WO1999047196A1 - Aerosolized active agent delivery - Google Patents
Aerosolized active agent delivery Download PDFInfo
- Publication number
- WO1999047196A1 WO1999047196A1 PCT/US1999/004654 US9904654W WO9947196A1 WO 1999047196 A1 WO1999047196 A1 WO 1999047196A1 US 9904654 W US9904654 W US 9904654W WO 9947196 A1 WO9947196 A1 WO 9947196A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- active agent
- flow rate
- insulin
- per minute
- liters per
- Prior art date
Links
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M15/00—Inhalators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M15/00—Inhalators
- A61M15/0001—Details of inhalators; Constructional features thereof
- A61M15/002—Details of inhalators; Constructional features thereof with air flow regulating means
Definitions
- the present invention is related to the pulmonary delivery of an active agent formulation More particularly, it is a method and device for pulmonary delivery of an active agent formulation for increased systemic bioavailability of the active agent via absorption in the deep lung. Average inspiratory flow rates of less than 17 liters per minute of active agent formulation must be maintained m order to achieve increased bioavailability.
- Effective delivery to a patient is a c ⁇ tical aspect of any successful drug therapy
- Na ⁇ ous routes of delivery exist and each has its own advantages and disadvantages
- Oral drug delivery of pills, capsules, elixirs, and the like is perhaps the most convenient method, but many drugs are degraded m the digestive tract before they can be absorbed
- Subcutaneous injection is frequently an effective route for systemic drug delivery, including the delivery of proteins, but enjoys a low patient acceptance Since injection of drugs, such as insulin, one or more times a day can frequently be a source of poor patient compliance, a variety of alternative routes of administration have also been developed, including transdermal, intranasal, intrarectal, intravagmal, and pulmonary delivery.
- Insulin is a 50 ammo acid polypeptide hormone having a molecular weight of about 6,000 daltons which is produced in the pancreatic ⁇ -cells of normal (non- diabetic) individuals. Insulin is necessary for regulating carbohydrate metabolism by reducing blood glucose levels Where the body's ability to regulate blood glucose levels has been impaired, diabetes will result. There are two mam types of diabetes. In Type I, the insuhn-secretmg cells of the pancreas are destroyed. Insulin production is therefore nearly completely halted. In Type II, either the body produces insulin but in quantities that are insufficient to regulate blood sugar levels to within a normal range or the insulin receptors are unable to adequately process the insulin in the blood. Survival of Type I diabetic patients depends on the frequent and long-term administration of insulin to maintain acceptable blood glucose levels. Type II diabetics may require insulin administration, but diet, exercise or oral medications are often used to avoid the necessity of daily injections of insulin.
- 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 basal insulin at least once or twice per day, with supplemental injections of rapid-acting insulin being administered when necessary, usually prior to meals. Blood glucose levels should typically remain between 50 mg/dl and 300 mg/dl, preferably between about 80 mg/dl and 120 mg/dl with a target blood glucose level of 100 mg/dl. Aggressive treatment of diabetes can require even more frequent injections, in conjunction with the close monitoring of blood glucose levels by patients using home diagnostic kits.
- Laube et al controlled the inspiratory flow rate at the time of aerosol inhalation at flow rates of less than 30 liters/minute and, preferably about 17 liters/minute.
- the delivery system included a medication chamber for receiving the insulin, an outlet aperture through which the insulin was withdrawn, and a flow rate limiting aperture to control the inspiratory flow rate.
- Rubsamen et al US Patent Nos. 5,364,838 and 5,672,581 describe the delivery of a measured amount of aerosolized insulin.
- the insulin is automatically released into the inspiratory flow path in response to information obtained from determining the inspiratory flow rate and inspiratory volume of a patient.
- a monitoring device continually sends information to a microprocessor, and when the microprocessor determines that an optimal point in the respiratory cycle is reached, the microprocessor actuates the opening of a valve allowing release of insulin.
- the inspiratory flow rate is in the range of from about 0.1 to 2.0 liters/second and the volume is in the range of from about 0.1 to 0.8 liters.
- the present invention is directed to a method for delivering an active agent formulation to the lungs of a human patient, said method comprising providing the active agent formulation at an inspiratory flow rate of below 17 liters per minute.
- the active agent formulation may be provided in dry powder or nebulized form, or it may be in the form of aerosolized particles in admixture with a propellant.
- the present invention is directed to a method for delivering insulin to the lungs of a human patient, said method comprising providing insulin at an inspiratory flow rate of below 17 liters per minute.
- The is preferably provided in dry powder form, but it may also be in nebulized form, or it may be in the form of aerosolized particles in admixture with a propellant.
- the present invention is directed to a device for increasing the bioavailability of an aerosolized active agent, said device comprising a flow restricter for limiting the flow of the aerosolized active agent formulation to below 17 liters per minute.
- the flow restricter may be in the form of a simple orifice, a valve that provides for increasing resistance with increasing flow rate, a valve that provides for decreasing resistance with increasing flow rate, or a valve that provides for high resistance at all flow rates except the desired flow rate.
- the present invention is directed to a device for delivering an active agent to the lungs of a human patient wherein the device delivers an aerosolized active agent formulation at an inspiratory flow rate of less than 17 liters per minute.
- the present invention is also directed to a device for delivering insulin to the lungs of a human patient wherein the device delivers an aerosolized insulin formulation at an inspiratory flow rate of less than 17 liters per minute.
- Figure 1A is a perspective view and Figure IB is an elevational view of an embodiment of a dry powder active agent formulation delivery device of the invention.
- Figure 2A is a cross-sectional view and Figure 2B is an elevational view of an embodiment of a nebulized active agent formulation delivery device of the invention.
- Figure 3A is a perspective view and Figure 3B is an elevational view of an embodiment of a propellant driven active agent formulation delivery device of the invention.
- Figure 4A is a perspective view of a simple o ⁇ fice and Figure 4B is a graph showing the type of resistance obtained therefrom
- Figure 5A is a perspective view of a valve that provides for increasing resistance with increasing flow rate and Figure 5B is a graph showing the type of resistance obtained therefrom.
- Figure 6A is a perspective view of a valve that provides for decreasing resistance with increasing flow rate and Figure 6B is a graph showing the type of resistance obtained therefrom.
- Figure 7A is a perspective view of a valve that provides for high resistance at all flow rates except the desired flow rate and Figure 7B is a graph showing the type of resistance obtained therefrom.
- the present invention provides a method and device for the pulmonary delivery of an active agent formulation where inspiratory flow rate of the active agent formulation is less than 17 liters/min.
- the invention is surpnsing in that it provides for increased blood levels of active agent than observed following higher inspiratory flow rates.
- Active agent as described herein includes an agent, drug, compound, composition of matter or mixture there which provides some pharmacologic, often beneficial, effect. This includes foods, food supplements, nutrients, drugs, vaccines, vitamins, and other beneficial agents. As used herein, the terms further include any physiologically or pharmacologically active substance that produces a localized or systemic effect in a patient.
- the active agent that can be delivered includes antibiotics, antiviral agents, anepileptics, analgesics, anti-inflammatory agents and bronchodilators, and may be inorganic and organic compounds, including, without limitation, drugs which act on the peripheral nerves, adrenergic receptors, cholinergic receptors, the skeletal muscles, the cardiovascular system, smooth muscles, the blood circulatory system, synoptic sites, neuroeffector junctional sites, endocrine and hormone systems, the immunological system, the reproductive system, the skeletel system, autacoid systems, the alimentary and excretory systems, the histamine system the central nervous system.
- Suitable agents may be selected from, for example, polysaccharides, steroid, hypnotics and sedatives, psychic energizers, tranquilizers, anticonvulsants, muscle relaxants, antiparkinson agents, analgesics, anti-inflammatories, muscle contractants, antimicrobials, antimalarials, hormonal agents including contraceptives, sympathomimetics, polypeptides, and proteins capable of eliciting physiological effects, diuretics, lipid regulating agents, antiandrogenic agents, antiparasitics, neoplasties, antineoplastics, hypoglycemics, nutritional agents and supplements, growth supplements, fats, antienteritis agents, electrolytes, vaccines and diagnostic agents.
- active agents useful in this invention include but are not limited to insulin, calcitonin, erythropoietin (EPO), Factor VIII, Factor IX, ceredase, cerezyme, cyclosporin, granulocyte colony stimulating factor (GCSF), alpha- 1 proteinase inhibitor, elcatonin, granulocyte macrophage colony stimulating factor (GMCSF), growth hormone, human growth hormone (HGH), growth hormone releasing hormone (GHRH), heparin, low molecular weight heparin (LMWH), interferon alpha, interferon beta, interferon gamma, interleukin-2, luteinizing hormone releasing hormone (LHRH), somatostatin, somatostatin analogs including octreotide, vasopressin analog, follicle stimulating hormone (FSH), insulin-like growth factor, insulintropin, interleukin-1 receptor antagonist, interleukin-3, interleukin-4, interleukin-6, macro
- Active agents may further comprise nucleic acids, present as bare nucleic acid molecules, viral vectors, associated viral particles, nucleic acids associated or incorporated within lipids or a lipid-containing material, plasmid DNA or RNA or other nucleic acid construction of a type suitable for transfection or transformation of cells, particularly cells of the alveolar regions of the lungs.
- the active agents may be in various forms, such as soluble and insoluble charged or uncharged molecules, components of molecular complexes or pharmacologically acceptable salts.
- the active agents may be naturally occurring molecules or they may be recombinantly produced, or they may be analogs of the naturally occurring or recombinantly produced active agents with one or more amino acids added or deleted.
- the active agent may comprise live attenuated or killed viruses suitable for use as vaccines.
- the active agent is insulin
- the term includes natural extracted human insulin, recombinantly produced human insulin, insulin extracted from bovine and/or porcine sources, recombinantly produced porcine and bovine insulin and mixtures of any of the above.
- the insulin may be neat, that is in its substantially purified form, but may also include excipients as commercially formulated.
- insulin are insulin analogs where one or more of the amino acids of the naturally occurring or recombinantly produced insulin has been deleted or added.
- “Aerosolized active agent formulation” means the active agent as defined above in a formulation that is suitable for pulmonary delivery.
- the aerosolized active agent formulation may be in the dry powder form, it may be a solution, suspension or slurry to be nebulized, or it may be in admixture with a suitable low boiling point, highly volatile propellant. It is to be understood that more than one active agent may be incorporated into the aerosolized active agent formulation and that the use of the term "agent" in no way excludes the use of two or more such agents.
- inspiratory flow rate or “average inspiratory flow rate” are used interchangeably here to mean the flow rate at which the aerosolized active agent formulation is delivered. For a continuous nebulizer, this is the flow rate over the entire breath. For a device that gives an aerosol bolus, such as a dry powder inhaler or an MDI, this is the average flow rate throughout the period during which the aerosol bolus is delivered plus the time taken for the aerosol to traverse the anatomical dead space, i.e. from the lips to beyond generation 6 or 8 of the airways (approximately 150 mis).
- the amount of active agent in the aerosolized active agent formulation will be that amount necessary to deliver a therapeutically effective amount of the active agent to achieve the desired result. In practice, this will vary widely depending upon the particular agent, the severity of the condition, and the desired therapeutic effect. However, the device is generally useful for active agents that must be delivered in doses of from 0.001 mg/day to 100 mg/day, preferably 0.01 mg/day to 50 mg/day.
- the present invention is based at least in part on the unexpected observation that when an active agent is delivered to a patient at an inspiratory flow rate of less than 17 liters per minute or preferably less than 12 liters per minute and more preferably 10 liters per minute or less and often between 5 and 10 liters per minute, the lung deposition and thus the bioavailability of the active agent increases as opposed to when the active agent is delivered at an inspiratory flow rate of 17 liters per minute or more. It was surprising that the lower flow rate would lead to a higher bioavailability since Laube et al (US Patent No. 5,320,094) determined the optimal flow rate of aerosolized insulin to be 17 liters per minute and that up to 30 liters per minute was desirable.
- Active agent formulations suitable for use in the present invention include dry powders, solutions, suspensions or slurries for nebulization and particles suspended or dissolved within a propellant.
- Dry powders suitable for use in the present invention include amorphous active agents, crystalline active agents and mixtures of both amorphous and crystalline active agents.
- the dry powder active agents have a particle size selected to permit penetration into the alveoli of the lungs, that is, preferably 10 ⁇ m mass median diameter (MMD), preferably less than 7.5 ⁇ m, and most preferably less than 5 ⁇ m, and usually being in the range of 0.1 ⁇ m to 5 ⁇ m in diameter.
- MMD mass median diameter
- the delivered dose efficiency (DDE) of these powders is >30%, usually >40%, preferably >50 and often >60% and the aerosol particle size distribution is about 1.0 - 5.0 ⁇ m mass median aerodynamic diameter (MMAD), usually 1.5 - 4.5 ⁇ m MMAD and preferably 1.5 - 4.0 ⁇ m MMAD.
- MMAD mass median aerodynamic diameter
- These dry powder active agents have a moisture content below about 10% by weight, usually below about 5% by weight, and preferably below about 3% by weight. Such active agent powders are described in WO 95/24183 and WO 96/32149, which are incorporated by reference herein.
- Dry powder active agent formulations are preferably prepared by spray drying under conditions which result in a substantially amorphous powder.
- Bulk active agent usually in crystalline form, is dissolved in a physiologically acceptable aqueous buffer, typically a citrate buffer having a pH range from about 2 to 9.
- the active agent 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 a conventional spray drier available from commercial suppliers such as Niro A S (Denmark), Buchi (Switzerland) and the like, resulting in a substantially amorphous powder.
- amorphous powders may also be prepared by lyophilization, vacuum drying, or evaporative drying of a suitable active agent solution under conditions to produce the amorphous structure.
- the amorphous active agent formulation so produced can be ground or milled to produce particles within the desired size range.
- Dry powder active agents may also be in a crystalline form.
- the crystalline dry powders may be prepared by grinding or jet milling the bulk crystalline active agent.
- the active agent 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 active agent concentration in the powder which is being delivered to a patient, but may also serve to improve the dispersability of the powder within a powder dispersion device in order to provide more efficient and reproducible delivery of the active agent and to improve handling characteristic of the active agent such as flowability and consistency to facilitate manufacturing and powder filling.
- excipients include but are not limited to (a) 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- ⁇ - cyclodextrin; and polysaccharides, scuh 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, tromethamin hydrochloride, and the like; (d) peptides and proteins such as aspartame, human serum
- the dry powder active agent formulations may be delivered using Inhale Therapeutic Systems' dry powder inhaler as described in WO 96/09085 which is incorporated herein by reference, but adapted to control the flow rate to 17 liters per minute or less as described below.
- the dry powders may also be delivered using a metered dose inhaler as described by Laube et al in US Patent No. 5,320, 094, which is incorporated by reference herein.
- Nebulized solutions may be prepared by aerosolizing commercially available active agent formulation solutions. These solutions may be delivered by a jet nebulizer such as the Raindrop, produced by Puritan Bennett, the use of which is described by Laube et al. Other methods for delivery of solutions, suspensions of slurries are described by Rubsamen et al, US Patent No. 5,672.581. A device that uses a vibrating,
- Propellant systems may include an active agent dissolved in a propellant or particles suspended in a propellant. Both of these types of formulations are described in Rubsamen et al, US Patent No. 5,672,581, which is incorporated herein by reference.
- the devices described above must be modified in order to restrict the inspiratory flow rate of the active agent formulation to 10 liters per minute or less.
- Figures 1A, IB, 2A, 2B, 3A, 3B, 4A and 4B show this restriction achieved by devices using a simple orifice.
- Figures 5 A, 5B, 6A, 6B, 7 A and 7B show alternative flow control methods useful in any of the Figure 1 A, 2A or 3A devices.
- the device 100 contains a flow restricter 102 with apertures 103 that limits the inspiratory flow to 10 liters per minute or less according to the invention.
- Figure 1A shows an exploded view of the device described in WO 96/09085.
- a patient inserts a blister of active agent into the base 106 of the device.
- the handle 108 is cocked to compress air for dispersion of the active agent.
- Lever 110 is lowered to lift the blister 104 into place.
- Button 116 is depressed which punctures the blister 104 and releases the active agent with the compressed air into the capture chamber 112.
- the patient puts his mouth over mouthpiece 114 and the aerosolized active agent formulation is withdrawn through flow restricter 102 at a rate of 10 liters per minute or less.
- FIGS. 2A and 2B show a rigid chamber 200 suitable for restricting the inspiratory flow rate delivered by a nebulizer according to the invention.
- a rigid chamber 200 is provided having a proximal end 202, a distal end 204 and a main body 206.
- the proximal end 202 has an aperture 208 that is sized to accept standard disposable mouthpieces for use with hospital nebulizers.
- the body of the device 206 has an opening has an opening 210 of a size suitable for coupling to an external source of aerosolized active agent.
- the aerosolized active agent formulation is delivered to the chamber 200 through opening 210.
- the opening 210 is then covered
- the distal end 204 contains a flow restricter 212, in this case a series of apertures 214 such that when a patient inhales the active agent formulation through a mouthpiece attached to the aperture 208, the inspiratory flow rate of the active agent formulation is maintained at or below 10 liters per minute.
- a metered dose inhaler (MDI) 300 may be provided with a flow restricter 302 as shown in Figures 3A and 3B and further described in Laube et al.
- the MDI 300 is shown with a mouthpiece 304 and a rigid chamber 306.
- the proximal end 308 of the mouthpiece 304 is adapted to be placed in the mouth of a patient.
- the distal end 310 of the mouthpiece 304 is rigidly attached to the proximal end 312 of chamber 306.
- the MDI is attached such that when operated, a dose of aerosolized active agent formulation is released into chamber 306.
- the distal end 314 of chamber 306 contains a flow restricter 302, in this case a series of apertures 318 as shown in Figure 3B, such that when a patient inhales the active agent formulation through the proximal end 308 of the mouthpiece 304, the inspiratory flow rate of the active agent formulation is maintained at or below 10 liters per minute.
- a flow restricter 302 in this case a series of apertures 318 as shown in Figure 3B, such that when a patient inhales the active agent formulation through the proximal end 308 of the mouthpiece 304, the inspiratory flow rate of the active agent formulation is maintained at or below 10 liters per minute.
- the devices of Figures 1-3 use a simple orifice as shown in Figure 4A to achieve the desired inspiratory flow rate.
- the rate of air flow through the orifice is proportional to the square root of the pressure drop across it, and in this case the resistance (R) is constant as shown in Figure 4B.
- the resistance required is approximately 1 cm H-O'VLmin '1 . This is accomplished by including a flow restricter with a total orifice area of approximately 2 to 4 mm 2 .
- there are 8-12 apertures of 0.5 - 0.9 mm diameter which will provide for this type of flow.
- Figure 5A shows a valving arrangement where the resistance increases with increasing flow rate.
- the proportionality of resistance to flow rate is shown in Figure 5B.
- Such an arrangement allows for comfortable inhalation at the desired flow rate.
- the resistance at 10 liters per minute would be approximately 1 cm H-O'VLmin '.
- Figure 6A shows a valvmg arrangement where the resistance decreases with increasing flow rate. This arrangement is useful where an aerosol bolus can be delivered slowly enough to ensure that it has entered the lower airway prior to the flow being allowed to increase to over 10 liters per minute.
- the proportionality of resistance to flow rate is shown in Figure 6B
- Figure 7A shows a valving arrangement where the resistance is high at all flow rates except for the desired flow rate.
- the proportionality of resistance to flow rate is shown in Figure 7B
- the resistance at 10 liters per minute would be .25 cm FLO ' ⁇ Lmin ' and greater than 1 cm H,O '/! /Lmin ' at other than the desired flow rate
- Crystalline human zinc insulin 26.3 U/mg was obtained from E Lilly and Company, Indianapolis, IN and found to be >99% pure as measured by rpHPLC.
- Low molecular weight hepa ⁇ n sodium salt (average molecular weight -6000) was obtained from Sigma Chemical, St. Louis, MO.
- HSA Human serum albumin
- Albuterol sulfate was obtained from Profarmaco (Milano, Italy)
- USP mannitol was obtained from Roquette Corporation (Gurnee, LL).
- Glycine was purchased from Sigma Chemical Company (St. Louis, Missou ⁇ )
- Ethanol 200 proof, USP, NF grade was obtained from Spectrum (New Brunswick, NJ).
- Insulin powders were made by dissolving bulk crystalline insulin sodium citrate buffer containing mannitol and glycine to give final solids concentration of 7.5 mg/ml and pH of 6.7 ⁇ 0.3.
- the spray dryer was operated with an inlet temperature between 110°C and 120°C and a liquid feed rate of 5 ml/mm, resulting in an outlet temperature between 70°C and 80°C
- the solutions were then filtered through a 0.22 ⁇ m filter and spray d ⁇ ed 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).
- Powders containing 26.7% human calcitonin were made by spray drying an aqueous mixture containing human calcitonin.
- the mixture was prepared by combining 1.9 mg human calcitonin per 1.0 mL deionized water with 4.3 mg/mL mannitol and 0.9 mg/mL citrate buffer at a pH of 3.85.
- the mixture was spray dried in a Buchi Spray Dryer that was operated with an inlet temperature between 110°C and 120°C and a liquid feed rate of 5.5 ml/mm, resulting in an outlet temperature between 70°C and 80°C Once the aqueous mixture was consumed, the outlet temperature was maintained at 80°C for about 10 minutes by slowly decreasing the inlet temperature to provide a secondary drying
- the resulting powders were stored in tightly capped containers in a dry environment ( ⁇ 10% RH)
- Powders containing 93% low molecular weight (lmw) hepann powders were made by spray drying an aqueous mixture containing lmw hepa ⁇ n.
- the mixture was prepared by combining 6.9 mg lmw heparin per 1.0 mL deionized water with 0.5 mg/mL HSA a pH of 6 9.
- the mixture was spray d ⁇ ed in a Buchi Spray Dryer that was operated with an inlet temperature of 140°C and a liquid feed rate of 3.8 ml/mm, resulting in an outlet temperature of 85°C. Once the aqueous mixture was consumed, the outlet temperature was maintained at 80°C for about 10 minutes by slowly decreasing the inlet temperature to provide a secondary drying.
- the resulting powders were stored in tightly capped containers in a dry environment ( ⁇ 10% RH).
- Powders containing cyclospo ⁇ n were made by spray drying an organic solution containing 1.5 g cyclospo ⁇ n A and 50 mL ethanol.
- the solution was spray d ⁇ ed in a Buchi Spray Dryer using a nitrogen atmosphere containing less than 5% oxygen (with N 2 atm ⁇ 5% O 2 that was operated with an inlet temperature of 100°C and a liquid feed rate of 5 mL/min, resulting m an outlet temperature of 70°C.
- the resulting powders were stored m tightly capped containers m a dry environment ( ⁇ 10% RH).
- Powders containing 2.3% albuterol sulfate were made by spray drying an aqueous mixture containing albuterol sulfate.
- the mixture was prepared by combining 0.60 mg albuterol sulfate and 25.68 mg lactose per 1.0 mL deionized water at a pH of
- the mixture was spray dried in a Niro Spray Dryer that was operated with an inlet temperature of 120°C and a liquid feed rate of 50 mL/min, resulting in an outlet temperature between 64.7°C and 67.2°C.
- the resulting powders were stored in tightly capped containers in a dry environment ( ⁇ 10% RH).
- 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-l 1 (Micrometrics, Norcross, GA).
- the moisture content of the powders was measured by the Karl Fischer technique using a Mitsubishi CA-06 Moisture Meter.
- the aerosol particle size distribution was measured using a cascade impactor (Graseby Andersen, Smyrna, GA).
- the delivered dose efficiency (DDE) is evaluated using the Inhale Therapeutic Systems' aerosol devices, similar to that described in WO96/09085.
- the DDE is defined as the percentage of the nominal dose contained within a blister package that exited the mouthpiece of the aerosol device and was captured on a glass fiber filter (Gelman, 47 mm diameter) through which a vacuum was drawn (30L/min) for 2.5 seconds following device actuation. DDE was calculated by dividing the mass of the powder collected on the filter by the mass of the powder in the blister pack.
- 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 the process. UV absorbance was used to determine insulin concentration (at 278 nm) and presence of 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 polarized light microscopy.
- Inhale Therapeutic Systems' (San Carlos, CA) dry powder inhaler was used to administer the aerosolized active agent powder.
- 3 mg of the amorphous insulin powders described above were filled into blister packages and inserted into the inhaler.
- the inhaler dispersed the powder and produced an aerosol cloud of medication which was held in a volume of approximately 240 ml in a holding chamber.
- the volume of the holding chamber was a minor fraction of a deep inspiratory breath (>2 liters).
- the chamber was designed so that during inhalation of the aerosol cloud, ambient air was pulled into the chamber thereby pushing the aerosol cloud out of the chamber and deep into the lungs.
- Each 3 mg dose of the dry powder contained 82.5 U of insulin.
- the subjects were trained in the breathing maneuvers for inhalation of active agent.
- the steps were: (1) Subject exhaled to functional residual capacity and wrapped lips around the mouthpiece of the inhaler; (2) A cloud of aerosolized active agent was dispersed from the blister pack into the holding chamber of the inhaler; (3) Subject inhaled at the designated rate until total lung capacity was reached (this should have removed all of the aerosol from the chamber); (4) Subject removed mouth from the inhaler and held breath for 5 seconds; and (5) Subject exhaled gently to normal expiratory level and resumed normal breathing.
- inhalation In order to obtain the appropriate inhaled flow rates, subjects were able to view the output from the inhalation measurement device and were instructed to try to match their inhalation rate to the desired rate on the output from the device. For the 10 L/min rate, inhalation lasted approximately 15 seconds. For the 25 L/min inhalation rate, inhalation required approximately 6 seconds. For the >35 L/min inhalation rate, the subjects were instructed to inhale as rapidly as possible.
- Insulin powders were prepared as described above and administered to patients also as described above.
- the bioavailibilities, peak insulin concentrations and time to peak insulin concentrations were as shown in Table I below.
- the figures show, surprisingly, that inspiratory flow rates of 10 liters per minute or less achieved higher bioavailabilities of insulin (AUC), and higher peak concentrations of insulin (Cmax) than did inspiratory flow rates of 17.0 liters per minute or greater. Further, blood glucose level control (AUC) was greater for an inspiratory flow rate of 9.1 liters per minute than for the higher flow rates, and the maximum concentration (Cmax) was lower for the lower flow rate. Accordingly, a flow rate below 17 liters per minute, preferably 10 liters per minute or less is desired for optimal insulin delivery and glucose blood level control.
- AUC blood glucose level control
- Human calcitonin powders are prepared as described above. Upon administration to patients, flow rates below 17 liters per minute will result in higher bioavailabilities and lower times to peak concentration than those above 17 liters per minutes.
- Low molecular weight heparin powders are prepared as described above. Upon administration to patients, flow rates below 17 liters per minute will result in higher bioavailabilities and lower times to peak concentration than those above 17 liters per minutes.
- Cyclosporin A powders are prepared as described above. Upon administration to patients, flow rates below 17 liters per minute will result in higher lung deposition and thus increased therapeutic effect than those above 17 liters per minutes.
- Albuterol sulfate powders are prepared as described above. Upon administration to patients, flow rates below 17 liters per minute will result in higher lung deposition and thus increased therapeutic effect than those above 17 liters per minutes
Abstract
Description
Claims
Priority Applications (22)
Application Number | Priority Date | Filing Date | Title |
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JP2000536435A JP4195191B2 (en) | 1998-03-16 | 1999-03-11 | Administration of aerosolized active agent |
NZ50628999A NZ506289A (en) | 1998-03-16 | 1999-03-11 | Aerosolized active agent delivery to the lungs at a flow rate of less than 17 liters per minute |
EP99911071A EP1066074A1 (en) | 1998-03-16 | 1999-03-11 | Aerosolized active agent delivery |
ROA200000909A RO121834B1 (en) | 1998-03-16 | 1999-03-11 | Device for the delivery of an active agent |
SK1363-2000A SK13632000A3 (en) | 1998-03-16 | 1999-03-11 | Aerosolized active agent delivery |
AU29803/99A AU750539B2 (en) | 1998-03-16 | 1999-03-11 | Aerosolized active agent delivery |
HU0100848A HUP0100848A3 (en) | 1998-03-16 | 1999-03-11 | Aerosolized active agent delivery |
SI9920017A SI20413A (en) | 1998-03-16 | 1999-03-11 | Aerosolized active agent delivery |
APAP/P/2000/001902A AP1342A (en) | 1998-03-16 | 1999-03-11 | Aerosolized active agent delivery. |
CA002322045A CA2322045C (en) | 1998-03-16 | 1999-03-11 | Aerosolized active agent delivery |
CN998037133A CN1292714B (en) | 1998-03-16 | 1999-03-11 | Aerosolized active agent delivery |
EA200000823A EA003196B1 (en) | 1998-03-16 | 1999-03-11 | Method for delivering an active agent as aerosolized active agent |
PL99343276A PL343276A1 (en) | 1998-03-16 | 1999-03-11 | Aerosolized active agent delivery |
IL13815399A IL138153A0 (en) | 1998-03-16 | 1999-03-11 | Methods and devices for delivering aerosolized active agents |
BR9908771-5A BR9908771A (en) | 1998-03-16 | 1999-03-11 | Processes for the release of an active agent and insulin into the lungs of a human patient, a device for increasing the bioavailability of an active agent, and devices for the release of an active agent and insulin into the lungs of a human patient |
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LT2000095A LT4818B (en) | 1998-03-16 | 1999-03-11 | Aerosolised active agent delivery |
EEP200000546A EE200000546A (en) | 1998-03-16 | 1999-03-11 | Aerosolized drug delivery system |
IS5595A IS5595A (en) | 1998-03-16 | 2000-08-22 | Spraying of active substances |
HR20000608A HRP20000608A2 (en) | 1998-03-16 | 2000-09-15 | Aerosolized active agent delivery |
NO20004627A NO20004627L (en) | 1998-03-16 | 2000-09-15 | Aerosolized delivery of active agents |
LVP-00-129A LV12586B (en) | 1998-03-16 | 2000-09-22 | A'erosolized active agent delivery |
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JP (1) | JP4195191B2 (en) |
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