WO2009051805A1 - Fabrication de formes posologiques pharmaceutiques solides qui présentent des surfaces micro- et nanostructurées et forme posologique pharmaceutique micro- et nanostructurée - Google Patents

Fabrication de formes posologiques pharmaceutiques solides qui présentent des surfaces micro- et nanostructurées et forme posologique pharmaceutique micro- et nanostructurée Download PDF

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Publication number
WO2009051805A1
WO2009051805A1 PCT/US2008/011889 US2008011889W WO2009051805A1 WO 2009051805 A1 WO2009051805 A1 WO 2009051805A1 US 2008011889 W US2008011889 W US 2008011889W WO 2009051805 A1 WO2009051805 A1 WO 2009051805A1
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WIPO (PCT)
Prior art keywords
micro
dosage form
pharmaceutical dosage
nanostructured
dosage forms
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PCT/US2008/011889
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English (en)
Inventor
Stefan Klocke
Harald Walter
Alexader Stuck
Original Assignee
Stefan Klocke
Harald Walter
Alexader Stuck
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Stefan Klocke, Harald Walter, Alexader Stuck filed Critical Stefan Klocke
Priority to CA2703610A priority Critical patent/CA2703610C/fr
Priority to EP08840036A priority patent/EP2231125A1/fr
Priority to AU2008314615A priority patent/AU2008314615B2/en
Publication of WO2009051805A1 publication Critical patent/WO2009051805A1/fr
Priority to US12/761,993 priority patent/US10363221B2/en

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    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms

Definitions

  • This invention relates to composite dosage forms such as pharmaceutical compositions and components thereof. More particularly, this invention relates to composite dosage forms comprising one or more features that provide anti-counterfeiting characteristics to such dosage forms.
  • Anti-counterfeiting strategies currently in use in the pharmaceutical industry have so far not been very successful in preventing forgery, illegal re-imports and other activities commonly summarized as counterfeiting.
  • Anti-counterfeiting features in the pharmaceutical market nowadays are generally only applied to packages. Holograms, optically variable inks, fluorescent dyes, special printing techniques like micro-printing, and other security features are attached to the packages by use of adhesive tags, or these are laminated to the carton, or they are directly applied to the packages. The main drawback of such labels is that they can be removed from the product or the packaging and reused or analyzed.
  • Some companies offer security features applied to the sealing foil of blister packages, but these features possess the same disadvantages.
  • Intagliations are impressed marks typically achieved by engraving or impressing a graphical representation, for example a figure, mark, character, symbol such as a letter, a name, a logo, a pictoral representation, and the like, or any combination thereof, in a tablet or other solid dosage form, such as by a punching procedure.
  • U.S. Patent No. 5,827,535 describes soft gelatin capsules with an external surface having defined thereon an impressed graphical representation.
  • 5,405,642 discloses a method of highlighting intagliations in white or color-coated tablets by spraying onto said tablets a suspension comprising a filling material having a different color, a waxy material and a solvent, then removing the solvent and the excess filling and waxy material.
  • a filling material having a different color e.g., a waxy material and a solvent
  • EP 088,556 relates to a method of highlighting intagliations in white or colored tablets by contacting said tablets with a dry, powdery material having a different color than that of the tablet surface, then removing the excess powdery material not deposited in the intagliations. Disadvantageously, it has been found that the adhesion of the powdery material to the intagliations is not satisfactory, as the material shows a tendency to loosen and fall out.
  • EP 060,023 discloses a method of emphasizing intagliations in colored (i.e., not white) solid articles, in particular tablets, by coating the tablet surface and filling up the intagliations with a coating film comprising an optically anisotropic substance.
  • An optical contrast between the tablet surface and the intagliations is obtained, presumably due to different orientation of the optically anisotropic substance on the tablet surface and in the intagliations.
  • tin ' s technique is limited to colored articles and only allows for the use of optically anisotropic filling materials.
  • microreliefs are a regular pattern of ridges and grooves and the like that may display a visual effect or optical information when exposed to suitable light.
  • a few ideas of applying a microrelief or hologram to edible products have been published. One is based on coating an edible product with a thermo-formable and thus embossable layer (WO 01/10464 Al). As this layer alters the composition of the product, as well as the production process, a new approval of the drug from certification authorities would be needed. Further the heating during the thermo-forming steps can harm -many active agents.
  • a polymer solution is brought into contact with a diffraction relief mold and then hardened upon drying (US 4,668,523).
  • the drying step can be accelerated by heating, and in the end the hardened edible polymer product possesses the diffractive relief of the mold.
  • This method is limited to polymer solutions, it is very slow, and the heating step can be harmful to active agents used in pharmaceutical products, as it may negatively affect the activity of the active pharmaceutical agents. Disadvantageous ⁇ , production difficulties could be encountered when using these methods to stamp microrelief patterns into tablets having irregular shapes and/or surfaces.
  • WO 2006/047695 shows a variety of methods to manufacture pharmaceutical dosage forms showing different kinds of microreliefs embedded into their surface. However, based on further review, it seems that the solutions proposed by WO 2006/047695 result in microreliefs that are not recognizable by the human eye. In particular, overcoating of microstructures usually makes them invisible because most overcoatings have a similar optical index of refraction as the pharmaceutical dosage form completely eliminating optical reflections from the interface between the two.
  • the present invention relates to the manufacturing of micro- and nanostructures in pharmaceutical dosage forms by direct compression under production conditions.
  • the invention describes how geometrical structures embossed into pharmaceutical dosage forms at high speed by direct compression give rise to visible and/or measurable optical contrast in the pill by locally changing the directional optical reflectivity and/or the absorption of the surface. This contrast is useful for branding and brand protection purposes, as well as for anti-counterfeiting.
  • this invention relates to pharmaceutical dosage forms incorporating dyes to enhance the contrast of visible and/or measureable effects based on micro- and nanostructures impressed in such forms during the direct compression process.
  • the use of certain dyes is necessary, as the resulting colors strongly increase the human perception of the optical microstructures.
  • Human perception is very sensitive to contrast, not absolute intensities.
  • a diffractive hologram on a diffuse white surface is not well visible for a human being, even if the measured diffraction efficiency of the hologram is very high. This is because the human eye not only perceives the light reflected from the hologram but also the intense light from the white surface surrounding it. The human being is "blinded" by the diffuse white surface. However, if the same hologram is on a darker background (black, dark blue, green or red for example) the rainbow colors of the hologram can be clearly seen even if the hologram is not very good. This is but one example how color and texture of a surface influence human perception.
  • Figs IA and IB are perspective views which schematically show two types of micro- and nanostructures, according to the invention.
  • Fig 2 is a reproduction of a photograph showing a compressed pill, with a diffractive micro-structure made by direct embossing, illuminated with white light.
  • Fig 3 is a perspective view which schematically shows the reflection/ scattering/diffraction of light on a micro- and nanostructured dosage form, according to the invention.
  • the present invention describes how well visible optical contrast in pharmaceutical dosage forms is achieved in a very fast, single manufacturing step by direct compression of suitable materials.
  • a punching tool with a micro- and/or nanostructured surface directly compresses a pharmaceutical formulation in a press. Under the proper manufacturing conditions a very fast transfer of the tool surface geometry into the surface of the pharmaceutical dosage form is achieved.
  • the modified surface geometry changes the local optical appearance of the surface, creating a well visible optical contrast.
  • a single or a combination of several optical mechanisms are responsible for contrast formation: interference, diffraction, diffuse single and/or multiple scattering, single and/or multiple reflection and single and/or multiple absorption of visible light.
  • microstructures can have a regular ordering or they can be irregular or random arranged. In the case of regular ordered microstructures, these structures are chosen to be larger than 2 ⁇ m, preferred larger than 5 ⁇ m, if a color contrast without or with low intense diffraction effects is the goal. Nevertheless the microstructure itself is not seen by the unaided eye.
  • the invention By locally changing the microstructure in the compression tool, the invention also allows to manufacture very complex geometrical contrast patterns in pharmaceutical dosage forms in a single manufacturing step.
  • the material to be compressed into the dosage form possess certain physical characteristics that lend themselves to processing in such a manner.
  • the material to be compressed must be free- flowing, must be lubricated, and importantly must possess sufficient cohesiveness to insure that the solid dosage form remains intact after compression.
  • the tablet is formed by pressure being applied to the material to be tabletted on a tablet press.
  • a tablet press includes a lower punch that fits into a die from the bottom and an upper punch having a corresponding shape and dimension that enters the die cavity from the top after the tabletting material fills the die cavity.
  • the tablet is formed by pressure applied on the lower and upper punches.
  • the ability of the material to flow freely into the die is important in order to insure that there is a uniform filling of the die and a continuous movement of the material from the source of the material, e.g., a feeder hopper.
  • the lubricity of the material is crucial in the preparation of the solid dosage forms because the compressed material must be readily ejected from the punch faces.
  • the material to be compressed into a solid dosage form includes one or more excipients that impart the free- flowing, lubrication, and cohesive properties to the drug(s) being formulated into a dosage form.
  • Lubricants are typically added to avoid the material(s) being tabletted from sticking to the punches.
  • Commonly used lubricants include magnesium stearate and calcium stearate. Such lubricants are commonly included in the final tabletted product in amounts of less than 1 % by weight.
  • solid dosage forms In addition to lubricants, solid dosage forms often contain diluents. Diluents are frequently added in order to increase the bulk weight of the material to be tabletted in order to make the tablet a practical size for compression. This is often necessary where the dose of the drug is relatively small.
  • Binders are agents that impart cohesive qualities to the powdered material(s). Commonly used binders include starch, and sugars such as sucrose, glucose, dextrose, and lactose.
  • Disintegrants are often included in order to ensure that the ultimately prepared compressed solid dosage form has an acceptable disintegration rate in an environment of use (such as the gastrointestinal tract).
  • Typical disintegrants include starch derivatives and salts of carboxymethylcellulose.
  • Dry granulation procedures may be used where one of the constituents, either the drug or the diluent, has sufficient cohesive properties to be tabletted.
  • the method includes mixing the ingredients, slugging the ingredients, dry screening, lubricating, and finally compressing the ingredients.
  • the wet granulation procedure includes mixing the powders to be incorporated into the dosage from in, e.g., a twin shell blender or double-cone blender and thereafter adding solutions of a binding agent to the mixed powders to obtain solutions of a binding agent to the mixed powders to obtain a granulation.
  • damp mass is screened, e.g., in a 6- or 8-mesh screen and then dried, e.g., via tray drying, the use of a fluid-bed dryer, spray-dryer, radio-frequency dryer, microwave, vacuum, or infra-red dryer.
  • direct compression the powdered material(s) to be included in the solid dosage form is compressed directly without modifying the physical nature of the material itself.
  • the use of direct compression is limited to those situations where the drug or active ingredient has a requisite crystalline structure and physical characteristics required for formation of a pharmaceutically acceptable tablet.
  • the drug itself is to be administered in a relatively high dose (e.g., the drug itself comprises a substantial portion of the total tablet weight)
  • Aerosil colloidal silica, anhydrous
  • Magnesium- ⁇ 10% stearat Magnesium- ⁇ 10% stearat (Mg-stearate)
  • polyethyleneglycol color and active agent
  • Most of the volume is made of binding and filling agents like Lactose and Cellulose. Because of their at least partially plastic deformation behavior these and similar materials are suited to emboss the micro -structure in.
  • Mg-stearate is used as a lubricant and Aerosil improves the powder flow.
  • An FDA-approved colorant may be added. While most pharmaceutical pills are white, notable examples such as Viagra® are blue,, others are red. Direct tabletting results in pills with a bright colored and scattering surface.
  • a high portion of plastic deformable materials in the formulation helps the formation of the micro-and nano-structure in the pill surface.
  • the portion of microcrystalline cellulose or plastic binders like PVP may be enhanced or these materials could replace less plastic ones.
  • compositions are made up of particles with different sizes.
  • a typical size distribution may is shown in table II: Table II: Typical particle size distribution in pharmaceutical formulations
  • microstructures ⁇ 2% > 500 micrometers
  • Most particles have a size between 75 and 250 microns. Embossing microstructures with a size of 100 microns or less into the pill surface therefore deforms most particles themselves, I.e. the microstructure is embossed into the surface of the grains.
  • the powder mixture is compressed between two punches, which apply axial mechanical forces in the range of 5-4OkN, but depend on the size of the pill in question. Compression reduces the volume of the mass and at the same time increase its mechanical strength.
  • the compression process is essentially a high-impact molding process and works at room temperature without heating. State-of-the-art single rotary presses work at high speed and produce about 30,000 to 300,000 pills per hour. This means that compression time per pill is well below 100ms. This time is long enough to compress the raw powder material to a hard pill, but the pill is still soluble after it is ingested.
  • the pressure parameters of the tablet press are set in a way that correlates with the mixture of ingredients used in the particular pharmaceutical dosage form.
  • pressure parameters generally have to be set at the upper end of the spectrum of commercially available tablet presses, good results for a flat pill with a diameter of 1 lmm were obtained for compression forces between 15 and 35 kN. This resulted in pills with a hardness between 100-250 N.
  • the tablet press parameters were set in a range of between 10 and 50 kN,
  • FIGS IA and 2 A schematically show two examples of such structures, designated 10a and 10b, respectively.
  • Structure 10a has a sinusoidal diffraction grating (with period 12 and depth 14), and structure 10b has a random scattering microstructure with an average lateral structure dimension 16 of a few ⁇ m and structure height 18.
  • the aspect ratio of the structures is the depth 14 (or 16) divided by the height 12 (or 18).
  • surface holograms show a distinctive rainbow pattern when illuminated by white light.
  • Regular pyramidal structures with sizes between 10 and 70 microns strongly diffuse light and give a satinated appearance.
  • Randomly oriented structures with an average size between 10-100 microns may also show satination.
  • Further such random microstructures can produce characteristic speckle pattern if illuminated by a coherent light source such as a laser of an LED.
  • GB221870A describes security devices based on such random microstructures. Small, but deep patterns with sizes ranging in between 100- 500nm's reduce reflection and darken a given surface. In this case deep means deeper or comparable to the lateral size.
  • Diffractive Reflection hologram rainbow aspect ratio: 0.05-1
  • grating shape grating colors sinusoidal, trapezoidal, square, triangular etc.
  • the regular structures shown in table III can be arranged regularly in 1 or 2 dimension in different patterns.
  • the gratings can be one or 2-dimensional. They may also be quasi-cristalline, i.e. exhibit a 5 fold symmetry. It is also possible to have locally regular arrangements which on a scale of several 10 microns to mm is randomly arranges, i.e. like in a 2 dimensional polycrystal. Other arrangements are conceivable as well.
  • R(D) is the reflectivity as a function of wavelength D of a smooth surface
  • R 2 (D corresponds to the amount of the twice reflected light on a structured surface
  • R 3 Q to the amount of three times reflected light on the structured surface and so on.
  • R is always smaller than one, this means that the more times the light is reflected, the weaker it becomes but it also means that the reflectivities which are closer to 1 get much less attenuated by multiple reflection than the smaller reflectivities, in effect narrowing the reflection spectrum around the maximum reflectivity. If the reflectivity spectrum contains several peaks this also means that the average reflected wavelength is shifted towards the wavelength with maximal reflectivity by multiple reflection.
  • This effect can be precisely controlled and gives simple possibility to manufacture a 2 colored pharmaceutical pill by combining 2 or more dyes in a given formulation. For example if a blue and red dye is added to a white formulation, the resulting flat pill may be violet. However, microstructuring parts of the surface will make this part of the pill more reddish or bluish, depending on relative reflectivities, giving a 2 colored pill.
  • micro-and nanostnictures with typical lateral sizes ranging between 0.2 ⁇ m and 100 microns and aspect ratios (ration between structure depth and lateral size) between 0.1 and 2 can be reliably and stably implemented in the surface of each pill during the direct tabletting process. Considering the restrictions of this process mentioned above, it seems more or less impossible.
  • the powders are not designed to be micro-structured. As the size of the micro-structures is smaller than the dimension of the particles, the surface of the particle itself must be micro-structured. Finally, the tabletting process is very fast making the time for the micro-structuring extremely short, i.e. less than 100ms.
  • micro-structure in the punch surface is adapted to the process and the dye formulation, strong color contrast can be achieved by micro- and nanostructuring of pill surfaces, as shown by the micro-structure 10c that appears on the surface of dosage form 19, within the dotted circle 20.
  • the micro-structured area can even be macroscopically structured to form logos, brand names, and the like. This conclusion required several findings.
  • the material of the tool which bears the micro-structure must be very hard for a long lifetime. At the same time it must be possible to implement the micro-structure in its surface.
  • Hardened steel, hard chromium coated steel, tungsten carbide or molybdenum carbide etc. are examples of materials used for direct tabletting.
  • a grating depth of about lOOnm or more is necessary. Also, if a lubricant is used the micro-structure must be deeper than the thickness of the lubricant between the punch and the tablet mass.
  • the microstructure needs to be protected, otherwise it may wear off. This can be done either by geometrical arrangements or by coating of the tablet.
  • the microstructures are embossed at the bottom of an intagliation in the pill surface. The walls of the intgliation geometrically protect the microstructure from abrasion. Other geometrical arrangements are conceivable which protect the microstructure geometrically from abrasion.
  • Is and Ib are the reflected light intensities from a structured part of the dosage form and an unstructured part respectively.
  • Ib is the background intensity.
  • Figure 3 schematically depicts the reflection and/or scattering and/or diffraction of light emitted from a light source 25 toward a pharmaceutical dosage form 119, with a circular micro- and/or nanostructure 1Od located in the center thereof, and eventually toward point of reference 27.
  • the contrast C is >0.1, especially preferred >0.2, in particular preferred >0.4 and most preferred >0.6.
  • excipients are added to the formulation to impart good flow and compression characteristics to the material as a whole that is to be compressed. Such properties are typically imparted to these excipients via a pre-processing step such as wet granulation, slugging, spray drying, spheronization, or crystallization.
  • Useful direct compression excipients include processed forms of cellulose, sugars, and dicalcium phosphate dehydrate, among others.
  • microcrystalline cellulose A processed cellulose, microcrystalline cellulose, has been used extensively in the pharmaceutical industry as a direct compression vehicle for solid dosage forms.
  • Microcrystalline cellulose is commercially available under the tradename, "EMCOCEL®®from Edward Mendell Co., Inc., and as Avicel® from FMC Corp. Compared to other directly compressible excipients, microcrystalline cellulose is generally considered to exhibit superior compressibility and disintegration properties.
  • Suitable polymers for inclusion in top coatings include polyvinylalcohol (PVA); water soluble polycarbohydrates such as hydroxypropyl starch, hydroxyethyl starch, pullulan, methylethyl starch, carboxymethyl starch, pre-gelantinized starches, and film-forming modified starches; water swellable cellulose derivatives such as hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), methyl cellulose (MC), hydroxyethylmethylcellulose (HEMC), hydroxybutylmethylcellulose (HBMC), hydroxyethylethylcellulose (HEEC), and hydroxyehtylhydroxypropylmethyl cellulose (HEMPMC); water soluble copolymers such as methacrylic acid and methacrylate ester copolymers, polyvinyl alcohol and polyethylene glycol copolymers, polyethylene oxide and polyvinylpyrrolidone copolymers; polyvinylpyrrolidone and poly
  • Suitable film-forming water insoluble polymers for inclusion in top coatings include for example ethylcellulose, polyvinyl alcohols, polyvinyl acetate, polycaprolactones, cellulose acetate and its derivatives, acrylates, methacrylates, acrylic acid copolymers; and the like and derivatives, copolymers, and combinations thereof.
  • Suitable film-forming pH-dependent polymers for inclusion in top-coatings include enteric cellulose derivatives, such as for example hydroxypropyl methylcellulosephthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate; natural resins, such as shellac and zein; enteric acetate derivatives such as for example polyvinylacetate phthate, cellulose acetate phthalate, acetaldehyde dimethylcellulose acetate; and enteric acrylate derivatives such as for example polymethacrylate-baserd polymers such as poly(methacrylic acid, methyl methacrylate) 1 :2, which is commercially available from Rohm Pharma GmbH under the tradename, "EUDRAGIT S;” and poly(methacrylic acid, methyl methacrylate) 1 :1, which is commercially available from Rohm Pharma GmbH under the tradename "EUDRAGIT L;” poly (butyl, methacrylate (dimethylaminoethyl)
  • the top coating includes coatings having a high rigidity, i.e., e.g., those coatings having a yield value sufficient to prevent deformation of the microrelief when exposed to normal manufacturing, handling, shipping, storage, and usage conditions.
  • Suitable top coatings having high rigidity include film formers, such as for example, the high tensile strength film-formers well known in the art.
  • suitable high tensile strength film- formers include, but are not limited to, methacrylic acid and methacrylate ester copolymers; polyvinylpyrrolidone; cellulose acetate; hydroxypropylmethylcellulose (HPMC), polyethylene oxide and polyvinylalcohol, which is commercially available from BASF under the tradename, "Kollicoat IR;” ethylcellulose; polyvinyl alcohols; and copolymers and mixtures thereof.
  • the top coatings may include the water-soluable high rigidity film formers selected from HPMC, polyvinylpyrrolidone, the aminoalkyl-methacrylate copolymers marketed under the trade mark, "EUDRAGIT E;” and copolymers and mixtures thereof.
  • the inventive dosage form may come in a variety of different shapes.
  • the dosage form may be in the shape of a truncated cone.
  • the dosage form may be shaped as a polyhedron, such as a cube, pyramid, prism, or the like; or may have the geometry of a space figure with some non-flat faces, such as a cone, cylinder, sphere, torus, or the like.
  • Exemplary shapes that may be employed include tablet shapes formed from compression tooling shapes described by "the Elizabeth Companies Tablet Design Training Manual" (Elizabeth Carbide Die Co., Inc., p. 7 (McKeesport, PA) (incorporated herein by reference). The tablet shape corresponds inversely to the shape of the compression tooling.
  • suitable fillers include, but are not limited to, water-soluble compressible carbohydrates such as sugars, which include dextrose, sucrose, isomaltalose, fructose, maltose, and lactose, polydextrose, sugar-alcohols, which include mannitol, sorbitol, isomalt, maltilol, xylitol, erythritol, starch hydrolysates, which include dextrins, and maltodextrins, and the like, water insoluble plastically deforming materials such as microcrystalline cellulose or other cellulosic derivatives, water-insoluble brittle fracture materials such as dicalcium phosphate, tricalcium phosphate, and the like and mixtures thereof.
  • water-soluble compressible carbohydrates such as sugars, which include dextrose, sucrose, isomaltalose, fructose, maltose, and lactose
  • polydextrose sugar-alcohols, which include mann
  • suitable binders include, but are not limited to, dry binders such as polyvinyl pyrrolidone, hydroxypropylmethylcellulose, and the like; wet binders such as water-soluble polymers, including hydrocolloids such as alginates, agar, guar gum, locust bean, carrageenan, tara, gum arabic, tragacanth, pectin, Whelan, rhamsan, zooglan, methylan, chitin, cyclodextrin, chitosan, polyvinyl pyrrolidone, cellulosics, starches, and the like; and derivatives and mixtures thereof.
  • dry binders such as polyvinyl pyrrolidone, hydroxypropylmethylcellulose, and the like
  • wet binders such as water-soluble polymers, including hydrocolloids such as alginates, agar, guar gum, locust bean, carrageenan, tara, gum arabic
  • suitable disintegrants include, but are not limited to, sodium starch glycolate, cross-lined polyvinylpyrrolidone, cross-linked carboxymethylcellulose, starches, microcrystalline cellulose, and the like.
  • suitable lubricants include, but are not limited to, long chain fatty acids and their salts, such as magnesium stearate and stearic acid, talc, and waxes.
  • suitable glidants include, but are not limited to, colloidal silicon dioxide, and the like.
  • the dosage form of the invention may also incorporate pharmaceutically acceptable adjuvants, including but not limited to preservatives, high-intensity sweeteners such as aspartame, acesulfame potassium, cyclamate, saccharin, sucralose, and the like; and other sweeteners such as dehydroalcones, grycyrrhizin, MonellinTM, stevioside, TalinTM, and the like; flavors, antioxidants, surfactants, and coloring agents.
  • pharmaceutically acceptable adjuvants including but not limited to preservatives, high-intensity sweeteners such as aspartame, acesulfame potassium, cyclamate, saccharin, sucralose, and the like; and other sweeteners such as dehydroalcones, grycyrrhizin, MonellinTM, stevioside, TalinTM, and the like; flavors, antioxidants, surfactants, and coloring agents.

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Abstract

L'invention concerne une forme posologique pharmaceutique [19] qui présente des micro- ou nanostructures [10a, 10b, 10c, 10d] imprimées à sa surface ou sur une de ses interfaces. La forme posologique [19] contient une quantité appropriée et une distribution appropriée d'ingrédients, tels qu'un ou plusieurs colorants, pour optimiser l'effet de contraste optique C causé par les micro- ou nanostructures, afin que les micro- ou nanostructures soient visibles par l'oeil humain et afin de fournir ainsi des caractéristiques anti-contrefaçon à la forme posologique.
PCT/US2008/011889 2007-10-17 2008-10-17 Fabrication de formes posologiques pharmaceutiques solides qui présentent des surfaces micro- et nanostructurées et forme posologique pharmaceutique micro- et nanostructurée WO2009051805A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CA2703610A CA2703610C (fr) 2007-10-17 2008-10-17 Fabrication de formes posologiques pharmaceutiques solides qui presentent des surfaces micro- et nanostructurees et forme posologique pharmaceutique micro- et nanostructuree
EP08840036A EP2231125A1 (fr) 2007-10-17 2008-10-17 Fabrication de formes posologiques pharmaceutiques solides qui présentent des surfaces micro- et nanostructurées et forme posologique pharmaceutique micro- et nanostructurée
AU2008314615A AU2008314615B2 (en) 2007-10-17 2008-10-17 Manufacturing solid pharmaceutical dosage forms with visible micro-and nanostructured surfaces and micro-and nanostructured pharmaceutical dosage form
US12/761,993 US10363221B2 (en) 2007-10-17 2010-04-16 Manufacturing solid pharmaceutical dosage forms with visible micro- and nanostructured surfaces and micro- and nanostructured pharmaceutical dosage form

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US98066507P 2007-10-17 2007-10-17
US60/980,665 2007-10-17
US10583308P 2008-10-16 2008-10-16
US61/105,833 2008-10-16

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US12/761,993 Continuation US10363221B2 (en) 2007-10-17 2010-04-16 Manufacturing solid pharmaceutical dosage forms with visible micro- and nanostructured surfaces and micro- and nanostructured pharmaceutical dosage form

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AU (1) AU2008314615B2 (fr)
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US4668523A (en) * 1985-03-06 1987-05-26 Eric Begleiter Holographic product
WO2001010464A1 (fr) * 1999-08-05 2001-02-15 Dimensional Foods Corporation Produits holographiques comestibles, notamment produits pharmaceutiques et procedes et appareil pour leur fabrication
WO2006047695A2 (fr) * 2004-10-27 2006-05-04 Mcneil-Ppc, Inc. Formes de doses possedant une surface a micro reliefs et procede et appareil de production de celles-ci

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Publication number Priority date Publication date Assignee Title
US20060088587A1 (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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EP2231125A1 (fr) 2010-09-29
AU2008314615B2 (en) 2014-03-13
CA2703610A1 (fr) 2009-04-23
CA2703610C (fr) 2017-11-28
AU2008314615A1 (en) 2009-04-23

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