HK1141715A - Laser marked dosage forms - Google Patents

Description

Laser-marked dosage form

The invention relates to a dosage form having a tablet core with at least two coatings which substantially surround the tablet core and at least partially overlap one another. The core is preferably in the form of a compressed core, wherein at least one of the coatings is disposed on an outer surface of the compressed core. An opening is provided through at least one of the coatings disposed over the compressed core.

Background

Oral dosage forms may be provided in a variety of forms. Solid dosage forms are generally understood to include a range of forms including compressed powder tablets to liquid filled capsules. These dosage forms may have a variety of shapes, colors, and/or printed information that serves to identify the dosage of the active ingredient of the product or its source. These dosage forms may also include one or more coatings, where such coatings may serve as a means for identifying the product and/or affecting the drug release profile.

One of the first type of film-coated elongated compressed tablets is called a "caplet". Similar to the case of capsules, the caplets enhance swallowability due to their elongated shape and film coated surface. Gelatin coated tablets and caplets are also well known solid dosage forms.

Published U.S. patent application 2005/0152971 relates to an improved gel-like coated dosage form having two end regions coated with a gel-like material and an exposed peripheral band. An opening is provided in at least the exposed perimeter band to reveal the core material. Gelatin coatings and methods of providing them are taught in a number of patents, including U.S. Pat. No.5,234,099, which relates to carrier devices for a variety of products having a plurality of collets for holding the products in a fixed orientation and enabling gelatin infusion.

Multi-colored dosage forms are also known, as shown in U.S. patent No.6,113,945, wherein the caplet or core has a clear or solid color uniform covering which can be applied by a coating process, by spraying or by a single dip coating step. The core itself has a first color or is colorless, and its outer surface of the transparent or single-color covering at one end or side is colored by a suitable dye, resulting in a two-color appearance. The dye may be applied by dip coating or sprayed with a suitable spray device. In a preferred embodiment, the cover is a transparent gel-like material. In this patent, the purpose of the staining protocol is to simulate the appearance of gelatin dipped type products.

There is a need for an apparatus and process that: solid oral dosage forms having visually discernible markings or identifiers are prepared without having to utilize a printer, or made more precise, consistent, stable, and compatible with a range of materials than are currently available without the use of added solvents or excessive amounts of printing ink.

Drawings

FIG. 1 is an enlarged isometric view of a compressed core having the form of an elongated tablet of generally cylindrical shape, referred to as a "gelcap core".

Fig. 2 is an enlarged isometric view of a dosage form showing a coated tablet with a portion of the subcoat exposed.

Fig. 3 shows an embodiment of the invention.

Fig. 4 shows an alternative embodiment of the invention.

Detailed Description

As used herein, the term "dosage form" applies to any solid, semi-solid, or liquid composition designed to contain a specific predetermined amount (dose) of a certain ingredient (e.g., an active ingredient as defined below). Suitable dosage forms may be drug delivery systems, including those for oral administration, buccal administration, rectal administration, mucosal delivery, or subcutaneous implants, or other implanted drug delivery systems; or compositions for delivering minerals, vitamins and other nutrients, oral care agents, flavorants, and the like. Preferably, the dosage form of the present invention is considered to be solid, however it may contain liquid components or semi-solid components. In a particularly preferred embodiment, the dosage form is an oral delivery system for delivering a pharmaceutically active ingredient into the gastrointestinal tract of a human. In another preferred embodiment, the dosage form is an oral "placebo" system containing non-pharmaceutically active ingredients, and the dosage form is designed to have the same appearance as certain pharmaceutically active dosage forms, e.g. for control purposes in clinical studies to test, e.g., the safety and efficacy of certain pharmaceutically active ingredients.

As used herein, the term "tablet" refers to a solid form prepared by compressing a powder on a tablet press, as is well known in the pharmaceutical art. Tablets may be prepared in a variety of shapes, including round or elongated, e.g., flat ovoid or cylindrical. As used herein, the term "caplet core" refers to an elongated, generally cylindrical or capsule-shaped tablet having straight or slightly arcuate sides, a generally circular cross-section, and a length to diameter ratio of about 2 to about 5 (e.g., about 2.5 to about 3.5, such as about 3).

A microcapsule is an elongated tablet. Fig. 1 shows a core 10 in the form of an elongate sheet having two ends 12 on opposite sides of a longitudinal axis. The binder 14 is formed along the longitudinal perimeter as the tablet contacts the die wall during compression.

The core may have any number of pharmaceutical tablet shapes. Tablets are intended to encompass shaped compressed dosage forms in the broadest sense. An elongated tablet is a tablet having an elongated shape. For the purposes of this patent application, the longitudinal axis passes through the center of the two ends of the core.

The core (or substrate) may be in any solid or semi-solid form. The core may be prepared by any suitable method, for example, the core may be in a compressed dosage form, or may be molded. As used herein, "substrate" refers to a surface or underlying support upon which another substance resides or acts, while "core" refers to a material that is at least partially encased or surrounded by another material. For the purposes of the present invention, the terms may be used interchangeably: that is, the term "core" may also be used to refer to a "substrate". Preferably, the core comprises a solid, for example, the core may be in the form of a compressed or moulded tablet, hard or soft capsule, suppository or confectionery, such as a lozenge, nougat, caramel, soft candy or fat-based composition. In certain other embodiments, the core may be in a semi-solid or liquid form in the finished dosage form. In embodiments where the core is prepared by compression, suitable excipients include fillers, binders, disintegrants, lubricants, glidants, and the like, as known in the art. In embodiments where the core is prepared by compression and additionally confers modified release properties to the active ingredient contained therein, such cores preferably further comprise release-modifying excipients.

Suitable fillers for preparing the core by compression include: water soluble compressible carbohydrates such as sugars (including dextrose, sucrose, maltose, and lactose), sugar alcohols (including mannitol, lactitol, sorbitol, maltitol, xylitol), starch hydrolysates (including dextrins and maltodextrins, and the like), water insoluble plastically deformable 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.

Suitable binders for preparing the core by pressing include: dry binders such as polyvinylpyrrolidone, microcrystalline cellulose, hydroxypropyl methylcellulose, and the like; wet binders, such as water soluble polymers, including hydrocolloids (e.g., gum arabic, alginates, agar, guar gum, locust bean, carrageenan, carboxymethylcellulose, tara gum, gum arabic, tragacanth gum, pectin, xanthan gum, gellan gum, gelatin, maltodextrin, galactomannan, saxilin, laminarin, scleroglucan, inulin, welan gum (whelan), rhamsan gum (rhamsan), zoogloea gum (zooglan), methylene gum (metalan), chitin, cyclodextrin, chitosan, polyvinylpyrrolidone, cellulose, sucrose, starch, and the like); and derivatives and mixtures thereof.

Suitable disintegrants for making the core by compression include: sodium starch glycolate, cross-linked polyvinylpyrrolidone, cross-linked carboxymethylcellulose, starch, and the like.

Suitable lubricants for preparing the core by compression include: long chain fatty acids and salts thereof, such as magnesium stearate and stearic acid, talc, glycerides and waxes.

Suitable glidants for preparing cores by compression include: colloidal silicon dioxide, silicified microcrystalline cellulose (e.g. under the trade nameProducts sold by FMC Corporation), and the like.

In one embodiment, the core has one or more major surfaces. The core may be of a variety of different shapes. For example, in one embodiment, the core may be frustoconical. In other embodiments, the core may be shaped as a polyhedron, such as a cube, pyramid, prism, or the like; or may have a geometry with some non-planar spatial profile, such as a cone, cylinder, sphere, torus, or the like. Exemplary core shapes that may be employed include tablet shapes formed from compression die shapes described by: "The Elizabeth company TabletDesign Training Manual" (Elizabeth carbide co., inc., page 7 (McKeesport, Pa.) (which is incorporated herein by reference) includes The following shapes:

1. shallow concave type

2. Standard concave

3. Deep concave type

4. Ultra-deep concave type

5. Improved concave ball

6. Standard bisection concave type

7. Standard double bisection concave type

8. Standard European style halving concave

9. Standard local bisection concave

10. Double radius shape

11. Inclined plane concave adding type

12. Is planar

13. Planar beveled edge shape (F.F.B.E.)

14. Bisected f.f.b.e.

15. Double halved f.f.b.e.

16. Ring shape

17. Micro-concave shape

18. Oval shape

19. Oval shape

20. Capsule shape

21. Rectangle

22. Square shape

23. Triangle shape

24. Hexagon shape

25. Pentagon

26. Octagon

27. Diamond shape

28. Arrow head shape

29. Bullet shape

30. Shallow concave type

31. Standard concave

32. Deep concave type

33. Ultra-deep concave type

34. Improved concave ball

35. Standard bisection concave type

36. Standard double bisection concave type

37. Standard European style halving concave

38. Standard local bisection concave

39. Double radius shape

40. Inclined plane concave adding type

41. Is planar

42. Plane inclined edge type (F.F.B.E.)

43. Bisected F.F.B.E.shape

44. Double bisection F.F.B.E. shape

45. Ring shape

46. Micro-concave shape

47. Oval shape

48. Oval shape

49. Capsule shape

50. Rectangle

51. Square shape

52. Triangle shape

53. Hexagon shape

54. Pentagon

55. Octagon

56. Diamond shape

57. Arrow head shape

58. Bullet shape

59. Cylindrical shape

60. Half moon shape

61. Shield shape

62. Heart shape

63. Almond shape

64. Book base plate shape

65. Parallelogram

66. Trapezoidal shape

67.8-shaped/barbell-shaped

68. Bowknot shape

69. Scalene triangle

The core 10 is compressed from a blend of suitable active ingredients and excipients, which may be naturally colored (including white) or may be colored in a conventional manner as desired to provide a conventional or elongated shaped core of any desired color.

The dosage form of the present invention preferably comprises one or more active ingredients. Suitable active ingredients may broadly include, for example: pharmaceuticals, minerals, vitamins and other nutrients, oral care agents, flavorants, and mixtures thereof. Suitable drugs include: analgesics, anti-inflammatory agents, antiarthritics, anesthetics, antihistamines, antitussives, antibiotics, anti-infective agents, antivirals, anticoagulants, antidepressants, antidiabetic agents, antiemetics, antiflatulents, antifungals, antispasmodics, appetite suppressants, bronchodilators, cardiovascular agents, central nervous system stimulants, decongestants, oral contraceptives, diuretics, expectorants, gastrointestinal agents, migraine agents, motion sickness products, mucolytics, muscle relaxants, osteoporosis agents, polydimethylsiloxanes, respiratory agents, sleep aids, urinary tract agents and mixtures thereof.

Suitable flavorants include: menthol, peppermint, mint flavors, fruit flavors, chocolate, vanilla, bubble gum flavors, coffee flavors, liqueur flavors and combinations thereof and the like.

In another embodiment, the at least one active ingredient is selected from: analgesics, anti-inflammatory agents and antipyretics, such as non-steroidal anti-inflammatory drugs (NSAIDs), including a) propionic acid derivatives, such as ibuprofen, naproxen, ketoprofen, and the like; b) acetic acid derivatives such as indomethacin, diclofenac, sulindac, tolmetin, and the like; c) fenamic acid derivatives such as mefenamic acid, meclofenamic acid, flufenamic acid, and the like; d) salicylic acid (biphenylcarbolic acid) derivatives such as diflunisal, flufenisal, and the like; e) oxicams, such as piroxicam, sudoxicam, isoxicam, meloxicam and the like; c) cyclooxygenase-2 (COX-2) selective NSAIDs; g) pharmaceutically acceptable salts of the foregoing.

In another embodiment of the invention, at least one active ingredient may be selected from the following analgesics: acetaminophen, acetylsalicylic acid, ibuprofen, naproxen, ketoprofen, flurbiprofen, diclofenac, cyclobenzaprine, meloxicam, rofecoxib, celecoxib, and pharmaceutically acceptable salts, esters, isomers, and mixtures thereof.

In another embodiment of the invention, at least one active ingredient may be selected from: pseudoephedrine, phenylephrine, chlorpheniramine, norephedrine, chlorpheniramine, dextromethorphan, diphenhydramine, astemizole, terfenadine, fexofenadine, loratadine, desloratadine, cetirizine, and mixtures thereof, and pharmaceutically acceptable salts, esters, isomers, and mixtures thereof.

In another particular embodiment, at least one active ingredient is an NSAID and/or acetaminophen and pharmaceutically acceptable salts thereof.

The active ingredient is present in the dosage form in a therapeutically effective amount, which is an amount that produces the desired therapeutic response when administered orally and can be readily determined by one skilled in the art. In determining such amounts, the particular active ingredient to be administered, the bioavailability characteristics of the active ingredient, the dosing regimen, the age and weight of the patient, and other factors must be considered, as is known in the art. Typically, the dosage form comprises at least about 0.1% by weight, preferably, the dosage form comprises at least about 5% (e.g., about 20%) by weight of the combination of one or more active ingredients. In a preferred embodiment, the core comprises a total of at least about 25% by weight (based on the weight of the core) of one or more active ingredients.

The active ingredient may be present in the dosage form in any form. For example, the active ingredient(s) may be dispersed (e.g., melted or dissolved, amorphous or crystallized) at the molecular level as one or more polymorphs within the dosage form, or may be in the form of particles, which in turn may be coated or uncoated. If the active ingredient is in the form of particles, the particles (whether coated or uncoated) typically have an average particle size of about 1-2000 microns. In a preferred embodiment, such particles are crystals having an average particle size of about 1-300 microns. In another preferred embodiment, the particles are granules or pellets having an average particle size of about 50-2000 microns (preferably about 50-1000 microns, most preferably about 100-800 microns).

In certain embodiments, at least a portion of one or more active ingredients may optionally be coated with a modified release coating, as is known in the art. Advantageously, this provides additional means for modulating the release profile of the active ingredient from the dosage form. For example, the core may contain coated particles of one or more active ingredients, wherein the particles are coated to provide a modified release function, as is well known in the art. Examples of suitable modified release coatings for particles are disclosed in U.S. patent nos. 4,173,626; no.4,863,742; no.4,980,170; no.4,984,240; no.5,86,497; no.5,912,013; no.6,270,805 and No.6,322,819. Commercially available active particles with a modified release coating may also be used. Thus, all or a portion of one or more of the active ingredients in the core may be coated with a modified release material.

In embodiments where it is desired that at least one active ingredient be absorbed into the systemic circulation of the animal, the active ingredient is preferably capable of dissolving upon contact with a dissolution medium (e.g., water, gastric fluid, intestinal fluid, etc.).

In one embodiment, the dissolution profile of at least one active ingredient meets USP specifications for immediate release tablets containing the active ingredient. For example, for acetaminophen tablets, USP 24 specifies that at least 80% of the acetaminophen contained in the dosage form is released from the dosage form within 30 minutes after administration using USP apparatus 2 (paddle) at 50rpm in pH 5.8 phosphate buffer, and for ibuprofen tablets, USP 24 specifies that at least 80% of the ibuprofen contained in the dosage form is released from the dosage form within 60 minutes after administration using USP apparatus 2 (paddle) at 50rpm in pH 7.2 phosphate buffer. See USP 24, 2000 edition, pages 19-20 and 856 (1999). In embodiments wherein the at least one active ingredient is immediate released, the immediate released active ingredient is preferably contained in the shell or on the surface of the shell, such as in an additional coating surrounding at least a portion of the shell. Within the USP definition of "immediate release", different active ingredients have different release characteristics. As used herein, the term "immediate release" means that the active ingredient is released in an immediate manner in a suitable dissolution medium, i.e. more than 80% of the active ingredient is released in less than 90 minutes, such as in less than 60 minutes.

In another embodiment, the dissolution characteristics of one or more active ingredients are adjusted: such as controlled release, sustained release, delayed release, retarded release, long acting, delayed release, etc. In preferred embodiments where one or more active ingredients are released in a modified release manner, the modified release active ingredient is preferably contained in the core. As used herein, the term "modified release" means that the active ingredient is released from the dosage form or a portion thereof in a manner other than immediate release (i.e., in a manner other than immediate release upon contact of the dosage form or a portion thereof with a liquid medium). As is known in the art, the type of modified release includes delayed or controlled release. Types of controlled release include long acting, sustained release, delayed release, retarded release, and the like. Modified release characteristics including delayed release characteristics include pH dependent release, pulsatile release, repetitive action, and the like. Further, as known in the art, suitable mechanisms to achieve modified release of the active ingredient include: diffusion, erosion, surface area control by geometry and/or impermeable or semi-permeable barriers, and other known mechanisms.

In certain preferred embodiments, the core 10 is covered with a first coating 12 and a second film coating 14, which may be any number of medical coatings. A first coating 12 is disposed on at least a portion of the core 10. The first coating 12 may be a material commonly understood by those skilled in the art as a subcoat. In one embodiment, the first coating 12 or subcoat may optionally contain an active ingredient. The use of a subcoat is well known in the art and is disclosed, for example, in U.S. Pat. No.5,234,099, which is incorporated herein by reference. Any composition suitable for film coating tablets may be used as a subcoating according to the present invention. Examples of suitable subcoatings are disclosed in U.S. Pat. Nos. 4,683,256, 4,543,370, 4,643,894, 4,828,841, 4,725,441, 4,802,924, 5,630,871, and 6,274,162, all of which are incorporated herein by reference. Suitable compositions for use as a subcoat include Colorcon, tradename, by the department of Berwind Pharmaceutical Services, Inc. (415 Moyer blvd., WestPoint, PA 19486) ""(dry concentrate, which contains film-forming polymer and optional plasticizer, colorant, and other excipients if applicable).

Additional suitable subcoatings include one or more of the following ingredients: cellulose ethers such as hydroxypropylmethylcellulose, hydroxypropylcellulose, and hydroxyethylcellulose; polyvinyl alcohols, polysaccharides such as xanthan gum, starch and maltodextrin; plasticizers, including, for example, glycerin, polyethylene glycol, polyvinyl alcohol polyethylene glycol copolymers, propylene glycol, dibutyl sebacate, triethyl citrate, vegetable oils (e.g., castor oil), surfactants (e.g., polysorbate-80, sodium lauryl sulfate, and sodium octylbuthylsulfonate); polysaccharides, pigments and opacifiers.

In one embodiment, the first coating 12 comprises about 0.1% to about 20% by weight (e.g., about 1% to about 5% by weight) of the core. The first coating 12 is typically present in an amount of about 0.1% to about 5% by weight (based on the dry weight of the core). The first coating 12 may be prepared by coating the core 10 in a conventional manner by spraying in a coating pan or fluidized bed. The composition used for the first coating 12 is optionally colored or dyed with a colorant (e.g., pigments, dyes, and mixtures thereof). Generally, pigments are distinguished from dyes in that pigments are insoluble in their liquid carrier, while dyes are either liquid or soluble in the chosen carrier. Lake pigments are pigments prepared with dyes by precipitation with metal salts. The core of compressed dosage forms is usually colored with lakes, since lakes facilitate mixing and coloring of the powder.

In one embodiment, the present invention is directed to a dosage form having a core with an outer surface, a first coating on at least a portion of the outer surface of the core, and a second coating on at least a portion of the first coating. Each of the first and second coatings contains at least one colorant, and the colorants in the first and second coatings are different from each other. The colorant is optionally opaque or translucent. At least one opening is provided through the first and second coatings to expose a portion of the outer surface of the core. The dosage form may further include at least one opening through the second coating and the first coating to expose a portion of the outer surface of the core. The dosage form may further comprise one or more clear coats disposed over at least a portion of the second coating.

In an alternative embodiment, the present invention is directed to a dosage form having a colored core with an outer surface, a first coating on at least a portion of the outer surface of the core, and a second coating on at least a portion of the first coating. The second coating contains at least one colorant, and the colorant in the first coating is a different color than the core. At least one opening is disposed through the second coating to expose a portion of the outer surface of the colored core. The dosage form may further comprise at least one opening through the second coating to expose at least a portion of the underlying first coating. One or more clear coats may be disposed on at least a portion of the second coat.

In an alternative embodiment, the present invention is directed to a dosage form having a core with an outer surface, a first coating over at least a portion of the outer surface of the core, and a second coating over at least a portion of the first coating. Each of the first and second coatings contains at least one colorant, and the colorants in the first and second coatings are different from each other. At least one opening is disposed through the second coating to expose at least a portion of the first coating.

In an alternative embodiment, the present invention is directed to a dosage form having a core with an outer surface, a first coating over at least a portion of the outer surface of the core, and a second coating over at least a portion of the first coating. Each of the first and second coatings contains at least one colorant, and the colorants in the first and second coatings are different from each other. At least one opening is disposed through the second coating to expose at least a portion of the first coating, and at least one opening is disposed through the second coating to expose a portion of the outer surface of the core. The one or more openings through at least the second coating expose less than 15%, preferably less than 10%, of the surface area of the first coating and the core. A transparent third coating may be provided on at least a portion of the second coating.

In one embodiment, the first coating 12 is initially applied to the entire outer surface of the core 10. First coating 12 may be coated as a clear, transparent coating so that the core may be seen. This choice is governed by the manufacturer's preferences and the economics of the product. In a preferred embodiment, the amount of commercially available pigment included in the basecoat composition is sufficient to provide an opaque film having a visually distinguishable color relative to the core. In certain embodiments, the first coating and the second coating differ in composition.

In one embodiment, the core 10 is a liquid or semi-solid fill of a liquid filled capsule, and the first coating 12 is a gel-like coating. In this embodiment, the active ingredient particles comprise from about 0.1% to about 60% (such as from about 0.1% to about 20%) by weight of filler. In this example, various capsule filling materials are used, including (but not limited to) alkalizing agents and suitable solvents and solubilizers.

Suitable solvents and solubilizers include the chemical class of vegetable oils, vegetable oil triglycerides and triacylglycerides, particularly, for example, corn oil.

Suitable solvents and solubilizers also include chemical classes of polyglycolyzed glycerides, particularly, for example, lauryl polyethylene glycol 32-glyceride and stearyl polyethylene glycol 32-glyceride, such as are known under the trade name44/14 and50/13 from Gattefose corporation; also, the chemical type of fatty acid glycerides, e.g. under the trade name33/01、39/01 and43/01 from Gattefosse Corporation, and mixtures thereof.

Suitable solvents and solubilizers also include the chemical classes of neutral oils and triglycerides, particularly, for example, medium chain triglycerides, fractionated coconut oil, caprylic triglyceride and capric triglyceride (e.g., under the trade names812 from Condea Vista Corporation), and mixtures thereof.

Suitable solvents and solventsSolvents also include polyethylene glycol and chemical classes of polyethylene glycol stearates, particularly, for example, polyethylene glycol 15 hydroxystearate (e.g., under the trade name polyethylene glycol 15 hydroxystearateProducts sold by BASF Corporation as HS 15), and mixtures thereof.

Suitable solvents and solubilizers also include the chemical classes of refined vegetable lecithins, soy lecithin and egg yolk lecithin, particularly, for example, phosphatidylcholine and 1, 2-diacyl-3-phosphocholine glycerol (e.g., under the trade name phosphatidyl cholineProducts sold under 90G by American leicistin), and mixtures thereof.

Suitable solvents and solubilizers also include the chemical type of lecithin mixed in propylene glycol, particularly, for example, standard mixtures of phosphatidyl choline, propylene glycol, mono-and diglycerides, ethanol, soy fatty acid, and ascorbyl palmitate (e.g., under the trade name phosphatidyl choline)Product sold under 50PG from American Lechitin).

Suitable solvents and solubilizers also include the chemical classes of octyl-hexanoyl polyethylene glycol-8-glyceride and hexanoyl polyethylene glycol-8-glyceride, such as those available from Gattefusse corporation under the trade nameThose sold for sale, and mixtures thereof. Suitable solvents and solubilizers also include the chemical classes of polyethoxylated hydrogenated castor oils, in particular, for example, glycerol-polyethylene glycol oxystearate (for example, under the trade name Glycerol stearate)Products sold as RH 40 from BASF Corporation), and mixtures thereof.

Suitable alkalizing agents include, but are not limited to, sodium bicarbonate, potassium hydroxide, and sodium hydroxide.

In this embodiment, suitable gel-like coatings may include: film-forming proteins, polymers or gums including, but not limited to, gelatin, tau carrageenan, lambda carrageenan, gellan gum, guar gum, xanthan gum, locust bean gum, agar, starch, modified starch and mixtures thereof.

As used herein, the term "compositionally different" means having a characteristic that can be readily distinguished by qualitative or quantitative chemical analysis, physical testing, or visual observation. For example, the first coating and the second coating may contain different ingredients, or different amounts of the same ingredient, or the first coating and the second coating may have different physical or chemical properties, different functional properties, or visually different properties. Examples of physical or chemical properties that may be different include: hydrophilic, hydrophobic, hygroscopic, elastic, plastic, tensile strength, crystallinity, and density. Examples of functional properties that may be different include: the rate and/or extent of dissolution of the material itself or its active ingredient, the rate of disintegration of the material, permeability to the active ingredient, permeability to water or aqueous media, and the like. Examples of visual differences include: size, shape, surface or other geometric features, color, hue, opacity and gloss.

The coating may be applied to the core by any suitable method, for example by spray coating, dip coating, enrobing or moulding. Suitable spray coating methods are described, for example, in U.S. Pat. Nos. 3,185,626, 4,683,256, 4,543,370, 4,643,894, 4,828,841, 4,725,441, 4,802,924, 5,630,871, and 6,274,162, the disclosures of which are incorporated herein by reference in their entirety. Suitable dip coating processes are described in U.S. Pat. Nos. 4,820,524, 5,538,125, 5,228,916, 5,436,026, 5,679,406, the disclosures of which are incorporated herein by reference in their entirety. Suitable coating methods are described in U.S. Pat. Nos. 5,146,730 and 5,459,983. Any film former known in the art is suitable for the flowable material. Examples of suitable film formers include, but are not limited to: film-forming water-soluble polymers, film-forming proteins, film-forming water-insoluble polymers, and film-forming pH-dependent polymers. In one embodiment, the film-forming agent may be selected from: cellulose acetate, quaternary ammonium methacrylate copolymer type B, shellac, hydroxypropyl methylcellulose, and polyethylene oxide, and combinations thereof.

Suitable water-soluble film-forming polymers include: water-soluble vinyl polymers such as polyvinyl alcohol (PVA); water-soluble polymeric carbohydrates such as hydroxypropyl starch, hydroxyethyl starch, pullulan, methylethyl starch, carboxymethyl starch, pregelatinized starch, and film-forming modified starch; water swellable cellulose derivatives such as hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC) (also known in the art as hypromellose), Methylcellulose (MC), hydroxyethyl methylcellulose (HEMC), hydroxybutyl methylcellulose (HBMC), hydroxyethyl ethylcellulose (HEEC) and hydroxyethyl hydroxypropyl methylcellulose (hempmmc); water-soluble copolymers such as methacrylic acid and methacrylate ester copolymers, polyvinyl alcohol and polyethylene glycol copolymers, polyethylene oxide and polyvinylpyrrolidone copolymers; and derivatives and combinations thereof.

Suitable film-forming proteins include those which may be natural or chemically modified and include: gelatin, whey protein, fibrillin, coagulable proteins such as albumin, casein, caseinate and casein isolates, soy protein and soy protein isolates, zein and the like; and polymers, derivatives and mixtures thereof.

Suitable film-forming water-soluble polymers include, for example: ethyl cellulose, polyvinyl alcohol, polyvinyl acetate, polycaprolactone, cellulose acetate and derivatives thereof, acrylates, methacrylates, acrylic copolymers, and the like, as well as derivatives, copolymers, and combinations thereof.

Suitable film-forming pH dependent polymers include enteric cellulose derivatives such as hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate; natural resins such as shellac and zein; enteric acetate derivatives such as polyvinyl acetate phthalate, cellulose acetaldehyde dimethyl acetate; and enteric acrylate derivatives such as polymethacrylate-based polymers (e.g., poly (methacrylic acid, methyl methacrylate) 1: 2 commercially available from Rohm Pharma GmbH under the trade name EUDRAGIT S, and poly (methacrylic acid, methyl methacrylate) 1: 1 commercially available from Rohm Pharma GmbH under the trade name EUDRAGIT L, and the like), and derivatives, salts, copolymers, and compositions thereof.

One suitable hydroxypropyl methylcellulose compound for use as a thermoplastic film-forming water-soluble polymer is "HPMC 2910", a cellulose ether having a degree of substitution of about 1.9 and a hydroxypropyl molar substitution of 0.23 and containing, based upon the total weight of the compound, from about 29% to about 30% methoxy groups and from about 7% to about 12% hydroxypropyl groups. HPMC 2910 is commercially available from Dow chemical under the trade name METHOCEL E. METHOCEL E5 is a grade of HPMC-2910 suitable for use in the present invention having a viscosity of about 4 to 6cps (4 to 6 mPa-sec) in a 2% aqueous solution at 20 ℃ as determined by an Ubbelohde viscometer. Similarly, METHOCEL E6 is another grade of HPMC-2910 suitable for use in the present invention having a viscosity of about 5 to 7cps (5 to 7 mPa-sec) in a 2% aqueous solution at 20 ℃ as determined by an Ubbelohde viscometer. METHOCEL E15 is another grade of HPMC-2910 suitable for use in the present invention having a viscosity of about 15000cps (15 mPa-sec) in a 2% aqueous solution at 20 deg.C as determined by an Ubbelohde viscometer. As used herein, the term "degree of substitution" means the average number of substituents attached to the anhydroglucose ring, while the term "hydroxypropyl molar substitution" means the number of hydroxypropyl moles per mole anhydroglucose.

One suitable polyvinyl alcohol and polyethylene glycol copolymer is commercially available from BASF Corporation under the tradename KOLLICOAT IR.

As used herein, the term "modified starch" includes starches that have been modified by crosslinking, chemical modification (for improved stability or optimized performance) or physical modification (for improved solubility characteristics or optimized performance). Examples of chemically modified starches are well known in the art and typically include starches that have been chemically treated to cause replacement of some of their hydroxyl groups with ester or ether groups. Crosslinking, as used herein, occurs when two hydroxyl groups on adjacent starch molecules are chemically linked. As used herein, the term "pregelatinized starch" or "instant starch" refers to a modified starch that has been pre-wetted and then dried to increase its cold-water solubility. Suitable modified starches are commercially available from several suppliers, for example from a.e. staley Manufacturing and National Starch & Chemical. One suitable film-forming modified Starch includes pregelatinized waxy corn-derived Starch (commercially available from National Starch & Chemical company under the tradenames PURITY GUM and FILMSET), and derivatives, copolymers, and mixtures thereof. Such waxy corn starches typically contain from about 0% to about 18% amylose and from about 88% to about 100% amylopectin, based on the total weight of the starch.

Other suitable film-forming modified starches include hydroxypropylated starches in which some of the hydroxyl groups of the starch have been etherified with hydroxypropyl groups, typically by treatment with propylene oxide. An example of a suitable hydroxypropyl starch having film-forming properties is available from GrainProcessing under the trade name PURE-COTE B790. In one embodiment, a suitable plasticizer may be used in the first coating or the second coating in an amount of from about 0.1% to about 40%, such as from about 1% to about 30% or from about 5% to about 20%, by total dry weight of the coating. Examples of suitable plasticizers include, but are not limited to: polyethylene glycol; propylene glycol; glycerol; sorbitol; triethyl citrate; tributyl citrate; dibutyl sebacate; vegetable oils such as castor oil, rapeseed oil, olive oil, and sesame oil; surfactants such as polysorbates, sodium lauryl sulfate and sodium dioctyl sulfosuccinates; monoacetate of glycerol; diacetic esters of glycerol; triacetates of glycerol; a natural gum; triacetin; acetyl triethyl citrate; diethyl oxalate; diethyl maleate; fumaric acid diethyl ester; malonic acid diethyl ester; dioctyl phthalate; diethyl succinate; glycerol tributyrate; glycerol monostearate; hydrogenated castor oil; substituted triglycerides and glycerides; and mixtures thereof.

The openings can be of any shape and size, and can optionally be arranged in a pattern. In embodiments where the openings are formed by laser etching, the width or diameter of the smallest opening is typically at least 1-2 times the wavelength of light provided by the laser used. At least a portion of the opening may be large enough to be visible to the unaided human eye and may range in width or diameter from about 400 nanometers to as much as any size of the exposed subcoat. Typically, such openings have a minimum width or diameter of at least about 500 nanometers (e.g., at least about 700 nanometers or at least about 70 microns). Typically, the maximum width or diameter of the visible opening is no greater than the tablet width or no greater than the exposed under-belt width, for example no greater than about 6.5 mm, or no greater than about 3.5 mm, such as no greater than about 2.5 mm. Alternatively, some or all of the openings may be microscopic in size, ranging in width or diameter from about 1 nanometer to less than about 400 nanometers. In embodiments where some or all of the openings are not visible to the unaided human eye, the plurality of openings can be arranged in a pattern that forms perforations or weak spots in the film that promote disintegration. Although it is not critical to the present invention that the initial opening be large enough to allow water to flow in, especially when a water soluble subcoat is employed, it should be noted that for certain preferred embodiments, an opening size of about 0.030 inches in width or diameter has been found to allow water to pass therethrough. For the purposes of this patent application, an opening means a generally continuous opening having a generally uniform shape, regardless of how many layers such an opening passes through. The openings "expose" the underlying surface by making the surface visible. Openings through at least one of the coatings to the core (where a transparent coating has been provided over the openings or a transparent intermediate layer has been provided between the top layer and the core) still leave the bottom layer "exposed".

In one embodiment, the core, first coating 12, or second coating 14 may contain a sensate, including a flavoring or aroma. The flavoring agent may include: volatile flavors, non-volatile flavors, cooling agents, warming agents, low intensity sweeteners, high intensity sweeteners, salivating agents, or acidulants. Suitable acidulants may include: acids, such as citric acid, malic acid, ascorbic acid, tartaric acid or fumaric acid. Suitable high intensity sweeteners include (but are not limited to): sucralose, aspartame, saccharin, acesulfame potassium, and talilin. In one embodiment, the core, first coating, or second coating contains different flavors, sweeteners, or acidulants to deliver multiple sensates simultaneously.

In one embodiment, the top coating is a dark blue, dark red or black color, and the openings expose the color of the lower layer (i.e., the core or first coating), which is a lighter color, such as yellow or white. The contrast of these colors aids in the identification of the dosage form.

In one embodiment, the one or more openings through the coating expose no more than 15% and no less than 10% of the underlying first coating 12 and/or core 10 surface area. In one embodiment, the one or more openings through the first and second coatings 12, 14 expose no more than 10%, preferably less than 5%, of the underlying core 10 surface area.

In one embodiment, the core is compressed and has a density of at least 0.9g/cc and the coating is non-gelatinous. As used herein, the term "non-gelatinous" is defined as a coating that is substantially free of gelatin (i.e., less than 1.0% gelatin content).

In one embodiment, the first coating or the second coating has additional indicia comprised of edible ink. The ink marks may be made with an ink that is visible to the naked eye under ambient (i.e., visible light). In a separate embodiment, the ink is only visible under ultraviolet light.

In one embodiment, the surface area of the outer film coating of first coating 12 or second coating 14 has at least about 0% to about 20%, or about 0% to about 10% (e.g., about 0% to about 5%) of its surface area removed by the laser.

A preferred method of preparing the intermediate dosage form 20 may begin by compressing or compacting the tablet core 10 into the desired drug shape. As used herein, the terms "compaction, compacted" and "compressing, pressed, compressed" are used interchangeably to describe the commonly used method of compacting a powder into tablets by conventional pharmaceutical tableting techniques well known in the art. One typical such process employs a rotary tablet press (often referred to as a "press" or "compactor") to compress the powder into tablets between an upper punch and a lower punch in a forming die. The core prepared by the method has two opposing surfaces formed by contacting the upper and lower punches and has a web formed by contacting the die wall. Typically, at least one of the major surfaces of such a compressed tablet is at least as large as the height of the binder between the major surfaces. Alternatively, the prior art has disclosed methods that enable "longitudinal compression" of tablet cores. When longitudinal compressed tablets are employed, it has been found that an aspect ratio (ratio of height between the major surfaces to width or diameter of the major surfaces) of from about 1.5 to about 3.5 (e.g., about 1.9) can be conveniently handled.

Tablets are typically compressed to a target weight and "hardness". Hardness is a term used in the art to describe the diametral breaking strength, as measured by conventional pharmaceutical hardness testing equipment such as the Schleuniger hardness tester. To compare values across differently sized tablets, the breaking strength was normalized for the breaking area (which can be approximated as the tablet diameter times the thickness). This normalized value (expressed in kp/cm 2) is sometimes referred to in the art as "tablet tensile strength". A review of the tablet hardness test can be found in the Pharmaceutical Dosage Forms-tables, Volume 2, 2nd ed., Marcel Dekker Inc., 1990, pp.213-217, 327 & lt- & gt 329 (Pharmaceutical Dosage form-tablet, 2nd edition, Vol.2, pp.213 & lt- & gt 217, p.327 & lt- & gt 329, 1990), Leiberman et al, which is incorporated herein by reference.

In certain preferred embodiments, the intermediate dosage form 20 prepared using any of the methods described above is subsequently subjected to a mechanical drilling process or a laser drilling process. Transverse excited gas (TEA) lasers are the preferred means for this step, particularly when used in conjunction with known tablet delivery devices such as those commercially available from Hartnett.

In one embodiment, the coated tablets are fed into a primary hopper from which they flow via a chute into the primary hopper of a "delta" printer (available from r.w. hartnett). The coated tablets were dropped from the initial hopper in an upward orientation (i.e., the longitudinal axis was oriented vertically) into a carrying link and then transported upward at an angle of about 45 degrees.

The coated tablets in the carrier link are transported between rubber impression rollers, which may be set at an "open" position or at a "print" position. The coated tablets in the carrier link are then transported through a "drilling section" where a laser beam is rapidly pulsed (at a frequency of once every 10 microseconds) to meet the coated tablets passing therethrough.

The laser beam source was an "Impact 2015" transverse excitation gas CO2 laser available from Lumonics inc. The laser initially emits a beam of 4 joules per square inch of energy to a turning mirror that redirects the beam 90 degrees (up) to a series of turning mirrors and a spherical field lens that focuses the beam from 1 inch by 1 inch to about 0.75 inch by 0.75 inch. The focused beam continues to the other turning mirror and then passes through a stainless steel mask having an opening that allows only a portion of the beam to continue to be emitted. The actual configuration of the series of lenses and mirrors is not essential to the invention and depends primarily on space and cost considerations.

After passing through the mask, the patterned beam is redirected by a series of turning mirrors to a final focusing lens, reducing the size of the patterned beam by a factor of about 5. The reduced, patterned beam ultimately illuminates the coated tablets through a "drill section" causing one or more of the coatings to be etched and form shaped openings having a pattern defined by a mask. Adjusting the height of the final turning mirror can change the incident position of the patterned beam. Steering mirrors and lenses are commercially available from companies such as LightMachinery, inc.

Fig. 3 shows a final dosage form 30 having at least two coating layers, coating 24 (first coating) and coating 26 (second coating). In one embodiment, openings 32 are provided through second coating 26 and first coating 24 to expose the outer coated surface of core 10. In another embodiment, opening 32 is provided through both second coating 26 and first coating 24 to expose a portion of the outer coated surface of core 10, and opening 33 is additionally provided through only second coating 26 to expose a portion of first coating 26. In yet another embodiment, an opening 32 is provided through both the second coating 26 and the first coating 24 to expose a portion of the outer coated surface of the core 10, and an opening 33 is additionally provided through only the second coating 26 to expose a portion of the core 10.

One or more openings 32/33 are formed with a mechanical drill or laser. In another embodiment, a mechanical drill or laser creates at least one, and preferably a plurality of openings 32/33 through first coating 24, and second coating 26, or a combination thereof. In certain optional embodiments, opening 32/33 is large enough to be visible to the unaided human eye. In this case, one skilled in the art can appreciate the advantage of using first 24 and/or second 26 coatings and/or cores 10 having different colors to highlight the presence of opening 32/33.

The color difference may be caused by a colorant or coloring agent contained in the first coating 24, the second coating 26, and/or the core 10. In an alternative embodiment, the colorant or coloring agent is incorporated into the compacted material used to make the core 10, and the first coating 24 and/or the second coating 26 have one or more colors that are different from the color of the core 10.

The coloring agent may be added in the form of a water-soluble dye or lake, and with or without an opacifier. Suitable opacifiers include, but are not limited to, titanium dioxide or mica.

Any type of marking may be prepared in various embodiments. In one embodiment, laser marking is used to provide readable numbers or written characters, such as DEC code values #49 through #57 (numbers) defined by ASCII (american standard code for information interchange); #65-78 and #80-90 (capital letters); and #97-110 and #112 to #122 (lower case letters) to communicate the type of active ingredient, the identity of the product, the name of the company (or abbreviation), the batch number, the date or the dosage, without being limited by the font type, size or form of expression. ASCII (american standard code for information interchange) is a character encoding based on the english alphabet. ASCII code represents text in computers, communication devices, and other devices that use text. Most modern character encodings that support more characters have historical evidence in ASCII.

In one embodiment, the laser markings provide a difference in texture that can be perceived by finger or tongue contact. This is particularly advantageous for those who might read characters by using Braille (Braille). The projections and depressions can be produced in the dosage form in a conventional manner by means of a mould, which is impressed onto the tablet during compression. In embodiments where laser marking is performed, the marking is provided in a more precise manner, such as where the characters are less than 5mm in diameter, or less than 1mm, such as less than 0.5 mm. In this embodiment, the depth is greater than 0.05mm, such as greater than 0.1 mm. In another embodiment, the laser mark is formed in the form of a bar code. In another embodiment, laser marking is used, resulting in a mixture of characters, pictures or pictures, characters and product information.

In certain types of ink printing applications on pharmaceutical dosage forms, it is difficult to produce substantially legible marks on dark colored tablets using light colored inks. In such cases, the light ink tends to blur or run, thereby making the mark illegible.

In one embodiment of the present invention, the color of the core and the color of the first coating or the second coating may be distinguished using the Monsell (Munsell) color system brightness value. The munsell color system is used in colorimetry to define a color space that specifies colors in terms of three color dimensions, namely hue, value (or luminance), and chroma (approximately saturation). In this embodiment, the color of the core is brighter than the color of the coating so that when a laser is projected into the surface of the coating and exposes the core, the definition of the indicia can be clearly read. To further define this example, the color of the core has a brightness value on the Monel scale of 8.5 to 10 and the coating color has a darkness of zero (0) to 2.5. In this embodiment, the indicia must be legible so that a person with at least 20/20 or better vision can recognize and read the ASCII image formed when the core is exposed by the absence of the coating at a distance of about 18 inches from the surface of the dosage form to the viewer. In a more specific embodiment, the ASCII image visible to the viewer at about 18 inches is from about 1mm to about 10mm, such as about 1mm to about 6mm, such as about 2mm to about 4mm in length.

The use of specific formulations that do not include wax in the coating more readily facilitates laser drilling for tablet marking purposes. Other benefits of laser drilling of characters of this size include: resulting in non-tamperable, non-removable markings (as with printed characters) and the ability to serialize each batch or multiple batches or change the markings within a batch. Moreover, laser-produced white characters are much clearer and easier to read due to the fact that titanium dioxide produces the least effective uniform opaque characters without showing some background. In addition, many inks designed to print "white" actually contain some small amount of colored pigment to make them more legible. But consumers are often unable to detect a slight tint of the tablet against a pigment or background. In identifying pharmaceutical products, the quality of the identifying indicia is critical and unique for each product, and thus, the methods described herein allow for improvements in the manufacturing field. In one embodiment, the line width in the laser marked characters is from about 0.005 inches to about 0.05 inches, such as from about 0.008 inches to about 0.02 inches. In one embodiment, any line length in the laser marked characters is from about 0.005 inches to about 0.10 inches or from about 0.01 inches to about 0.08 inches, or from about 0.02 inches to about 0.07 inches.

In one embodiment, the surface area of the tag is about 0.0100cm²To about 0.0500cm². In one embodiment, the surface area of the indicia is from about 0.05% to about 1.00%, such as from about 0.10% to about 0.50% of the surface area of the tablet.

It will become apparent to those skilled in the art that various modifications to the preferred embodiment of the invention as described herein can be made without departing from the spirit or scope of the invention as defined by the appended claims.

The invention can be further illustrated by the following non-limiting examples.

Example 1: preparation of a blend of white placebo caplets and round tablets

Will be available under the trade name Avicel pHCommercially available from FMC Corporation as 18, 562.5g microcrystalline cellulose and sodium carboxymethylcellulose NF and available under the trade name Starch6250g of pregelatinized starch, commercially available from Colorcon Corporation, was manually passed through a 20 mesh screen and mixed in a suitable plastic bag. 187.5g of magnesium stearate was mixed with approximately one third of the Avicel/Starch mixture and passed through a 20 mesh screen. Half of the remaining Avicel/Starch mixture was added to a 2 quart V blender, then the magnesium stearate/Avicel/Starch mixture and the remaining Avicel/Starch mixture were added and blended for 5 minutes.

Part A: approximately half of the above blend was used to compress white placebo tablets on a rotary tablet press equipped with 27/64 "x 0.081" round dies. The tablets were compressed to a weight of about 492mg, a thickness of about 7.12mm and a hardness of about 9.3 kp.

Part B: approximately half of the above blend was used to compress white placebo caplets on a rotary tablet press equipped with 687.5 "x 281.2" mock capsule shape ("caplet") molds. The caplets were compressed to a weight of about 502mg, a thickness of about 7.30mm and a hardness of about 8.5 kp.

Example 2: preparation of orange placebo caplet and round tablet blend

Will be available under the trade name Avicel pHCommercially available from FMC Corporation as 18, 437.5g microcrystalline cellulose and sodium carboxymethylcellulose NF, available under the trade name Starch6250g of pregelatinized starch commercially available from Colorcon Corporation and 125.0g of FD&C Yellow #6 was manually passed through a 20 mesh screen and mixed in a suitable plastic bag. 187.5g of magnesium stearate was mixed with approximately one third of the Avicel/Starch/Yellow #6 mixture and passed through a 20 mesh screen. Half of the remaining Avicel/Starch/Yellow #6 mixture was added to a 2 quart V-blender, then the magnesium stearate/Avicel/Yellow #6/Starch mixture and the remaining Avicel/Starch/Yellow #6 mixture were added and stirred for 5 minutes.

Part A: about half of the above blend was used to compress orange placebo tablets on a rotary tablet press equipped with 27/64 "x 0.081" round dies. The tablets were compressed to a weight of about 484mg, a thickness of about 7.05mm and a hardness of about 10.2 kp.

Part B: approximately half of the above blend was used at a formulation 687.5 "x 281.2 "mock capsule (" caplet ") die on a rotary tablet press to compress orange placebo caplets. The caplets were compressed to a weight of about 506mg, a thickness of about 7.27mm and a hardness of about 8.6 kp.

Example 3: preparation of Black film coating solution

1760g of sterile water for rinsing was added to a 5 liter stainless steel container. The Lightning laboratory stirrer was set at 50RPM and 440.0g of hypromellose-based film coating polymer (tradename: HPMC) containing black colorant was addedCommercially available from Colorcon Corporation) and mixed for 45 minutes.

Example 4: black film coating of core

2.75kg of tablets and caplets (total 11kg) from each of part a (white tablets) and part B (white caplets) of example 1 and part a (orange tablets) and part B (orange caplets) of example 2 were added to a 24 inch vented (Acela Cota) coating pan. The batch was sprayed at a rate of about 44 g/min (about 14RPM) with an inlet air temperature of about 85 ℃ and an atomizing air pressure of about 55 psi. 1500g of coating solution, equivalent to 300g of dried coating or about 2.7% weight gain, are sprayed.

Example 5: preparation of silver coating solution

185g of sterile water for rinsing are added to a 1 liter stainless steel container. The Lightning laboratory stirrer was set at 50RPM and 15.0g of hypromellose-based film coating polymer (tradename: silver colorant) containing silver colorant was addedCommercially available from Colorcon Corporation) and mixed for 45 minutes.

Example 6: silver top layer of coreCoating film

1kg of the black coated tablet and caplet from example 4 (250 g each) was added to a 15 "Compu-Lab tablet coating apparatus and sprayed at a rate of about 7 g/min with an inlet air temperature of about 75 deg.C, an atomizing air pressure of 20psi and a rotational speed of 15RPM to obtain a weight gain equivalent to 1.5%.

Example 7: red-yellow top coat for cores

The experiment of example 6 was repeated with a red-yellow top coat solution, wherein the coating is available under the trade name "RevNOA hydroxypropyl cellulose based coating containing Yellow #6 colorant commercially available from Colorcon Corporation equivalent to a 1.5% weight gain.

Example 8: laser drilling of tablets

The tablets of example 4, example 6 and example 7 were drilled to expose the underlying layer. The film coating was drilled through using a transverse excited gas (TEA) CO2 laser. A wavelength of about 10.6 nanometers and a pulse duration of about 10 microseconds is used. Any shape of aperture can be formed by placing a mask in the laser beam path. For ease of calculation, a simple circle is used. For the purposes of this example, the designation "Motrin 100 mg" was drilled out. The diameter of the holes in the tablets may vary from 1.5mm to 2.0 mm. The larger the area etched by the laser, the more energy is required.

Two sets of holes were drilled in the tablet from example 6. In the first set of holes, the core was drilled to show the orange color in the core. In the second set of holes, only the first layer was drilled through to reveal the black first coating layer. About 0.15-0.20J/mm²The laser intensity of (a) may be such that the outer coating is completely etched (the inner coating is exposed) in one pulse. About 0.4-0.8J/mm²The laser intensity of (a) can be such that the outer and inner coatings are completely etched (the core is exposed) in one pulse.

Example 9 (laser drill coated tablet with printed identification mark)：

The black film coated laser-drilled caplet placebo dosage forms from example 4 (single coat) and example 8 (followed by laser drilling of the "Motrin 100 mg" word) were passed through a hartnettda tablet printer, marked with additional print indicia, and printed with a silver food ink the word "Store at RT" where RT represents room temperature.

Example 10: preparation of a blend of white placebo caplets and round tablets

Will be available under the trade name Avicel pHCommercially available from FMC Corporation as 18, 562.5g microcrystalline cellulose and sodium carboxymethylcellulose NF and available under the trade name Starch6250g of pregelatinized starch, commercially available from Colorcon Corporation, was manually passed through a 20 mesh screen and mixed in a suitable plastic bag. 187.5g of magnesium stearate and approximately one third of the Avicel/Starch mixture were mixed and passed through a 20 mesh screen. Approximately half of the remaining Avicel/Starch mixture was added to a 2 quart V blender, then the magnesium stearate/Avicel/Starch mixture and the remaining Avicel/Starch mixture were added and blended for 5 minutes.

Part A: approximately half of the above blend was used to compress white placebo tablets on a rotary tablet press equipped with 27/64 "x 0.081" round dies. The tablets were compressed to a weight of about 492mg, a thickness of about 7.12mm and a hardness of about 9.3 kp.

Part B: using approximately half of the above blend, a white ampoule was pressed on a rotary tablet press equipped with 687.5 "x 281.2" mock capsule form ("caplet") diesPlacebo small capsules. The caplets were compressed to a weight of about 502mg, a thickness of about 7.30mm and a hardness of about 8.5 kp.

Example 11: preparation of Black film coating solution comprising HPMC and polyethylene glycol

1760g of sterile water for rinsing was added to a 5 liter stainless steel container. The Lightning laboratory stirrer was set at 50RPM and 440.0g of hypromellose-based film coating polymer (which is tradename black colorant) containing a black colorant was addedCommercially available from Colorcon Corporation) and mixed for 45 minutes.

Example 12: black film coating of cores with HPMC coatings containing polyethylene glycol

2.75kg of tablets and caplets (5.5 kg total) from each of part a (white tablets) and part B (white caplets) of example 10 were added to a 24 inch vented (Acela Cota) coating pan. The batch was sprayed at a rate of about 44 g/min (about 14RPM) with an inlet air temperature of about 85 ℃ and an atomizing air pressure of about 55 psi. 750g of coating solution, equivalent to 300g of dried coating or about 2.7% weight gain, was sprayed.

Example 13: preparation of Black coating solution containing HPMC and polydextrose

185g of sterile water for rinsing are added to a 1 liter stainless steel container. The Lightning laboratory stirrer was set at 50RPM and 15.0g of hypromellose-based film coating polymer (which may be tradename) containing black colorant was addedCommercially available from Colorcon Corporation) and mixed for 45 minutes.

Example 14: using a solution containing HPMC and polydextroseBlack top coating for cores Treatment of

2.75kg of tablets and caplets (5.5 kg total) from each of part a (white tablets) and part B (white caplets) of example 10 were added to a 24 inch vented (AcelaCota) coating pan. The batch was sprayed at a rate of about 44 g/min (about 14RPM) with an inlet air temperature of about 85 ℃ and an atomizing air pressure of about 55 psi. 750g of coating solution, equivalent to 300g of dried coating or about 2.7% weight gain, was sprayed.

Example 15: coated caplet with temporary gelatin infusion

Part A: preparation of colourless gelatin-based impregnation dispersions

A 20 liter batch of a colorless gelatin-based dipping solution was prepared using the ingredients in the table below. Purified water at about 85 ℃ was added to a jacketed vacuum-fitted mixing tank. Sodium Lauryl Sulfate (SLS) was added to the water followed by Gelatin 275Bloom and Gelatin 250Bloom with mixing. The temperature of the mixture after addition of the gelatin blend was about 57 ℃. The gelatin solution was mixed for 10 minutes and then degassed under vacuum for 4 hours.

Composition (I)	Percent Dispersion w/w	Percentage of Capsule tablets w/w
			Purified water USP	67.01	--
Sodium lauryl sulfate	0.03	0.006
			Gelatin NF (275Bloom Skin)	10.15	1.8
Gelatin NF (250Bloom Bone)	22.80	4.2

And part B: preparation of yellow gelatin-based dipping solution

5kg of the colorless gelatin-based dipping solution prepared according to example 15A was transferred to a jacketed mixing tank. 0.22kg of opatant Yellow DD2125 was added. The solution was mixed at low speed for 4 hours at ambient pressure to degas while maintaining the tank at a solution temperature of about 55 ℃.

Part C: preparation of Red gelatin-based dipping solution

5kg of the colorless gelatin-based dipping solution prepared according to example 15A was transferred to a jacketed mixing tank. 0.22kg of Optint Red DD1761 was added. The solution was mixed at low speed for 4 hours at ambient pressure to degas while maintaining the tank at a solution temperature of about 55 ℃.

And part D: gel impregnation of subcoated cores for conventional capsule tablets

The caplet cores with subcoat prepared according to example 10 were placed in a plastic pipette and briefly dipped into the solutions from parts a and B manually, exposing approximately 2-4mm of the subcoat (black film coated) band.

Example 16: laser drilling of tablets

Tablets from part D of examples 12, 14 and 15 were mark etched with a laser through the subcoat or film coating layer to expose the subcoat core. The film coating was drilled through using a transverse excited gas (TEA) CO2 laser. A wavelength of about 10.6 nm and a pulse duration of about 20 pulses/second were used. About 197.5W/cm was used²Power of (3) to prepare the desired indicia. Any shape of mark can be prepared by placing a mask in the optical path of the laser beam. For the purposes of this example, a 0.0131cm surface area was drilled onto the caplet²Is marked with a "Z", and each tablet has a surface area of about 11.69cm². The length of the first top line in the "Z" character was 0.04864 inches, the length of the middle second line in the "Z" character was 0.05594 inches, and wherein the length of the bottom third line was 0.05286 inches, as measured using an optical microscope. The width of the first top line in the "Z" character was 0.01370 inches, the width of the middle second line in the "Z" character was 0.01105 inches, and wherein the width of the bottom third line was 0.015789 inches, as measured using an optical microscope. The larger the laser etched area, the more energy is required.

And (4) observing results: the caplets prepared in example 12, wherein the coating contained polyethylene glycol, performed poorly in laser drilling because they did not produce clear marks upon laser drilling. The caplets of example 14 performed well in laser drilling, produced well-defined marks, and the coating solution used to coat these caplets was free of polyethylene glycol.

Example 17 (laser drilled coated tablet with printed identification mark)：

Laser drilled and briefly impregnated capsules from example 16, black film coated (single layer coated) were passed through a Hartnett Delta tablet printer with additional printed indicia only on the end of the lighter colored gelatin coating and printed with silver food ink as "Store at RT" where RT represents room temperature.

Claims (39)

1. A dosage form, comprising:

a) a core having an outer surface;

b) a first coating on at least a portion of the outer surface of the core; and

c) a second coating on at least a portion of the first coating;

wherein each of the first and second coatings contains at least one colorant, and the colorants in the first and second coatings are different from each other; and is

Wherein at least one opening is provided through the first coating and the second coating to expose a portion of the outer surface of the core.

2. The dosage form of claim 1, further comprising at least one opening through the second coating and through the first coating to expose a portion of the outer surface of the core.

3. The dosage form of claim 1, further comprising a transparent third coating disposed on at least a portion of the second coating.

4. The dosage form of claim 1, wherein the core is a compressed tablet.

5. The dosage form of claim 1, wherein the compressed tablet has an elongated shape.

6. The dosage form of claim 1, wherein a print is provided on the outer surface of at least one of the first and second coatings.

7. The dosage form of claim 1, wherein the core comprises acetaminophen and at least about 90% of the acetaminophen is released from the dosage form after stirring for 6 minutes in USP type II apparatus (paddle method) in USP pH 5.8 phosphate buffer at a speed of 50 rpm.

8. A dosage form, comprising:

a) a colored core having an outer surface;

b) a first coating on at least a portion of the outer surface of the core; and

c) a second coating on at least a portion of the first coating;

wherein the second coating contains at least one colorant and the colorant in the first coating is a different color than the core; and is

Wherein at least one opening is provided through the second coating to expose a portion of the outer surface of the colored core.

9. The dosage form of claim 8, wherein at least one opening passes through the second coating to expose at least a portion of the underlying first coating.

10. The dosage form of claim 8, wherein a print is provided on the outer surface of at least one of the first and second coatings.

11. The dosage form of claim 8, further comprising a transparent third coating disposed on at least a portion of the second coating.

12. The dosage form of claim 8, wherein the core comprises acetaminophen and at least about 90% of the acetaminophen is released from the dosage form after stirring for 6 minutes in USP type II apparatus (paddle method) in USP pH 5.8 phosphate buffer at a speed of 50 rpm.

13. A dosage form, comprising:

a) a core having an outer surface;

b) a first coating on at least a portion of the outer surface of the core; and

c) a second coating on at least a portion of the first coating;

wherein each of the first and second coatings contains at least one colorant, and the colorants in the first and second coatings are different from each other; and is

Wherein at least one opening is provided through the second coating to expose at least a portion of the first coating.

14. The dosage form of claim 13, wherein the core comprises acetaminophen and at least about 90% of the acetaminophen is released from the dosage form after stirring for 6 minutes in USP type II apparatus (paddle method) in USP pH 5.8 phosphate buffer at a speed of 50 rpm.

15. A dosage form, comprising:

a) a core having an outer surface;

b) a first coating on at least a portion of the outer surface of the core; and

c) a second coating on at least a portion of the first coating;

wherein each of the first and second coatings contains at least one colorant, and the colorants in the first and second coatings are different from each other; and is

Wherein at least one opening is provided through the second coating to expose at least a portion of the first coating and at least one opening is provided through the second coating to expose a portion of the outer surface of the core; and wherein less than 15% of the surface area of the first coating and the core is exposed through the one or more openings of at least the second coating.

16. The dosage form of claim 15, further comprising a transparent third coating disposed on at least a portion of the second coating.

17. The dosage form of claim 15, wherein a print is provided on the outer surface of at least one of the first and second coatings.

18. The dosage form of claim 15, wherein the first coating or second coating is non-gelatinous.

19. The dosage form of claim 15, wherein the core comprises acetaminophen and at least about 90% of the acetaminophen is released from the dosage form after stirring for 6 minutes in USP type II apparatus (paddle method) in USP pH 5.8 phosphate buffer at a speed of 50 rpm.

20. The dosage form of claim 15, further comprising at least one opening through the second coating and the first coating to expose a portion of the outer surface of the core.

21. A dosage form, comprising:

a) a colored liquid core or a colored semi-solid core having an outer surface;

b) a first gelatinous coating on at least a portion of the outer surface of the core; and

c) a second coating on at least a portion of the first coating;

wherein said second coating contains at least one colorant and said colorant in said second coating is a different color than said first coated core; and is

Wherein at least one opening is provided through the second coating to expose a portion of the outer surface of the coated colored liquid core or semi-solid core.

22. A method for preparing a dosage form comprising:

a) providing a first coating having a first color on at least a portion of an outer surface of the solid core;

b) providing a second coating having a second color over at least a portion of the first coating;

c) at least one opening is provided through the second coating to expose a portion of the first coating.

23. The method of claim 22, wherein the at least one opening through the second coating is provided by removing a portion of the second coating with a laser.

24. A method for preparing a dosage form comprising:

a) providing a first coating having a first color on at least a portion of an outer surface of the solid core;

b) providing a second coating having a second color over at least a portion of the first coating;

c) providing at least one opening through the second coating to expose a portion of the solid core.

25. The method of claim 24, wherein the at least one opening through the second coating is provided by removing a portion of the second coating with a laser.

26. A method for preparing a dosage form comprising:

a) providing a first coating having a first color on at least a portion of the outer surface of the core;

b) providing a second coating having a second color over at least a portion of the first coating; and there is no particular order in which,

c) providing at least one opening through the second coating to expose a portion of the first coating;

d) at least one opening is provided through at least the second coating to expose a portion of the core.

27. The method of claim 26, wherein the at least one opening through the second coating to expose a portion of the first coating is provided by removing a portion of the second coating with a laser at a first energy level; and providing the at least one opening through at least the second coating to expose a portion of the core by removing a portion of the second coating with a laser at a second energy level.

28. The method of claim 26, wherein the at least one opening through the second coating to expose a portion of the first coating is provided by removing a portion of the second coating with a laser having a first filter that can generate a light beam having a first energy level; and providing the at least one opening through at least the second coating to expose a portion of the core by removing a portion of the second coating with a laser at an energy level different from the beam emitted from the first filter.

29. A method of identifying a dosage form with a unique character and color, wherein the dosage form has:

a) a core having an outer surface;

b) a first coating on at least a portion of the outer surface of the core; and

c) a second coating on at least a portion of the first coating;

wherein each of the first and second coatings contains at least one colorant, and the colorants in the first and second coatings are different from each other; and is

Wherein at least one opening is provided through the second coating to expose a portion of the outer surface of the core.

30. A dosage form, comprising:

a) a core having an outer surface;

b) a single layer film coating on at least 80% of the outer surface of the core; and

c) an image formed by the absence of exposure of the core by the film coating layer, the image being comprised of at least two or more characters as defined by a subset of ASCII characters having DEC code values of #49 to #57 (numbers); #65-78 and #80-90 (capital letters); and #97-110 and #112 to #122 (lower case letters).

31. The dosage form of claim 30, wherein the image is visually detectable by detecting a difference in color.

32. The dosage form of claim 30, wherein the core is non-white in color.

33. The dosage form of claim 30, wherein the active ingredient is immediate release.

34. A process for preparing a dosage form according to claim 30, wherein a laser is used to remove up to 20% of the outer surface, resulting in an image formed by the absence of a film coating.

35. A process for preparing a dosage form according to claim 30, wherein a laser is used to remove up to 20% of the outer surface, resulting in an image formed by the absence of a film coating.

37. The dosage form of claim 30, wherein the dosage form has additional indicia comprised of ink on the film coating portion.

38. The dosage form of claim 30, wherein said core has a brightness value of 8.5 to 10 and said coating has a brightness value of 0 to 2.5.

39. The dosage form of claim 34, wherein the ink is not detectable by the naked eye, but is only visible under ultraviolet light.

40. The dosage form of claim 31, wherein additional indicia formed by the ink layer on the film coating portion is detectable by the human eye.