FIELD OF THE INVENTION
The present is directed to a delivery device and method for the oral administration of therapeutic agents in powder form for gastrointestinal deposition.
BACKGROUND OF THE INVENTION
The most prominent mode of delivery of therapeutic agents is by the oral route by means of solid dosage forms such as tablets and capsules. Oral administration of solid dosage forms is more convenient and accepted than other modes of administration, e.g. parenteral administration. However, the manufacture, dispensing and administration of solid dosage forms are not without associated problems and drawbacks.
With the manufacture of solid dosage forms, in addition to the active agent, it is necessary to combine other ingredients in the formulations for various reasons, such as to enhance physical appearance, to provide necessary bulk for tableting or capsuling, to improve stability, to improve compressibility or to aid in disintegration after administration. However, these added excipients have been shown to adversely influence the release, stability and bioavailability of the active ingredient. The added excipients are a particular problem with drugs which require a high dose in order to provide a therapeutic effect, e.g., biphosphonate drugs. The inclusion of the additional excipient can make the final tablet extremely large which could result in esophogeal damage due to the physical characteristics of the dosage form if it is not swallowed properly. Esophogeal damage can also be caused by toxicity caused by the drug itself, if the tablet becomes lodged in the throat or has an increased transit time through the esophagus, due to its increased size.
Further, the tableting of certain drugs has many associated production problems. In particular, many drugs, e.g., acetaminophen, have poor compressibility and cannot be directly compressed into solid dosage forms. Consequently, such drugs must either be wet granulated or manufactured in a special grade in order to be tableted which increases manufacturing steps and production costs.
The adherence to good manufacturing practices and process controls is essential in order to minimize dosage form to dosage form and batch to batch variations of the final product. Even strict adherence to these practices still is not a guarantee that acceptable variation will occur.
With the high cost of industrial scale production and governmental approval of solid dosage forms, such formulations are often available in a limited number of strengths, which only meet the needs of the largest sectors of the population. Unfortunately, this practice leaves many patients without acceptable means of treatment and physicians in a quandary with respect to individualizing dosages to meet the clinical needs of their patients.
The dispensing of oral solid dosage forms also makes the formulations susceptible to degradation and contamination due to repackaging, improper storage and manual handling.
There are also many patients who are unable or unwilling to take conventional orally administered dosage forms. For some patients, the perception of unacceptable taste or mouth feel of a dose of medicine leads to a gag reflex action that makes swallowing difficult or impossible. Other patients, e.g., pediatric and geriatric patients, find it difficult to ingest typical solid oral dosage forms, e.g., due to tablet size.
Other patients, particularly elderly patients, have conditions such as achlorhydria which hinders the successful use of oral solid dosage forms. Achlorhydria is a condition wherein there is an abnormal deficiency or absence of free hydrochloric acid in the gastric secretions of the stomach. This condition hinders the disintegration and/or dissolution of oral solid dosage forms, particularly dosage forms with high or insoluble excipient payloads
Flavored solutions/suspensions of some therapeutic agents have been developed to facilitate the oral administration of oral agents to patients normally having difficulty ingesting conventional solid oral dosage forms. While liquid formulations are more easily administered to the problem patient, liquid/suspension formulations are not without their own significant problems and restrictions. The liquid dose amount is not as easily controlled compared with tablet and capsule forms and many therapeutic agents are not sufficiently stable in solution/suspension form. Indeed, most suspension type formulations are typically reconstituted by the pharmacist and then have a limited shelf life even under refrigerated conditions. Another problem with liquid formulations which is not as much a factor with tablets and capsules is the taste of the active agent. The taste of some therapeutic agents is so unacceptable that liquid formulations are not a viable option. Further, solution/suspension type formulations are typically not acceptable where the active agent must be provided with a protective coating, e.g. a taste masking coating or an enteric coating to protect the active agent from the strongly acidic conditions of the stomach.
Another alternative to oral dosage forms for certain medications is aerosol dosage forms which administer therapeutic agents for deposition to the pulmonary systern. The use of aerosol dosage forms has many advantages for the patient. The packaging of the active agent is convenient and easy to use, generally with limited manual manipulation. As the medicine is sealed within the device, direct handling of the medication is eliminated and the contamination of the contents from air and moisture can be kept to a minimum. Further, a metering valve can be included in the device in order to individualize the dose for particular patients. However, such formulations also have drawbacks such as decreased bioavailability of the drug due to improper administration by the patient. For example, if a patient's breathing is not coordinated with the activation of the device, the active agent will not reach its intended site of action which will lead to a decrease in therapeutic benefit.
Another alternative is dry powder dosage forms. For example, International Patent Application WO 94/04133, hereby incorporated by reference, describes a powder composition for inhalation which contains a microfine drug such as salbutamol sulfate and a carrier containing an anti-static agent. The carrier is calcium carbonate or a sugar, especially lactose. The amount of carrier is 95-99.99 weight percent. The compositions are said to be useful for delivery of the active agent to the lungs while providing reduced side effects such as nausea by maximizing its proportion of drug reaching the lungs.
U.S. Pat. No. 4,590,206, hereby incorporated by reference, describes capsules, cartridges or aerosol containers containing spray-dried sodium cromoglycate in finely divided and un-agglomerated form. A substantial proportion of the individual drug particles have sizes and shapes which allow deep penetration into the lung and yet are free-flowing so as to allow capsule filling.
International Patent Application WO 93/25198, hereby incorporated by reference, is directed to an ultrafine powder for inhalation. The powder comprises a drug and hydroxypropyl cellulose and/or hydroxypropylmethylcellulose. More than 80 weight percent of the particles in the powder are said to have a particle diameter of 0.5-10 microns. The powder is said to be able to reach the lower windpipe and bronchi.
Due to the disadvantages of known drug delivery discussed above (as well as other disadvantages) there exists a need in the art for the development of a device and method for facilitating delivery of a wide range of therapeutic agents for gastrointestinal deposition and which minimize pulmonary deposition of materials having undesirable or unknown pulmonary toxicology but which are approved for oral delivery.
OBJECTS OF THE INVENTION
It is an object of the invention to provide a method and system for the delivery of a dose of a therapeutic agent in multiparticulate form for gastrointestinal deposition.
It is an object of the invention to provide a method and system for the oral administration of a dose of a therapeutic agent in multiparticulate form into the oral cavity of a patient for gastrointestinal deposition.
It is an object of the invention to provide a method and system for the dispensing of a dose of a therapeutic agent in multiparticulate form, for subsequent administration into the oral cavity for gastrointestinal deposition.
It is a further object of the invention to provide a method and system for delivery of multiple doses of a therapeutic agent in multiparticulate form which minimizes the need for inert pharmaceutical excipients.
It is a further object of the invention to provide a method and system for delivery of multiple doses of a therapeutic agent in multiparticulate form for fast, standard, sustained, controlled, or targeted release.
It is a further object of the invention to provide a method and system for the delivery of a dose of a therapeutic agent for gastrointestinal deposition which protects the active ingredient from contamination and moisture.
It is a further object of the invention to provide a method and system for the delivery of a dose of a therapeutic agent for gastrointestinal deposition which allows for the dosing to be adjustable based on the needs of an individual patient or patient population.
It is a further object of the invention to provide a method and system for the delivery of a dose of a therapeutic agent for gastrointestinal deposition which can be used for a wide variety of agents for a wide variety of therapies, e.g. to treat systemic and/or local conditions.
It is a further object of the invention to provide a method and system for the delivery of two or more different drugs in multiparticulate form simultaneously or at different times. The device of the system can hold the 2 or more drugs in separate compartments or together in the same compartment.
It is a further object of the invention to provide a method and system for the delivery of a dose of a therapeutic agent for gastrointestinal deposition which provides an acceptable variability from dose to dose and batch to batch.
It is a further object of the invention to provide a method of producing a unit dose of a drug without limitation to the compressibility or dose amount of the drug.
It is a further object of the invention to provide a method and system for the delivery of a dose of a therapeutic agent for gastrointestinal absorption which can be administered and swallowed without the aid of a fluid.
It is a further object of the invention to provide novel oral dosage forms in multiparticulate form.
The above objects of the invention and others are achieved by virtue of the present invention, which in certain embodiments provides a drug delivery system for delivery of a drug for gastrointestinal deposition. The system comprises a multiple unit dosing device comprising a housing and an actuator, the device containing multiple doses of multiparticulates comprising drug particles, the device upon actuation delivering a unit dose of the multiparticulates for gastrointestinal deposition, the multiparticulates having a mean particle size of greater than 10 μm and preferably less than about 1 mm in order to minimize pulmonary deposition of the multiparticulates and such that an effective dose of the drug cannot be delivered into the lower lung of a human patient. The drug delivery system can be used to administer the unit dose of multiparticulates into the oral cavity of the patient (in-vivo) or to dispense the unit dose into an intermediate receptacle (ex-vivo) for subsequent gastrointestinal deposition.
In certain embodiments, the invention provides a device for delivery of a drug comprising a housing and an actuator, the device capable of containing multiple doses of multiparticulates comprising drug particles, the device upon actuation capable of delivering a unit dose of the multiparticulates wherein the multiparticulates have a mean diameter of greater than 10 μm, and preferably less than about 1 mm in order to minimize pulmonary deposition of the multiparticulates and such that an effective dose of the drug cannot be delivered into the lower lung of a human patient. The device can be used to administer the unit dose of multiparticulates into the oral cavity of the patient (in-vivo) or to dispense the unit dose into an intermediate receptacle (ex-vivo) for subsequent gastrointestinal deposition.
In certain embodiments, the invention provides a device for delivering multiple unit doses of a drug in multiparticulate form comprising a housing for containing multiple unit doses of a multiparticulates comprising drug particles, the housing having an opening for delivering a unit dose of the multiparticulates; a metering component operable between a first position in which it receives a unit dose from said housing and a second position in which it delivers the unit dose of drug to the opening in the housing; the unit dose being delivered from the device to the exterior of the device through the opening of the housing with an air flow of less than about 20 litres/min. In preferred embodiments the device does not include a propellant to facilitate the delivery of the unit dose and preferably the unit dose is delivered through the opening substantially by gravitational force.
In certain embodiments, the invention provides a device for delivering multiple unit doses of a drug in multiparticulate form comprising a housing to contain multiple unit doses of multiparticulates comprising drug particles, the housing having a mouthpiece for delivering a unit dose of the multiparticulates into the oral cavity of a patient; means for removing a unit dose of the multiparticulates from the housing and delivering the unit dose to the mouthpiece, the mouthpiece having a drug receiving end connected to the removing means and a drug delivery end through which the unit dose is delivered outside the device, the mouthpiece being positioned on the device such that drug particles expelled through the mouthpiece can be deposited in the oral cavity of a patient substantially without deposition of drug particles into the lungs of the patient.
In certain embodiments, the invention provides a device for delivering multiple unit doses of a drug in multiparticulate form comprising a housing to contain multiple unit doses of multiparticulates comprising drug particles; the housing having a mouthpiece for delivering a unit dose of the multiparticulates into the oral cavity of a patient; a metering component for removing a unit dose of the multiparticulates from the housing and delivering the unit dose to the mouthpiece, the mouthpiece having a drug receiving end connected to the metering component and a drug delivery end through which the unit dose is delivered outside the device, the mouthpiece being positioned on the device such that drug particles expelled through the mouthpiece can be deposited in the oral cavity of a patient substantially without deposition of the drug particles the lungs of the patient.
In certain embodiments, the invention provides a method of preparing a drug delivery system for delivering multiple doses of a drug for gastrointestinal deposition comprising preparing a multiparticulate drug formulation in a manner to provide particles which when placed in the oral cavity and swallowed are deposited to the gastrointestinal tract and not deposited in any substantial amount to the lungs; and placing multiple unit doses of said drug formulation in a device which meters a single unit dose for delivery.
In certain embodiments, the invention provides a method of treating a patient in need of multiple doses of a drug for gastrointestinal deposition comprising preparing multiparticulates comprising drug particles in a manner wherein the drug particles when placed in the oral cavity and swallowed are deposited to the gastrointestinal tract and not deposited in any substantial amount to the lungs; placing multiple unit doses of the multiparticulates in a device which meters a single unit dose for delivery; and either (a) administering the unit dose into the oral cavity of a patient or(b) dispensing the unit dose into an intermediate receptacle and thereafter administering the unit dose into the oral cavity of the patient.
In certain embodiments, the invention provides a drug formulation for gastrointestinal deposition comprising a non-compressed free flowing plurality of particles comprising a drug and a pharmaceutically acceptable excipient, the particles having a mean diameter of greater than 10 μm to about 1 mm, the particles comprising at least about 80% drug, preferably at least about 90% drug.
In certain embodiments, the drug formulation can further comprise a facilitating agent (e.g., an absorbability enhancer, a texture modifier, a taste masking agent, a sweetener, a flavorant, a salivary stimulant, an effervescent compound or combinations thereof) which enhances the oral administrability of the unit dose.
In certain embodiments, the drug formulation can further comprise a material to provide fast, standard, sustained, controlled, or targeted release.
In certain embodiments, the invention provides a method for delivery of a drug comprising delivering multiparticulates comprising drug particles via the use of a multiple unit dosing device comprising a housing and an actuator, the device upon actuation delivering a unit dose of the multiparticulates, and thereafter re-using said device to deliver additional unit doses of multiparticulates at appropriate dosing intervals, the drug particles having a mean diameter of greater than 10 μm, and preferably less than about 1 mm to minimize pulmonary deposition and such that an effective dose of the drug cannot be delivered into the lower lung of a human patient. In certain embodiments of the method, upon actuation, the delivery is by administering the unit dose into the oral cavity of the patient (in vivo). Alternatively upon actuation, the delivery is the dispensing of the unit dose into an intermediate receptacle (ex vivo) for subsequent gastro-intestinal deposition.
In certain embodiments of the invention, greater than about 80% of the unit dose is deposited in the gastrointestinal tract, preferably greater than about 90% or greater than about 95%, and most preferably, about 100% of the unit dose is deposited in the gastrointestinal tract.
In preferred embodiments of the invention, the unit dose comprises a discreet collection of multiparticulates. For purposes of the invention, a “discreet collection” means that the multiparticulates are in the form of a non-compressed free flowing unit and not dispersed in a cloud or mist, which effectively minimizes inhalation of the active agent into the lungs of the patient. The unit dose can be, e.g., from about 0.01 mg to about 1.5 g, depending on the dose of the active agent being delivered. For example, the unit dose can be from about 1 mg to about 100 mg or from about 10 mg to about 50 mg. Preferably, the unit dose is administered to the tongue, most preferably towards the front of the tongue behind the teeth, where it can be easily swallowed with or without the need for an additional fluid. However the invention does contemplate delivery to any portion of the tongue, taking into account, e.g., the taste sensations of different sections of the tongue and/or individual patient preference associated with comfort, e.g. mouth position.
In certain embodiments of the invention, the mean diameter of the drug particles is of a size which mininizes their capacity to be inhaled into the lower lung. Typically, the agglomerate mean particle size of the drug particles is greater than 10 μm, preferably greater than about 50 μm or greater than about 75 μm. In certain embodiments of the invention, the mean particle size range of the drug particles is from about 100 μm to about 1 mm. In preferred embodiments, greater than 80% of the drug particles have the above disclosed diameter (not mean diameter), e.g. 80% of the drug particles have a diameter of greater than 10 μm, or a diameter of from about 100 μm to about 1 mm. In other embodiments, greater than about 90% of the drug particles have the above disclosed diameter.
In certain embodiments of the invention, the mean diameter of the drug particles does not vary by greater than about 20%, preferably not greater than about 15% and most preferably not greater than about 10%.
In certain embodiments of the invention, the multiparticulates comprise a pharmaceutically acceptable excipient. The excipient preferably does not comprise more than about 20% of the multiparticulates by weight, preferably not more than about 10% by weight.
In certain embodiments of the invention, the excipient is coated with the drug, or the drug is coated with the excipient. Alternatively, the drug and the excipient can be a mixture of powders, each preferably being greater than 10 μm, preferably greater than about 50 μm or greater than about 75 μm.
In certain embodiments of the invention, the excipient can provide taste masking of the drug. In taste masking embodiments and other embodiments, the excipient can include flavors and/or sweeteners. In other embodiments, the excipient can provide a sustained or delayed release of the drug.
In certain embodiments of the invention, the multiple doses of the drug are contained in a reservoir. The reservoir can contain an amount of multiparticulates to provide any number of unit doses, e.g. from about 2 doses to about 400 doses. For ease in patient compliance, the reservoir has a sufficient quantity of to provide e.g. a days supply, a months supply or a years supply of doses, e.g. 30 or 365 for once daily dosing for a month or year, respectively.
In certain embodiments, the system can contain multiple dosing mechanisms in order to provide different dosage amounts for different times. For example, the system can comprise two dosing mechanisms which can provide a different dosage amount in the morning and the evening. In other embodiments, the dosing mechanism can be adjusted in order to increase or decrease the size of the dose.
In certain embodiments, the system can contain more than one reservoir, each containing a different drug or enantiomeric form of drug. Upon actuation, the desired amount of each drug is metered out for delivery, such metering being present in the factory or other place, e.g., a pharmacy. Such a system would be beneficial for combination therapy and would eliminate the need for multiple systems and would allow a much wider range of possible doses and dose combinations than hereto possible.
In certain embodiments of the invention, the system delivers up to about 80%, preferably up to about 90% of the doses supplied in the system, thus eliminating waste by providing an efficient system.
In certain embodiments of the invention, the variability between dose to dose is not greater than 5%. In certain embodiments of the invention, the delivery of the unit dose is facilitated by a gas, which may be provided by the patients own breath maneuvers or which can be contained in the system in the form of pressurized gas or liquid gas. Alternatively, the delivery of the unit dose can be facilitated by a liquid carrier. In such an embodiment, the liquid and the unit dose are mixed during or after the unit dose is discharged from the reservoir.
In certain embodiments of the invention, the device comprises a mouthpiece. Preferably, the mouthpiece is of sufficient length to minimize moisture exposure of the reservoir from outside the device. Preferably, the mouthpiece comprises a mouthpiece cap or closure to minimize the ingress of moisture (e.g., from saliva or humidity) into the device. In order to minimize moisture exposure of the reservoir, the invention can also include a desiccant. Further measures can be taken by making the device from a material which has water repellant properties to inhibit the accumulation of moisture. For example, the device can consist of a non-wetting material such as silicone, which if contaminated with moisture, would promote the formation of droplets which would run off and not adhere to the surface of the device and would not result in the accumulation of water. In certain embodiments, the device (especially the mouthpiece) can comprise a silver containing plastic or other material resistant to microbial growth.
In order to aid in patient compliance, certain embodiments of the invention include a counter or indicator to display the number of doses remaining in the system or the number of doses actuated.
In certain embodiments of the invention, the unit doses are individually metered prior to actuation, e.g., in the form of capsules or blisters, wherein each blister contains one individual unit dose. The system can be capable of containing any multiple of pre-metered unit doses, e.g. from about 2 to about 400 blisters.
In certain embodiments of the invention, the system is capable of being reloaded with additional doses (in reservoir or pre-metered form) upon full or partial depletion. Alternatively, the system can be manufactured wherein the device is disposable and is not capable of being reloaded with additional unit doses.
The present invention is also directed to a method of administering a drug to a patient for gastrointestinal deposition comprising formulating the drug in multiparticulate form; containing the multiparticulates in a drug delivery device capable of delivering multiple unit doses of the multiparticulates into the oral cavity; administering a unit dose of the multiparticulates to the oral cavity of the patient wherein greater than about 80% of the drug is deposited in the gastrointestinal tract. This method can be achieved, e.g., by controlling at least one at least one of the following factors: a) formulating the multiparticulates to have a mean diameter of greater than 10 μm; b) administering the multiparticulates with a device having a mouthpiece which directs the multiparticulates onto the tongue of the patient; c) administering the multiparticulates with a device which delivers the unit dose as a discreet collection; and d) administering the multiparticulates with a device having a flared mouthpiece.
The invention is also directed to methods of delivery (e.g., in vivo administration and ex vivo dispensing) and methods of treatment utilizing any of the disclosed embodiments directed to compositions of matter. The invention is also directed to methods of preparation of all of the disclosed embodiments.
The present invention is also directed to systems which contain particles greater than 10 μm of a particulate drug and particles of 10 μm or less of the same or a different drug which upon actuation, deliver a unit dose for oral and pulmonary administration.
The present invention is also directed to mouthpieces adapted to fit onto a drug delivery device for administering a drug in multiparticulate form into the oral cavity of a patient, the improvement being that the mouthpiece protrudes from the drug delivery device at an angle in order to direct the multiparticulates onto the tongue of the patient.
The present invention is also directed to mouthpieces which are conical or rectangular in shape and which provide a flared opening, wherein the area of the outlet of the mouthpiece is larger than the area of the inlet of the mouthpiece. This reduces the velocity of the delivered multiparticulates in order to minimize pulmonary deposition.
The present invention is also directed to mouthpieces and devices which drop the unit dose vertically onto the tongue with minimal or no horizontal velocity. This action directs the unit dose down to the tongue and minimizes movement of particles toward the back of the throat in order to minimize or avoid pulmonary deposition. In preferred embodiments, when the device is utilized as intended, greater than 80% of the unit dose is administered from the device in a downward direction from about 45 degrees to about 135 degrees based on a vertical baseline independent of the device. Preferably greater than 90% of the drug follows this direction.
The invention is also directed to methods of providing a therapeutic effect to a patient comprising administering to the patient a unit dose of a drug utilizing the systems, devices and formulations disclosed herein. The invention is also directed to methods of preparing the systems, devices and formulations disclosed herein.
The invention is also directed to novel powders for oral administration which are disclosed herein.
For purposes of the present invention, the term “device” refers to an apparatus capable of delivering a unit dose of drug.
The term “system” refers to a drug delivery device in combination with the disclosed multiparticulate drug having the specifications disclosed herein, e.g. drug particle size, excipient type, etc.
The term “discreet collection” refers to a non-compressed free flowing unit of multiparticulates with minimal particulate matter being dispersed in the surrounding environment (e.g., as a cloud or mist).
The term “drug” refers to any agent which is capable of providing a therapeutic effect to a patient upon gastrointestinal deposition. This encompasses all drugs which are intended for absorption for a systemic effect (regardless of their actual bioavailability) as well as drugs intended for a local effect in the gut and/or oral cavity, e.g. nystatin, antibiotics or local anesthetics.
The term “particle size” refers to the diameter of the particle.
The term “deposition” means the deposit of the unit dose at the intended point of absorption and/or action. For example, gastrointestinal deposition means the intended deposit of the unit dose in the gastrointestinal system for e.g., absorption for a systemic effect or to exert a local effect. Pulmonary deposition means the intended deposit of drug into the lungs in order to provide a pharmaceutical effect, regardless that the unit dose may enter the oral cavity prior to pulmonary deposition.
The term “dispense”, when used in connection with the devices and systems of the present invention, means that the device or system delivers the unit dose ex vivo with the intent of subsequent administration to a mammal. For example, the device or system can dispense the unit dose into a food, a liquid, a spoon, or another intermediate receptacle.
The term “administer”, when used in connection with the devices and systems of the present invention, means that the device or system delivers the unit dose in vivo, i.e., directly into the gastrointestinal tract of a mammal.
The term “deliver” is meant to cover all ex vivo and in vivo delivery, i.e.; dispensing and administering, respectively.
The term “patient” refers to humans as well as other mammals in need of a therapeutic agent, e.g., household pets or livestock. This term also refers to humans or mammals in need of or receiving prophylactic treatment.
In certain embodiments, the particulates are defined functionally with respect to the fact that they are of a size such that an effective dose cannot be delivered into the lower lung of a human patient. However, this definition should be understood to mean that a small percentage of drug (but not an amount effective to render a therapeutic effect) may in fact be inadvertently delivered to the lungs of the patient. Also, this definition is meant to define the particles, but not to limit the use of the invention to the treatments of humans only. The invention may be used for delivering doses of drugs to other mammals as well.
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