Búsqueda Imágenes Maps Play YouTube Noticias Gmail Drive Más »
Iniciar sesión
Usuarios de lectores de pantalla: deben hacer clic en este enlace para utilizar el modo de accesibilidad. Este modo tiene las mismas funciones esenciales pero funciona mejor con el lector.


  1. Búsqueda avanzada de patentes
Número de publicaciónUS20020192164 A1
Tipo de publicaciónSolicitud
Número de solicitudUS 10/141,044
Fecha de publicación19 Dic 2002
Fecha de presentación7 May 2002
Fecha de prioridad7 Mar 1994
También publicado comoCA2183577A1, CA2183577C, CN1098679C, CN1152867A, DE69532884D1, DE69532884T2, DE69535897D1, EP0748213A1, EP0748213A4, EP0748213B1, EP1462096A1, EP1462096B1, EP2036541A1, US5997848, US6685967, US6737045, US7521069, US20030053959, US20040096400, US20040096401, WO1995024183A1
Número de publicación10141044, 141044, US 2002/0192164 A1, US 2002/192164 A1, US 20020192164 A1, US 20020192164A1, US 2002192164 A1, US 2002192164A1, US-A1-20020192164, US-A1-2002192164, US2002/0192164A1, US2002/192164A1, US20020192164 A1, US20020192164A1, US2002192164 A1, US2002192164A1
InventoresJohn Patton, Linda Foster, Robert Platz
Cesionario originalPatton John S., Foster Linda S., Platz Robert M.
Exportar citaBiBTeX, EndNote, RefMan
Enlaces externos: USPTO, Cesión de USPTO, Espacenet
Methods and compositions for the pulmonary delivery insulin
US 20020192164 A1
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.
Previous page
Next page
What is claimed is:
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. A method as in claim 1, wherein the insulin is substantially free from penetration enhancers.
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. A method as in claim 3, wherein the powder carrier comprises a carbohydrate, organic salt, amino acid, peptide, or protein.
5. A method as in claim 1, wherein the insulin dry powder comprises particles having an average size below 10 μm.
6. A method as in claim 1, wherein the dry powder comprises individual particles including both insulin and a carrier material.
7. A method a in claim 6, wherein the insulin is present in the individual particles at from 5% to 99% by weight.
8. An improved method for the respiratory delivery of insulin, wherein the improvement comprises delivering the insulin as a dry powder.
9. An improved method as in claim 8, wherein the insulin is substantially free from penetration enhancers.
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. An improved method as in claim 10, wherein the powder carrier comprises a carbohydrate, organic salt, amino acid, peptide, or protein.
12. An improved method as in claim 8, wherein the insulin dry powder comprises particles having an average size below 10 μm.
13. An improved method as in claim 8, wherein the dry powder comprises individual particles including both insulin and a carrier material.
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. 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. 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. 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. A method as in claim 17, wherein the carbohydrate is selected from the group consisting of mannitol, raffinose, lactose, malto dextrin and trehalose.
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. 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. An insulin composition as in claim 20, wherein the composition is substantially free from penetration enhancers.
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. 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. An insulin composition produced by the method of claim 15.
25. An insulin composition consisting essentially of dry powder insulin having an average particle size below 10 μm.
  • [0001]
    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.
  • [0002]
    1. Field of the Invention
  • [0003]
    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.
  • [0004]
    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.
  • [0005]
    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.
  • [0006]
    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.
  • [0007]
    A variety of such alternative insulin administration roots have been proposed, including intranasal, intrarectal, and intravaginal.
  • [0008]
    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 cases1 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.
  • [0009]
    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.
  • [0010]
    2. Description of the Background Art
  • [0011]
    The respiratory delivery of aerosolized aqueous insulin solutions is described in a number of references, beginning with Gansslen (1925) 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.
  • [0012]
    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.
  • [0013]
    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.
  • [0014]
    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.
  • [0015]
    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.
  • [0016]
    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.
  • [0017]
    [0017]FIG. 1 is a schematic illustration of a system for aerosolizing a dose of insulin according to the method of the present invention.
  • [0018]
    [0018]FIG. 2 is a schematic illustration of a patient inhaling an aerosolized dose of insulin from the system of FIG. 1.
  • [0019]
    [0019]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.
  • [0020]
    [0020]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.
  • [0021]
    [0021]FIG. 5A is a graph illustrating the mean insulin concentration over time for subcutaneous injection (∘) and for inhalation of three puffs () in humans.
  • [0022]
    [0022]FIG. 5B shows the mean glucose concentration corresponding to the insulin concentrations of FIG. 5A.
  • [0023]
    [0023]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.
  • [0024]
    [0024]FIG. 6B is a graph illustrating the serum glucose levels corresponding to the insulin levels in FIG. 6A.
  • [0025]
    [0025]FIGS. 7A and 7B provide a comparison of the intersubject variability of serum insulin (7A) and glucose levels (7B) for subcutaneous administration (∘) and aerosol administration ().
  • [0026]
    [0026]FIGS. 8A, 8B, and SC show rpHPLC chromatograms of a human insulin.
  • [0027]
    [0027]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.
  • [0028]
    [0028]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.
  • [0029]
    [0029]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.
  • [0030]
    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.
  • [0031]
    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., 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.
  • [0032]
    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.
  • [0033]
    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.
  • [0034]
    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.
  • [0035]
    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.
  • [0036]
    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.
  • [0037]
    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.
  • [0038]
    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.
  • [0039]
    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.
  • [0040]
    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.
  • [0041]
    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 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.
  • [0042]
    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.
  • [0043]
    The following examples are offered by way of illustration, not by way of limitation.
  • Experimental
  • [0044]
    Materials and Methods
  • [0045]
  • [0046]
    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.).
  • [0047]
    Powder Production
  • [0048]
    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).
  • [0049]
    Powder Analyses
  • [0050]
    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.
  • [0051]
    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.
  • [0052]
    Rat Aerosol Exposures
  • [0053]
    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 H2O) 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.
  • [0054]
    Rat Aerosol Chamber Calibration
  • [0055]
    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.
  • [0056]
    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.
  • [0057]
    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.
  • [0058]
    Primate Exposure System
  • [0059]
    Young, wild-captured, male cynomolgus monkeys strain 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).
  • [0060]
    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.
  • [0061]
    Human Trials
  • [0062]
    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.
  • [0063]
    Serum Assays
  • [0064]
    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%.
  • [0065]
    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.
  • [0066]
    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.
  • [0067]
    Results of Insulin Absorption in Rats
  • [0068]
    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.
  • [0069]
    The following three insulin powder formulations were tested in rats as aerosols in the In-Tox 48 port, exposure chamber.
  • [0070]
    1. 87.9% insulin; 11.5% sodium citrate; 0.6% citric acid.
  • [0071]
    2. 20% insulin; 66% mannitol: 12.4% sodium citrate: 0.6% citric acid.
  • [0072]
    3. 20% insulin; 66% raffinose; 12.4% sodium citrate: 0.6% citric acid.
  • [0073]
    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.
    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
  • [0074]
    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 tmax, 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 
    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%***
  • [0076]
    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.
  • [0077]
    Primate Results
  • [0078]
    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%.
    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
  • [0079]
    Human Results
  • [0080]
    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.
    TABLE 5
    Serum Insulin and Glucose Results in Humans
    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%
    7-24 76.0 U 31.9 U 6.1-28.5 20 min  22.8%
    (3 puffs)
    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%
    7-24 91.8-67.6 24.2 60 min 84.3% 27.4%
    (3 puffs)
  • [0081]
    The results of the human trials are further presented in FIGS. 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.
  • [0082]
    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.
  • [0083]
    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.
Citas de patentes
Patente citada Fecha de presentación Fecha de publicación Solicitante Título
US558085 *17 Jul 188914 Abr 1896 And william c
US2598525 *8 Abr 195027 May 1952E & J Mfg CoAutomatic positive pressure breathing machine
US3202731 *3 Abr 196124 Ago 1965Philips CorpMethod of forming free flowing particles, containing a biologically valuable substance
US3300474 *12 Feb 196424 Ene 1967Pharmacia AbSucrose ether copolymerizates
US3314803 *26 Ene 196618 Abr 1967Gen Foods CorpMannitol fixed flavor and method of making same
US3362405 *6 Abr 19649 Ene 1968Hamilton O. HazelMethod and apparatus for admixing gas with solid particles
US3425600 *11 Ago 19664 Feb 1969Abplanalp Robert HPressurized powder dispensing device
US3554768 *1 Ago 196712 Ene 1971Gen Foods CorpCarbohydrate fixed acetaldehyde
US3666496 *3 Sep 196930 May 1972Firmenich IncWater soluble,powdered,terpene-containing flavors
US3674901 *27 Abr 19704 Jul 1972Nat Patent Dev CorpSurgical sutures
US3937668 *6 Nov 197210 Feb 1976Ilse ZolleMethod for incorporating substances into protein microspheres
US3964483 *13 Ene 197522 Jun 1976Syntex Puerto Rico, Inc.Inhalation device
US3971852 *12 Jun 197327 Jul 1976Polak's Frutal Works, Inc.Process of encapsulating an oil and product produced thereby
US4036223 *20 Ene 197619 Jul 1977Obert Jean ClaudeApparatus for generating aerosols of solid particles
US4069819 *5 Ago 197624 Ene 1978Societa Farmaceutici S.P.A.Inhalation device
US4098273 *5 Nov 19764 Jul 1978Syntex Puerto Rico, Inc.Inhalation device
US4109019 *8 Feb 197722 Ago 1978William Percy MooreProcess for improved ruminant feed supplements
US4153689 *15 Ago 19778 May 1979Takeda Chemical Industries, Ltd.Stable insulin preparation for nasal administration
US4206200 *25 Oct 19783 Jun 1980Behringwerke AktiengesellschaftStabilizer for polysaccharides
US4211769 *17 Ago 19788 Jul 1980Takeda Chemical Industries, Ltd.Preparations for vaginal administration
US4249526 *12 Abr 197910 Feb 1981Fisons LimitedInhalation device
US4253468 *14 Ago 19783 Mar 1981Steven LehmbeckNebulizer attachment
US4338931 *28 Abr 198013 Jul 1982Claudio CavazzaDevice for the quick inhalation of drugs in powder form by humans suffering from asthma
US4446862 *30 Oct 19808 May 1984Baum Eric ABreath actuated devices for administering powdered medicaments
US4452239 *24 Mar 19815 Jun 1984Hilal MalemMedical nebulizing apparatus
US4503035 *14 Feb 19835 Mar 1985Hoffmann-La Roche Inc.Protein purification process and product
US4533552 *11 May 19836 Ago 1985Nippon Shinyaku Co., Ltd.Stabilization of azulene derivatives
US4534343 *27 Ene 198413 Ago 1985Trutek Research, Inc.Metered dose inhaler
US4590206 *3 May 198420 May 1986Fisons PlcInhalation pharmaceuticals
US4599311 *13 Ago 19828 Jul 1986Kawasaki Glenn HGlycolytic promotersfor regulated protein expression: protease inhibitor
US4649911 *7 Mar 198617 Mar 1987Baylor College Of MedicineSmall particle aerosol generator for treatment of respiratory disease including the lungs
US4659696 *22 Abr 198321 Abr 1987Takeda Chemical Industries, Ltd.Pharmaceutical composition and its nasal or vaginal use
US4677975 *16 Oct 19857 Jul 1987The University Of AucklandMethod of dispensing and/or a dispenser
US4719762 *18 Nov 198619 Ene 1988Toshiba Heating Appliances Co., Ltd.Stored ice detecting device in ice making apparatus
US4729754 *15 Oct 19868 Mar 1988Rexnord Inc.Sealed bushing joint for chain
US4806343 *13 Mar 198621 Feb 1989University Of Southwestern LouisianaCryogenic protectant for proteins
US4807814 *3 Ene 198628 Feb 1989Saint Gobain VitragePneumatic powder ejector
US4811731 *29 Jul 198614 Mar 1989Glaxo Group LimitedDevices for administering medicaments to patients
US4819629 *20 Oct 198711 Abr 1989Siemens AktiengesellschaftMethod and apparatus for delivering aerosol to the airways and/or lungs of a patient
US4820534 *10 Jun 198811 Abr 1989General Foods CorporationFixation of volatiles in extruded glass substrates
US4823784 *2 Nov 198725 Abr 1989Cadema Medical Products, Inc.Aerosol inhalation apparatus
US4824938 *31 Ago 198725 Abr 1989Kabushiki Kaisha Hayashibara Seibutsu Kagaku KenkyujoWater-soluble dry solid containing proteinaceous bioactive substance
US4830858 *11 Feb 198516 May 1989E. R. Squibb & Sons, Inc.Spray-drying method for preparing liposomes and products produced thereby
US4833125 *21 May 198723 May 1989The General Hospital CorporationMethod of increasing bone mass
US4855157 *25 Ene 19888 Ago 1989Fuji Oil Company, LimitedProcess for producing fat powder
US4857319 *21 May 198715 Ago 1989The Regents Of The University Of CaliforniaMethod for preserving liposomes
US4891319 *9 Jul 19862 Ene 1990Quadrant Bioresources LimitedProtection of proteins and the like
US4895719 *6 Mar 198723 Ene 1990Liposome Technology, Inc.Method and apparatus for administering dehydrated liposomes by inhalation
US4897353 *30 Oct 198630 Ene 1990University Of Southwestern LouisianaCryogenic protection of phosphofructokinase using amino acids and zinc ions
US4907583 *16 Dic 198813 Mar 1990Aktiebolaget DracoDevice in powder inhalators
US4919962 *22 Sep 198824 Abr 1990General Foods CorporationCoffee flakes and process
US4926852 *30 Sep 198822 May 1990The Johns Hopkins UniversityMedication delivery system phase one
US4927763 *28 Jun 198822 May 1990Chr. Hansen's Laboratory, Inc.Stabilization of dried bacteria extended in particulate carriers
US4931361 *18 Nov 19885 Jun 1990California Institute Of TechnologyCryoprotective reagents in freeze-drying membranes
US4942544 *14 Abr 198917 Jul 1990Kenneth B. McIntoshMedication clock
US4946828 *20 Jul 19877 Ago 1990Novo Nordisk A/SNovel insulin peptides
US4952402 *17 Mar 198828 Ago 1990Elan Corporation, P.L.C.Controlled release powder and process for its preparation
US4956295 *27 Abr 198711 Sep 1990Chr. Hansen's Laboratory, Inc.Stabilization of dried bacteria extended in particulate carriers
US4984158 *14 Oct 19888 Ene 1991Hillsman DeanMetered dose inhaler biofeedback training and evaluation system
US4995385 *23 Feb 199026 Feb 1991Phidea S.P.A.Inhaler with regular complete emptying of the capsule
US5006343 *29 Dic 19889 Abr 1991Benson Bradley JPulmonary administration of pharmaceutically active substances
US5011678 *1 Feb 198930 Abr 1991California Biotechnology Inc.Composition and method for administration of pharmaceutically active substances
US5017372 *19 Oct 198821 May 1991Medicis CorporationMethod of producing antibody-fortified dry whey
US5026566 *29 Jun 198825 Jun 1991Quadrant Bioresources, LimitedDried food containing trehalose and method for preparing same
US5033463 *22 Oct 199023 Jul 1991Miat S.P.A.Multi-dose inhaler for medicaments in powder form
US5035237 *27 Dic 198830 Jul 1991Newell Robert EDevices for administering medicaments to patients
US5042975 *7 May 198727 Ago 1991Rutgers, The State University Of New JerseyIontotherapeutic device and process and iontotherapeutic unit dose
US5081228 *13 Oct 198814 Ene 1992Immunex CorporationInterleukin-1 receptors
US5093316 *2 Oct 19903 Mar 1992John LezdeyTreatment of inflammation
US5098893 *12 Feb 199024 Mar 1992Pafra LimitedStorage of materials
US5099833 *19 Feb 199131 Mar 1992Baxter International Inc.High efficiency nebulizer having a flexible reservoir
US5113855 *14 Feb 199019 May 1992Newhouse Michael TPowder inhaler
US5124162 *26 Nov 199123 Jun 1992Kraft General Foods, Inc.Spray-dried fixed flavorants in a carbohydrate substrate and process
US5139016 *29 Dic 198918 Ago 1992Sorin Biomedica S.P.A.Process and device for aerosol generation for pulmonary ventilation scintigraphy
US5180812 *21 Dic 198919 Ene 1993Immunex CorporationSoluble human interleukin-1 receptors, compositions and method of use
US5186164 *15 Mar 199116 Feb 1993Puthalath RaghuprasadMist inhaler
US5200399 *1 Abr 19916 Abr 1993Boyce Thompson Institute For Plant Research, Inc.Method of protecting biological materials from destructive reactions in the dry state
US5204108 *10 Oct 198820 Abr 1993Danbiosyst Uk Ltd.Transmucosal formulations of low molecular weight peptide drugs
US5206200 *22 Abr 199127 Abr 1993W. R. Grace & Co.-Conn.Tin catalysts for hydrolysis of latent amine curing agents
US5225183 *30 Ene 19916 Jul 1993Riker Laboratories, Inc.Medicinal aerosol formulations
US5230884 *11 Feb 199227 Jul 1993University Of Wales College Of CardiffAerosol formulations including proteins and peptides solubilized in reverse micelles and process for making the aerosol formulations
US5290765 *11 Feb 19921 Mar 1994Boyce Thompson Institute For Plant Research, Inc.Method of protecting biological materials from destructive reactions in the dry state
US5295479 *15 Abr 199122 Mar 1994Leiras OyDevice intended for measuring a dose of powdered medicament for inhalation
US5302581 *22 Ene 199212 Abr 1994Abbott LaboratoriesPulmonary surfactant protein fragments
US5309900 *9 Oct 199110 May 1994Paul Ritzau Pari-Werk GmbhAtomizer particularly for use in devices for inhalation therapy
US5320094 *10 Ene 199214 Jun 1994The Johns Hopkins UniversityMethod of administering insulin
US5320714 *16 Feb 199114 Jun 1994Byk Gulden Lomberg Chemische Fabrik GmbhPowder inhalator
US5331953 *2 Mar 199026 Jul 1994Aktiebolaget DracoDevice in connection with an inhaler
US5384133 *29 Jun 199324 Ene 1995Innovata Biomed LimitedPharmaceutical formulations comprising microcapsules
US5482927 *23 Feb 19949 Ene 1996Massachusetts Institute Of TechnologyControlled released microparticulate delivery system for proteins
US5506203 *23 Jun 19949 Abr 1996Ab AstraSystemic administration of a therapeutic preparation
US5518998 *23 Jun 199421 May 1996Ab AstraTherapeutic preparation for inhalation
US5619984 *8 May 199515 Abr 1997Astra AktiebolagDry powder inhalation device having a powder-loaded elongate carrier
US5755221 *24 Oct 199426 May 1998Bisgaard; HansAerosol inhaler with piston dump
US6012454 *10 Jun 199711 Ene 2000Minnesota Mining And Manufacturing CompanyDry powder inhalation device
US6019968 *16 Oct 19971 Feb 2000Inhale Therapeutic Systems, Inc.Dispersible antibody compositions and methods for their preparation and use
US6051256 *8 May 199618 Abr 2000Inhale Therapeutic SystemsDispersible macromolecule compositions and methods for their preparation and use
US6099517 *27 Sep 19938 Ago 2000Genentech, Inc.Intrapulmonary delivery of polypeptide growth factors and cytokines
US6402733 *19 Abr 200011 Jun 2002Genentech, Inc.Intrapulmonary delivery of polypeptide growth factors and cytokines
Citada por
Patente citante Fecha de presentación Fecha de publicación Solicitante Título
US774492520 May 200529 Jun 2010Quadrant Drug Delivery LimitedSolid dose delivery vehicle and methods of making same
US778099120 May 200524 Ago 2010Quadrant Drug Delivery LimitedSolid dose delivery vehicle and methods of making same
US778563120 May 200531 Ago 2010Quadrant Drug Delivery LimitedSolid dose delivery vehicle and methods of making same
US816822321 Jun 20011 May 2012Novartis Pharma AgEngineered particles and methods of use
US82469343 Sep 201021 Ago 2012Novartis AgRespiratory dispersion for metered dose inhalers comprising perforated microstructures
US840421722 Jul 200526 Mar 2013Novartis AgFormulation for pulmonary administration of antifungal agents, and associated methods of manufacture and use
US870948424 Oct 200829 Abr 2014Novartis AgPhospholipid-based powders for drug delivery
US871562331 Oct 20076 May 2014Novartis AgPulmonary delivery of aminoglycoside
US88771626 Dic 20124 Nov 2014Novartis AgStable metal ion-lipid powdered pharmaceutical compositions for drug delivery
US20050276846 *20 May 200515 Dic 2005Roser Bruce JSolid dose delivery vehicle and methods of making same
EP2060268A1 *15 Nov 200720 May 2009Novo Nordisk A/SPharmaceutical compositions for pulmonary or nasal delivery of peptides
Clasificación de EE.UU.424/46, 514/5.9, 514/6.9, 514/1.2
Clasificación internacionalA61K9/12, A61K9/14, A61K47/06, A61P3/08, A61K9/00, A61K47/26, A61K9/16, A61K38/28, A61K47/12, A61K47/18
Clasificación cooperativaY10S514/866, A61K9/1617, A61K38/28, A61K47/12, A61K47/183, A61K47/26, A61K9/1623, A61K9/0075
Clasificación europeaA61K9/00M20B3, A61K38/28, A61K9/16H4B
Eventos legales
25 Feb 2003ASAssignment
Effective date: 20030113
7 Ene 2009ASAssignment
Effective date: 20081231