US20080019925A1 - Edible holographic products, particularly pharmaceuticals and methods and apparatus for producing same - Google Patents
Edible holographic products, particularly pharmaceuticals and methods and apparatus for producing same Download PDFInfo
- Publication number
- US20080019925A1 US20080019925A1 US11/881,230 US88123007A US2008019925A1 US 20080019925 A1 US20080019925 A1 US 20080019925A1 US 88123007 A US88123007 A US 88123007A US 2008019925 A1 US2008019925 A1 US 2008019925A1
- Authority
- US
- United States
- Prior art keywords
- dosage form
- holographic
- coating
- layer
- production method
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
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- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4891—Coated capsules; Multilayered drug free capsule shells
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B30—PRESSES
- B30B—PRESSES IN GENERAL
- B30B11/00—Presses specially adapted for forming shaped articles from material in particulate or plastic state, e.g. briquetting presses, tabletting presses
- B30B11/02—Presses specially adapted for forming shaped articles from material in particulate or plastic state, e.g. briquetting presses, tabletting presses using a ram exerting pressure on the material in a moulding space
- B30B11/08—Presses specially adapted for forming shaped articles from material in particulate or plastic state, e.g. briquetting presses, tabletting presses using a ram exerting pressure on the material in a moulding space co-operating with moulds carried by a turntable
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B30—PRESSES
- B30B—PRESSES IN GENERAL
- B30B11/00—Presses specially adapted for forming shaped articles from material in particulate or plastic state, e.g. briquetting presses, tabletting presses
- B30B11/02—Presses specially adapted for forming shaped articles from material in particulate or plastic state, e.g. briquetting presses, tabletting presses using a ram exerting pressure on the material in a moulding space
- B30B11/14—Presses specially adapted for forming shaped articles from material in particulate or plastic state, e.g. briquetting presses, tabletting presses using a ram exerting pressure on the material in a moulding space co-operating with moulds on a movable carrier other than a turntable or a rotating drum
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B30—PRESSES
- B30B—PRESSES IN GENERAL
- B30B15/00—Details of, or accessories for, presses; Auxiliary measures in connection with pressing
- B30B15/06—Platens or press rams
- B30B15/065—Press rams
-
- G—PHYSICS
- G03—PHOTOGRAPHY; CINEMATOGRAPHY; ANALOGOUS TECHNIQUES USING WAVES OTHER THAN OPTICAL WAVES; ELECTROGRAPHY; HOLOGRAPHY
- G03H—HOLOGRAPHIC PROCESSES OR APPARATUS
- G03H1/00—Holographic processes or apparatus using light, infrared or ultraviolet waves for obtaining holograms or for obtaining an image from them; Details peculiar thereto
- G03H1/02—Details of features involved during the holographic process; Replication of holograms without interference recording
- G03H1/024—Hologram nature or properties
- G03H1/0244—Surface relief holograms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J2205/00—General identification or selection means
- A61J2205/20—Colour codes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J2205/00—General identification or selection means
- A61J2205/40—General identification or selection means by shape or form, e.g. by using shape recognition
-
- G—PHYSICS
- G03—PHOTOGRAPHY; CINEMATOGRAPHY; ANALOGOUS TECHNIQUES USING WAVES OTHER THAN OPTICAL WAVES; ELECTROGRAPHY; HOLOGRAPHY
- G03H—HOLOGRAPHIC PROCESSES OR APPARATUS
- G03H1/00—Holographic processes or apparatus using light, infrared or ultraviolet waves for obtaining holograms or for obtaining an image from them; Details peculiar thereto
- G03H1/0005—Adaptation of holography to specific applications
- G03H2001/0055—Adaptation of holography to specific applications in advertising or decorative art
-
- G—PHYSICS
- G03—PHOTOGRAPHY; CINEMATOGRAPHY; ANALOGOUS TECHNIQUES USING WAVES OTHER THAN OPTICAL WAVES; ELECTROGRAPHY; HOLOGRAPHY
- G03H—HOLOGRAPHIC PROCESSES OR APPARATUS
- G03H2270/00—Substrate bearing the hologram
- G03H2270/10—Composition
Abstract
An edible product such as a unit dosage form of a pharmaceutically active substance includes a layer of a material that can receive and retain a high resolution microrelief that can convey information. The microrelief is themo-formable, preferably formed from an aqueous solution of HPMC and/or HPC plus a plasticizer and colorant. Other additives such as strengtheners, surfactants and adherents may be used depending on the application. The materials are selected and proportioned to control the fading or change in color of the visual image or effect produced by the relief to indicate exposure to an unacceptable degree of heat or humidity. The dosage form can be the relief-containing layer itself with the pharmaceutical carried therein. In a preferred form, the layer is an outer coating over a core containing the pharmaceutically active substance. Coated tablets are configured to resist twinning. To produce such dosage forms, the coated core is transported in unison with a flexible mold or transfer plate that can heat-replicate the microrelief on the outer layer of the dosage form, followed by a cooling and release of the transfer plate from the coating.
Description
- This invention relates in general to solid dosage forms bearing diffraction reliefs capable of conveying information, such as the reconstruction of holographic images, as well as methods and apparatus for producing same.
- The creation of holographic images using fine diffraction patterns illuminated with laser light is well known. White-light “holograms” are also well known. A common example of Benton white-light “holograms” is the creation of images on credit cards and the like to prevent tampering with information carried on the cards, and to enhance their visual aesthetics. Known images include rainbow-like color patterns, pictures, and changes in color or location of pictures or parts of pictures with a change in viewing angle.
- While it is also known to emboss a suitable relief on a section of a generally flat sheet of plastic material, such as that forming a credit card, with a heated metal die, the production of high resolution diffraction reliefs on edible products presents special problems. Materials suitable for receiving and retaining diffraction reliefs on edible products must not only be capable of receiving a fine pattern, e.g., 1,000 to 5,000 lines per mm, and be capable of retaining that fine pattern (be stable), but they must also be food safe and palatable. Retention requires resistance to mechanical degradation during routine handling as well as the adverse effects of water, especially air-borne humidity and heat. Ingestibles should also be digestible, which typically means they should be water-soluble. (Pharmaceutical delivery systems are known which rely on stomach acid to dissolve a coating, or which have a substantially indigestible coating with small holes through which a pharmaceutically active substance is released.)
- U.S. Pat. No. 4,668,523 to Begleiter discloses the first system for applying a high resolution diffraction gratings to a food product to produce edible holograms.
- While such diffraction reliefs produced by dehydration in molds have proven to be able to provide color and other visual effects on candies and other food products, they have not heretofore been used commercially on dosage forms such as pharmaceuticals. Indeed, the commercial production of small, holographic-bearing dosage forms introduces problems, enumerated below, not encountered using the known general methods for creating holographic foods such as lollipops.
- Pharmaceutical products are typically sold and used in a variety of forms, each providing a known unit dosage of a pharmaceutically active ingredient. Typical forms include common compressed powder tablets and coated tablets. The term also includes hard shell capsules and soft-gel capsules. For the purposes of this application, these and other unit dosage delivery forms are termed “dosage forms”. These dosage forms typically include a core which, in turn, include a pharmaceutically active ingredient and a pharmaceutically acceptable inert carrier. In many instances, the dosage form also includes an outer layer that encloses the core, protects it, contains it (e.g., a capsule holding a granular, powdery, or viscous core material), and/or provides a vehicle for carrying a material that facilitates use of the dosage form, e.g., a “buffered” coating on an aspirin tablet.
- In the pharmaceutical field, it is important to identify and differentiate one product from another reliably. The consumer needs to be sure of what medicine he/she is taking. The manufacturer is interested in establishing brand identity and extending brand loyalty. It is also of interest to be able to deter counterfeits and to covertly differentiate dosage forms, e.g., for use in double blind tests.
- Pharmaceuticals and food products have been limited to the use of certain FDA and other internationally approved colors produced chemically by dyes and lakes. Many countries have different regulations governing the use of these chemicals leading to difficulty in creating uniform product identities for pharmaceutical companies across international borders. Further, it would be desirable to have the capability of producing a greater variety of colors beyond the few that have regulatory approval—especially “rainbow-like” effects produced by the juxtaposition of multiple colors of gradually varying wavelength.
- Monitoring of storage conditions is important in preserving product integrity.
- “Edible Holography: The application of holographic techniques to food processing”, SPIE, Vol. 1461, “Practical Holography V” (1991) at pages 102-109 discusses the use of a punch die to compress a powder into a tablet while simultaneously using a metal die plate to impress a microrelief as the powder becomes a solid core in a tablet press. Rapid die wear and difficulty in releasing the compressed core from the die are just some of the problems that limit this technique.
- More generally, a commercially viable system for holographically conveying information on pharmaceuticals must address a variety of requirements beyond those discussed above for food products. A major difference is that pharmaceutical dosage forms are “non-deposited”, that is, they are not poured into a mold as a liquid to be formed, as with hard candy. Also pharmaceutical dosage forms are small as compared to present commercial edible products such as lollipops, and they can have non-planar outer surfaces where it would be desirable to carry a holographic diffraction pattern. In addition, the material in which the microrelief is formed cannot interact adversely with the pharmaceutically active ingredient(s) to reduce its efficacy, and should not otherwise be objectionable when ingested, e.g., allergenic. The image-producing microrelief on a dosage form must also be reliably durable and stable during manufacture, packaging, shipment, and under acceptable storage conditions, that is, conditions that do not adversely affect the efficacy or required product life of the dosage form. The microrelief should have a long shelf life, which requires a high resistance to changes in shape on the micron scale due to applied mechanical stresses, and degradation due to temperature changes or to the absorption of moisture. Such a microrelief is termed “stable”. If applied as a layer on a core, the layer containing the relief should not delaminate or “bubble”. Bubbling is a particular concern when heat is used in applying or processing the layer.
- Suitable microreliefs used on pharmaceuticals should be compatible with modern dosage form manufacturing equipment and techniques and be economical in its implementation. A microrelief must also be non-detrimental to the efficacy of the pharmaceutical. Any heat used as part of the manufacturing process for implementing a microrelief should not degrade the efficacy of pharmaceutically active ingredient(s). While holograms transfer and reconstruct best on flat surfaces, coated tablets with flat faces tend to adhere to one another, or “twin”, during the coating process. The production of diffraction microreliefs on coated products should resist twinning in order to maintain acceptable yield ratios. Suitable microreliefs should also be formed using materials that do not require new regulatory approval.
- It is also desirable to know if an ingestible product is likely to have retained its efficacy after it has been manufactured and stored. Stated in other words, it would be useful to have a readily visible indicator of the environmental history of any given dosage form. Such an indicator, for example, would usefully indicate whether a dosage form had been exposed to high temperatures, e.g., over 100° F., and high humidities, e.g., over 80% relative humidity (RH), for any extended period of time during storage or prior to sale or use. This problem is commonly addressed by printing an expiration date on a container for the product. However, it would be better if there was some visual indication of efficacy on the product itself.
- It is therefore a principal object of this invention to provide an edible product, including a dosage form in any of a wide variety of shapes and configurations, that has a stable microrelief whose stability can be controlled, and that conveys information such as visual holographic images and effects.
- Another principal object is to provide specific, approved materials, methods and apparatus for producing such a product that are cost effective and compatible with modern high-speed production equipment and techniques such as tablet coating apparatuses.
- Yet another object of this invention is to provide a system for introducing holographic brand identification for a wide range of edible products in a wide range of forms.
- Another object is to provide a visual quality control indication on each dosage form in the form of a hologram that visibly changes if the dosage form has been exposed to severe adverse conditions of temperature or humidity.
- A further object is to provide a system for controlling and detecting counterfeit dosage forms.
- Still another object is to provide dosage forms with covert identifiers suitable for use in double blind studies.
- Another object is to provide the foregoing advantages without requiring a new regulatory approval of the dosage form.
- Yet another object is to provide color and visual images and effects for food products and for pharmaceuticals, (1) without the use of FDA regulated colors, dyes, inks, or metals, or (2) with colors other than those which are FDA approved, or (3) with the use of FDA approved colorant only as a contrast color to make holographic effects and images more readily visible.
- Broadly stated, the invention provides pharmaceutical dosage forms and other edibles products bearing a microrelief, and in particular a high resolution diffraction relief. The diffraction relief is thermoformed in a layer of a suitable material, and once formed, is stable. The invention further provides the materials, apparatus and processes whereby such diffraction reliefs can be applied. By means of this invention, a microrelief capable of diffracting light may be applied directly to a product such as a dosage form.
- The present invention allows monitoring of storage conditions to preserve product integrity. Edible diffractive gratings as a structural component of a dosage form have the ability to make visible to the unaided eye microscopic changes, caused by heat and moisture, which can alter the depth and spacing of the grating and so change the ways in which it interacts with light. Thus over-all coating changes such as expansion even as small as the wavelength of light can be detected by the unaided eye through changes in color reconstruction angles and diffraction efficiency.
- The invention provides the economical production of edible colors without the necessity of adding to the product objectionable materials such as certain dyes, inks, aluminum lakes, metals such as gold or silver or minerals such as mica.
- In one embodiment of this aspect, the invention provides a dosage form comprising:
- a core which comprises a pharmaceutically active substance and a pharmaceutically acceptable carrier;
- athermoformable solid outer layer overlaying said core, and a microrelief in said layer.
- The layer of material that retains the microrelief in one form is pan coated onto the core and completely encloses it. In another form this layer partially covers the core. It can be printed or laminated onto the core. In still another form, the layer itself can contain a pharmaceutically active material and constitute the entire dosage form.
- This layer is formed from an aqueous solution of a thermoformable material selected from the group consisting of modified cellulose, modified food starch, gelatin, waxes, vegetable gums, and combinations thereof. The preferred material comprises a modified cellulose, namely, hydroxyproplymethlcellulose (HPMC), hydroxypropylcellulose (HPC), and mixtures thereof.
- The material also preferably includes a plasticizer and a colorant. The choice of plasticizer and/or thermoformable material and the relative portions are adjusted to control the response of the microrelief over time to humidity. Oils and waxes with varying melting points admixed to this layer provide control over the response of the microrelief over time to temperature. Fading or change of color (due to a change in the reconstruction angle) of the visual image or effect produced by the microrelief provides a visual indication of the environmental history of the dosage form and its integrity. Suitable waxes include paraffin (a low melting point) and carnuba (a high melting point). Suitable hygroscopic plasticizers include sugars such as dextrose (highly hygroscopic) and proplyeneglycol.
- When the dosage forms are made by pan coating, the cores are configured to resist twinning by reducing the amount of the flat area at the outermost surface of the dosage form and by convexly curving the outermost surfaces, particularly the faces of tablets. Flat area reduction includes forming a recess in each face of a tablet with a generally flat bottom that receives and retains the microrelief.
- Broadly stated, a method of producing a microrelief on a dosage form according to the present invention includes the steps of:
-
- a. coating the core with a layer of a thermoformable material that can receive and retain a holographic diffraction pattern;
- b. providing a plate having a holographic diffraction pattern formed on at least a portion of a first surface thereof;
- c. transporting said coated cores to a position opposite that first plate surface;
- d. heating at least one of the plate and the coated layer during or prior to the time when they are in said opposed relationship;
- e. pressing the first plate surface into the coated layer to replicate the holographic diffraction pattern in the coated layer;
- f. cooling the coated layer thus replicated; and
- g. demolding the first plate surface from the coated layer.
- Broadly stated, apparatus for the continuous (non-batch) production of a mircorelief on a core which can contain a pharmaceutically active substance and which is coated with a thin layer of a thermo-formable, includes
-
-
- a conveyor that carriers the coated cores in a first direction,
- a plate containing a holographic diffraction pattern on one surface thereof facing the coated cores on the conveyor, the plate being movable along the first direction in coordination with the carrying, and with the one plate surface spaced from the coated cores,
- a heater for rapidly raising the temperature of one of the plate and the thin layer of coating to a level where the coating layer is formable,
- apparatus for pressing the one plate surface into the coating layer after the heating to replicate the diffraction pattern in the coating layer,
- a cooler to rapidly lower the temperature of the coating layer to stabilize the diffraction pattern in the coating layer, and
- apparatus to separate the one plate surface from the coating layer.
-
- These and other features and objects will be readily understood from the following detailed description of the preferred embodiments that should be read in light of the accompanying drawings.
-
FIG. 1 is a view in end elevation of a coated, curved-face tablet according to the present invention; -
FIG. 2 is a top plan view of an alternative coated, curved-face tablet according to the present invention with lettering on one face; -
FIG. 2A is a view in end elevation of the tablet shown inFIG. 2 ; -
FIG. 2B is a view in side elevation of the tablet shown inFIGS. 2 and 2 B; -
FIG. 2C is a detailed view in vertical section of the lettering taken along theline 2C-2C inFIG. 2 ; -
FIG. 3 is a top plan view corresponding toFIG. 2 of an alternative embodiment according to the present invention with flat faces and sloped edges; -
FIG. 3A is a view in end elevation of the coated tablet ofFIG. 3 ; -
FIG. 3B is a view in side elevation of the tablet shown inFIG. 3 ; -
FIG. 3C is a detailed view in vertical section of the lettering taken along theline 3C-3C inFIG. 3 ; -
FIG. 4 is a top plan view corresponding toFIG. 3 of another coated tablet according to the present invention with flat central faces and rounded edges; -
FIG. 4A is a view in end elevation of the tablet shown inFIG. 4 ; -
FIG. 4B is a view in side elevation of the tablet shown inFIG. 4 ; -
FIG. 4C is a detailed view in vertical section taken along theline 4C-4C inFIG. 4 ; -
FIG. 5 is a top plan view of a flat-faced, coated tablet according to the present invention with a central recess and rounded edges; -
FIG. 5A is a view in end elevation of the tablet shown inFIG. 5 ; -
FIG. 5B is a view in side elevation of the tablet shown inFIG. 5 ; -
FIG. 5C is a detailed view in vertical section taken along theline 5C-5C inFIG. 5 ; -
FIG. 6 is a top plan view of an alternative embodiment of a flat-faced, coated table with a double recess according to the present invention; -
FIG. 6A is a view in end elevation of the tablet shown inFIG. 6 ; -
FIG. 6B is a view in side elevation of the tablet shown inFIG. 6 ; -
FIG. 6C is a view in vertical section taken along the line 6C-6C inFIG. 6 ; -
FIG. 7 is a view in side elevation of a tablet according to the present invention with a section of a layer containing a microrelief pattern, and adhered to a tablet core; -
FIG. 8 is a perspective view of a capsule according to the present invention with a portion broken away to show a loose or viscous core material contained therein and where the capsule itself has a microrelief pattern formed therein; -
FIG. 9 is a perspective view of a soft gel capsule according to the present invention with a portion broken away to show a viscous core material contained therein and where the capsule itself has a microrelief pattern formed therein; -
FIG. 10 is a view in side elevation of a holographic dosage form according to the present invention where a layer carrying a microrelief pattern itself has a pharmaceutically active ingredient(s) therein; -
FIG. 11 is a perspective view of a package of plural dosage forms; - FIGS. 12A-H each show alternative arrangements in both top plan and side elevational views, except
FIG. 12C which is in plan view only, according to the present invention for controlling twinning of coated tablets; -
FIG. 13 is a simplified view in perspective of a belt-type apparatus according to the present invention with a moving transfer plate for manufacturing holographic pharmaceuticals also according to the present invention; -
FIG. 14 is a view in side elevation of the apparatus shown inFIG. 13 ; -
FIG. 15 is a detailed view in perspective of the moving transfer plate thermoforming assembly shown inFIGS. 13 and 14 ; -
FIG. 16 is a simplified perspective view of a belt-type, twin moving transfer plate apparatus according to the present invention for manufacturing holographic pharmaceuticals also according to the present invention; -
FIG. 17 is a view in side elevation of the apparatus shown inFIG. 16 ; -
FIG. 18 is a simplified perspective view of an alternative embodiment of a belt-type, twin moving transfer plate apparatus according to the present invention for manufacturing holographic pharmaceuticals; -
FIG. 19 is a view in side elevation of the apparatus shown inFIG. 18 ; -
FIG. 20 is a top plan view of a slat-segment conveyor belt according to the present invention; -
FIG. 20A is a view in section taken along theline 20A-20A inFIG. 20 ; -
FIG. 21 is a simplified view in perspective of a linear frame-and-transfer plate type of apparatus for manufacturing holographic pharmaceuticals according to the present invention; -
FIG. 22 is a detailed view in perspective of the frame-and-transfer-plate unit shown inFIG. 21 ; -
FIG. 23 is a top plan view of an apparatus using the constructions and a method of operation according toFIGS. 20 and 21 ; -
FIGS. 24A and 24B are views in side elevation of the apparatus shown inFIG. 23 taken along thelines 24A-24A and 24B-24B, respectively; -
FIG. 25 is a view in perspective of an alternative embodiment of a rotary apparatus according to the present invention operating on frame-and-transfer-plate units of the type shown inFIG. 22 ; -
FIG. 26 is a view in perspective of an alternative rotary frame-and-transfer-plate-type apparatus according to the present invention; -
FIG. 27 is a view in side elevation of the apparatus shown inFIG. 27 ; -
FIG. 28 is a detailed view in perspective of the replication assembly shown inFIGS. 26 and 27 ; -
FIG. 29 is a view in perspective of a rotary die punch apparatus according to the present invention; -
FIG. 30 is a detailed view in perspective of several die punches shown inFIG. 29 with a pivoted central tab operable to eject a tablet; -
FIG. 31 is a flow diagram showing a highly generalized process according to the present invention for thermal forming a microrelief pattern on a solid, coated dosage form; -
FIG. 32 is a schematic view in perspective of an apparatus according to the present invention for direct laser imprinting a diffraction relief pattern in an outer coating layer of a dosage form; and -
FIG. 33 is a view in perspective of an alternative apparatus according to the present invention that operates in the style of a high speed printer. - While the present invention can be used to create reliefs in a variety of ingestible dosage forms, including confections, it is described primarily with respect to use on pharmaceutical products.
- As used herein, “microrelief” means a regular pattern of grooves and ridges or the like that displays optical information or a visual effect, when exposed to suitable radiant energy. “Diffraction relief” or “grating” and “microrelief” include both (1) patterns of the grooves and ridges produced through laser light interference, with ruling engines, and with other known techniques which can be subsequently transferred to the dosage form by a mold or radiant energy and (2) visual information, images and effects produced by these patterns of grooves and ridges when properly illuminated. A true hologram records the interference pattern produced from a laser (coherent) light source with its output beam split, and the image or effect is its laser light reconstruction. As used herein, “hologram” and “holographic” are intended to include the production of optical information, images and effects on the dosage form as well as their reconstruction, using either laser light or white, incoherent light.
- In a preferred embodiment, the diffraction relief is a high resolution diffraction relief. “High resolution” refers to a diffraction relief that is capable of diffracting visible light and having at least 400, and typically 1,000 to 5,000, lines per mm (a ½ to 1 micron phase displacement of grating). The dimensions of the diffraction relief are proportional to the wavelength of the light it is to interact with. The Information recorded and conveyed by the microrelief can be color, depth, image, optical data, and or a kinetic effect.
-
FIGS. 1-12 show various unit dosage forms 10 for the delivery of pharmaceuticals by oral ingestion. “Pharmaceutically active substance” refers to ethical pharmaceuticals as well as other orally administered, ingested products such as over-the-counter medicines. Thus, the term is used in its conventional sense to mean a pharmaceutically active compound or mixture of compounds for the treatment of a disease or condition. The term can also refer to nutritional and diet supplements which are in the form of a solid dosage form. Dosage forms utilized in the invention include all of the currently known forms such as compressed powder tablets, coated tablets (caplets), hard and soft gelatin capsules, as well as new forms such as injection-molded starch tablets, and thin-layer “sections” as shown inFIG. 10 . For the purpose of this invention the dosage forms 10 which are useful within its scope will sometimes be referred to collectively simply as “dosage forms”. It is understood that the dosage form core can be created with or without pharmaceutically active compounds (such as in placebos, double blind tests and confections). “Pharmaceutical dosage form” refers to a dosage form that includes a pharmaceutically active ingredient. These forms are included within the scope of the invention and can be manufactured with the disclosed methods and apparatuses. In the pharmaceutically active tablet, hard or soft gelatin capsule, and injection molded starch tablet forms, the pharmaceutically active ingredient or ingredients are typically mixed with a carrier comprising excipients that do not react with the active ingredient. A core can contain conventional pharmaceutical excipients associated with making solid dosage forms of the type previously mentioned, as well as others known to the art. Thus such excipients may, depending on the exact formula, include one or more binders, flavorings, buffers, diluents, colors, lubricants, sweetening agents, thickening agents, and glidants. Some excipients can serve multiple functions, for example as both a binder and disintegrant. Carriers and excipients are well documented in the art. See, for example Remington's Pharmaceutical Sciences, Eighteenth Edition, Mack Publishing Company, 1990, which is herein incorporated by reference. - The present invention creates dosage forms bearing diffraction reliefs that can convey information, visible and/or covert, to the human eye in normal (e.g., daylight and/or incandescent) and/or special (e.g., laser) illumination. In at least the preferred forms, these reliefs are formed by thermal-forming in ways compatible with current high-volume, high-speed dosage form production apparatus and methods.
- One aspect of the present invention is the use of an
outer layer 12 of a material that can receive a highresolution diffraction relief 16, and retain that relief pattern reliably for the intended life of the product, under anticipated conditions of manufacture, handling, storage and use. In particular, it has been found that certain materials can be: (1) formed into solid outer layers or coatings around a core, (2) subsequently heated to soften (including liquefy) the layers, (3) molded to form a high resolution diffraction relief, and then (4) cooled to retain that relief pattern in a solid form when (5) released or de-molded. General characteristics of these materials are that they have a controllable water-stability, are heat-formable, and are capable of being applied to the dosage form by known pan coating, printing, or laminating techniques. Such materials advantageously also produce coatings that are resistant to cracking, wrinkling, and/or crystallizing, can be made to flow or bond at a temperature lower then that which will adversely effect the core, can retain a grating with a phase displacement on the scale of the wave length of light, are palatable, will not interfere with the release of the cores contents, and have controllable heat and water stability in storage so as to accurately control the fading or color. This controllable changes seen as a fading or color provides a readily visible indication of the environmental history of the dosage form, and its quality. - Reference to a thermoformable “layer” 10 shall be understood to include plural thermoformable layers coated and/or deposited adjacent to each other, for example a thermoformable base coat which is colored to provide a background overlayed by a clear thermoformable layer which receives a microrelief.
- More specifically, food grade materials which can function to some degree, albeit with varying degrees of stablilty, as a thermoformable outer coating to receive and retain diffraction relief include: food grade sugars (i.e., glucose, fructose, sucrose, dextrose, maltose and mixtures thereof); proteins and/or polypeptides such as albumin, casein, fibrin, and collagen and gelatins, particularly Bloom
strength 150 to 250 gelatins; lipids such as oils, triglycerides, and fats; controllable melting point waxes such as paraffin, carnuba, and bees; and various polysaccharides, namely, carbohydrates such as cellulose and starches, complex gels, modified cellulose, and hydrocolloids. Suitable modified celluloses, which are presently preferred, include hydroxypropylcellulose (HPC) and hydroxypropylmethycellulose (HPMC). - For the
dosage form 10 of the present invention, the diffractiverelief containing layer 12 is preferably formed in two coats of (1) a color coating or layer of an aqueous solution of the modified cellulose HPC and/or HPMC, a plasticizer, and a contrast colorant to make the hologram more readily visible (2) a second clear coat of HPMC that overlies and covers the color coat. If no colorant is used, either in the core or thethermoformable layer 12, a microrelief carried in thelayer 12 may not be readily visible. It can function in the nature of a watermark in quality papers. Such holograms, using no colorant in the core and aclear layer 12, can function to control counterfeits and provide the advantages of covert information. - For the
holographic pharmaceutical 10 of the present invention, adherents such as a water-based shellac, and gum starches such as gum acacia, are used in some formulations, particularly where it is desired to adhere thelayer 12 to a core 14 or to adhere a label of thelayer 12 to a core or to an outer coating on a dosage form. - The following Table I are examples of materials which have been mixed in an aqueous solution and tried as high resolution relief-containing layers for the pharmaceuticals dosage forms 10:
TABLE I Other Modified Constituent Cellulose Plasticizer Colorant Ingredient 1. HPMC P5/6 Maltodextrin DE 40 2. HPMC P5/6 HPC LF 3. HPMC 606 4. HPMC E-15 Shellac (adherent) 5. HPMC Triacetin Spectraspray ™ Purple (0-340) 6. HPMC monodiglyceride (surfactant) Shellac (adherent) 7. HPMC 606, Spectraspray Peg 400, 14.8 g 100 g red D360a, 8 g (surfactant) Water, 51.8 g 8. HPMC 606, Spectraspray Peg 400, 2 g 100 g 1072, 8 g (surfactant) Water, 16 g 9. HPMC 600, Triacetin, 2 g Spectraspray Water, 14 g 100 g 1072, 8 g 10. HPMC 606, Myracet, 2 g Spectraspray Marcoat ™ 125 50 g monodiglyceride 1072, 8 g Shellac, 20 g (surfactant) Aspartame 0.015 g (sweetener) a. Undercoat Titanium dioxide 11. HPMC Triacetin DF&C blue #2, Lactose Lactose aluminum lake (flavoring) b. Overcoat HPMC 12. HPMC Polyethyleneglycol Titanium dioxide 2910 3350 a. Undercoat Polyethyleneglycol Titanium dioxide 13. HPMC e-5 3350 FD&C blue #2, b. Overcoat Polyethyleneglycol aluminum lake PHMC e-5 3350 14. Gelating, Yes Corn syrup 250 Bloom (strengthener) strength glycerin
The HPMC grades (e.g., “P5/6”) above those of its manufacturer, Dow Chemical Co. “Spectraspray” is a trade description of a liquid colorant of Warner-Jenkines, Inc. “Marcoat” is a trade description of an aqueous shellac solution of Emerson, Inc. “DE 40” means “dextrose equivalency of 40%”. - Examples Nos. 11 and 13 use two complete coatings; both can be applied using conventional rotating drum “pan” coaters on tablets. The undercoat preferably carries colorant; the overcoat is clear and shiny as well as highly stable on holding and maintaining a microrelief pattern. Strengtheners such as shellac, low conversion glucose syrup, and other such high molecular weight, highly cross-linked materials can be added to toughen the layer, both to retain the pattern during release from a thermal-forming die, and afterwards in handling, storage, and use. In general, long chain, high molecular weight, highly cross-linked materials add strength and stability to the
microrelief carrying layer 12. Surfactants reduce the surface tension of thelayer 12; they control “beading”. - Colorants produce a desired background or contrast color for the dosage form and the holographic image or effect produced by the microrelief. Colorants can make the relief more readily observable.
- Because the
layer 12 is ingested and is taken by the mouth, thelayer 12 can also include sweeteners to facilitate sucking and/or swallowing the dosage form or food product. - This example illustrates practicing a preferred embodiment using standard materials and coating equipment.
- A first solution for applying a first (color) layer using a standard, side-vented rotating pan coater (available under the registered trademark ACCELACOTA from Thomas Engineering, Chicago, Ill.) was made by mixing the following components:
Component Amount, wgt % aqueous solution containing 10% 78% by weight HPMC triacetin (plasticizer) 1.6% Black FD&C color, FD&C Blue 2 6.4% Lake, Red 40 Lake, FD&C Yellow 6Lake Water 14%
The final coating solution contained approximately 12% solids by weight. - 2 kg of compressed powder tablet cores of the type shown in
FIG. 3 (an arc diamond shape, 0.4020 inch wide by 0.5540 inch long and about 0.243 inch thick at its center) and described further below were coated in the aforementioned ACCELACOTA rotating pan cooling machine with a 15 inch rotating pan and operated under the operating conditions shown in Table 1, wherein the conditions designated in the Table are those commonly understood in the art.TABLE 1 Atm. Time Inlet Exhaust Air Spray Minute Wt./ml Temp C. Temp C. RPM CFM PSI g/ min 0 0 70 52.5 12 240 45.9 0 5 89 70 51 12 240 45.9 17.8 10 185 70 50.5 13 240 46.2 19.2 15 280 70 50.9 14 240 45.7 19 20 381 69 51 15 240 45.5 20.2 25 481 68 50.5 15 240 45.6 20 30 640 70 50.2 15 240 45.8 17.7 - In Examples 1 and 2 “Wt/ml” is the accumulated weight increase during the pancoating process in the dosage forms being coated, “ml” or “milliliter” being an approximate weight measure in grams given that one ml of water weighs one gram. Inlet and outlet Temp C are the air inlet and outlet temperatures to and from the coater in dgrees Centigrade. “CFM” is cubic feet per minute of this air flow through the coater and “Atm Air PSI” is the air pressure in coater in pounds per square inch. “RPM” is revolutions per minutes, the speed at which the drum of the coater rotates. “Spray g/min” is the rate in grams per minute that the aqueous solution of the material being coated is sprayed into the drum of the coater. “Time minute” is the elapsed during operation of the pancoating for that coating. +
- After applying the first coat, a second (clear) layer was applied from a solution containing the following components, the coat being applied under the pan coater operating conditions shown in Table 2:
Component Amount, wgt % aqueous solution containing 10% by wgt 45% of HPMC triacetin 0.5% water 54.5% - The final solution contained about 5% solids by weight.
TABLE 2 Atom. Time Inlet Exhaust Air Spray Minute Wt./ml Temp C. Temp C. RPM CFM PSI g/ min 4 53 68 50.2 15 240 45.8 13.3 8.5 117 68 51 16 240 45.9 15.5 - The final weight for color layer was 3%, based on the weight of the final tablet (i.e., the core coated with both layers). The final weight gain for clear layer was 0.25%, based on the weight of the final tablet.
- A microrelief was thermally transferred to the tablets using an
apparatus 69 andtransfer plate 76 as shown and described inFIGS. 21-24 at the preferred values given in the specification, the thermoformed microrelief being applied for about 2 seconds at a pressure of about 10 Kg/tablet and at a temperature of about 125° C. - The coated tablets were stored for 3 weeks at 85° F. and 65% relative humidity (RH). After the three week period, the tablets still retained an 80-90% detraction efficiency. Tablets stored at similar temperatures, but at 80% RH, reached the point at which the microrelief started to fade, i.e., the point at which changes in the image on effect it produced became visible and/or detectable.
- As described in Example 1, a first color layer was formed on tablets of the type described in Example 1 by pan coating a solution containing the following components:
Component Amount, wgt % aqueous solution containing 10% 68% by weight HPMC triacetin 0.5% FDA color (Blue 2 aluminum 5% lake) lactose 1% titanium dioxide 0.6% water 24.9%
The final solution contained approximately 12% by weight of solids. - 2.2 kg of compressed tablets of the type shown in
FIG. 1 (an arcuate diamond shaped, 0.4020 inch wide by 0.5540 inch long and approximately 0.198 inch thick at its highest point) and described further below were coated in the same 15 inch pan coater as described in Example 1, operated as shown in Table 3.TABLE 3 Atom. Time Inlet Exhaust Air Spray Minute Wt./ml Temp C. Temp C. RPM CFM PSI g/ min 0 0 70 53.2 11 240 44.3 0 5 102 70 50.7 11 240 44.3 20.4 10 201 70 50.8 12 240 44.5 19.8 17 335 69 50.7 12 240 44.8 20 25 494 69 51 13 240 43.1 19.5 33 650 68 52 13 240 44.5 19.8 - After applying the first coat, a second (clear) layer was applied from a solution containing the following components, the coat being applied under the pan coater operating conditions shown in Table 4:
Component Amount, wgt % aqueous HPMC (10% solution) 42% triacetin 0.5% water 57.5% -
TABLE 4 Atom. Time Inlet Exhaust Air Spray Minute Wt./ml Temp C. Temp C. RPM CFM PSI g/ min 0 0 69 53.6 13 240 44.3 0 10 159 69 52.5 13 240 43.8 15.9 20 324 69 51.2 14 240 43.5 16.5 35 618 70 51 14 240 44.2 19.6 - The final weight gain for the first layer (expressed as wgt %) was about 2% based on the weight of the final tablet. The final weight gain for clear layer was 1.25%, based in the weight of the final tablet.
- A microrelief was thermally transferred to the tablets using an
apparatus 69 andtransfer plate 76 described inFIGS. 21-24 at the preferred values given in the specification, the thermoformed microrelief being applied as described in Example 1. - The coated tablets were stored for 3 weeks at 55° F. and 50% relative humidity. After the three week period, the tablets still retained an 80-90% diffraction efficiency. Tablets stored at over 100° F. faded.
- In the above preferred examples the
outer coating 12 comprised two complete coatings, both being applied using conventional rotating drum “pan” coaters for tablets. Colorants in the first coating produce a desired background color for the dosage form and provide contrast for the holographic image or effect produced by the microrelief. It is also possible to add color to the core before compression. Often the particle size of the aluminum lakes and titanium dioxide utilized in the first coating—if not fine enough—can interfere with the transfer process by sticking to the mold. This results in spotty, ineffective patterns. Thus, preferably, only the undercoat or the core carries a colorant; the overcoat is clear, and it is more stable. - A plasticizer in the overcoat has been found to be particularly helpful in controlling cracking. In general, a plasticizer provides flexibility to the
layer 12. Plasticizers also provide a way to control the response, over time, of thelayer 12 to air-borne moisture (humidity). Plasticizers such as propylene glycol, and sweeteners such as lactose, increase the effects of moisture on thelayer 12 and the diffraction relief it carries. By varying the amount and type of such hygroscopic materials, one can readily vary the hygroscopic nature of the coating making it more likely to swell in humid weather. As noted above, overall hygroscopic swelling of the coating on the scale of the wavelength of light will change the relief pattern sufficiently to be visible through changes in the effect produced by the diffraction relief. Control over the response of thelayer 12 to humidity can also determine the choice and proportion of the thermoformable materials. Some suitable other plasticizers which are hygroscopic include polyethyleneglycols. Plasticizers which have been found to be not as hygroscopic, include polyhydrolic alcohols, glycerin, and triacetin. - HPC is more hygroscopic than HPMC, and the two can be mixed in various proportions to vary in a corresponding manner the stability of the grating structure in response to humidity.
- Oils and waxes can be used similarly but to show the effects of heat, instead of moisture, on the
layer 12 and the microrelief it carries. Some suitable waxes include mixtures of low melting point paraffin, and high melting point carnuba waxes which can be added during the pan coating process to affect the melting point of the diffraction grating. One skilled in the art can readily adjust the mixtures, and thereby control the fading of the holographic relief, over time, in response to temperature. - If the
layer 12 is not coated onto a core or container (e.g., a capsule), it may be formed separately as a printed section or as a laminated section. Even without a separate adherent layer, materials in the solution forming thelayer 12 can be used to enhance the ability of the layer to adhere to a core, or to a capsule, or to another coating on the core. When heated, HPMC will flow into and adhere to HPMC. The same is true of HPC. Thelayer 12, when used as a fully-enclosing coating for a tablet, is in the approximate range of 0.25% to 7.5% of the total weight of the dosage form. - The formulations identified above can be (1) formed into solid outer layers or coatings around a core, (2) subsequently heated to soften (including liquefy) the layers, (3) molded to form a high resolution diffraction relief, and then (4) cooled to retain that relief pattern in a solid form when (5) released or de-molded. General characteristics of these materials are that they can be made to flow or bond at a temperature lower than that which will affect the core, can retain a grating with a phase displacement on the scale of the wave length of light, are palatable, will not interfere with the release of the cores contents, and have a controllable heat and water stability in storage.
- These materials are also capable of retaining a fine pattern, e.g., a ½-1 micron spacing between raised portions, when exposed to the temperature and humidity variations that are normally encountered in shipment, storage and use world-wide. Materials exhibiting these qualities are termed herein “stable”. It is also significant that the materials release from a mold easily, cleanly, and without damage to the microrelief when they are cooled. They are also materials that have been approved by the responsible U.S. and international regulatory agency for use in foods and pharmaceuticals.
-
Layers 12 formed of these materials are used to enclose the cores as in pan coating, or partially enclose a section of the core, as when they are applied using known printing or lamination techniques. If the layers themselves are formed into sections, the sections themselves can be used as dosage forms after being made to absorb therein the contents of the pharmaceutically active agent, as described below in more detail with reference toFIG. 10 . -
FIG. 1 illustrates a tablet form of adosage form 10 formed according to the present invention carrying acoating 12 which fully covers acore 14. This tablet core is typically one formed by standard powder compression techniques. Thelayer 12 is preferably formed of the materials described above, in particular, ones including as their principal constituent a modified cellulose consisting of HPMC, HPC, or combination thereof. Amicrorelief 16 capable of conveying information when exposed to suitable radiant energy, typically a diffraction relief exposed to sunlight and/or a conventional artificial light, is thermally formed, by direct and indirect methods, using apparatus and techniques described below with respect toFIGS. 13-33 . The microrelief is shown as being produced on both curved andflat faces 18 of thedosage form 10. Theside surface 20 of the dosage form is generally straight (viewed in vertical section or side elevation) and follows the overall outline of the dosage form when viewed from the top or bottom. This outline can, of course, assume a wide variety of shapes such as circular, oval, diamond, rounded-corner arc diamond, polygonal, or many other shapes. - A particular feature of a preferred embodiment of the invention is that the
faces 18 as shown inFIGS. 1-12 are characterized by 1) a shallow, convex curvature, generally along a circular arc as shown, or 2) a small flat recess. In general it is more difficult to transfer onto and then reconstruct a microrelief on a curved surface than a flat surface. Functionally, the degree of the curvature and the amount of the flat area at the outer surface of the dosage form should be such so as to resist the twinning of tablets during the coating process and allow for a good diffraction relief to be created (the pattern of ridges and grooves in the layer 12) and reconstructed (the viewed hologram). As a functional test of the appropriate degree of twinning, preferably twinning should be controlled to limit rejected twinned tablets to less than 0.5% of the total yield. As a functional test of the appropriate degree of pattern reconstruction, preferably diffraction efficiency should be not less then 80%. Increase of pan-coating rotation speed (RPM), spray rate (g/min), run time, as well as inlet and exhaust temperature and air pressure in the coater, all affect the amount of flat area and/or degree of shallowness of curvature that can be used before twinning affects limit yield. Preferred speeds rates and temperatures are described in the above examples. -
FIGS. 2-2C show an alternative curved-face dosage form (coated tablet) 10 where both faces 18 are curved to resist twinning, but curved to an enhanced degree as compared with the shallow face curvature shown inFIG. 1 . Thistablet 10 is also fully covered with a thermoformableouter layer 12. Both curved faces terminate at astraight side wall 20. One face of theFIG. 2 embodiment includes letters formed in one convexlycurved surface 18 of the dosage form. Thelettering 22 is cut into theupper face 18 of the dosage form, as best seen inFIG. 2C , thereby reducing the face area subject to twinning. The microrelief can, for example, produce a diffracted rainbow-like array of colors over thesurfaces 18 and around thelettering 22. On the upper surface this effect enhances and highlights therelief lettering 22, as well as providing an aesthetically distinctive and attractive appearance. -
FIGS. 3-3C disclose yet another embodiment of a tablet form of adosage form 10 according to the present invention which is fully coated with alayer 12 and carrieslettering 22. In this embodiment, the holographic pattern is applied only to a generally flat, central portion 18 a of the upper and lower faces 18, 18 (as shown) during the thermal forming. Again, thelettering 22 is preferably depressed from the upper surface to protect it and to surround it with a holographic effect. The upper surface 18 a terminates in asurrounding shoulder portion 18 b that is inclined. In the embodiment shown it is generally flat in cross section and terminates in a “straight”side 20. The simultaneous provision of a flat central portion 18 a facilitates the replication of a microrelief in thelayer 12 because the replication occurs on a flat surface. Depression of thelettering 22 also serves to assist in controlling twinning. Themicrorelief 16 typically produces color, preferably a rainbow-effect, which surrounds and highlights thelettering 22. - By way of illustration, but not of limitation, in the tablet form shown in
FIGS. 3-3C , with a diamond plan configuration where thedosage form 10 has a major axis length of about 0.55 inch and a minor axis width of approximately 0.40 inch, theshoulder 18 b extends laterally approximately 0.13 inch and has a height of approximately 0.02 inch. Thelettering 22 is cut downwardly into theface 18 approximately 0.008 inch and preferably has sloping side, as shown inFIG. 3C this slope is preferably about 37.5°. -
FIGS. 4-4C show another alternative embodiment of a tablet form of adosage form 10 according to the present invention that is fully coated with alayer 12 over acore 14. A principal difference between theFIG. 4 andFIG. 3 embodiments is that theshoulder portions 18 b surrounding the flat central portion 18 a are curved, preferably along a circular arc when viewed in vertical cross-section or side or end elevation. Theshoulders dosage form 10 with the illustrative shape and size described above with respect toFIGS. 3-3C , of 0.06 inch. They each extend laterally for a distance of approximately 0.10 inch. This amount of rounded shoulder embodiment has also proven to be effective in controlling twinning despite having flat face portions 18 a, 18 a.FIGS. 4-4C represents the currently preferred form for a holographiclyenhanced dosage form 10 when a dosage form is formed as a compressed pharmaceutical or sugar core enclosed in acoated layer 12 of a food grade thermally-formable material capable of receiving and retaining a fine resolution diffraction relief. -
FIGS. 5-5C show another alternative embodiment of a tablet form of adosage form 10 according to the present invention which is fully coated with alayer 12. Like theFIGS. 4-4C embodiment, it utilizes flat central faces 18 a, 18 a, androunded shoulders FIGS. 5-5C embodiment also has acentral recess recesses 24 each have a depth substantially equal to the height of thelettering 22 set into the recess. As with the other preceding embodiments, the configuration and dimensions can vary depending on factors such as the overall dosage form configuration and size, the nature and extent of thecoating 12, and the presence of the other twinning control mechanisms. The depth of the recess into which the microrelief is transferred also helps to protect it from abrasion. In a tablet with an overall arc diamond shape as shown inFIG. 5 , and with the dosage form having a major axis length of about 0.55 inch and a minor axis width of approximately 0.40 inch, the curved shoulder extends over a depth of 0.028 inch and extends laterally for approximately 0.07 inch with a curvature subtending on angle of about 0.1 radian, and thecentral recess 24 has a depth of approximately 0.0064 inch. The upper surface of thelettering 22 is generally co-planar with the flat surface of the surrounding face portion 18 a. As shown, only theupper recess 24 contains thelettering 22. Themicrorelief 16 is stamped into the generally flat and co-planar portions of thelettering 22 and the surrounding regions of the flat face portion 18 a. -
FIGS. 6-6C show yet another embodiment for adosage form 10 in the form of a tablet with a core 14 coated with alayer 12 and having roundedshoulders 18 b and acentral recess 24 to control twinning, all according to the present invention. TheFIGS. 6-6C embodiments differ from theFIGS. 5-5C embodiment principally in that thelettering 22 projects down rather then up in thecentral recess 26.FIG. 6C is a detailed sectional view taken along line C-C inFIG. 6 to illustrate the configuration of the recesses and the relative heights thereof. Amicrorelief 16 is typically formed in thelayer 12 coveringsection 24. It may also be thermoformed in the surrounding bottom surface as well as the flat surface 18 a surrounding bothrecesses flat surface 26 to receive adiffraction relief 16, while at the same time accenting the area aroundlettering 22. For purposes of illustration only, the dosage form shown inFIGS. 6-6C , with the same general configuration and dimensions as the dosage forms shown inFIGS. 4 and 5 , has a maximum depth in thefirst recess 24 of approximately 0.0054 inch, and a the maximum depth of the second recess of approximately 0.0064 inch. As before the depth of the recess into which the microrelief is transferred also helps to protect it from abrasion. Again, these values are merely illustrative, and in no way should be construed as limiting the scope of this invention to that particular value, or even a near range of values. -
FIG. 7 shows a tablet in which a section has been applied through lamination. Acompressed core 14 carrying asection 28 oflayer 12, e.g., 1 to 2 microns thick, which has a highresolution diffraction relief 16 formed on its outer surface. Anadherent layer 30bonds section 28 to the outer surface of the core. The thickness oflayers FIG. 7 for clarity. Suitable adherents are water and/or alcohol-soluble and non-reactive with the materials forming the core or thelayer 12. They are preferably heat-activated and reliably secure the core to thesection 28. A suitable adherent is wax or vegetable gum. In practice, it has been found however that the adherent will extrude or “squeeze out” along the edges of the section when it is affixed to the dosage form. To avoid this problem, the presently preferred arrangement (shown inFIG. 7 as an alternative arrangement) of adheringsection 28′ carrying a relief to a dosage form is to form theouter layer 12 of the dosage form and thesection 28′ of a material that will fuse to itself when heated. It is preferred to form thesection 28′ and to coat thedosage form core 14 or encapsulate thecore material 14 in the same material, HPMC. Alternatively, the section applied does not have to have a preformed microrelief and so the degree of heating used to form the relief will cause the materials ofsection 28′ and this coating or capsule to flow into one another to adhere them. This allows a smaller amount of coating to be applied during panning and so further reduce twinning. HPMC will also form a shiny surface when heat stamped which is attractive independent of a diffraction relief. -
Section 28 can be applied in a continuous high-speed operation using alayer 12 in the form of a ribbon. Thelayer 12 is then advanced in coordination with a movement ofcores 14 that place theadhesive coating 30 of eachsection 28 in contact with an associatedcore 14. They are heated when the core and sections are in an opposed relationship and in contact with one another. The heating promotes the adherence of the section to the core, and can also thermoform the microrelief pattern in thelayer 12 if this replication has not occurred earlier. The adhered sections are then cooled, and thesection 28 is transferred. Theedible layer 12 can be a combination of HPMC, HPC and modified starch. An edible adhesive coating 30 (if a direct thermal bond is not utilized) can be a combination of waxes and vegetable gum plus triglycerides and a solvent. The transfer can be controlled and localized by using a stamper or thermal printer to transfer the section in a predetermined letter or shape by pressing against the dosage form. - As stated above, in order to address twinning issues on tablets with flat areas it is also possible to apply a section of
outer coating layer 12 by lamination or printing. When printing,layer 12 is applied in a traditional tablet marking machine. The layer can be applied as a continuous section or in the form of ground solid particles of material forming thelayer 12, as described above. As well as printing sections oflayer 12 onto the core, machines of this type can also be used to augmentlayer 12 before and/or after the transfer of diffractive reliefs to accent areas and print letters to be used with the diffractive images. When printing complex images, each printed layer can be created from a different composition oflayer 12, as is described in other areas of this application, so to retain the images and effects produced by its grating at different temperatures and humidity conditions. Thus complex patterns can be created which record the effects of maximum storage conditions over a range of environmental factors (i.e., ranges of temperature and humidity). By way of example, two stripes (likesections 28′ described above) oflayer 12 can be applied, each of which changes its image at different relative humidities. The stripes can be printed onto the dosage form, one using alayer 12 formed using the materials of Example 1 herein and the other using the materials described above with reference to Example 2. -
FIG. 8 shows ahard capsule 10 that carries acore 14 within the capsule as a powdery, granular or viscous mass. The capsule shell contains and protects the core material, but in accordance with the present invention, it is also formed of a heat-formable layer 12 that can be thermal-formed with amicrorelief pattern 16 directly into the inner or outer surface of the capsule. Suitable materials for the formation of the capsule include gelatin, starch, and HPMC, or mixtures therof. -
FIG. 9 illustrates asoft gel capsule 10 according to the present invention which is similar in function to the hard capsule described with respect toFIG. 8 , The hard and soft capsules are preferably formed of a gelatin material, preferably with a Bloom strength of 200 to 250, according to the present invention. -
FIG. 10 shows aunit dosage form 10 according to the present invention where the layers themselves are formed into sections, and are used as dosage forms themselves after being made to absorb or are formed with, the contents of the pharmaceutically active agent therein. Typicallylayer 12 absorbs the pharmaceutical in the manner of ink blotter carrying absorbed ink, or is formed with it from a common aqueous solution. Absorption, e.g., by spraying the pharmaceutical into thepre-formed layer 12, is presently preferred. Preferred materials for this section type dosage form are HPMC, gelatins, dextrins, and vegetable gums such as gum acacia, pollulan gum, and mixtures thereof. -
FIG. 11 shows a temperature and humidity controlled container for multiple dosage forms 10. It contains sections forstorage 29 and abacking layer 27 which can include a thermal and hygroscopic humidity barrier to further control the moisture and temperature thedosage form 10 is made to interact with. - FIGS. 12A-H each show, in top plan and side elevation, a tablet-
type dosage form 10 that is coated with aouter layer 12 that carries amicrorelief 16. Thetablets 10 each have an overall arcuate diamond shape in plan view and have two generally flat faces 18, 18. They differ from one another in the mechanism used to reduce the area of thefaces coating layer 12. -
FIG. 12A illustrates a series oflateral grooves 19 formed in thecore 14 of the tablet. The area of thefaces grooves 19 at thefaces -
FIG. 12B shows thesame tablet 10, but with a series ofconcentric grooves 19′. -
FIG. 12C shows a table 10 using a combination of thegrooves -
FIG. 12D shows atablet 10 with acoating 12 with two central, generally flat faces 18, 18 surrounded by an eight-sided, diamond-like array of flat-faced, inclined,shoulder portions 18 b′. -
FIG. 12E shows atablet 10 with acoating 12 carryinglettering 22 cut into at least oneface 18 together with a set ofdepressions 21 also formed in the otherwise generally flat faces 18, 18. Twinning is reduced in proportion to the combined surface area (at face 18) of thelettering 22 and thedepressions 21. -
FIG. 12F shows atablet 10 with acoating 12 that has raised,enlarged portions end portions face 18 to face 18 contact betweentablets 10. -
FIG. 12G is a variant on theFIG. 12F embodiment when the raisedend portion 23′ smoothly merges with the body of the tablet at both ends to reinforce theportions 23′, 23′. -
FIG. 12H shows another embodiment of thetablet 10 with generally flat faces 18, 18 and a central, generally hemispherical,projection 27 generally centered on eachface 18. Theprojection 27 can, of course, take a variety of shapes and can be used in plural form on each face. - Turning now to apparatus and techniques and modes of processing suitable for producing the dosage forms 10,
FIGS. 13-15 illustrate anapparatus 30 which uses a semi-elastic mold, or “transfer plate” 32 configured as a belt and adapted to move in coordination with an array of the dosage forms 10 each carried in suitable aligneddepressions 33 on aconveyor belt 34. - As shown, the dosage forms 10, have been coated, at least in part, with a
layer 12 and are arrayed across the conveyingbelt 34 in a series of mutually-spaced lines. A like pattern of thedepressions 33 each receives one of the tablet or capsule types of the dosage forms 10 to establish this array. One of therolls 36 a, 36 b that carry thebelt 34 is driven to advance the dosage forms, right to left as shown, to a firstrelief replicating assembly 38 having a frame 38 a, and threerolls belt transfer plate 32. At least one of these rolls is also driven to move the transfer plate in coordination with movement of thebelt 34. - The
transfer plate 32 is preferably formed as a thin, temperature resistant sheet of a material that can retain a high resolution microrelief such as a diffraction pattern on its outer surface, which is preferably thermally conductive and able to flex sufficiently to transfer the relief to a heat-softened and/or liquefiedlayer 12 on one face 18 (FIGS. 1-12H ) ofdosage form 10 while accommodating to its shape. The preferred material is a diffractive surface composed of an electoformed metal or a heat resistant plastic, both with a thickness in the range of 1 to 5 mils. The tension in thetransfer plate 32 produces a downward pressure urging the microrelief pattern on the transfer plate to be replicated in thelayer 12 on the dosage forms as they pass through a nip defined by the belt 34 (at the roll 36 a) and the opposed portion of thetransfer plate 32. - The
coating 12 is heated, preferably just before and/or during this replication, to a degree that softens it sufficiently to receive the microrelief. A typical temperature of thelayer 12 produced by this heating is in the range of 90° C. to 150° C., and preferably about 125° C. It can be effected by heating the transfer plate, thedosage form coating 12, or both. The heat source can be a stream of hot air, an electric resistance heater, a pulse of a laser, a source of infra-red radiant energy, a fluid-heated cylinder, or any of a wide variety of known devices. In the apparatus shown, preferably theroll 38 b is heated, and it in turn heats the transfer plate. If the dosage form is heated, it can be heated as a whole, or heated with a controlled burst of radiant energy (e.g., laser light) that heats only theouter layer 12, but does not significantly increase the temperature of thecore 14. The transfer of the relief can occur in a fraction of a second, with 0.3 to 3 second being typical, and with a pressure of between 5 and 10 kg per pill. After transferring the microrelief to thelayer 12, the layer is rapidly cooled to set the microrelief in the layer. Where release is a significant concern, a sliding mechanism is employed to shift the belt that holds the dosage form array to the side effecting the release. Again, a wide variety of cooling techniques can be used such as jets of chilled air, cold rolls, ambient air and radiant cooling, or the action of the cool core 14 (FIGS. 1-12H ) as a heat sink. In the apparatus shown, preferably roll 38 d and 36 a are cooled, which cools thetransfer plate 32, and the dosage forms carried on thebelt 34. The cooling also aids the release of theouter layer 12 from the transfer plate. - The
belt 34 andtransfer plate 32 move in coordination until the cooling has set the microrelief. Aguide member 40 retains the dosage forms in thebelt 34 as it rotates around a cushioned roll 36 a to allow for variations in dosage form thickness and to invert the dosage forms 10 just embossed. While a continuous belt is shown, other conveyance arrangements can be used, e.g., a chain drive carrying a series of mutually spaced, slat-like segments 35 (FIGS. 20 and 20 A) that carry the dosage forms and transfer plate. Eachslat segment 35 can then be jogged along its length independently of the movement of the other segments to facilitate the release of the dosage forms from the transfer plate. The slates are preferably mounted on bolts or pins 37 captured in elongated openings 35a that guide the jogging movements.Springs 39 hold the slats in a normal position. A fixedcam plate 41 at the side of thebelt 34 engages the slats as they travel and produces the jogging movement in opposition to the spring force. - The dosage forms 10 transfer to an array of
depressions 33′ inbelt 34′. It carries them to asecond print assembly 38′ that transfers a diffraction microrelief on the opposite face of eachdosage form 10. Theassembly 38′ has the same construction as theassembly 38. The microrelief pattern, of course, may differ. The presenting coated dosage form face or surfaces are heated, the microrelief pattern thermally transferred, cooled, and released, as with theassembly 38, as they are continuously carried through theassembly 38′. Upon leaving theassembly 38′, the dosage forms 10 travel inbelt 34′ and fall onto a take-awayconveyor 44. -
FIGS. 16 and 17 show analternative apparatus 45 according to the present invention which, like theapparatus 30 ofFIGS. 13-15 , uses twotransfer plates opposite faces 18 of dosage forms 10 carried in opening 48 of moving conveyor belt 50. The upper rim of belts 50 moves right to left, as shown, as dosage forms 10 are fed into theopenings 48 which aligns and transports the dosage forms. Theopenings 48 extend through the belt 50. Apanel 52—or a belt or other equivalent member—supports the dosage forms at their bottom to retain them in theopenings 48 before and after thetransfer plates transfer plates rolls 54 a, 54 b that drive the transfer plates in coordination with the movement of the belt 50. The transfer plates sandwich the dosage forms there between.Rolls 55 disposed behind each transfer plate adjacent the dosage forms are heated to heat the dosage forms through the transfer plates to a suitable temperature, again, preferably 90° C. to 150°C. Cooling rollers 56 then help in demolding. Note that the thinness of the transfer plates not only facilitates rapid heat transfer, but also facilitates the application of a generally uniform pressure over the dosage form surface receiving the microrelief, despite the fact that the surface might not be flat, e.g., thecurved surfaces 18 of the dosage forms 10 shown inFIGS. 1-2 . A uniform distribution of the pressure can be promoted by using a resilient pressure member, e.g., a foam sleeve on alternatingrolls - The
transfer plates holes 48 by a conforming guide member 40a. As the dosage forms clear the guide, they fall onto a take away conveyor 44 a. -
FIGS. 18-19 show a twin moving belt-liketransfer plate apparatus 59 according to the present invention, which is an alternative embodiment employing features of theFIGS. 13-15 andFIGS. 16-17 apparatus FIGS. 13-15 embodiments. An array of dosage forms 10 withcoatings 12 on at least some portions of their upper and lower faces are transported inopenings 61 formed in acontinuous belt 60. Theopenings 61 extend through thebelt 60, which acts both as a transport and an alignment grid. Its upper run travels right to left, as shown inFIG. 18 , over afirst roll 62 and then between a replicatingassembly 38 and abacking roll 64. The first roll 38 a of theassembly 38 heats thetransfer plate 32 containing the microrelief pattern to be transferred, here a diffraction relief with a holographic image, which then is pressed into alayer 12 to replicate the structure. The belt tension and nip dimensions set the pressure. Preferably the backer roll and/or the transfer plate have a resilient layer that distributes the applied force generally uniformly, and urges the thin transfer plate into thelayer 12 even if it is in recessed or curved portion of the dosage form.Roll 38 b of theassembly 38 is cooled to set the microrelief. De-molding is as with the previously discussed embodiments. - Continued transport then carries the dosage forms through a mirror-
image print assembly 38′ and cooperatingbacking roll 64 that replicates a relief on the opposite face of the dosage forms 10. Aguide 66 carries the dosage forms around to a take-awayconveyor 68. -
FIGS. 21-24 show anotherapparatus 69 according to the present invention for transferring a microrelief pattern into thecoating 12 of adosage form 10. This embodiment uses apallet assembly 71 that has arectangular frame 70 that supports a registration plate, or grid, 72 that in turn holds an array of the dosage forms 10 inopenings 74 that extend through the grid. A thin,rectangular transfer plate 76, preferably formed of metal, and having a microrelief pattern etched or otherwise formed on one face is placed in the frame. Thetransfer plate 76 is registered on pins or surfaces (e.g., the interior surfaces of the sidewalls of the frame 70) if it is desired to have precise registration between the relief pattern and the dosage forms. Anelastic base 77 also held in theframe 70 supports the dosage forms from the bottom. It can have depressions aligned with the openings to accommodate curved or thick dosage forms and to protect the supported surface from mechanical abrasion. The apparatus carries thepallet 71 along a generally linear processing path that includes intermittent stops at a series of stations. - The frames are carried on a continuous conveyor belt, as best seen in
FIG. 23 , in two stages that each transfer amicrorelief pattern 16 onto oneface 18 of eachdosage form 10. At asecond station 82, a pick-and-place mechanism 84transfers plate 76 on a parallel transfer plate-return conveyor 86 and move it onto aframe 70, over an array of the dosage forms 10 loaded into thegrid 72. At station 88 a thermal-pressure element 90 lowers onto the transfer plate, heats at least the portions of thecoatings 12 adjacent the transfer plate to the desired temperature (90° C.-150° C., and preferably about 125° C.), and presses the transfer plate into theheated coating 12 to replicate the microrelief pattern. This typically requires about ½ second, but can fall in the range of 0.3 to 3.0 second. The thermal transfer element, as seen inFIG. 21 , preferably has aheated pressure plate 91 that is generally co-extensive with the transfer plate to heat it and apply pressure to it uniformly. As noted above, a resilient layer, here thefoam rubber base 77, helps to promote an even distribution of the applied force. A typical pressure is 5 kg to 30 kg/per pill with about 10 kg/per pill being preferred. After imprinting, theheat transfer element 90 moves and lifts from the transfer plate and thepallet 71 moves through several air cooling stations 92 (e.g., regions under cooled air outlets 93) which set the microrelief. Atstation 94, the transfer plate is then lifted from thepallet 71 to de-mold it from the dosage forms 10, and transfer it to the conveyor 86 for recirculation back tostation 82. - A
turnover mechanism 98 flips the dosage form array sandwiched between the two frame assemblies through 180° onto a secondlinear conveyor 100 of the second stage. This second stage repeats the microrelief replication process of stage one to place a microrelief on theopposite face 18 eachdosage form 10. After thetransfer plate 32 is removed atstation 94, the registration grid and frame are carried aroundroll 102 to discharge the dosage forms to a take-awayconveyor 104 feeding acollection bin 106. -
FIG. 25 shows arotary apparatus 108 for thermoforming a high resolution diffraction relief onto alayer 12 on an array of dosage forms 10 carried in apallet 71. A diffractionpattern transfer plate 76 is placed on eachincoming pallet 71 at 110. The pallet is then transported to aposition 112 where it is gripped between a pair ofmembers arm 118 rotated by ahub 120. At least onearm 118 of each pair of pivots to open, close, and press the transfer plate towards the dosage forms. As the hub rotates, a gripped assembly is heated and pressed at angular position 119, cooled atposition 120, and released by opening themembers position 122 where the assembly is transported to a de-molding and transferplate removal station 124. -
FIGS. 26 and 27 show arotary apparatus 126 according to the present invention that receives an intake of dosage forms 10 that are fed vertically into a registration frame 128. An associatedshuttle apparatus 130 moves both upper microstructure (relief) transfer element (“MTE”) 132 andlower MTE plate 134 into and out of positions aligned with the frame 128. At theintake position 126, theupper MTE 132 is “open”, that is, shuttled to the side, while thelower MTE 134 is “closed”, that is, in position under the frame 128 to support thedosage form 10 in opening 136 in the MTE 128. The upper MTE then closes—as the apparatus rotates the dosage form(s) and MTE's through thermoforming andcooling positions position 142, thelower MTE 134 shuttles to an open position to allow the dosage forms to fall out of the frame 128 onto a chute, belt or other off-take arrangement. - It will be understood that the shuttle mechanism can include cam action or other equivalent mechanical arrangement to develop force that presses the MTE's toward the heated dosage form layers 12, and/or facilitates the release of the dosage forms from the MTE's. Also, pressing can utilize a separate pressure and/or heat applying member operating in the manner of the
thermal transfer element 90. -
FIGS. 29 and 30 show anotherapparatus 138 according to the present invention that rotates a set of tablet punch dies 140 each having abody 142 with a central bore that defines the outline of this dosage form and upper andlower punches body 142. The punch dies are generally of standard design for the manufacture of compressed powder tablets, except that (1) the end face of eachpunch tab 148 is mounted in aslot 150 in the side of thebody 142 to execute a pivotal movement between the dosage form-in-die position 148 a, shown at the left-most die inFIG. 30 , and the dosage form-ejected-from-die position 148 b, shown in the right-most die inFIG. 30 . Alternatively, a small, movable clamp (not shown) can grip and move the dosage into, and hold them in position in, the dies 14, and then remove them from the dies 14. - In the
apparatus 138 thedosage form 10 itself, not the punch or the die, is heated to soften thelayer 12 before it is introduced to theapparatus 138. The heated dosage form is then fed into the die through theslot 150 with the tab in position 148 b. Movement of the dosage form fully into the die is effected by rotating thetab 148 to position 148 a. The apparatus then rotates to index the die, with the hot dosage form loaded therein, to a position where thecold punches layer 12. Because the punches are relatively cold and have a large mass as compared to the heated dosage form, they quickly cool thelayer 12. The punches are then withdrawn to de-mold the microrelief thus formed. Further step-wise rotation of theapparatus 138 brings the coateddosage form 10 with the microrelief(s) 16 to a discharge position. Operation of thetab 148 to the position 148 b ejects thedosage form 10 from the die. The die punch is then ready to receive another heated dosage form. Alternatively, of course, thepunches -
FIG. 31 is a flow diagram showing the thermoforming manufacturing process of the present invention in its most general form. At block 152 alayer 12 is solid state is provided, whether as a full or partial covering of a core 14, a hard or soft capsule shell, a label to be affixed to a core or capsule, or itself as a carrier of a pharmaceutical dispersed therein. Atblock 154 the layer is heated, whether by a mold or die or directly, to a degree sufficient to receive the microrelief. Atblock 156, the microrelief pattern is transferred into the heated layer. Atblock 158, the microrelief thus formed in thelayer 12 is cooled to set the microrelief sufficiently that it does not degrade when de-molded. Atblock 160 thelayer 12 is released from the mold (transfer plate, MTE, etc.). -
FIG. 32 shows an alternative arrangement for the formation of a holographic microrelief pattern directly into anouter layer 12 on adosage form 10. A high energy laser light source 161 (shown as two sources 161, but typically it is one source whose output beam is split) produces two beams 162, 162 of laser light that interfere in a region 164 to produce a desiredinterference pattern 16 of light intensity maxima and minima. A dosage form is positioned with itslayer 12 in the region 164. Lines of maximum light energy creates corresponding grooves (a microrelief) into thelayer 12. Lines of minimum light intensity produce corresponding ridges in thelayer 12. A microrelief pattern is thus formed directly by a pattern of light energy “burned into” thelayer 12. Note that because the interference pattern occurs over a region, it automatically adjusts to variations of thelayer 12 from a perfectly flat condition. -
FIG. 33 shows a furtheralternative apparatus 170 according to the present invention that transfers a high resolution microrelief into theouter coating 12 of dosage forms 10, particularly tablets. This embodiment is similar in its construction and mode of operation to known high speed printing apparatuses. The dosage forms 10 are fed to anintake hopper 172. Afeeding apparatus 174 takes the dosage forms from thehopper 172, orients and aligns them, and presents them for transfer to afirst conveyor wheel 176. An array of depressions in the outer layer of thewheel 176, or other known arrangements, carry an array of the dosage forms on the outer periphery of thewheel 176. Aguard rail 178 holds the dosage forms 10 in place on theconveyor 176 as it rotates them from thefeeder 174 to asecond conveyor wheel 180. The rotation of theconveyors conveyor 176 to that of theconveyor 180 at thenip 182. - The
conveyor wheel 180 then rotates the dosage forms to a nip 184 where aheated cylinder 186 that carries amicrorelief transfer plate 32′ on its outer surface. A microrelief pattern, preferably a high resolution diffraction relief, is electroformed or otherwise created using known techniques on the outer surface of theplate 32′ and positioned to contact thelayers 12 on a first face of the dosage forms 10 as they pass through thenip 184. The heat of thecylinder 186 softens thelayer 12 to replicate the microrelief pattern in it. The size of the nip spacing, in conjunction with particular dosage forms, transfer plates and carrier wheel constructions (e.g., with or without a resilient backing layer under the dosage forms likelayer 77 in theFIGS. 21-24 embodiment) produces the desired degree of pressure to affect the replication for a givenlayer 12 and a given degree of heating. Also, with the foregoing embodiments, a pressure in the range of 5 to 15 kg/pill, and preferably about 10 kg/pill, is preferred. A guard rail (not shown) likerail 176 may be used over the run to the nip 184, and in conjunction with other conveyor wheels runs, e.g.,to hold the dosage forms on thewheel 180 after they leave the nip 184 and continue to nip 188 where the dosage forms again transfer toconveyor wheel 190. -
Conveyor wheel 190, constructed likeconveyor wheels outer layer 12 and carries them to a secondheated cylinder 192 that rotates in registration with thewheel 190 to replicate a microrelief on a second face of the dosage forms in the manner described above with respect toheated cylinder 186 atnip 194. After replication of the microrelief at thenips layer 12 is cooled in any of the ways discussed above to retain the microrelief in thelayer 12 and facilitate a demolding from thetransfer plates 32′, 32′. - Having been embossed with a
microrelief 16 on two opposite faces, the dosage forms 10 leaving thenip 194 are carried on theconveyor wheel 190 to an output chute 196 where the demolder dosage forms fall off thewheel 190 assisted by the force of gravity and slide down the chute 196. - There has been described a dosage form that can selectively retain and reconstruct optical information and effects while being compatible with modern high-speed production techniques. The dosage form can take a variety of configurations, including a coated tablet, a capsule, and If the layers themselves are formed into sections, they can be used as dosage forms after being made to absorb the contents of the pharmaceutically active agent of the core therein. The holographic images or effects can provide brand identification, control counterfeiting, and provide quality control. The dosage forms can be made using materials that have regulatory approval for foods or pharmaceutical uses.
- There has also been described a variety of machines and processes for the production of these dosage forms. These machines and processes are compatible with modern production speeds and techniques. In the manufacture of dosage unit forms such as tablets, they also resist twinning.
- While this invention has been described with respect to its presently preferred embodiments, other modifications and variations will occur to those skilled in this art. For example, those skilled in the art will readily understand that the products, apparatus, and manufacturing processes described herein can also be adapted to the production of non-pharmaceutical cores such as placebos and include cores made of materials such as sugar, gum, hard jellies, or a variety of confections. Such modifications and variations are intended to fall within the scope of the appended claims.
Claims (35)
1-28. (canceled)
29. A method of producing a microrelief on an ingestible dosage form having a core which can contain a pharmaceutically active substance and a pharmaceutically acceptable carrier, comprising the steps of:
a. coating said core with a layer of a thermo-formable material that can receive and retain a holographic diffraction pattern;
b. providing a plate having a holographic diffraction pattern formed on at least a portion of a first surface thereof;
c. heating at least one of said plate and said coating during or prior to the time when they are in said opposed relationship;
d. pressing said first surface into said coating to replicate said holographic diffraction pattern in said coating;
e. cooling said coating thus replicated; and
f. demolding said first plate surface from said coating.
30. The holographic dosage form production method of claim 29 wherein said coating is pan coating and further comprising the step of controlling twinning of said coated tablets.
31. The holographic dosage form production method of claim 30 wherein said twinning control comprises forming said core with at least one curved face that receives said coating and said pressing.
32. The holographic dosage form production method of claim 31 wherein said curvature is sufficient to resist twinning, but not sufficient to distort the holographic image pressed into in said coating.
33. The holographic dosage form production method of claim 32 wherein said core face is generally circular and, measured as an angle in a plane through the face, the curvature is in the range of about 0.6 radian to about 0.9 radian.
34. The holographic dosage form production method of claim 30 wherever said twinning control comprises forming said core with a recess within at least one face of said coat, said recess having a generally flat bottom that receives said coating layer.
35. The holographic dosage form production method of claim 34 wherein said recess is sufficiently shallow that said pressing transfers said holographic pattern reliably.
36. The holographic dosage form production method of claim 42 wherein said recess is less than about 0.01 mm.
37. The diffractive dosage form production method of claim 29 wherein said coating includes said thermo-formable material bonding reliably with said core.
38. The holographic dosage form production method of claim 29 or 37 wherein said thermo-formable material selected from the group consisting of: gelatin, hydroxypropylmethylcellulose (HPMC), hydroxyproplycellulose (HPC), modified food starches, waxes, vegetable gums and combinations thereof.
39. The holographic dosage form production methods of claim 38 wherein said material includes solids of a modified cellulose, a plasticizer, and a colorant.
40. The holographic dosage form production method of claim 38 wherein said coating produces a layer in the range of 0.25% to 7.25% of the weight of said dosage form.
41. The holographic dosage form production method of claim 29 further comprising transporting said coated cores to a position opposite said first surface, and wherein said plate providing comprises continuously advancing a belt of a semi-flexible material containing said pattern on at least one surface thereof in coordinating with said transporting of said coated dosage forms.
42. The holographic dosage form production method of claim 41 wherein said semi-flexible material is selected from the group consisting of: a thin sheet metal, rubber, a laminate of thin sheet metal and a layer of a resilient backing material opposite said first surface, and a rubber and metal composite.
43. The holographic dosage form production method of claim 42 wherein said thin sheet metal is a nickel composite with a thickness of 1 mils to 5 mils, and said holographic diffraction pattern is electroformed on said first surface.
44. The holographic dosage form production method of claim 41 wherein said transporting also aligns said coated cores.
45. The holographic dosage form production method of claims 41 or 43 wherein said coated core facing said plate during said pressing is non-planar, and said belt flexibility is sufficient to allow said belt to conform to said non-planar coating desiring said pressing.
46. The holographic dosage form production method of claim 41 wherein said transporting comprises conveying of a linear array of said coated cores in a parallel, closely spaced relationship with a portion of said belt, and moving said belt in coordination with said conveying.
47. The holographic dosage form production method of claim 46 wherein said heating is a rapid, localized heating of said belt during said pressing.
48. The holographic dosage form production method of claim 47 wherein said heating raises the temperature of said diffraction pattern on said belt to a temperature in the range of 90-150 C.
49. The holographic dosage form production method of claim 47 wherein said pressing comprises a brief deflection of said heated belt that places said diffraction pattern in said coating to create said replication of said diffraction pattern in said coating.
50. The holographic dosage form production method of claims 29 and 47 wherein said pressing occurs for about 0.3 to 3.0 second.
51. The holographic dosage form production method of claim 46 wherein said cooling is a rapid, localized cooling that begins immediately after said pressing has formed said diffraction pattern in said coating.
52. The holographic dosage form production method of claim 51 wherein said demolding comprises a resumption of said mutually spaced relationship between said coating as said coated and said belt as they continue to move in coordination, after said cooling has begun.
53-62. (canceled)
63. A method of producing a microrelief on an ingestible dosage form which can contain a pharmaceutically active substance and a pharmaceutically acceptable carrier, comprising the steps of:
a. providing a layer of material forming at least a part of the dosage form having a first surface, said material being thermoformable to receive, and once formed, retain, a holographic diffraction pattern on said first surface;
b. providing a holographic diffraction pattern;
c. replicating said holographic diffraction pattern to said first surface by thermoforming said pattern onto said first surface; and
d. rapidly cooling said thermoformed holographic diffraction pattern thus replicated.
64. The method of claim 63 , wherein providing a holographic diffraction pattern comprises producing an interference pattern using laser light.
65. The method of claim 64 , wherein said laser light is constituted by two laser light beams split from a single laser light source.
66. The method of claim 63 , wherein said active substance and carrier are contained in a core and said layer overlies said core.
67. A method of producing an optical pattern on a surface of an edible article, where the optical pattern interacts with incident light to produce a visible image or effect, comprising the steps of:
67. A method of producing an optical pattern on a surface of an edible article, where the optical pattern interacts with incident light to produce a visible image or effect, comprising the steps of:
providing a laser;
causing said laser to emit first and second beams of light; and
causing said first and second beams of light to interfere to produce an interference pattern on the surface of the edible article, and wherein the interference pattern produces the optical pattern on the surface of the edible article.
68. The method of claim 67 , wherein said interference pattern is comprised of light intensity maxima and minima.
69. The method of claim 67 , wherein the optical pattern is comprised of a plurality of grooves produced by lines of maximum light intensity in said interference pattern, and a plurality of ridges produced by lines of minimum light intensity in said interference pattern.
70. The method of claim 68 , wherein the optical pattern is a microrelief.
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JP2018111655A (en) * | 2017-01-10 | 2018-07-19 | 株式会社Screenホールディングス | Tablet, reading device, and printing device |
WO2020185639A1 (en) * | 2019-03-08 | 2020-09-17 | Tri-Star Technologies | System and method for applying patterns on articles and inspection thereof |
Families Citing this family (103)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003005839A2 (en) | 1999-08-05 | 2003-01-23 | Dimensional Foods Corporation | Edibles containing edible optical elements and methods |
US20060226234A1 (en) * | 2003-06-11 | 2006-10-12 | Kettinger Frederick R | Pharmaceutical dosage forms having overt and covert markings for identification and authentification |
US7431956B2 (en) | 2003-06-20 | 2008-10-07 | Sensient Imaging Technologies, Inc. | Food grade colored fluids for printing on edible substrates |
US8235302B2 (en) | 2004-04-20 | 2012-08-07 | Nanolnk, Inc. | Identification features |
CN101005769B (en) | 2004-06-10 | 2011-03-16 | 森辛特成像科技公司 | Food grade ink jet inks fluids for printing on edible substrates |
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US20060088587A1 (en) * | 2004-10-27 | 2006-04-27 | Bunick Frank J | Dosage forms having a microreliefed surface and methods and apparatus for their production |
US20060088586A1 (en) * | 2004-10-27 | 2006-04-27 | Bunick Frank J | Dosage forms having a microreliefed surface and methods and apparatus for their production |
US20100294147A1 (en) * | 2004-12-20 | 2010-11-25 | Nanoink, Inc. | Apparatus and methods for preparing identification features including pharmaceutical applications |
US8069782B2 (en) * | 2004-12-20 | 2011-12-06 | Nanoink, Inc. | Stamps with micrometer- and nanometer-scale features and methods of fabrication thereof |
US20100297027A1 (en) * | 2004-12-20 | 2010-11-25 | Nanolnk, Inc. | Overt authentication features for compositions and objects and methods of fabrication and verification thereof |
PT1867324T (en) * | 2005-03-31 | 2016-08-29 | Takeda Pharmaceuticals Co | Tablet |
EP3827747A1 (en) | 2005-04-28 | 2021-06-02 | Otsuka Pharmaceutical Co., Ltd. | Pharma-informatics system |
US8912908B2 (en) | 2005-04-28 | 2014-12-16 | Proteus Digital Health, Inc. | Communication system with remote activation |
US9198608B2 (en) | 2005-04-28 | 2015-12-01 | Proteus Digital Health, Inc. | Communication system incorporated in a container |
US8802183B2 (en) | 2005-04-28 | 2014-08-12 | Proteus Digital Health, Inc. | Communication system with enhanced partial power source and method of manufacturing same |
US8836513B2 (en) | 2006-04-28 | 2014-09-16 | Proteus Digital Health, Inc. | Communication system incorporated in an ingestible product |
US8730031B2 (en) | 2005-04-28 | 2014-05-20 | Proteus Digital Health, Inc. | Communication system using an implantable device |
CA2614547C (en) * | 2005-07-08 | 2014-10-21 | Takeda Pharmaceutical Company Limited | Tablet |
JP5714210B2 (en) * | 2005-09-01 | 2015-05-07 | プロテウス デジタル ヘルス, インコーポレイテッド | Implantable wireless communication system |
JP2007117181A (en) * | 2005-10-25 | 2007-05-17 | Nissei Kosan Kk | Soft capsule |
US7796335B2 (en) * | 2006-04-03 | 2010-09-14 | William Karszes | Microlens windows and interphased images for packaging and printing and methods for manufacture |
JP2009544338A (en) * | 2006-05-02 | 2009-12-17 | プロテウス バイオメディカル インコーポレイテッド | Treatment regimen customized to the patient |
DE102007026958B4 (en) * | 2006-06-13 | 2014-10-09 | Csem Centre Suisse D'electronique Et De Microtechnique S.A. | Press tool with diffractive microstructure and method for producing such a tool and tableting press |
CH699631B1 (en) * | 2007-01-12 | 2010-04-15 | Suisse Electronique Microtech | Realizing a diffractive microstructure in a pill surface. |
DE102007026957B4 (en) * | 2006-06-13 | 2012-04-05 | Csem Centre Suisse D'electronique Et De Microtechnique S.A. | Pharmaceutical tablets with diffractive microstructure |
WO2007144826A2 (en) * | 2006-06-13 | 2007-12-21 | Csem Centre Suisse D'electronique Et De Microtechnique Sa | Pharmaceutical tablets with diffractive microstructure and compression tools for producing such tablets |
US20080020037A1 (en) * | 2006-07-11 | 2008-01-24 | Robertson Timothy L | Acoustic Pharma-Informatics System |
EP2083680B1 (en) | 2006-10-25 | 2016-08-10 | Proteus Digital Health, Inc. | Controlled activation ingestible identifier |
EP2069004A4 (en) | 2006-11-20 | 2014-07-09 | Proteus Digital Health Inc | Active signal processing personal health signal receivers |
ES2930588T3 (en) | 2007-02-01 | 2022-12-19 | Otsuka Pharma Co Ltd | Ingestible Event Marker Systems |
KR101528748B1 (en) | 2007-02-14 | 2015-06-15 | 프로테우스 디지털 헬스, 인코포레이티드 | In-body power source having high surface area electrode |
ES2384941T3 (en) | 2007-02-16 | 2012-07-16 | Csem Centre Suisse D'electronique Et De Microtechnique Sa - Recherche Et Developpement | Verification method |
EP2124725A1 (en) | 2007-03-09 | 2009-12-02 | Proteus Biomedical, Inc. | In-body device having a multi-directional transmitter |
US9270025B2 (en) | 2007-03-09 | 2016-02-23 | Proteus Digital Health, Inc. | In-body device having deployable antenna |
US8115618B2 (en) | 2007-05-24 | 2012-02-14 | Proteus Biomedical, Inc. | RFID antenna for in-body device |
US20090004231A1 (en) | 2007-06-30 | 2009-01-01 | Popp Shane M | Pharmaceutical dosage forms fabricated with nanomaterials for quality monitoring |
IL185130A0 (en) * | 2007-08-08 | 2008-01-06 | Semi Conductor Devices An Elbi | Thermal based system and method for detecting counterfeit drugs |
FI2192946T3 (en) | 2007-09-25 | 2022-11-30 | In-body device with virtual dipole signal amplification | |
GB0719095D0 (en) * | 2007-10-01 | 2007-11-07 | Bioprogress Technology Ltd | Indelibly marked polymeric films |
EP2211843B8 (en) | 2007-10-17 | 2012-10-17 | GONIC International Ltd. | Pharmaceutical moire pill |
US10363221B2 (en) | 2007-10-17 | 2019-07-30 | I-Property Holding Corp. | Manufacturing solid pharmaceutical dosage forms with visible micro- and nanostructured surfaces and micro- and nanostructured pharmaceutical dosage form |
EP2231125A1 (en) * | 2007-10-17 | 2010-09-29 | I-Property Holding Corp. | Manufacturing solid pharmaceutical dosage forms with visible micro-and nanostructured surfaces and micro-and nanostructured pharmaceutical dosage form |
US20100297228A1 (en) * | 2007-10-29 | 2010-11-25 | Nanolnk, Inc. | Universal coating for imprinting identification features |
KR101586193B1 (en) * | 2007-11-27 | 2016-01-18 | 프로테우스 디지털 헬스, 인코포레이티드 | Transbody communication systems employing communication channels |
GB2455805B (en) * | 2007-12-21 | 2009-11-18 | Valtion Teknillinen | Diffractive microstructure and a method of producing the same |
AU2009221781B2 (en) | 2008-03-05 | 2014-12-11 | Otsuka Pharmaceutical Co., Ltd. | Multi-mode communication ingestible event markers and systems, and methods of using the same |
US10531681B2 (en) | 2008-04-25 | 2020-01-14 | Sensient Colors Llc | Heat-triggered colorants and methods of making and using the same |
FI20085611A0 (en) * | 2008-06-18 | 2008-06-18 | Valtion Teknillinen | Indicator |
MY154234A (en) | 2008-07-08 | 2015-05-15 | Proteus Digital Health Inc | Ingestible event marker data framework |
US8626672B2 (en) * | 2008-07-23 | 2014-01-07 | I-Property Holding Corp. | Secure tracking of tablets |
WO2010011833A1 (en) | 2008-07-23 | 2010-01-28 | Alexander Stuck | Secure tracking of tablets |
AU2009281876B2 (en) * | 2008-08-13 | 2014-05-22 | Proteus Digital Health, Inc. | Ingestible circuitry |
US9113647B2 (en) | 2008-08-29 | 2015-08-25 | Sensient Colors Llc | Flavored and edible colored waxes and methods for precision deposition on edible substrates |
US8055334B2 (en) | 2008-12-11 | 2011-11-08 | Proteus Biomedical, Inc. | Evaluation of gastrointestinal function using portable electroviscerography systems and methods of using the same |
WO2013012869A1 (en) | 2011-07-21 | 2013-01-24 | Proteus Digital Health, Inc. | Mobile communication device, system, and method |
EP3395333A1 (en) | 2009-01-06 | 2018-10-31 | Proteus Digital Health, Inc. | Pharmaceutical dosages delivery system |
JP2012514799A (en) | 2009-01-06 | 2012-06-28 | プロテウス バイオメディカル インコーポレイテッド | Methods and systems for ingestion related biofeedback and individual pharmacotherapy |
FR2943268B1 (en) * | 2009-03-20 | 2014-02-28 | Arcil | THERMALLY INSULATING THERMOFROMING MOLD AND ASSOCIATED METHOD. |
WO2010111403A2 (en) | 2009-03-25 | 2010-09-30 | Proteus Biomedical, Inc. | Probablistic pharmacokinetic and pharmacodynamic modeling |
CN102458236B (en) | 2009-04-28 | 2016-01-27 | 普罗秋斯数字健康公司 | The Ingestible event marker of high reliability and using method thereof |
US9149423B2 (en) | 2009-05-12 | 2015-10-06 | Proteus Digital Health, Inc. | Ingestible event markers comprising an ingestible component |
US9189728B2 (en) | 2009-07-23 | 2015-11-17 | I-Property Holding Corp. | Method for the authentication of dosage forms |
JP5493570B2 (en) * | 2009-08-06 | 2014-05-14 | 大日本印刷株式会社 | Method for producing pharmaceutical capsules |
JP2011036278A (en) * | 2009-08-06 | 2011-02-24 | Dainippon Printing Co Ltd | Capsule for medicine |
US8558563B2 (en) | 2009-08-21 | 2013-10-15 | Proteus Digital Health, Inc. | Apparatus and method for measuring biochemical parameters |
CN102686203B (en) * | 2009-10-08 | 2014-02-12 | 基伊埃制药系统有限公司 | Method and drum coater for coating small items, such as tablets, and coating system comprising such drum coaters |
US7961014B2 (en) * | 2009-10-26 | 2011-06-14 | Analog Devices, Inc. | Apparatus and method for providing multi-mode clock signals |
TWI517050B (en) | 2009-11-04 | 2016-01-11 | 普羅托斯數位健康公司 | System for supply chain management |
UA109424C2 (en) * | 2009-12-02 | 2015-08-25 | PHARMACEUTICAL PRODUCT, PHARMACEUTICAL TABLE WITH ELECTRONIC MARKER AND METHOD OF MANUFACTURING PHARMACEUTICAL TABLETS | |
BR112012025650A2 (en) | 2010-04-07 | 2020-08-18 | Proteus Digital Health, Inc. | miniature ingestible device |
TWI557672B (en) | 2010-05-19 | 2016-11-11 | 波提亞斯數位康健公司 | Computer system and computer-implemented method to track medication from manufacturer to a patient, apparatus and method for confirming delivery of medication to a patient, patient interface device |
US20110290694A1 (en) | 2010-05-27 | 2011-12-01 | Monosol Rx, Llc | Oral film dosage form having indicia thereon |
BR112013003331A2 (en) * | 2010-08-13 | 2017-07-11 | l kraft Daniel | systems and methods for the production of custom drug products |
FR2966731B1 (en) * | 2010-11-03 | 2013-04-26 | Sanofi Aventis | SOLID PHARMACEUTICAL FORM MARKERED AND METHOD OF MANUFACTURING BY LASER MARKING |
JP2014504902A (en) | 2010-11-22 | 2014-02-27 | プロテウス デジタル ヘルス, インコーポレイテッド | Ingestible device with medicinal product |
EP2701668A1 (en) | 2011-04-29 | 2014-03-05 | Massachusetts Institute of Technology | Layer processing for pharmaceuticals |
WO2015112603A1 (en) | 2014-01-21 | 2015-07-30 | Proteus Digital Health, Inc. | Masticable ingestible product and communication system therefor |
US9756874B2 (en) | 2011-07-11 | 2017-09-12 | Proteus Digital Health, Inc. | Masticable ingestible product and communication system therefor |
US9235683B2 (en) | 2011-11-09 | 2016-01-12 | Proteus Digital Health, Inc. | Apparatus, system, and method for managing adherence to a regimen |
US9271897B2 (en) | 2012-07-23 | 2016-03-01 | Proteus Digital Health, Inc. | Techniques for manufacturing ingestible event markers comprising an ingestible component |
WO2014043553A1 (en) * | 2012-09-15 | 2014-03-20 | Slaboden Jeffery K | Dissolvable tablet |
SG11201503027SA (en) | 2012-10-18 | 2015-05-28 | Proteus Digital Health Inc | Apparatus, system, and method to adaptively optimize power dissipation and broadcast power in a power source for a communication device |
JP2016508529A (en) | 2013-01-29 | 2016-03-22 | プロテウス デジタル ヘルス, インコーポレイテッド | Highly expandable polymer film and composition containing the same |
US11744481B2 (en) | 2013-03-15 | 2023-09-05 | Otsuka Pharmaceutical Co., Ltd. | System, apparatus and methods for data collection and assessing outcomes |
JP5941240B2 (en) | 2013-03-15 | 2016-06-29 | プロテウス デジタル ヘルス, インコーポレイテッド | Metal detector device, system and method |
US20160066595A1 (en) | 2013-04-19 | 2016-03-10 | Nestec S.A. | Molded food product |
US9796576B2 (en) | 2013-08-30 | 2017-10-24 | Proteus Digital Health, Inc. | Container with electronically controlled interlock |
US10084880B2 (en) | 2013-11-04 | 2018-09-25 | Proteus Digital Health, Inc. | Social media networking based on physiologic information |
WO2015179461A1 (en) | 2014-05-20 | 2015-11-26 | Massachusetts Institute Of Technology | Plasticity induced bonding |
EP3305271B1 (en) * | 2015-06-05 | 2020-01-01 | Shibaura Mechatronics Corporation | Tablet printing device and tablet printing method |
US11051543B2 (en) | 2015-07-21 | 2021-07-06 | Otsuka Pharmaceutical Co. Ltd. | Alginate on adhesive bilayer laminate film |
KR102051875B1 (en) | 2016-07-22 | 2019-12-04 | 프로테우스 디지털 헬스, 인코포레이티드 | Electromagnetic detection and detection of ingestible event markers |
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JP7423425B2 (en) | 2020-05-29 | 2024-01-29 | エステー株式会社 | tablet |
JP2024510484A (en) * | 2021-03-17 | 2024-03-07 | アクテリオン ファーマシューティカルズ リミテッド | Formulation administration system |
WO2024018406A1 (en) * | 2022-07-22 | 2024-01-25 | Luigi Lavazza S.P.A. | Tablet for the extraction of a beverage and method for the production thereof |
Citations (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4029757A (en) * | 1975-12-15 | 1977-06-14 | Hoffmann-La Roche Inc. | Manufacture of pharmaceutical unit dosage forms |
US4031200A (en) * | 1975-12-15 | 1977-06-21 | Hoffmann-La Roche Inc. | Manufacture of pharmaceutical unit dosage forms |
US4661367A (en) * | 1982-06-10 | 1987-04-28 | Imperial Chemical Industries Plc | Process for the manufacture of colored intagliated articles |
US4668523A (en) * | 1985-03-06 | 1987-05-26 | Eric Begleiter | Holographic product |
US4668521A (en) * | 1985-03-04 | 1987-05-26 | Chocolate Pix, Inc. | Method of forming an image with photographic likeness on chocolate |
US4847090A (en) * | 1986-11-07 | 1989-07-11 | Warner-Lambert Company | Confection product and method for making same |
US4973469A (en) * | 1986-02-03 | 1990-11-27 | Elan Corporation, Plc | Drug delivery system |
US5002775A (en) * | 1982-03-08 | 1991-03-26 | Sumitomo Chemical Company, Limited | Tablets having clear impressed marks and method for making same |
US5189531A (en) * | 1988-10-17 | 1993-02-23 | August DeFazio | Hologram production |
US5510171A (en) * | 1995-01-19 | 1996-04-23 | Minnesota Mining And Manufacturing Company | Durable security laminate with hologram |
US5834047A (en) * | 1996-06-10 | 1998-11-10 | Ahn; Sung-Ae | Method for imprinting confectionery products with edible ink |
US6054158A (en) * | 1998-06-23 | 2000-04-25 | Candy Novelty Works Ltd. | Magnifying lollipop |
US6103278A (en) * | 1999-01-12 | 2000-08-15 | Lluch; Alex | Lenticular lollipop |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1097619C (en) | 1994-07-12 | 2003-01-01 | 伯温德药品服务公司 | Moisture barrier film coating composition, method, and coated products |
US5992742A (en) * | 1994-08-05 | 1999-11-30 | Sullivan; Scott L. | Pill printing and identification |
BG103081A (en) * | 1999-01-14 | 2000-07-31 | Николай МАРЧЕВ | Method and automatic capsulation machine for making capsules of thermoshrinkable foil |
US6975765B2 (en) * | 2003-05-06 | 2005-12-13 | New Light Industries, Ltd. | Optically variable form birefringent structure and method and system and method for reading same |
-
2000
- 2000-07-31 HN HN2000000165A patent/HN2000000165A/en unknown
- 2000-08-02 PA PA20008499001A patent/PA8499001A1/en unknown
- 2000-08-03 BR BR0012920-8A patent/BR0012920A/en not_active IP Right Cessation
- 2000-08-03 MX MXPA02001176A patent/MXPA02001176A/en active IP Right Grant
- 2000-08-03 GE GE4669A patent/GEP20043376B/en unknown
- 2000-08-03 AU AU65135/00A patent/AU772936C/en not_active Ceased
- 2000-08-03 PL PL00353615A patent/PL353615A1/en unknown
- 2000-08-03 CA CA002378591A patent/CA2378591A1/en not_active Abandoned
- 2000-08-03 HU HU0203796A patent/HUP0203796A2/en unknown
- 2000-08-03 EA EA200200089A patent/EA004895B1/en not_active IP Right Cessation
- 2000-08-03 NZ NZ516741A patent/NZ516741A/en unknown
- 2000-08-03 YU YU7602A patent/YU7602A/en unknown
- 2000-08-03 CZ CZ2002207A patent/CZ2002207A3/en unknown
- 2000-08-03 WO PCT/US2000/021149 patent/WO2001010464A1/en not_active Application Discontinuation
- 2000-08-03 CN CN008113300A patent/CN1216643C/en not_active Expired - Fee Related
- 2000-08-03 SK SK179-2002A patent/SK1792002A3/en not_active Application Discontinuation
- 2000-08-03 KR KR1020027001610A patent/KR20020059358A/en not_active Application Discontinuation
- 2000-08-03 EP EP00952433A patent/EP1206280A4/en not_active Withdrawn
- 2000-08-03 UY UY26270A patent/UY26270A1/en not_active Application Discontinuation
- 2000-08-03 EE EEP200200058A patent/EE200200058A/en unknown
- 2000-08-03 OA OA1200200031A patent/OA12044A/en unknown
- 2000-08-03 TR TR2002/00309T patent/TR200200309T2/en unknown
- 2000-08-03 AP APAP/P/2002/002434A patent/AP2002002434A0/en unknown
- 2000-08-03 CN CNA2004101049346A patent/CN1650844A/en active Pending
- 2000-08-03 IL IL14794300A patent/IL147943A0/en unknown
- 2000-08-03 JP JP2001514980A patent/JP2003506415A/en active Pending
- 2000-08-03 GT GT200000126A patent/GT200000126A/en unknown
- 2000-08-04 CO CO00058852A patent/CO5200853A1/en not_active Application Discontinuation
- 2000-08-04 AR ARP000104030A patent/AR028158A1/en not_active Application Discontinuation
- 2000-08-04 PE PE2000000782A patent/PE20010664A1/en not_active Application Discontinuation
-
2002
- 2002-01-22 IS IS6244A patent/IS6244A/en unknown
- 2002-01-23 ZA ZA200200605A patent/ZA200200605B/en unknown
- 2002-01-25 CR CR6572A patent/CR6572A/en not_active Application Discontinuation
- 2002-02-04 NO NO20020545A patent/NO20020545L/en not_active Application Discontinuation
- 2002-02-21 BG BG06424A patent/BG106424A/en unknown
- 2002-03-04 HR HR20020199A patent/HRP20020199A2/en not_active Application Discontinuation
- 2002-11-21 HK HK02108455.9A patent/HK1048437A1/en unknown
-
2005
- 2005-09-14 US US11/227,214 patent/US7083805B2/en not_active Expired - Fee Related
-
2007
- 2007-07-26 US US11/881,230 patent/US20080019925A1/en not_active Abandoned
Patent Citations (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4031200A (en) * | 1975-12-15 | 1977-06-21 | Hoffmann-La Roche Inc. | Manufacture of pharmaceutical unit dosage forms |
US4069086A (en) * | 1975-12-15 | 1978-01-17 | Hoffmann-La Roche Inc. | Novel dosage form |
US4029757A (en) * | 1975-12-15 | 1977-06-14 | Hoffmann-La Roche Inc. | Manufacture of pharmaceutical unit dosage forms |
US5002775A (en) * | 1982-03-08 | 1991-03-26 | Sumitomo Chemical Company, Limited | Tablets having clear impressed marks and method for making same |
US4661367A (en) * | 1982-06-10 | 1987-04-28 | Imperial Chemical Industries Plc | Process for the manufacture of colored intagliated articles |
US4668521A (en) * | 1985-03-04 | 1987-05-26 | Chocolate Pix, Inc. | Method of forming an image with photographic likeness on chocolate |
US4668523A (en) * | 1985-03-06 | 1987-05-26 | Eric Begleiter | Holographic product |
US4973469A (en) * | 1986-02-03 | 1990-11-27 | Elan Corporation, Plc | Drug delivery system |
US4847090A (en) * | 1986-11-07 | 1989-07-11 | Warner-Lambert Company | Confection product and method for making same |
US5189531A (en) * | 1988-10-17 | 1993-02-23 | August DeFazio | Hologram production |
US5510171A (en) * | 1995-01-19 | 1996-04-23 | Minnesota Mining And Manufacturing Company | Durable security laminate with hologram |
US5834047A (en) * | 1996-06-10 | 1998-11-10 | Ahn; Sung-Ae | Method for imprinting confectionery products with edible ink |
US6054158A (en) * | 1998-06-23 | 2000-04-25 | Candy Novelty Works Ltd. | Magnifying lollipop |
US6103278A (en) * | 1999-01-12 | 2000-08-15 | Lluch; Alex | Lenticular lollipop |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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US20060088585A1 (en) * | 2004-10-27 | 2006-04-27 | Bunick Frank J | Dosage forms having a microreliefed surface and methods and apparatus for their production |
US20070190133A1 (en) * | 2004-10-27 | 2007-08-16 | Bunick Frank J | Dosage forms having a microreliefed surface and methods and apparatus for their production |
US20070281022A1 (en) * | 2004-10-27 | 2007-12-06 | Bunick Frank J | Dosage forms having a microreliefed surface and methods and apparatus for their production |
US20060088593A1 (en) * | 2004-10-27 | 2006-04-27 | Bunick Frank J | Dosage forms having a microreliefed surface and methods and apparatus for their production |
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US9969134B2 (en) | 2006-11-03 | 2018-05-15 | Trustees Of Tufts College | Nanopatterned biopolymer optical device and method of manufacturing the same |
US20100065784A1 (en) * | 2006-11-03 | 2010-03-18 | Trustees Of Tufts College | Electroactive biopolymer optical and electro-optical devices and method of manufacturing the same |
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