US4599311A (en) * 1982-08-13 1986-07-08 Kawasaki Glenn H Glycolytic promotersfor regulated protein expression: protease inhibitor
US4649911A (en) * 1983-09-08 1987-03-17 Baylor College Of Medicine Small particle aerosol generator for treatment of respiratory disease including the lungs
US4659696A (en) * 1982-04-30 1987-04-21 Takeda Chemical Industries, Ltd. Pharmaceutical composition and its nasal or vaginal use
US4677975A (en) * 1984-10-16 1987-07-07 The University Of Auckland Method of dispensing and/or a dispenser
US4719762A (en) * 1985-11-21 1988-01-19 Toshiba Heating Appliances Co., Ltd. Stored ice detecting device in ice making apparatus
US4729754A (en) * 1986-10-15 1988-03-08 Rexnord Inc. Sealed bushing joint for chain
US4806343A (en) * 1986-03-13 1989-02-21 University Of Southwestern Louisiana Cryogenic protectant for proteins
US4807814A (en) * 1985-01-04 1989-02-28 Saint Gobain Vitrage Pneumatic powder ejector
US4811731A (en) * 1985-07-30 1989-03-14 Glaxo Group Limited Devices for administering medicaments to patients
US4820534A (en) * 1984-03-19 1989-04-11 General Foods Corporation Fixation of volatiles in extruded glass substrates
US4819629A (en) * 1986-10-28 1989-04-11 Siemens Aktiengesellschaft Method and apparatus for delivering aerosol to the airways and/or lungs of a patient
US4824938A (en) * 1984-06-06 1989-04-25 Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo Water-soluble dry solid containing proteinaceous bioactive substance
US4823784A (en) * 1982-04-30 1989-04-25 Cadema Medical Products, Inc. Aerosol inhalation apparatus
US4830858A (en) * 1985-02-11 1989-05-16 E. R. Squibb & Sons, Inc. Spray-drying method for preparing liposomes and products produced thereby
US4833125A (en) * 1986-12-05 1989-05-23 The General Hospital Corporation Method of increasing bone mass
US4855157A (en) * 1987-01-29 1989-08-08 Fuji Oil Company, Limited Process for producing fat powder
US4857319A (en) * 1985-01-11 1989-08-15 The Regents Of The University Of California Method for preserving liposomes
US4891319A (en) * 1985-07-09 1990-01-02 Quadrant Bioresources Limited Protection of proteins and the like
US4895719A (en) * 1985-05-22 1990-01-23 Liposome Technology, Inc. Method and apparatus for administering dehydrated liposomes by inhalation
US4897353A (en) * 1986-03-13 1990-01-30 University Of Southwestern Louisiana Cryogenic protection of phosphofructokinase using amino acids and zinc ions
US4907583A (en) * 1986-03-07 1990-03-13 Aktiebolaget Draco Device in powder inhalators
US4919962A (en) * 1988-08-12 1990-04-24 General Foods Corporation Coffee flakes and process
US4927763A (en) * 1984-03-21 1990-05-22 Chr. Hansen's Laboratory, Inc. Stabilization of dried bacteria extended in particulate carriers
US4926852A (en) * 1986-06-23 1990-05-22 The Johns Hopkins University Medication delivery system phase one
US4931361A (en) * 1988-11-18 1990-06-05 California Institute Of Technology Cryoprotective reagents in freeze-drying membranes
US4942544A (en) * 1985-02-19 1990-07-17 Kenneth B. McIntosh Medication clock
US4946828A (en) * 1985-03-12 1990-08-07 Novo Nordisk A/S Novel insulin peptides
US4952402A (en) * 1984-10-30 1990-08-28 Elan Corporation, P.L.C. Controlled release powder and process for its preparation
US4956295A (en) * 1984-05-21 1990-09-11 Chr. Hansen's Laboratory, Inc. Stabilization of dried bacteria extended in particulate carriers
US4984158A (en) * 1988-10-14 1991-01-08 Hillsman Dean Metered dose inhaler biofeedback training and evaluation system
US4995385A (en) * 1989-02-23 1991-02-26 Phidea S.P.A. Inhaler with regular complete emptying of the capsule
US5006343A (en) * 1988-12-29 1991-04-09 Benson Bradley J Pulmonary administration of pharmaceutically active substances
US5011678A (en) * 1989-02-01 1991-04-30 California Biotechnology Inc. Composition and method for administration of pharmaceutically active substances
US5017372A (en) * 1986-04-14 1991-05-21 Medicis Corporation Method of producing antibody-fortified dry whey
US5026566A (en) * 1987-06-29 1991-06-25 Quadrant Bioresources, Limited Dried food containing trehalose and method for preparing same
US5033463A (en) * 1989-10-27 1991-07-23 Miat S.P.A. Multi-dose inhaler for medicaments in powder form
US5042975A (en) * 1986-07-25 1991-08-27 Rutgers, The State University Of New Jersey Iontotherapeutic device and process and iontotherapeutic unit dose
US5081228A (en) * 1988-02-25 1992-01-14 Immunex Corporation Interleukin-1 receptors
US5093316A (en) * 1986-12-24 1992-03-03 John Lezdey Treatment of inflammation
US5098893A (en) * 1989-02-16 1992-03-24 Pafra Limited Storage of materials
US5099833A (en) * 1991-02-19 1992-03-31 Baxter International Inc. High efficiency nebulizer having a flexible reservoir
US5113855A (en) * 1990-02-14 1992-05-19 Newhouse Michael T Powder inhaler
US5124162A (en) * 1991-11-26 1992-06-23 Kraft General Foods, Inc. Spray-dried fixed flavorants in a carbohydrate substrate and process
US5139016A (en) * 1987-08-07 1992-08-18 Sorin Biomedica S.P.A. Process and device for aerosol generation for pulmonary ventilation scintigraphy
US5180812A (en) * 1987-11-25 1993-01-19 Immunex Corporation Soluble human interleukin-1 receptors, compositions and method of use
US5186164A (en) * 1991-03-15 1993-02-16 Puthalath Raghuprasad Mist inhaler
US5200399A (en) * 1990-09-14 1993-04-06 Boyce Thompson Institute For Plant Research, Inc. Method of protecting biological materials from destructive reactions in the dry state
US5204108A (en) * 1987-10-10 1993-04-20 Danbiosyst Uk Ltd. Transmucosal formulations of low molecular weight peptide drugs
US5206200A (en) * 1991-04-22 1993-04-27 W. R. Grace & Co.-Conn. Tin catalysts for hydrolysis of latent amine curing agents
US5225183A (en) * 1988-12-06 1993-07-06 Riker Laboratories, Inc. Medicinal aerosol formulations
US5230884A (en) * 1990-09-11 1993-07-27 University Of Wales College Of Cardiff Aerosol formulations including proteins and peptides solubilized in reverse micelles and process for making the aerosol formulations
US5295479A (en) * 1991-04-15 1994-03-22 Leiras Oy Device intended for measuring a dose of powdered medicament for inhalation
US5302581A (en) * 1989-08-22 1994-04-12 Abbott Laboratories Pulmonary surfactant protein fragments
US5309900A (en) * 1991-03-21 1994-05-10 Paul Ritzau Pari-Werk Gmbh Atomizer particularly for use in devices for inhalation therapy
US5320714A (en) * 1990-02-16 1994-06-14 Byk Gulden Lomberg Chemische Fabrik Gmbh Powder inhalator
US5320094A (en) * 1992-01-10 1994-06-14 The Johns Hopkins University Method of administering insulin
US5331953A (en) * 1989-03-07 1994-07-26 Aktiebolaget Draco Device in connection with an inhaler
US5384133A (en) * 1986-08-11 1995-01-24 Innovata Biomed Limited Pharmaceutical formulations comprising microcapsules
US5482927A (en) * 1991-02-20 1996-01-09 Massachusetts Institute Of Technology Controlled released microparticulate delivery system for proteins
US5506203A (en) * 1993-06-24 1996-04-09 Ab Astra Systemic administration of a therapeutic preparation
US5518998A (en) * 1993-06-24 1996-05-21 Ab Astra Therapeutic preparation for inhalation
US5619984A (en) * 1989-04-28 1997-04-15 Astra Aktiebolag Dry powder inhalation device having a powder-loaded elongate carrier
US5755221A (en) * 1990-09-12 1998-05-26 Bisgaard; Hans Aerosol inhaler with piston dump
US6012454A (en) * 1989-04-28 2000-01-11 Minnesota Mining And Manufacturing Company Dry powder inhalation device
US6019968A (en) * 1995-04-14 2000-02-01 Inhale Therapeutic Systems, Inc. Dispersible antibody compositions and methods for their preparation and use
US6051256A (en) * 1994-03-07 2000-04-18 Inhale Therapeutic Systems Dispersible macromolecule compositions and methods for their preparation and use
US6099517A (en) * 1986-08-19 2000-08-08 Genentech, Inc. Intrapulmonary delivery of polypeptide growth factors and cytokines

Family Cites Families (154)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US979993A (en) 1910-03-24 1910-12-27 Joseph Francis O'byrne Projectile.
US1855591A (en) * 1926-02-03 1932-04-26 Wallerstein Co Inc Invertase preparation and method of making the same
DE1812574U (en) 1960-04-05 1960-06-02 Felix Duerst Concrete mixer.
DE1567290B1 (en) 1964-07-04 1972-06-29 Nippon Shiryo Kogyo Kk A method of processing sucrose solutions
US3620776A (en) 1968-06-28 1971-11-16 Nestle Sa Spray drying process
US3619294A (en) 1968-07-15 1971-11-09 Penick & Ford Ltd Method of combining crystalline sugar with impregnating agents and products produced thereby
US3555717A (en) * 1968-10-24 1971-01-19 Victor Comptometer Corp Artificial fishing lure
DE1812574A1 (en) 1968-12-04 1970-06-11 Riedel De Haen Ag A process for preparing a biocidal granules
US3632357A (en) * 1969-07-29 1972-01-04 Standard Brands Inc Method of producing hard candy
US3655442A (en) * 1969-08-27 1972-04-11 California & Hawaiian Sugar Method of making sugar and sugar products
US3764716A (en) 1970-11-16 1973-10-09 American Potato Co Preparation of dehydrated mashed potatoes
US3745682A (en) 1971-09-28 1973-07-17 Pneu Dart Inc Gun for propelling a drug or medicine projectile
GB1479283A (en) 1973-07-23 1977-07-13 Bespak Industries Ltd Inhaler for powdered medicament
FR2257351B1 (en) 1974-01-11 1978-03-24 Obert Jean Claude
FI56489C (en) 1974-03-18 1980-02-11 Isf Spa Inhalationsapparat Foer by inhalation of pulverformiga aemnen
DE2415159A1 (en) 1974-03-29 1975-10-09 Hoechst Ag spray products Alkalialkansulfonathaltige and process for their manufacture
US3948263A (en) * 1974-08-14 1976-04-06 Minnesota Mining And Manufacturing Company Ballistic animal implant
JPS5318335B2 (en) 1974-09-19 1978-06-14
US4102999A (en) 1975-02-10 1978-07-25 Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai Process for producing stable macromomycin powder
US3991304A (en) 1975-05-19 1976-11-09 Hillsman Dean Respiratory biofeedback and performance evaluation system
GB1527605A (en) 1975-08-20 1978-10-04 Takeda Chemical Industries Ltd Insulin preparation for intranasal administration
US3994421A (en) 1975-09-29 1976-11-30 American Cyanamid Company Unitary therapeutic aerosol dispenser
NL7704348A (en) 1977-04-21 1978-10-24 Philips Nv A process for the preparation of a geattenueer- the transmissible gastroenteritis (TGE) -virusstam for use in live vaccines.
US4180593A (en) 1977-04-29 1979-12-25 Cohan Allan N Process for producing round spherical free flowing blown bead food products of controlled bulk density
US4127502A (en) 1977-06-10 1978-11-28 Eastman Kodak Company Stabilizers for reconstituted, lyophilized samples
NL7712041A (en) 1977-11-01 1979-05-03 Handelmaatschappij Voorheen Be Suction equipment for powdery material - incorporates ejector type suction pump and cyclone type separator
US4244949A (en) * 1978-04-06 1981-01-13 The Population Council, Inc. Manufacture of long term contraceptive implant
US4158544A (en) 1978-07-17 1979-06-19 Beckman Instruments, Inc. Process for preparing a biological composition for use as a reference control in diagnostic analysis
US4588744A (en) * 1978-09-19 1986-05-13 Mchugh John E Method of forming an aqueous solution of 3-3-Bis(p-hydroxyphenyl)-phthalide
GB2037735B (en) 1978-12-21 1983-11-09 Standard Telephones Cables Ltd Glass composition
DE3061384D1 (en) 1979-02-21 1983-01-27 Ici Plc A process for the extraction of poly-3-hydroxy-butyric acid from microbial cells
JPS6034925B2 (en) 1979-07-31 1985-08-12 Teijin Ltd
US4294624A (en) 1980-03-14 1981-10-13 Veltman Preston Leonard Drying co-mingled carbohydrate solution and recycled product by dielectric heating
JPS56138110A (en) * 1980-03-28 1981-10-28 Teijin Ltd Suppository containing citric acid or salt thereof
EP0111216A3 (en) 1980-03-31 1985-01-16 Takeda Chemical Industries, Ltd. Method for enzyme immunoassay and peptide-enzyme conjugate, its lyophilizate, antibody and kit therefor
US4423079A (en) 1980-07-14 1983-12-27 Leo Kline Growth promoting compositions for Lactobacillus sanfrancisco and method of preparation
US4326524A (en) * 1980-09-30 1982-04-27 Minnesota Mining And Manufacturing Company Solid dose ballistic projectile
US4327076A (en) * 1980-11-17 1982-04-27 Life Savers, Inc. Compressed chewable antacid tablet and method for forming same
US4371557A (en) * 1981-01-21 1983-02-01 General Foods Corporation Maintenance of protein quality in foods containing reducing sugars
US4327077A (en) * 1981-05-29 1982-04-27 Life Savers, Inc. Compressed chewable antacid tablet and method for forming same
US4484577A (en) 1981-07-23 1984-11-27 Key Pharmaceuticals, Inc. Drug delivery method and inhalation device therefor
GB2105189B (en) 1981-07-24 1985-03-20 Fisons Plc Inhalation drugs
US5260306A (en) 1981-07-24 1993-11-09 Fisons Plc Inhalation pharmaceuticals
DE3141498C2 (en) 1981-10-20 1991-09-12 Bayer Ag, 5090 Leverkusen, De
NL193099C (en) 1981-10-30 1998-11-03 Novo Industri As Stabilized insulin solution.
US4713249A (en) 1981-11-12 1987-12-15 Schroeder Ulf Crystallized carbohydrate matrix for biologically active substances, a process of preparing said matrix, and the use thereof
EP0113749B1 (en) * 1982-07-09 1988-06-01 Ulf SCHRÖDER A process of preparing a crystallised carbohydrate matrix for biologically active substances
US4457916A (en) 1982-08-31 1984-07-03 Asahi Kasei Kogyo Kabushiki Kaisha Method for stabilizing Tumor Necrosis Factor and a stable aqueous solution or powder containing the same
US4591552A (en) * 1982-09-29 1986-05-27 New York Blood Center, Inc. Detection of hepatitis B surface antigen (or antibody to same) with labeled synthetic peptide
LU85034A1 (en) 1982-10-08 1985-06-19 Glaxo Group Ltd Devices for administering drugs to patients
US4778054A (en) 1982-10-08 1988-10-18 Glaxo Group Limited Pack for administering medicaments to patients
US4559298A (en) 1982-11-23 1985-12-17 American National Red Cross Cryopreservation of biological materials in a non-frozen or vitreous state
ES519619A0 (en) 1983-02-08 1984-03-16 Gandariasbeitia Aguirreche Man continuous process for the production of proteolytic enzymes and aminoliticas from plant microorganisms.
JPS6237016B2 (en) * 1983-03-09 1987-08-10 Teijin Ltd
JPH0541946B2 (en) 1983-08-05 1993-06-25 Wako Pure Chem Ind Ltd
DE3345722C2 (en) 1983-12-17 1991-03-21 Boehringer Ingelheim Kg, 6507 Ingelheim, De
US4758583A (en) 1984-03-19 1988-07-19 The Rockefeller University Method and agents for inhibiting protein aging
US4617272A (en) 1984-04-25 1986-10-14 Economics Laboratory, Inc. Enzyme drying process
US4620847A (en) 1984-06-01 1986-11-04 Vsesojuzny Nauchno-Issledovatelsky Institut Meditsinskikh Polimerov Device for administering powdered substances
JPH0528239B2 (en) 1984-06-05 1993-04-23 Ss Pharmaceutical Co
US4721709A (en) * 1984-07-26 1988-01-26 Pyare Seth Novel pharmaceutical compositions containing hydrophobic practically water-insoluble drugs adsorbed on pharmaceutical excipients as carrier; process for their preparation and the use of said compositions
US4624251A (en) 1984-09-13 1986-11-25 Riker Laboratories, Inc. Apparatus for administering a nebulized substance
DE3445010A1 (en) 1984-12-10 1986-06-19 Boehringer Mannheim Gmbh Control or calibration serum for lipid-diagnostics
FR2575923B1 (en) 1985-01-15 1988-02-05 Jouveinal Sa laxative lactulose-based composition, and process for its manufacturing
JPH0430926B2 (en) 1985-02-25 1992-05-25
GB8508173D0 (en) 1985-03-28 1985-05-01 Standard Telephones Cables Ltd Controlled delivery device
DE3686343T2 (en) 1985-04-04 1993-01-28 Gen Hospital Corp A pharmaceutical preparation for administration for the enrichment of bone mass.
US4847079A (en) 1985-07-29 1989-07-11 Schering Corporation Biologically stable interferon compositions comprising thimerosal
US4680027A (en) 1985-12-12 1987-07-14 Injet Medical Products, Inc. Needleless hypodermic injection device
JPH0529235B2 (en) * 1985-12-16 1993-04-28 Ss Pharmaceutical Co
JPH0710344B2 (en) * 1985-12-26 1995-02-08 株式会社林原生物化学研究所 Anhydrous glycosyl fructosyl - method of dehydrating hydrous material by scan
US4739754A (en) 1986-05-06 1988-04-26 Shaner William T Suction resistant inhalator
US4762857A (en) 1986-05-30 1988-08-09 E. I. Du Pont De Nemours And Company Trehalose as stabilizer and tableting excipient
US4790305A (en) 1986-06-23 1988-12-13 The Johns Hopkins University Medication delivery system
US5049388A (en) 1986-11-06 1991-09-17 Research Development Foundation Small particle aerosol liposome and liposome-drug combinations for medical use
JPH0768149B2 (en) 1986-12-16 1995-07-26 ノボ ノルディスク アクティーゼルスカブ For intranasal administration preparations and their preparation
US4906463A (en) * 1986-12-22 1990-03-06 Cygnus Research Corporation Transdermal drug-delivery composition
US5089181A (en) * 1987-02-24 1992-02-18 Vestar, Inc. Method of dehydrating vesicle preparations for long term storage
FR2611501B1 (en) * 1987-03-04 1991-12-06 Corbiere Jerome New pharmaceutical compositions for buccal was based acetylsalielylate lysine and the process for obtaining
US4855326A (en) 1987-04-20 1989-08-08 Fuisz Pharmaceutical Ltd. Rapidly dissoluble medicinal dosage unit and method of manufacture
JP2656944B2 (en) 1987-04-30 1997-09-24 アメリカ合衆国 Aerosol of proteinaceous therapeutic agent
US4876241A (en) 1987-05-22 1989-10-24 Armour Pharmaceutical Company Stabilization of biological and pharmaceutical products during thermal inactivation of viral and bacterial contaminants
US4790824A (en) 1987-06-19 1988-12-13 Bioject, Inc. Non-invasive hypodermic injection device
US5059587A (en) * 1987-08-03 1991-10-22 Toyo Jozo Company, Ltd. Physiologically active peptide composition for nasal administration
DE3862907D1 (en) 1987-08-17 1991-06-27 Miat Spa An inhaler for administering pulverfoermiger, in capsules pre-dosed drug.
US4968607A (en) 1987-11-25 1990-11-06 Immunex Corporation Interleukin-1 receptors
GB8801338D0 (en) 1988-01-21 1988-02-17 Quadrant Bioresources Ltd Preservation of viruses
DE68915062D1 (en) 1988-06-22 1994-06-09 Chiesi Farma Spa Means for delivering metered quantities aerosol for inhalation.
EP0360340A1 (en) 1988-09-19 1990-03-28 Akzo N.V. Composition for nasal administration containing a peptide
EP0363060B1 (en) 1988-10-04 1994-04-27 The Johns Hopkins University Aerosol inhaler
JPH02104531A (en) 1988-10-14 1990-04-17 Toyo Jozo Co Ltd Physiologically active peptide composition for nasal application
GB8824897D0 (en) 1988-10-24 1988-11-30 Ici Plc Biocatalysts
US5049389A (en) * 1988-12-14 1991-09-17 Liposome Technology, Inc. Novel liposome composition for the treatment of interstitial lung diseases
GB8904370D0 (en) 1989-02-25 1989-04-12 Cosmas Damian Ltd Liquid delivery compositions
CA2020137C (en) 1989-07-07 1995-10-24 Luca Ramella Medicament inhalation device
GB8918879D0 (en) 1989-08-18 1989-09-27 Danbiosyst Uk Pharmaceutical compositions
US5562608A (en) * 1989-08-28 1996-10-08 Biopulmonics, Inc. Apparatus for pulmonary delivery of drugs with simultaneous liquid lavage and ventilation
GB2237510B (en) * 1989-11-04 1993-09-15 Danbiosyst Uk Small particle drug compositions for nasal administration
JPH0662607B2 (en) * 1989-11-28 1994-08-17 シンテックス(ユー・エス・エイ) インコーポレイテッド New tricyclic compounds
US5376386A (en) 1990-01-24 1994-12-27 British Technology Group Limited Aerosol carriers
GB9001635D0 (en) 1990-01-24 1990-03-21 Ganderton David Aerosol carriers
US5621094A (en) * 1990-05-14 1997-04-15 Quadrant Holdings Cambridge Limited Method of preserving agarose gel structure during dehydration by adding a non-reducing glycoside of a straight-chain sugar alcohol
DE69105106D1 (en) * 1990-07-11 1994-12-15 Eurand Int In the water quickly suspendable pharmaceutical composition.
US5207217A (en) 1990-07-16 1993-05-04 Promo Pack Sa Multiple single-dose inhaler for medicaments in powder form
US5037912A (en) 1990-07-26 1991-08-06 The Goodyear Tire & Rubber Company Polymerization of 1,3-butadiene to trans-1,4-polybutadiene with organolithium and alkali metal alkoxide
FR2667509B1 (en) 1990-10-04 1995-08-25 Valois Powder inhaler, microdoses of conditioner powder form adapted bands for use in an inhaler powder, and method of making such strips.
US5149543A (en) 1990-10-05 1992-09-22 Massachusetts Institute Of Technology Ionically cross-linked polymeric microcapsules
US5217004A (en) 1990-12-13 1993-06-08 Tenax Corporation Inhalation actuated dispensing apparatus
DE69230220T2 (en) * 1991-02-08 2000-06-21 Cambridge Neuroscience Res guanidine and substituted derivatives thereof, as modulators of neurotransmitter release and new method for identification of inhibitors of neurotransmitter-release
US5182097A (en) * 1991-02-14 1993-01-26 Virginia Commonwealth University Formulations for delivery of drugs by metered dose inhalers with reduced or no chlorofluorocarbon content
US5404871A (en) * 1991-03-05 1995-04-11 Aradigm Delivery of aerosol medications for inspiration
CA2082951C (en) * 1991-03-15 1999-12-21 Robert M. Platz Pulmonary administration of granulocyte colony stimulating factor
GB9106648D0 (en) 1991-03-28 1991-05-15 Rhone Poulenc Rorer Ltd New inhaler
EP0906951A3 (en) 1991-06-26 1999-05-19 Inhale Therapeutic Systems Storage of materials
US6673335B1 (en) * 1992-07-08 2004-01-06 Nektar Therapeutics Compositions and methods for the pulmonary delivery of aerosolized medicaments
DK0592540T3 (en) 1991-07-02 2000-06-26 Inhale Inc Method and device for delivering aerosolized medications
US6681767B1 (en) * 1991-07-02 2004-01-27 Nektar Therapeutics Method and device for delivering aerosolized medicaments
US6582728B1 (en) * 1992-07-08 2003-06-24 Inhale Therapeutic Systems, Inc. Spray drying of macromolecules to produce inhaleable dry powders
US6509006B1 (en) * 1992-07-08 2003-01-21 Inhale Therapeutic Systems, Inc. Devices compositions and methods for the pulmonary delivery of aerosolized medicaments
GB9116610D0 (en) 1991-08-01 1991-09-18 Danbiosyst Uk Preparation of microparticles
US5161524A (en) 1991-08-02 1992-11-10 Glaxo Inc. Dosage inhalator with air flow velocity regulating means
US5253468A (en) 1991-09-03 1993-10-19 Robert Raymond Crop chopping machine
US6013638A (en) * 1991-10-02 2000-01-11 The United States Of America As Represented By The Department Of Health And Human Services Adenovirus comprising deletions on the E1A, E1B and E3 regions for transfer of genes to the lung
US5387431A (en) * 1991-10-25 1995-02-07 Fuisz Technologies Ltd. Saccharide-based matrix
CA2125148C (en) 1991-12-05 1999-05-11 Siva N. Raman A carbohydrate glass matrix for the sustained release of a therapeutic agent
CA2127877A1 (en) * 1992-01-21 1993-07-22 Robert M. Platz Improved process for preparing micronized polypeptide drugs
CA2115444C (en) * 1992-06-12 2000-10-03 Yuji Makino Preparation for intratracheobronchial administration
ES2177544T3 (en) * 1992-06-12 2002-12-16 Teijin Ltd ultrafinno powder inhaler and method for its preparation.
US5376359A (en) 1992-07-07 1994-12-27 Glaxo, Inc. Method of stabilizing aerosol formulations
DE69332105T2 (en) * 1992-09-29 2003-03-06 Inhale Therapeutic Systems San Pulmonary delivery of active fragments of parathyroid hormone
US5380473A (en) * 1992-10-23 1995-01-10 Fuisz Technologies Ltd. Process for making shearform matrix
US5364838A (en) 1993-01-29 1994-11-15 Miris Medical Corporation Method of administration of insulin
US5558085A (en) 1993-01-29 1996-09-24 Aradigm Corporation Intrapulmonary delivery of peptide drugs
US5672581A (en) 1993-01-29 1997-09-30 Aradigm Corporation Method of administration of insulin
JPH08509465A (en) 1993-01-29 1996-10-08 マイリス メディカル コーポレーション Pulmonary delivery of hormone
US5354934A (en) 1993-02-04 1994-10-11 Amgen Inc. Pulmonary administration of erythropoietin
GB9314886D0 (en) * 1993-07-19 1993-09-01 Zeneca Ltd Production of a biological control agent
EP0655237A1 (en) * 1993-11-27 1995-05-31 Hoechst Aktiengesellschaft Medicinal aerosol formulation
EP1462096B1 (en) * 1994-03-07 2008-12-10 Nektar Therapeutics Methods and compositions for pulmonary delivery of insulin
GB2288732B (en) * 1994-04-13 1998-04-29 Quadrant Holdings Cambridge Pharmaceutical compositions
DK0968722T3 (en) * 1994-05-10 2007-09-24 Wyeth Corp Modified Improved BRSV vaccine
CA2190502A1 (en) * 1994-05-18 1995-11-23 Robert M. Platz Methods and compositions for the dry powder formulation of interferons
US20030035778A1 (en) * 1997-07-14 2003-02-20 Robert Platz Methods and compositions for the dry powder formulation of interferon
US5591453A (en) * 1994-07-27 1997-01-07 The Trustees Of The University Of Pennsylvania Incorporation of biologically active molecules into bioactive glasses
US5512547A (en) * 1994-10-13 1996-04-30 Wisconsin Alumni Research Foundation Pharmaceutical composition of botulinum neurotoxin and method of preparation
US6290991B1 (en) * 1994-12-02 2001-09-18 Quandrant Holdings Cambridge Limited Solid dose delivery vehicle and methods of making same
US5705482A (en) * 1995-01-13 1998-01-06 Novo Nordisk A/S Pharmaceutical formulation
US6165463A (en) * 1997-10-16 2000-12-26 Inhale Therapeutic Systems, Inc. Dispersible antibody compositions and methods for their preparation and use
DE69634246D1 (en) * 1995-04-14 2005-03-03 Nektar Therapeutics San Carlos A powdered pharmaceutical formulations with improved dispersibility
US6190859B1 (en) * 1995-04-17 2001-02-20 The United States Of America As Represented By The Secretary Of The Army Method and kit for detection of dengue virus
GB9508691D0 (en) * 1995-04-28 1995-06-14 Pafra Ltd Stable compositions
US5611344A (en) * 1996-03-05 1997-03-18 Acusphere, Inc. Microencapsulated fluorinated gases for use as imaging agents
US6001336A (en) * 1996-12-31 1999-12-14 Inhale Therapeutic Systems Processes for spray drying aqueous suspensions of hydrophobic drugs and compositions thereof
ES2254164T3 (en) * 1999-10-29 2006-06-16 Nektar Therapeutics Dry powder compositions with improved dispersibility.

Patent Citations (104)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US558085A (en) * 1896-04-14 And william c
US2598525A (en) * 1950-04-08 1952-05-27 E & J Mfg Co Automatic positive pressure breathing machine
US3202731A (en) * 1960-04-07 1965-08-24 Philips Corp Method of forming free flowing particles, containing a biologically valuable substance
US3300474A (en) * 1964-02-12 1967-01-24 Pharmacia Ab Sucrose ether copolymerizates
US3362405A (en) * 1964-04-06 1968-01-09 Hamilton O. Hazel Method and apparatus for admixing gas with solid particles
US3314803A (en) * 1966-01-26 1967-04-18 Gen Foods Corp Mannitol fixed flavor and method of making same
US3674901A (en) * 1966-07-26 1972-07-04 Nat Patent Dev Corp Surgical sutures
US3425600A (en) * 1966-08-11 1969-02-04 Abplanalp Robert H Pressurized powder dispensing device
US3554768A (en) * 1967-08-01 1971-01-12 Gen Foods Corp Carbohydrate fixed acetaldehyde
US3666496A (en) * 1969-09-03 1972-05-30 Firmenich Inc Water soluble,powdered,terpene-containing flavors
US3937668A (en) * 1970-07-15 1976-02-10 Ilse Zolle Method for incorporating substances into protein microspheres
US4069819A (en) * 1973-04-13 1978-01-24 Societa Farmaceutici S.P.A. Inhalation device
US3971852A (en) * 1973-06-12 1976-07-27 Polak's Frutal Works, Inc. Process of encapsulating an oil and product produced thereby
US3964483A (en) * 1975-01-13 1976-06-22 Syntex Puerto Rico, Inc. Inhalation device
US4098273A (en) * 1975-01-13 1978-07-04 Syntex Puerto Rico, Inc. Inhalation device
US4036223A (en) * 1975-01-29 1977-07-19 Obert Jean Claude Apparatus for generating aerosols of solid particles
US4153689A (en) * 1975-06-13 1979-05-08 Takeda Chemical Industries, Ltd. Stable insulin preparation for nasal administration
US4109019A (en) * 1975-11-18 1978-08-22 William Percy Moore Process for improved ruminant feed supplements
US4211769A (en) * 1977-08-24 1980-07-08 Takeda Chemical Industries, Ltd. Preparations for vaginal administration
US4206200A (en) * 1977-10-27 1980-06-03 Behringwerke Aktiengesellschaft Stabilizer for polysaccharides
US4249526A (en) * 1978-05-03 1981-02-10 Fisons Limited Inhalation device
US4253468A (en) * 1978-08-14 1981-03-03 Steven Lehmbeck Nebulizer attachment
US4503035A (en) * 1978-11-24 1985-03-05 Hoffmann-La Roche Inc. Protein purification process and product
US4503035B1 (en) * 1978-11-24 1996-03-19 Hoffmann La Roche Protein purification process and product
US4338931A (en) * 1979-04-27 1982-07-13 Claudio Cavazza Device for the quick inhalation of drugs in powder form by humans suffering from asthma
US4446862A (en) * 1979-10-30 1984-05-08 Baum Eric A Breath actuated devices for administering powdered medicaments
US4452239A (en) * 1980-03-25 1984-06-05 Hilal Malem Medical nebulizing apparatus
US4590206A (en) * 1981-07-24 1986-05-20 Fisons Plc Inhalation pharmaceuticals
US4533552A (en) * 1982-03-09 1985-08-06 Nippon Shinyaku Co., Ltd. Stabilization of azulene derivatives
US4659696A (en) * 1982-04-30 1987-04-21 Takeda Chemical Industries, Ltd. Pharmaceutical composition and its nasal or vaginal use
US4823784A (en) * 1982-04-30 1989-04-25 Cadema Medical Products, Inc. Aerosol inhalation apparatus
US4823784B1 (en) * 1982-04-30 1991-11-26 Cadema Medical Products Inc
US4599311A (en) * 1982-08-13 1986-07-08 Kawasaki Glenn H Glycolytic promotersfor regulated protein expression: protease inhibitor
US4649911A (en) * 1983-09-08 1987-03-17 Baylor College Of Medicine Small particle aerosol generator for treatment of respiratory disease including the lungs
US4534343A (en) * 1984-01-27 1985-08-13 Trutek Research, Inc. Metered dose inhaler
US4820534A (en) * 1984-03-19 1989-04-11 General Foods Corporation Fixation of volatiles in extruded glass substrates
US4927763A (en) * 1984-03-21 1990-05-22 Chr. Hansen's Laboratory, Inc. Stabilization of dried bacteria extended in particulate carriers
US4956295A (en) * 1984-05-21 1990-09-11 Chr. Hansen's Laboratory, Inc. Stabilization of dried bacteria extended in particulate carriers
US4824938A (en) * 1984-06-06 1989-04-25 Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo Water-soluble dry solid containing proteinaceous bioactive substance
US4677975A (en) * 1984-10-16 1987-07-07 The University Of Auckland Method of dispensing and/or a dispenser
US4952402A (en) * 1984-10-30 1990-08-28 Elan Corporation, P.L.C. Controlled release powder and process for its preparation
US4807814A (en) * 1985-01-04 1989-02-28 Saint Gobain Vitrage Pneumatic powder ejector
US4857319A (en) * 1985-01-11 1989-08-15 The Regents Of The University Of California Method for preserving liposomes
US4830858A (en) * 1985-02-11 1989-05-16 E. R. Squibb & Sons, Inc. Spray-drying method for preparing liposomes and products produced thereby
US4942544A (en) * 1985-02-19 1990-07-17 Kenneth B. McIntosh Medication clock
US4946828A (en) * 1985-03-12 1990-08-07 Novo Nordisk A/S Novel insulin peptides
US4895719A (en) * 1985-05-22 1990-01-23 Liposome Technology, Inc. Method and apparatus for administering dehydrated liposomes by inhalation
US4891319A (en) * 1985-07-09 1990-01-02 Quadrant Bioresources Limited Protection of proteins and the like
US4811731A (en) * 1985-07-30 1989-03-14 Glaxo Group Limited Devices for administering medicaments to patients
US5035237A (en) * 1985-07-30 1991-07-30 Newell Robert E Devices for administering medicaments to patients
US4719762A (en) * 1985-11-21 1988-01-19 Toshiba Heating Appliances Co., Ltd. Stored ice detecting device in ice making apparatus
US4907583A (en) * 1986-03-07 1990-03-13 Aktiebolaget Draco Device in powder inhalators
US4897353A (en) * 1986-03-13 1990-01-30 University Of Southwestern Louisiana Cryogenic protection of phosphofructokinase using amino acids and zinc ions
US4806343A (en) * 1986-03-13 1989-02-21 University Of Southwestern Louisiana Cryogenic protectant for proteins
US5017372A (en) * 1986-04-14 1991-05-21 Medicis Corporation Method of producing antibody-fortified dry whey
US4926852B1 (en) * 1986-06-23 1995-05-23 Univ Johns Hopkins Medication delivery system phase one
US4926852A (en) * 1986-06-23 1990-05-22 The Johns Hopkins University Medication delivery system phase one
US5042975A (en) * 1986-07-25 1991-08-27 Rutgers, The State University Of New Jersey Iontotherapeutic device and process and iontotherapeutic unit dose
US5384133A (en) * 1986-08-11 1995-01-24 Innovata Biomed Limited Pharmaceutical formulations comprising microcapsules
US6099517A (en) * 1986-08-19 2000-08-08 Genentech, Inc. Intrapulmonary delivery of polypeptide growth factors and cytokines
US6402733B1 (en) * 1986-08-19 2002-06-11 Genentech, Inc. Intrapulmonary delivery of polypeptide growth factors and cytokines
US4729754A (en) * 1986-10-15 1988-03-08 Rexnord Inc. Sealed bushing joint for chain
US4819629A (en) * 1986-10-28 1989-04-11 Siemens Aktiengesellschaft Method and apparatus for delivering aerosol to the airways and/or lungs of a patient
US4833125A (en) * 1986-12-05 1989-05-23 The General Hospital Corporation Method of increasing bone mass
US5093316A (en) * 1986-12-24 1992-03-03 John Lezdey Treatment of inflammation
US4855157A (en) * 1987-01-29 1989-08-08 Fuji Oil Company, Limited Process for producing fat powder
US5026566A (en) * 1987-06-29 1991-06-25 Quadrant Bioresources, Limited Dried food containing trehalose and method for preparing same
US5139016A (en) * 1987-08-07 1992-08-18 Sorin Biomedica S.P.A. Process and device for aerosol generation for pulmonary ventilation scintigraphy
US5204108A (en) * 1987-10-10 1993-04-20 Danbiosyst Uk Ltd. Transmucosal formulations of low molecular weight peptide drugs
US5180812A (en) * 1987-11-25 1993-01-19 Immunex Corporation Soluble human interleukin-1 receptors, compositions and method of use
US5081228A (en) * 1988-02-25 1992-01-14 Immunex Corporation Interleukin-1 receptors
US4919962A (en) * 1988-08-12 1990-04-24 General Foods Corporation Coffee flakes and process
US4984158A (en) * 1988-10-14 1991-01-08 Hillsman Dean Metered dose inhaler biofeedback training and evaluation system
US4931361A (en) * 1988-11-18 1990-06-05 California Institute Of Technology Cryoprotective reagents in freeze-drying membranes
US5225183A (en) * 1988-12-06 1993-07-06 Riker Laboratories, Inc. Medicinal aerosol formulations
US5006343A (en) * 1988-12-29 1991-04-09 Benson Bradley J Pulmonary administration of pharmaceutically active substances
US5011678A (en) * 1989-02-01 1991-04-30 California Biotechnology Inc. Composition and method for administration of pharmaceutically active substances
US5098893A (en) * 1989-02-16 1992-03-24 Pafra Limited Storage of materials
US4995385A (en) * 1989-02-23 1991-02-26 Phidea S.P.A. Inhaler with regular complete emptying of the capsule
US5331953A (en) * 1989-03-07 1994-07-26 Aktiebolaget Draco Device in connection with an inhaler
US6012454A (en) * 1989-04-28 2000-01-11 Minnesota Mining And Manufacturing Company Dry powder inhalation device
US5619984A (en) * 1989-04-28 1997-04-15 Astra Aktiebolag Dry powder inhalation device having a powder-loaded elongate carrier
US5302581A (en) * 1989-08-22 1994-04-12 Abbott Laboratories Pulmonary surfactant protein fragments
US5033463A (en) * 1989-10-27 1991-07-23 Miat S.P.A. Multi-dose inhaler for medicaments in powder form
US5113855A (en) * 1990-02-14 1992-05-19 Newhouse Michael T Powder inhaler
US5320714A (en) * 1990-02-16 1994-06-14 Byk Gulden Lomberg Chemische Fabrik Gmbh Powder inhalator
US5230884A (en) * 1990-09-11 1993-07-27 University Of Wales College Of Cardiff Aerosol formulations including proteins and peptides solubilized in reverse micelles and process for making the aerosol formulations
US5755221A (en) * 1990-09-12 1998-05-26 Bisgaard; Hans Aerosol inhaler with piston dump
US5290765A (en) * 1990-09-14 1994-03-01 Boyce Thompson Institute For Plant Research, Inc. Method of protecting biological materials from destructive reactions in the dry state
US5200399A (en) * 1990-09-14 1993-04-06 Boyce Thompson Institute For Plant Research, Inc. Method of protecting biological materials from destructive reactions in the dry state
US5099833A (en) * 1991-02-19 1992-03-31 Baxter International Inc. High efficiency nebulizer having a flexible reservoir
US5482927A (en) * 1991-02-20 1996-01-09 Massachusetts Institute Of Technology Controlled released microparticulate delivery system for proteins
US5186164A (en) * 1991-03-15 1993-02-16 Puthalath Raghuprasad Mist inhaler
US5309900A (en) * 1991-03-21 1994-05-10 Paul Ritzau Pari-Werk Gmbh Atomizer particularly for use in devices for inhalation therapy
US5295479A (en) * 1991-04-15 1994-03-22 Leiras Oy Device intended for measuring a dose of powdered medicament for inhalation
US5206200A (en) * 1991-04-22 1993-04-27 W. R. Grace & Co.-Conn. Tin catalysts for hydrolysis of latent amine curing agents
US5124162A (en) * 1991-11-26 1992-06-23 Kraft General Foods, Inc. Spray-dried fixed flavorants in a carbohydrate substrate and process
US5320094A (en) * 1992-01-10 1994-06-14 The Johns Hopkins University Method of administering insulin
US5518998A (en) * 1993-06-24 1996-05-21 Ab Astra Therapeutic preparation for inhalation
US5506203C1 (en) * 1993-06-24 2001-02-06 Astra Ab Systemic administration of a therapeutic preparation
US5518998C1 (en) * 1993-06-24 2001-02-13 Astra Ab Therapeutic preparation for inhalation
US5506203A (en) * 1993-06-24 1996-04-09 Ab Astra Systemic administration of a therapeutic preparation
US6051256A (en) * 1994-03-07 2000-04-18 Inhale Therapeutic Systems Dispersible macromolecule compositions and methods for their preparation and use
US6019968A (en) * 1995-04-14 2000-02-01 Inhale Therapeutic Systems, Inc. Dispersible antibody compositions and methods for their preparation and use

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050276846A1 (en) * 1994-12-02 2005-12-15 Roser Bruce J Solid dose delivery vehicle and methods of making same
US7744925B2 (en) 1994-12-02 2010-06-29 Quadrant Drug Delivery Limited Solid dose delivery vehicle and methods of making same
US7780991B2 (en) 1994-12-02 2010-08-24 Quadrant Drug Delivery Limited Solid dose delivery vehicle and methods of making same
US7785631B2 (en) 1994-12-02 2010-08-31 Quadrant Drug Delivery Limited Solid dose delivery vehicle and methods of making same
US8246934B2 (en) 1997-09-29 2012-08-21 Novartis Ag Respiratory dispersion for metered dose inhalers comprising perforated microstructures
US8168223B1 (en) 1997-09-29 2012-05-01 Novartis Pharma Ag Engineered particles and methods of use
US9554993B2 (en) 1997-09-29 2017-01-31 Novartis Ag Pulmonary delivery particles comprising an active agent
US8404217B2 (en) 2000-05-10 2013-03-26 Novartis Ag Formulation for pulmonary administration of antifungal agents, and associated methods of manufacture and use
US8709484B2 (en) 2000-05-10 2014-04-29 Novartis Ag Phospholipid-based powders for drug delivery
US8877162B2 (en) 2000-05-10 2014-11-04 Novartis Ag Stable metal ion-lipid powdered pharmaceutical compositions for drug delivery
US9439862B2 (en) 2000-05-10 2016-09-13 Novartis Ag Phospholipid-based powders for drug delivery
US8715623B2 (en) 2001-12-19 2014-05-06 Novartis Ag Pulmonary delivery of aminoglycoside
US9421166B2 (en) 2001-12-19 2016-08-23 Novartis Ag Pulmonary delivery of aminoglycoside
EP2060268A1 (en) * 2007-11-15 2009-05-20 Novo Nordisk A/S Pharmaceutical compositions for pulmonary or nasal delivery of peptides

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