Abstract:
Patient-specific polypills, or similar drug products with potential to benefit from reduced need for bulking agent and preferably having multiple active ingredients, producible via appropriately adapted “micro-dosing” technologies not requiring fluid-jet or like substrate and solvent dependent approaches, having less need for excipient, particularly filler, so that the products may contain a larger number of different drug substances having a lower overall number or amount of excipient materials and/or may contain drug substances having comparatively less need for formulation development or pre-production processing and/or may contain fewer potential causes of side effects.

Description:
CROSS-REFERENCE 
       [0001]    This filing is a US continuation application claiming priority to (and reiterating select portions of) U.S. continuation application Ser. No. 13/757,828, filed on Feb. 3, 2013, which claims priority to international patent application PCT/US2011/062167, filed on Nov. 26, 2011, which claims priority to U.S. provisional application 61/426,576, filed on Dec. 23, 2010, all of which are hereby incorporated by reference in their entireties. 
     
    
     FIELD 
       [0002]    This application relates to pharmaceuticals, and more particularly, relates to patient-specific drug products having high drug loads achievable by “micro-dosing” dispensing technology with filler-free capability for reducing diluent used. 
       BACKGROUND 
       [0003]    This section provides background information related to the present disclosure, which is not necessarily prior art. Separate and distinct topics addressed for background in this section include: 1) the traditional and current practice of pharmaceutical “compounding,” 2) benefits and challenges of combination drugs or “polypills,” 3) “inkjet” based dispensing approaches for customizing drug oral dosage forms, and 4) current “micro-dosing” technologies for expediting manufacturability of pills for clinical trials. 
         [0004]    Pharmaceutical “compounding” is when a pharmacist prepares medication uniquely for a particular patient, based on a physician&#39;s prescription. Before the prevalence of mass-produced drugs, this was a very common practice, but now it has largely been relegated to special cases where a mass-produced version of a drug is either unavailable or unsuitable for a patient. Provided that each compounded medication is uniquely prepared for an individual patient pursuant to a physician&#39;s order, compounding generally falls outside the jurisdiction of the FDA and instead within the regulation of the practice of Pharmacy under relevant state law. 
         [0005]    Most compounding is either manual or partially-automated with the help of certain tools or equipment. So-called Automated Compounding Devices (ACDs), having full automation, exist at this time only for parenteral/intravenous (I.V.) medications, which are prepared as comparatively high-volume liquid solutions administered from bags (typically in a hospital). There is a noteworthy distinction between “reconstitution” which is performed according to a manufacturer&#39;s instruction versus “compounding” which is performed according to a doctor&#39;s prescription. Compounding of solid oral dosage forms is relatively rare today for several reasons, including the time and skill involved compared to the relative logistical ease of using mass-produced products instead. 
         [0006]    “Polypills” or “combopills” are pills (capsules or tablets) containing multiple medications, manufactured to have combinations and dosages that would get prescribed together. For example, one particular “5-in-1 polypill” is targeted for heart-disease patients and it contains three blood pressure medications, a cholesterol reducer, and aspirin. Polypills are not presently common—especially for more than two drugs—partly because each permutation of drugs and dosages to be marketed must first be developed (including blends with appropriate inactive ingredients), trialed (for a suitable population), FDA-approved, manufactured, and stocked. To be worthwhile for a drug manufacturer, a particular drug/dosage permutation would need to prove suitable for a large number of people. Hence, manufactured polypills lack much personalizability. Alternatively, personalized polypills are possible via custom-compounding by a pharmacist, but very few pharmacies offer such service. 
         [0007]    Much research has been done over many years on the potential to use inkjet printing based technologies for producing oral drug dosage forms, which may have applicability for facilitating patient-customized pills or polypills, including with customized formulations; Hewlett-Packard has published and patented significantly on inkjet-related approaches (e.g. U.S. Pat. Nos. 6,962,715, 7,727,576, and 7,707,964), which can offer precision and accuracy for spraying or jetting liquid drops of fluid API-in-solution onto an ingestible substrate such as a sheet or film, as well as for facilitating layer-by-layer deposition of powder substances (which is useful in making controlled-release tablets, via binding agents for “3-dimensional printing.” Ink-jet principles have also been adapted for dispensing liquid drugs into vials, or onto porous tablet substrates. All such ideas have been suggested to offer benefits for R&amp;D, mass production, and customized dosage forms—including for multiple drugs. However, their dispensation is restricted to liquids, and to work with capsules they require an intermediary substrate. 
         [0008]    In another development which is wholly unrelated to compounding or polypills, there have emerged some technologies to aid the manufacturability of new drugs for clinical trials. To manufacture drug capsules for clinical trial patients, traditionally this had required a choice between either developing a formulation with appropriate excipient(s) to permit automated manufacture (which was not precise enough to accurately handle raw drug substance without bulking), or else manually weighing the active pharmaceutical ingredient (API) for each capsule (requiring much time and skill, especially for potent substances). In recent years, certain manufacturing equipment has solved this dilemma and thus expedited many candidate drugs&#39; manufacturability. 
         [0009]    In order to allow automated manufacture without needing to develop a formulation, certain capsule filling machines have been developed which possess ability for “micro-dosing” very small amounts of powder with great precision, speed, and reliability. These are utilized to place raw API directly into capsules, in order to postpone the need to develop blends until initial studies can be done. This can save several months of delays before trials, thereby allowing failures to occur faster and with less sunk-cost. Simple formulations or select excipients can be included as well when desired, which may still involve significantly less mass than would otherwise be needed without micro-dosing. The most successful of such systems have used a “pepper-shaker” means (e.g. U.S. patent application Ser. Nos. 11/571,169 and 12/035,037). 
         [0010]    For example, the “Xcelodose” line of products by Capsugel can produce “API only” capsules—thus enabling sooner human trials without needing to first develop a formulation or perform compatibility or preformulation studies. Precise “micro-dosing” or “micro-filling” can be accurate to 100 micrograms, with minimal waste/attrition owing partly to the lack of a powder bed. Also, capsule type/size and powder properties can vary significantly. Other systems featuring similar capability, using significantly different technological means, are available from other companies: Mettler-Toledo has the “Quantos” and Symyx has the “Powdernium,” which employ other precision-dispensing mechanisms. Known usage and exploitation of all such capabilities has only extended to research and development (R&amp;D) applications &amp; clinical trial product manufacturing—and only for single-drug products. 
       SUMMARY 
       [0011]    This section is not a comprehensive disclosure of the invention&#39;s scope or features. 
         [0012]    The present invention involves medications prescribed for individual patients. Aspects of inventive items and processes herein include precision micro-dosing technology, which enables very small amounts of drug substance to be reliably and accurately dispensed without requiring non-therapeutic diluent. 
         [0013]    Applications include custom-prescribed polypills in pharmacies (e.g., hospital, retail, or mail-order), including customized dosage levels (beyond the mass-produced options). This could facilitate use of compliance-packaging, and potentially reduce medication error by reducing pill-burden. 
         [0014]    Further inventive details and areas of applicability will become apparent from the description provided herein. The description, drawings, and examples in this specification are intended for purposes of illustrative purposes only and are not intended to limit the scope of the present disclosure. 
     
    
     
       DRAWINGS 
         [0015]    The drawings described herein are for illustrative purposes. 
           [0016]      FIG. 1  is an example of a simple and generalized conceptual-relational diagram of a polypill-capable micro-dosing compounding system. It features a base unit comprising micro-dosing capsule-filling instrumentality as a central component of the overall system  105  which allows the inputs of patient information via user interface  101  and ingredient substances  104  via various possible logistical approaches to result in the output of said patient&#39;s pills  106  being produced in the specified quantity. Appropriately programmed software  102  could feasibly reside in various locations and it controls a plurality of dispensing mechanisms such as heads  103  which are operationally integrated with each other as well as said central instrumentality. Optional integrated accessories  107  may facilitate the system itself processing select ingredient material(s) among other functions. Capsule shells are not shown, but would of course be an input also. 
           [0017]    The remaining figures depict a particular example for dispensing, using the “salt/pepper-shaker” approach. 
           [0018]    Specifically, in  FIG. 2  there is an overall view of such a system, including a monitor for display  201 , a keyboard  202  for entry or retrieval of information such as a given patient&#39;s drug(s) and dosage(s), and a casing  203  with internal components of the dispensing mechanism. A separate cartridge tray  204  holds dispending heads/cartridges not being used in a given run. 
           [0019]      FIG. 3  shows a view of this same system without the casing to reveal the central processing unit or CPU  301 , a pill rack tray  302 , and a rotor to hold and position dispensing heads/cartridges  303 . 
           [0020]      FIG. 4  zooms further to show the tips of dispensing heads  401 , the solenoid  402  having a pointed rod to tap the head, rubber padding  403  to isolate vibration from other heads not being tapped, and a highly-sensitive scale or micro-balance such as a Zeta scale  404  under the capsule being filled to provide continuous feedback during filling to influence the rate of tapping. 
           [0021]      FIG. 5  shows a cross-sectional cutaway of a dispensing head secured to the rotor via magnets  501  built in to the rotor holder and configured to pull and hold the head against said rubber padding with sufficient force to be stable without being so tight as to defeat the isolative function of the rubber padding. 
           [0022]      FIG. 6  shows a pill rack  601  which slides within in said pill rack tray, and which contains enough holes  602  for a particular prescription run. 
           [0023]      FIG. 7  shows a cross-sectional cutaway of a portion of the pill rack tray showing how example capsule pieces  701  may fit therein. Moreover, in this particular configuration, the curvature of the capsule shell bottom  702  is exploited as it partially protrudes through a comparatively smaller hole in the bottom of the pill rack (not large enough in diameter to let the full capsule fall through), which in turn facilitates weighing each pill from below—as the rack slides/advances between capsules going over the scale. 
       
    
    
     DESCRIPTION 
       [0024]    Important characteristics are provided so that this disclosure will convey the full inventive scope to those skilled in the art. It will be apparent to those of ordinary knowledge of existing relevant technologies that some details need not be employed, that some attributes may be embodied in many different forms, and that neither should be construed to limit the scope. 
         [0025]    The present invention encompasses pills tailored to individual patient needs. Embodiments combine the principle of pharmaceutical compounding with the technology of precision micro-dosing. 
         [0026]    While most embodiments are expected to be for solid-form APIs, the invention encompasses embodiments for semi-solid (i.e. lipid-based, poorly water-soluble compounds) and some fluidic means—as well as applications for the output produced. Likewise, most embodiments are expected to be for non-biological (“small-molecule”) drugs, however, some biopharmaceuticals are feasible to incorporate—such as peptides/proteins suitable for oral delivery via appropriate formulations under development capable of preventing enzymatic degradation in vivo, and overcoming their unique obstacles to dissolution and intestinal permeation. Furthermore, while the primary uses and benefits of the invention are expected to focus on human patients, many concepts are readily adaptable to analogous veterinary applications (where legally permitted). 
         [0027]    The ability to avoid the need for diluents (also sometimes known as “fillers” or “bulking agents”), made possible by the micro-dosing/insertion features presently being directed at clinical-trial pill manufacture—is an aspect of making it practical to have automated compounding of multi-drug polypills and/or personalized-dosage pills. For example, grinding tablets to put into capsules would be prohibitively voluminous for many polypills, and likewise for using powder blends that fail to omit much unnecessary material. (Often such “non-functional” excipients are used now to facilitate handling, measuring, manufacturability, controllability, etc.—and a significant part of their role is to add volume or mass.) This is partly because of the space-saving consequences of limiting unnecessary content, along with the reduced need for usage or validation of formulations, reduced waste, and the net overall reduction of ingredient processing and preparation. By contrast, pharmacologically functional excipients, or stability-enhancing or inter-substance barrier excipients could add relatively little mass or volume and thus can still be usefully employed where appropriate. Of course, any remaining free space in a capsule may optionally be filled with diluent if desired. 
         [0028]    Embodiments cover API or formulation in sufficiently small and exact quantities as to substantially eliminate need for non-therapeutic diluent, along with packaging for enhancing patient adherence. 
         [0029]    Existing technical approaches found in today&#39;s automated capsule-filling machines may be used. Such operational principles can be adapted directly from existing micro-dosing machines such as by Capsugel (“Xcelodose”), Mettler-Toledo (“Quantos”), and Symyx (“Powdernium”). 
         [0030]    Some feasible ways to adapt current micro-dosing design principles toward multi-drug capability involve coordinating multiple dispensing arms and heads, for multiple frequently-used APIs/drugs, some of which could remain on “stand-by” during any given prescription when not among the APIs being selected—for embodiments where supplies of all available ingredients need not be loaded by the operator between every use. This could be arranged such that the chosen heads travel to each capsule—or vice versa. With these approaches, a microbalance weighing the capsules being filled may provide only an aggregate reading for total accumulated content dispensed, hence the feedback algorithm might also continuously calculate the subset of weight attributable to each additional drug being dispensed in succession (or re-tare between). Additional coordination and control algorithms could be included to handle issues of sequence management, non-interference, etc. Many such adaptations are possible, with varying degrees of complexity but with comparable feasibility as for many similar electro-mechanical pharmaceutical devices. 
         [0031]    Embodiments may comprise barriers between APIs that should not be in contact within capsules (i.e. for inter-drug stability concerns in vitro). One way to achieve intra-capsule separation is a “capsule-in-capsule” approach: preparing a small capsule  703  containing API(s)  704  to be segregated from other(s), for subsequent insertion into a larger capsule  705  containing said other(s)  706 . This would require a machine amenable to varying capsule sizes (and perhaps capsule substances), and could incorporate a mechanism for automated insertion of the smaller capsule into the larger capsule—performed along with API-dispensing into the larger capsule. Micro-encapsulated API particles  707  may instead provide separation on the particle-level, and could also be utilized to achieve sustained/delayed release characteristics if desired. (Note that controlled-release or inter-drug separation might be achieved inherently if excipient blending or granulation is employed for some simple formulation. Alternatively, delayed-release and/or multi-compartment capsules  708  could be used.) Such possibilities could also help control taste, when capsules are expected to be re-opened for consumption rather than being swallowed whole. Embodiments may use current or later-developed means of achieving sufficient separation, such as exploiting hydrophobicity/hyrdophilicity, microcapsules  709 , or nanoparticles. 
         [0032]    Implementation methods include usage of custom polypills for outpatients with high pill-burden, including compliance packaging for outpatients, as well as hospital or long-term-care inpatients—for whom medication dispensation and administration errors occur in correlation to the quantity and frequency of medication. 
         [0033]    Another related use is in conjunction with blister-packing or the like (which is often required for pills of nursing-home patients) or other unit-dose packaging or even specialized dispensing apparatuses; or, in the case of health-system pharmacies, the small plastic packets/pouches that hold one or more pills designated for inpatients (often with printed labeling on the outside). Note that inpatients&#39; drugs and dosages are often not “settled” and can thus change often, so adaptation there would require having low pill quantities per machine run. 
         [0034]    A preferred embodiment of the immediate output of the system and methods, where applicable, is a capsule containing multiple drugs of patient-customized selection and dosage, which may be granulated blends, encapsulated particles, or microspheres. A preferred embodiment of the eventual ultimate output of the system and methods herein, for nursing-home patients or hospital outpatients having high pill-burden, is compliance-package blister-packs designating a single pill to be taken at particular time(s) or with a particular meal(s) each day. The latter requires combined implementation with appropriate packaging equipment. 
         [0035]    Some notable advantages which help to elucidate how to target and apply the invention include (without limitation) enabling more pharmacies to offer prescription-compounded capsules suited to individual patients, thereby expanding access to personalized drug dosages and combinations thereof such as via customized polypills—with resultant benefits to patient convenience, compliance, and health. This can facilitate adherence to multi-drug regimens, whether for different conditions or combination therapy for a single condition. When using unsealed or re-openable capsules, this also facilitates subsequent mixing or dissolving the dispensed powder with food or drink or other solvent. And in contrast to inkjet methods, the invention notably entails the ability to custom-compound by placing pharmaceutical materials into capsules without necessarily requiring first dissolution into solvent and deposition onto a substrate/sheet. 
         [0036]    One safety application and benefit especially applicable to hospitals or long-term care facilities or the like is the potential to reduce inpatient medication errors (particularly dispensation or administration errors pertaining to incorrect drugs or dosages, including omission and wrong-dose and wrong-time errors) by significantly reducing the number of pills needing to be administered, handled, etc., which is a significant factor in medication error risk. Medication errors among highly-medicated patients have been documented to account for many injuries and costs. High rates of medication errors in assisted-living facilities and the like occur with the following medication classes: cardiovascular, anti-convulsant, anti-psychotic, anti-infective, anti-platelet, anti-diabetic, laxative, anti-hyperlipidemic, anti-depressant, and others. 
         [0037]    Regarding outpatients, important applications involve patient compliance, and thus safety, as patient noncompliance among high pill-burden patients has been documented to account for many injuries and costs. High pill-burden outpatient groups often include transplant, HIV, cancer, mental-health, and others. Extensions of the drug-consolidation potential of polypills include, for example, the ability to prescribe two separate polypills (perhaps using labeled capsules) for morning and night, with compatible medications being clustered and incompatible medications separated for patient safety (certain drugs could also overlap between them). Another variation on this could include four daily polypills—in conjunction with “compliance packaging” or the like—as some highly medicated patient groups require multiple medications with breakfast, lunch, dinner, and at bedtime. (Of course, such packaging could also be useful for nursing home inpatients, where blister-packing is often a legal requirement.) Furthermore, select niche patient groups may be targeted who are at unique risk of error (e.g., blind patients). 
         [0038]    An additional niche application/advantage lies in being able to gradually increase or decrease a patient&#39;s dosage of any particular drug in small increments, such as when tapering or phasing one off of a drug to discontinue a therapy no longer needed—while also avoiding withdrawal adverse events. 
         [0039]    Institutional settings whose principal purposes is not healthcare but which nonetheless provide healthcare, such as prison facilities, are another context in which consolidating and streamlining medications could provide organizational efficiencies as well as patient benefits. 
         [0040]    Practitioners&#39; options may also be broadened to more often prescribe drugs whose manufactured forms may be discontinued or unavailable. In some cases it could in effect ease drug shortages—whose causes include production delays, forecasting uncertainties, inventory planning issues, or manufacturing problems—by eliminating intermediary steps or bottlenecks in the supply chain. It can also address drugs whose mass-produced dosage levels are not optimal for a patient&#39;s weight, age (e.g. pediatrics), size, genetic profile, or condition severity—as mass-produced drug products have few dosing options, often based upon clinical trials which can have limited subject demographics (e.g. due to difficulty in patient recruitment, which has been notably documented regarding cancer drug trials). Further, custom dosing reduces demand for pill splitting—a practice which presents various safety and efficacy concerns, as has been advised against by the FDA. 
         [0041]    While the text and drawings herein describe to and enable those of ordinary skill, such persons will also understand and appreciate the existence of enumerable variations. Hence the foregoing description is not intended to be exhaustive, and any references herein to the “invention” are intended in such a spirit.