Patent Grant
10010509
Oral administration of pharmaceuticals is one of the most widely used methods for providing effective therapy for a variety of illnesses. For example, many powdered medications are administered orally to a person in dosage form such as tablets or capsules, while other medications are administered in liquid form.
Many individuals suffer from chronic health problems that require the regular administration of medicines, supplements, or other like substances. Diseases including, but not limited to, diabetes, allergies, epilepsy, heart problems, AIDS, and cancer all require the regular delivery of precise doses of medicine if patients are to survive over long periods of time. In some cases, some such medicines have a narrow therapeutic range and must be precisely dosed. If the patient falls below the range, the desired effect will not occur, and if the patient is above the range, then, the risk of toxic side effects increases. Additionally, in some cases, treatment plans require multiple medications that need to be taken all at once.
However, many pharmaceutical doses in tablet or capsule form are made in formulations of a predetermined amount of an active ingredient, such as 50 mg, 100 mg, etc. and/or a predetermined set of one or more active ingredients. Accordingly, it is often difficult or virtually impossible to split or divide a tablet or capsule to decrease or customize the dose administered. In fact, splitting or breaking of such tablets or capsules often results in fragments of unequal sizes. Therefore, researchers continue to seek improvements to pharmaceutical manufacturing processes such that variable doses of medicine and other pharmaceuticals can be easily formed.
The detailed description will make reference to the following drawings, in which like reference numerals may correspond to similar, though perhaps not identical, components. For the sake of brevity, reference numerals having a previously described function may or may not be described in connection with other drawings in which they appear.
Reference is now made in detail to specific examples of the disclosed device to make a bioactive dose and specific examples of ways for making a bioactive dose. When applicable, alternative examples are also briefly described.
As used herein, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise.
As used in this specification and the appended claims, “approximately” and “about” mean a ±10% variance caused by, for example, variations in manufacturing processes.
As used herein, “bioactive agent” means a composition that affects a biological function of a vertebrate directly or as a result of a metabolic or chemical modification associated with the vertebrate or its vicinal environment. An example of a bioactive agent is a pharmaceutical substance, such as a drug, which is given to alter a physiological condition of the vertebrate, such as a disease. In other words, a bioactive agent is meant to include any type of drug, medication, medicament, vitamin, nutritional supplement, other compound or combination thereof that is designed to affect a biological function of a vertebrate.
As used herein, “cold” means any temperature at which the evaporation rate of the carrier fluid is insufficient to remove a majority of the liquid during manufacture of the bioactive dose.
As used herein, “inactive” shall mean not biologically active.
As used herein, “ingestible” means any composition that is suitable for human consumption and is non-toxic. Furthermore, as used herein, “suitable for human consumption” means any substance that complies with applicable standards, such as food, drug, and cosmetic regulations in the United States.
In the following detailed description, reference is made to the drawings accompanying this disclosure, which illustrate specific examples in which this disclosure may be practiced. The components of the examples can be positioned in a number of different orientations and any directional terminology used in relation to the orientation of the components is used for purposes of illustration and is in no way limiting. Directional terminology includes words such as “top,” “bottom,” “front,” “back,” “leading,” “trailing,” etc.
It is to be understood that other examples in which this disclosure may be practiced exist, and structural or logical changes may be made without departing from the scope of the present disclosure. Therefore, the following detailed description is not to be taken in a limiting sense. Instead, the scope of the present disclosure is defined by the appended claims.
Traditionally, pharmaceuticals and dietary supplements have been manufactured by mixing bioactive agents with secondary ingredients, and then mechanically pressing the mixture into the form of a tablet or encapsulating the powder version of the mixture in an ingestible capsule. Such batch processing may be inherently inflexible with respect to manufacturing of desired dosages of bioactive agents and requires costly cleaning of equipment when switching between products. Additionally, in some cases, patients may require more personalized treatment, resulting in, as discussed above, the prescription of tablets or ingestible capsules with more than one bioactive agent for treating one or more health conditions or the prescription of tablets or ingestible capsules containing non-standard amounts of bioactive agents.
Recently, researchers have proposed inkjet printing processes as a way of manufacturing pharmaceuticals (see, e.g., Brian Craig Lee, U.S. Pat. No. 6,962,175, Nov. 8, 2005 and Iddys D. Figueroa, U.S. Pat. No. 7,727,576, Jun. 1, 2010). In the case of jettable formulations of bioactive agents, up to 95 weight % (wt %) of the formulation may be inactive carrier fluid. Removal of this inactive carrier fluid prior to encapsulation of the bioactive agents in a capsule is critical in order to manufacture commercial pharmaceuticals. In the past, evaporation by heating, or thermal evaporation, has been proposed. However, bioactive agents are often temperature sensitive and may degrade in the presence of heat. Additionally, the energy required to evaporate the excess carrier fluid can be substantial, and the cost of extra equipment necessary to accommodate the longer web path required in order to accomplish evaporation may be high.
In one example illustrating the disadvantages of thermal evaporation, 1 milligram (mg) of a bioactive agent and 9 mg of water, acting as a carrier fluid, may be deposited onto 5 square centimeters (cm2) of an ingestible substrate. In this example, the thickness of the jetted mixture is 18 μm and the areal density is 0.0018 g/cm2. Evaporating this quantity of water may require about 4.1 Joules/cm2, which translates to a power consumption of 4.1 kilowatts (kW) total, if the inkjet process has a substrate with a width of 20 cm and is at a print speed of 0.5 meters per second (m/s), about a quarter of the speed of a commercial high speed inkjet printer. Additionally, assuming that the time required to evaporate the 18 μm of water is limited by the diffusion of water vapor from a substrate at 50° C., the inkjet printing equipment may need to allow for 9 m of drying distance. Faster processing speeds may require proportionally more power and longer drying distances. Therefore, pharmaceutical manufacturing by inkjet printing processes with thermal evaporation may be unattractive because bioactive agents may be sensitive to heat and the necessary equipment may be expensive and may require high power consumption.
In accordance with the teachings herein, a device and corresponding method for manufacturing doses of bioactive agents by inkjet printing onto and in between ingestible sheets and removing excess inactive carrier fluid by cold fluid removal is presented. In this method, and as further discussed below, removal of the inactive carrier fluid by cold fluid removal may be accomplished by using a charge generating device to draw bioactive particles to a substrate and then using a contact roller or other cold fluid removal device to remove excess carrier fluid. Cold fluid removal may remove a sufficient amount of excess carrier fluid from the bioactive particles such that the remaining fluid may evaporate without the need for additional equipment. As a result, the upper surface of the ingestible substrate is left substantially free of liquid so that the bioactive agents may be readily encapsulated.
The device and corresponding method of manufacturing doses of bioactive agents utilizing the cold fluid removal approach disclosed herein has multiple advantages. First, in comparison to a method utilizing thermal evaporation, using cold removal of excess carrier fluid may use 30 times less drying power and may require 30 times less roller distance for drying. For example, the power necessary for removing about 10 μm thick of excess carrier fluid using the cold fluid removal process may be only a few watts, while the power necessary for completing the same process using thermal evaporation may be on the order of a kilowatt. Additionally, in this example, the roller space needed in the cold fluid removal process may be less than 0.5 m, whereas 5 to 10 m of roller space may be needed in a fluid removal process using thermal evaporation. Second, the cold fluid removal process may be inexpensive and the necessary equipment may be enabled to recycle carrier fluid with little additional production floor space resulting in cost savings. Third, the process does not subject the bioactive agents to elevated temperatures and therefore, there may be a decreased risk of degradation of the bioactive agents due to heat.
It should be noted that inkjet printing systems using cold fluid removal have been studied in the past (e.g. Omer Gila, U.S. Published Application 20110058001 Mar. 10, 2011). However, as further described below, the apparatus capable of producing controlled dosages of bioactive agents may include a printer capable of producing larger sized drops of bioactive agents; the apparatus disclosed herein may be capable of producing between 50 to 1000 ng sized drops whereas previous inkjet printing systems may be capable for producing between 3 to 15 ng sized drops.
A suitable formulation including a bioactive agent 106 may be produced by mixing the bioactive agent 106 with an inactive carrier fluid 104. In one example, the bioactive agent 106 may be made in powder form using standard chemical manufacturing processes and then, introduced into the carrier fluid using high shear mixing, bead milling, ultrasonic agitation or microfluidization in order to create a particulate dispersion of bioactive agent in carrier fluid. In other examples, the bioactive agent may be dissolved in the carrier fluid or dissolved in a secondary liquid vehicle that is immiscible in the carrier fluid. In the example wherein a secondary liquid vehicle is used, an emulsion may be created when the secondary liquid vehicle (including the soluble bioactive agent) and a dispersing agent are added to the carrier fluid. In one such example, food-grade mineral oil may be used as the carrier liquid, and water may be used as a secondary vehicle. In some examples, dispersing agents such as lecithin may be added to stabilize the dispersion. Furthermore, in some examples, the bioactive agent 106 may be insoluble in the carrier fluid 104, and in other examples, as further discussed below, the bioactive agent 106 may be soluble in the carrier fluid 104 but may precipitate out of the solution when it makes contact with the substrate 120 it is jetted on.
In some examples, the bioactive agent particles 106 may be between 25 nanometers (nm) and 500 nm in diameter, and as described above, may be any material that alters a physiological condition of the vertebrate, such as a disease. In some examples, the bioactive agent may include more than one type of bioactive particle, such as, for example, a vitamin and a medicament or two types of medicaments.
In one example, the bioactive agent 106 may be mixed with a non-polar, food-grade liquid, such as PURETOL® mineral oil (Suncor Energy, Calgary, Alberta). In other examples, vegetable oils, such as safflower, sunflower, corn, soybean, canola, peanut or palm oils, other similar dielectric liquids, or a combination thereof may be used as a carrier liquid. As discussed below, in some examples wherein the device for drawing the bioactive agent 106 to the substrate 120 is a charge generating device, such non-polar, food-grade liquids may act as an inactive carrier fluid 104 during the electrical process that may be employed to charge the bioactive agent and then, draw such bioactive agent to an ingestible substrate. In such examples, a non-polar (dielectric) carrier fluid may enable electrical separation of bioactive agent particles from the carrier liquid. On the other hand, a conductive, highly polar carrier, such as water, may screen injected charge, which may prevent electrical separation of particles from a carrier. Furthermore, in some examples, as briefly discussed above, additional ingestible dispersants such as lecithin may further be mixed in to introduce either steric or charge stabilization of the bioactive agent particles.
Next, in some examples, the bioactive agent mixture 108 may be introduced into any printing device 102 including, but not limited to, suitable production digital jetting devices. In some examples, these apparatuses may contain an apparatus 100 for jetting the mixture of bioactive agent 108 to a substrate 120, an apparatus 110 for drawing or pinning the bioactive agent 106 to the ingestible substrate 120, and an apparatus 116 for removing excess carrier fluid 104 using cold fluid removal. In some examples, the substrate may move from the jetting apparatus 100 to the pinning apparatus 110 to the fluid removal apparatus on a belt, drum or any other mechanical device capable of moving the substrate 120.
The bioactive agent mixture 108 may be jetted onto a suitable ingestible substrate 120. The suitability of a substrate 120 may vary depending on the nature of the bioactive agent 106 but may, in general, be safely edible or ingestible. In some examples, the substrate 120 may dissolve or degrade in body fluids or enzymes. However, the substrate 120 may alternatively be made of non-degradable materials that may be readily eliminated by the body's natural processes. In some examples, the substrate 120 may be hydrophilic and may readily disintegrate in water, and in other examples, the dissolution or disintegration of the substrate 120 may be enhanced by the pH of the fluids in the stomach or upper intestine. In some examples, the materials of the substrate 120 may be chosen specifically to minimize unintended interactions with bioactive agents 106 when the bioactive agent mixture 108 is jetted onto the surface of the substrate. In some examples, other properties of the ingestible substrate 120 that may be desirable may include the ability to remain stable over extended periods of time at elevated temperatures or at high or low levels of relative humidity, being a poor medium for microorganism growth, or having reasonable mechanical properties. In some examples, the substrate 120 may have a tensile strength sufficient to allow it to be free-standing without need for any additional backing material.
In some examples, the substrate 120 may include one or more suitable, ingestible organic materials. In some examples, such suitable materials may be any material that does not adversely affect the mechanical integrity of the substrate as a free-standing web. Examples of such materials may include, but are not limited to, natural or chemically modified starch; glycerin; proteins such as gelatin or other similar compounds; cellulose derivatives such as hydroxypropylmethylcellulose or other similar compounds; polysaccharides such as pectin, xanthan gum, guar gum, algin or other similar compounds; synthetic polymers such as polyvinyl alcohol, polyvinylpyrrolidone or other similar compounds; or restructured fruits or vegetables such as milk proteins, rice paper, potato wafer sheets or other films made from restructured fruits or vegetables.
In some examples, the ingestible substrate 120 may further contain a water-expandable foam to aid in the rapid release of bioactive agents 106, such as oxidized regenerated cellulose commercially available from Johnson and Johnson under the trademark SURGICEL® (New Brunswick, N.J.) or a porcine derived gelatin powder commercially available from Pharmacia Corporation under the trademark GELFOAM® (New York, N.Y.). Additionally, in some examples, the ingestible substrate 1210 may further contain flavoring additives to make ingestion easier.
Regarding a suitable form for the ingestible substrate 120, in some examples, the substrate 120 may be in any form recognized in the printing industry such as paper, cardboard or polymeric films. In some examples, the ingestible substrate 120 may be uniform in thickness and in width. In some examples, the thickness of the ingestible substrate 120 may depend on the interactions between a particular substrate 120 and a desired bioactive agent 106 and the particular method of manufacture used. In some examples, the thickness of the ingestible substrate 120 may range from about 10 to about 350 microns.
The ingestible substrate 120 may be produced by a wide variety of methods including, but not limited to, roll coating, extruding, spray coating, and inkjetting. In some examples, a doctor blade may be employed to regulate the thickness of the deposited layer. In other examples, other similar devices may be used to regulate thickness. The ingestible substrate 120 may be a free-standing layer (i.e. without additional backing) or may be adhered to a sacrificial backing material. In examples wherein a sacrificial backing material is used, such backing material may serve multiple purposes. In some examples, such backing material may offer mechanical support to the ingestible substrate 120, may provide an electrically conductive surface which may serve as a ground plane during electrostatic pinning, or may serve as a medium on which information relevant to the consumer (e.g., medication name, dosage, manufacturing date, patient name, administration schedule, etc.) may be printed, as further discussed below. In some examples, the sacrificial backing material may be removed prior to packaging or may be included as a peel-off component that a user of the bioactive dose may remove prior to taking the bioactive dose.
While
The printer for jetting the bioactive agent mixture 108 onto the ingestible substrate 120 may include any suitable components and as discussed previously, has been studied in the past. In some examples, an inkjet ink head may be used. In such an example, the inkjet head may be a piezo-electric inkjet head, a thermal inkjet head or any other type of inkjet head. In other examples, a spray or nozzle may be used. In some examples, the printer is capable of jetting a 50 nanogram (ng) to 1000 ng sized drop onto the substrate 120.
In some examples, the printer may further include a digital controller or other control device which may control the volume of bioactive agent mixture 108 jetted onto the substrate 120. Additionally, in some examples, the printer may further include a device for printing information onto the substrate 120, including information about the date of manufacture, information about the bioactive agent or other information. The information may be in any form for conveying information, such as text, characters or graphics. In other examples, such a device may be a separate device from the printer and adjacent to the charge generator or the cold fluid removal device.
In some examples and as further described below in
As seen in
Then, the bioactive agent 106 may be encapsulated in an ingestible layer. Such encapsulation may be accomplished in any suitable way. In one example, a second ingestible layer may be applied to the top of the substrate 120 and bioactive agent 106 by jetting such second ingestible layer from any inkjet printhead. Other suitable methods include using a lamination device, a pulsed spray nozzle or a roll coater to apply the second ingestible layer. In another example, the substrate 120 itself may be cut, folded, sealed or otherwise manipulated such that it encapsulates the bioactive agent.
In some examples, individual doses may be defined by cutting or perforating the web of encapsulated bioactive agents to desired sizes using any suitable devices and processes. In one example, individual doses may be defined by perforating the ingestible substrate in a manner similar to a roll of postage stamps, such that a dose can be easily detached from a roll of doses. In other examples, other suitable devices and processes may be used.
Finally, in some examples, the printer to jet doses of a bioactive agent onto an ingestible substrate 100, the device to draw the bioactive agent to the ingestible substrate 110, and the cold fluid removal device to remove excess carrier fluid 116 may be in series with like devices. In one example, the printer 100, the device to draw the bioactive agent to the ingestible substrate 110 and the cold fluid removal device 116 are together one set of devices that are in series with one or more additional sets of devices including at least one printer 100, one device to draw the bioactive agent to the ingestible substrate 110, and one cold fluid removal device 116 as described herein. In other examples, the apparatus may include one or more printers 100 in a row, one or more devices to draw the bioactive agent to the ingestible substrate 110 in a row, and one or more cold fluid removal devices 116 in a row.
As described above, after the bioactive agent mixture 108 is jetted onto the substrate 120, the bioactive agents 106 may be drawn to the substrate 120. In
In some examples, additional interactions between the substrate 120 and the bioactive agents 206 may further bind or pin the bioactive agent 206 to the substrate 120. In other examples, as described above, other devices and processes may be used.
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/US2011/058244 | 10/28/2011 | WO | 00 | 4/21/2014 |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO2013/062570 | 5/2/2013 | WO | A |
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| Number | Date | Country | |
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| 20140248416 A1 | Sep 2014 | US |
