Certain diseases and medical conditions that are systemic, intra-cranial or local are treatable via the administration of drugs and therapeutic agents taken topically or systemically through the eye, ear, mouth, nose, lungs or dermal skin layer. There are a growing number of medicaments that are most effectively manufactured, stored, delivered, and administered as a dry powder formulation. A number of pharmaceutical agents are deliverable as powders or particles orally to the lungs, sublingual, buccal or intra-nasally (including nose to brain), and may be administered for topical, systemic or intracranial deposition, including but not limited to antibiotics, antipyretics, anti-inflammatories, biologics, biosimilars, vitamins, botanicals, co-factors, enzymes, inhibitors, activators, nutrients, vaccines including DNA based killed or live virus or microorganisms, nucleic acids, proteins, peptides, antibodies, peptide mimetics, prophylactic or therapeutic immune-modulators, anti-viral and anti-bacterial compounds, biologics, diagnostic agents and other agents, pharmaceutical compositions or medicaments.
Solid formulated medicaments have a number of recognized advantages. Compound stability for certain agents is greater in solid form especially polypeptide and protein based biologics whose conformational and higher structure may tend to degrade or denature when in solution thus affecting their biological activity. Similarly, certain drug chemical compounds may tend to dissociate and degrade due to incremental pH shifts, Van der Waals and other forces resulting in diminished shelf life and drug efficacy. Consequently, unstable medicaments formulated as liquids must be refrigerated or even frozen to preserve their potency or effectiveness which adds cost and complicates deployment. This is especially troublesome in such cases whereby vaccines and other unstable medicaments must be distributed to remote areas and underdeveloped regions or very rapidly to large populations during a public health crisis under austere field conditions. Often unstable drugs must then be shipped in solid form and reconstituted back to liquid form at the time of administration thus delaying deployment and adding expense and the need for skilled personnel for proper utilization.
In certain other cases medicaments are designed in solid form to facilitate controlled release to result in sustained pharmacological concentrations of active ingredients over an extended period of time. For systemic treatments, powder based drugs delivered to mucosal surfaces via the nose, lungs or oral cavity offer a number of advantages including rapid drug uptake due to large mucosal surface area capable of systemic uptake, the avoidance of the harsh environment of the stomach and intestinal tract as in the case of pills, tablets, and capsules, and the avoidance of broad systemic and side effects often associated with parenterally administered drugs. Other advantages include enhanced bioavailability, reduced dose volume, and improved patient compliance and ease of self-administration. Powders can be formulated and dispensed to deliver medications topically to wounds, into the ear or nose to reach the upper respiratory tract for the treatment of a localized condition or as a prophylactic.
Typically these agents and medicaments are formulated and prepared from solution by recrystallization followed by milling, but for improved control over particle crystallinity, shape, mean size, and size distribution; lyophilization or various spray drying techniques known in the art are relied upon to produce a bulk powder with precise characteristics to aid in administration. Key characteristics include primarily the mean particle size as well as the distribution of sizes within the bulk powder. For a given inspiratory velocity initiated either nasally or orally, a certain mean particle size and mass is required to result in deposition to the targeted tissue location within the targeted area within the respiratory tract. Generally, smaller particles will tend to deposit deeper in the respiratory tract, more particularly; particles of 3 or fewer microns in diameter have a greater probability to reach the tissues of the lower lungs, with even smaller aerodynamic diameters preferred for enhanced systemic uptake. Conversely, larger particles of greater than 5 microns to the tens of microns or larger, owing to their larger mass are more likely to deposit proximally to the point of administration; most typically within the nasal cavity and passages when administered intranasally, or in the oral cavity or pharynx, larynx, or trachea if orally administered. The dispersity or polydispersity index describes the range and proportion of sizes within the bulk powder. Depending upon the targeted application location, a less disperse or mono-disperse powder may be desired to assure a specific deposition location or a more disperse powder may be necessary in order to impact a larger range of tissues such as the case with certain anti-viral therapies and vaccines where the intent is to contact the virus residing in several tissue areas and locations with the respiratory tract.
Other aspects of powder engineering are intended to impact the flowability, absorption efficiency and reduce the aggregation of the powders in order to aid in the friability of the material to increase the delivery efficiency, efficacy and rate of uptake. For that reason, certain excipients, carriers, or other matrix components may be added in defined quantity to the active dry pharmaceutical agent to impact particle shape, texture and surface properties for reduced adhesive and electrostatic forces in order to facilitate the breaking apart of settled or aggregated particles prior to and during dispense. Other excipients, carriers, or other matrix components may be added in defined quantity to the active dry pharmaceutical agent to impact mucosal absorption or dwell time on the targeted deposition site. Further, micro and nano particle formulations of drugs are often employed using biocompatible and degradable polymers as carriers.
All of these and other powder engineering principles play an important role in conjunction with the design of packaging and dispensing systems and devices to achieve precise delivery and dispense characteristics of powdered drugs. A variety of packaging and devices are known for delivering a controlled quantity of a dry pharmaceutical preparation to the ear, dermis, nose, nasal mucosa, sublingual, buccal, oral mucosa, pharyngeal, tracheal, and lower respiratory tissues.
Unlike liquid drug formulations, whereby a simple pump can deliver a precisely controlled quantity of drug as droplets with the required spray characteristics; drugs formulated as dry materials present additional challenges owing to the propensity of powders to settle and physically and chemically agglomerate. Thus it is necessary that the device must not only contain a single dose of material or be capable of metering it from a bulk source, but must also impart sufficient energy to agitate the material to break up the particles and propel them to the deposition site in the correct quantity and mean particle size in order to provide optimum deposition characteristics, and consequently the most advantageous therapeutic effect.
There exists numerous systems and devices to dispense powders to a human or other type of mammal; the basic designs of which vary depending upon the site of administration, target deposition zone and intended topical, systemic or intracranial application. For example, Dry Powder Inhalers (DPIs) is the class of devices that is a common type of device for delivering dry pharmaceutical preparations to a user most typically for pulmonary deposition via oral administration. Typically such devices require an external propellant, pressurizer or other external energy source which classified those devices generally as Active Dry Powder Inhalers (ADPIs). Alternatively, other devices rely solely on the inspiratory airflow of the user and hence are breath actuated and referred to as Passive Dry Powder Inhalers (PDPIs). Both approaches suffer from significant drawbacks. In the case of ADP's, owing to the need for a propellant or electromechanical componentry and often bulk storage of drug; the device itself can be complex, large, expensive, cumbersome, and inconvenient to handle and use. Passive devices while often smaller, less expensive and containing one or more individualized unit doses; often deliver inconsistent quantity of drug to the user with the variability of delivered dose a function of user inspiratory flowrate. Further, the passive devices often operate at a reduced efficiency as given by the fraction of the dose quantity actually delivered to the user. The reduced efficiency diminishes the cost effectiveness of the passive devices due to wasted drug material. The undispensed portion of the drug that remains is also left behind to contaminate the device, and in the case of multi-dose devices, possibly contaminate subsequent doses of drug.
In the case of pulmonary deposition, very small particles (1-5 microns) are preferred but smaller particles typically suffer from an increased tendency to form clumps due to hygroscopicity, adhesion and electrostatic forces. Prior art devices commonly rely on high velocity propellants or electromechanical agitation to de-aggregate the powder particles and deliver the material to the target deposition zone of the user. The means of providing the external energy source are widely varied and include pressurized canisters, propeller type agitators, mechanical, solenoid or piezoelectric based vibration to aid in particle deaggregation and delivery. For example, Gumaste in U.S. Pat. No. 7,950,390 discloses a microelectronic piezo vibrator to aid breaking apart the agglomerated particles and suspending them into the flow field. Such microelectronic systems offer improvements in the bulk size of the device as compared to Wilke et. al., who in U.S. Pat. No. 3,948,264 discloses a battery driven electro-mechanical vibrator to facilitate dispersion and release of the particles. These schemes, while incrementally different, consistently suffer from the disadvantage of system complexity due to the need for circuitry, motors, and electrical power sourcing. Additionally, these prior art devices often entail capsule based dosage forms externally pierced by various means often including retractable mechanical or motor driven pins, often arranged in multiple pin arrays and channels to facilitate increasing the fraction ejected from the dosage form.
Alternatively, passive devices rely upon the forceful inhalation of the user to disperse the particles and deliver them to the airway and the targeted tissues. In most prior art active and passive devices, the operation often entails a series of steps to facilitate administration of drug. Additionally, the dosage forms are often singularized into the form of capsules containing the prescribed dose quantity that must first be externally pierced in order to expose the compound to the velocity field. The other dosage form common in such devices are individual blisters either singularized or in strips or cartridges that are loaded into the dispensing device and also first require either piercing of the blister or peeling of the upper lidding layer to expose the contents. For example, Davies et al in U.S. Pat. Nos. 5,590,645; 5,860,419; 5,873,360; 6,032,666 discloses an inhalation device with a multi-dosage configuration in the form of a strip of individual blisters containing the medicament. The base and lid materials are peeled apart as the strip is rotated into an opening station position and the two ends taken up on separate spools. Once in position and the contents exposed, the user then inhales the drug compound. This prior art device has the advantage of simplicity owing to the reliance upon the users inhalation as the primary means of particle dispersion and delivery. However, that approach may result in poor dose consistency; as measured by patient to patient variability or dose to dose variability of an individual patient. This variability is a consequence of the natural range of possible patient inspiratory rates and velocities. Further, the passive scheme as disclosed whereby no means are provided to augment the ejection of the blisters, may result in incomplete dosing and low efficiency of delivery whereby medication is left in the blister. Further, the undelivered quantity continues to reside within the opened blister and once indexed may fall out into the device interior, contaminating both the device and possibly subsequent doses.
Various devices within the prior art include measured quantities of dry powdered formulations and pharmaceutical compositions contained in a crushable ampoule, blister or other dosage form that entail forcing the form against an external piercing device during use, in order to pierce the dosage form and release the contents. The inherent disadvantages involve the reliance on external energy sources and/or solely upon the inhalation force of the user to adequately break apart the settled and aggregated dose material into individual particles. Often such prior art devices incorporate various aspects on the exterior of the dosage form or in the device itself such as channels, variously configured inlets, outlets, and orifices or other turbulence promoting means for improving the dispersion of the particles.
However, such schemes typically result in modest improvement in dose efficiency. The present invention addresses these disadvantages in the prior art devices by providing for an internally pierced dosage form that also includes one or more adjacent gas filled blister chamber(s) expressed in a manner to provide improved powder dosage delivery efficiency. Device technology has lagged current powder formulation and powder engineering capabilities such that the enhanced precision and effectiveness of new and existing powdered drugs can be fully harnessed. The present disclosure provides dosage forms with integrated dispense energetics for delivery of predetermined quantities of dry powder or granular pharmaceutical or medical compositions for local, intracranial and/or systemic action. Integrating the device energetics into the dosage form reduces overall device cost, complexity, and bulk to improve patient compliance and ease of use.