JP2006517183A - Immediate release dosage form having a shell with an opening - Google Patents

Abstract

The present invention provides an immediate release dosage form having a solid core and a shell that dissolves easily in gastrointestinal fluid. The dosage form further has one or more openings provided in the shell.

Description

Detailed Description of the Invention

Reference to Related Applications This application is based on international applications PCT / US02 / 31129 filed on September 28, 2002, PCT / US02 / 31117 filed on September 28, 2002, and September 28, 2002. PCT / US02 / 31062 filed, PCT / US02 / 31024 filed September 28, 2002, PCT / US02 / 31163 filed September 28, 2002 (each of which was 2001) U.S. Patent Application No. 09 / 966,939 filed on September 28, U.S. Patent Application No. 09 / 966,509 filed on Sep. 28, 2001, filed on Sep. 28, 2001 U.S. Patent Application No. 09 / 966,497, U.S. Patent Application No. 09 / 967,414 filed on September 28, 2001, and filed on Sep. 28 Which is a continuation-in-part of U.S. patent application Ser. No. 09 / 966,450, which is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION This invention relates to dosage forms that allow immediate release of active ingredients. The dosage form consists of a solid core and a shell surrounding the core. The shell is provided with one or more openings.

BACKGROUND OF THE INVENTION Certain dosage forms are known that are provided with holes or embossments. For example, “osmotic pump” type dosage forms for administration of pharmaceutically active ingredients are known in the art. These dosage forms typically have a semi-permeable wall surrounding a reservoir containing the drug. The wall is permeable to the passage of external fluid and impermeable to the passage of drug, which wall is provided through the semi-permeable wall to remove the drug from the osmotic system. It has a passage to send out. For example, U.S. Pat. No. 4,576,604 discloses an osmotic device having a drug compartment surrounded by a wall (coating) provided with a passage. The wall may contain a single immediate release dose of drug and the internal drug compartment may contain a sustained release dose of drug.

  U.S. Pat. No. 4,449,983 discloses another osmotic device, which has two separately contained medicaments to be dispensed separately. The device has two compartments separated by a divider, one for each drug. Each compartment has an orifice that leads to the exterior of the instrument.

  U.S. Pat. No. 3,823,816 discloses a water-soluble package provided in the form of a hard shell capsule filled with powder, granules and the like. The capsule is provided with holes, which are covered with a water-soluble barrier film. The film is more water soluble than the capsule, so when the package comes into contact with water, the film, not the capsule, will melt first, leaving the capsule intact and free for dissolution and / or release through the pores. Expose things.

  U.S. Pat. No. 5,256,440 relates to an engraved dosage form having one or more circumscribed areas on the surface. The dosage form is spray coated with latex polymer. When placed in the environment of use, the latex coating in the circumscribing area is reproducibly extruded, leaving behind a pre-determined coated core tablet with a hole that separates a separate portion of the core surface from the environment of use. To expose.

  One known method for producing gelatin-coated dosage forms is by a cosmetic method, in which two separate films made of gelatinous material are treated, for example, in US Pat. No. 5,146,730. And 5,559,983, a pair of rotating dies are applied to opposite sides of the tablet. Film formulations for producing gel caps and gel tabs prepared or made by a cosmetic method as disclosed in US Pat. Nos. 5,146,730 and 5,459,983 are: Typically, it comprises an aqueous gelatin formulation containing about 45% gelatin by weight and about 9% plasticizer (glycerin and / or sorbitol). Glycerin and sorbitol can be used as a single plasticizer or can be used in combination with each other. In addition, other sugars and polyhydroxy compounds can be used as additives and plasticizers. If a gelatin-coated pharmaceutical tablet that can be tampered with is the desired final product, the ratio of plasticizer to gelatin in the gelatin formulation should be about 1: 5.

  Another conventional method of forming the shell (or coating) on the core (or substrate) is the method disclosed in International Publication No. WO 01/57144 utilizing the principle of electrostatic coating to form the coating. . At least one of the core or shell is preferably from about 1% to about 10% of one or more “charge control agents” of the weight of the shell, such as metal salicylates, such as zinc salicylate, magnesium salicylate and calcium salicylate, quaternary ammonium. Salts, benzalkonium chloride, benzethonium chloride, trimethyltetradecyl ammonium bromide (cetrimide) and cyclodextrins and their adducts.

  Applicants have now discovered that an immediate release dosage form can be made with a solid core and a shell surrounding the core, the density of the core being at least about 0.9 g / cc. The shell is provided with one or more openings, which are easily soluble in the gastrointestinal fluid. The shell is preferably applied to the core by a decorative hook.

SUMMARY OF THE INVENTION The present invention is a dosage form comprising at least one active ingredient, having a core and a shell surrounding at least a portion of the core, wherein the density of the core is at least about 0.9 g / cc, The shell has one or more openings, the shell dissolves easily in the gastrointestinal fluid and the dosage form is characterized by allowing immediate release of at least one active ingredient upon contact with the liquid medium A dosage form is provided.

  The present invention is also a dosage form comprising a core with an outer surface and a shell with an outer surface and an inner surface, wherein at least a portion of the shell is substantially conformal with the inner surface of the shell on the outer surface of the core. And at least a portion of the shell is provided with one or more openings, wherein one or more of the openings have a diameter or width of about 200 to about 2,000 microns. , At least a portion of the shell is readily soluble in gastrointestinal fluid, the average thickness of the shell is from about 100 to about 400 microns, the shell contains no more than about 50% crystalline sugar, Substantially free of charge control agent, the dosage form provides a dosage form characterized by allowing immediate release of at least one active ingredient upon contact with the liquid medium.

DETAILED DESCRIPTION OF THE INVENTION The term “dosage form” as used herein is any term designed to include a certain component, eg, a predetermined amount (dose) of an active ingredient as shown below. This applies to solid, semi-solid or liquid compositions. Suitable dosage forms include pharmaceutical administration systems including oral administration, buccal administration, rectal administration, topical administration, transdermal administration, mucosal administration or subcutaneous implantation, or another implantable pharmaceutical administration system, or It may be a composition for administering minerals, vitamins and other dietary supplements, dental care agents, flavorings and the like. The dosage form of the present invention is preferably considered solid, but may contain liquid or semi-solid components. In a particularly preferred embodiment, the dosage form is an oral administration system for administering a pharmaceutically active ingredient to a human gastrointestinal tract.

  Suitable active ingredients for use in the present invention include, for example, pharmaceuticals, minerals, vitamins and other dietary supplements, dental care agents, flavorings and mixtures thereof. Suitable drugs include analgesics, anti-inflammatory agents, anti-arthritic agents, anesthetics, antihistamines, antitussives, antibiotics, anti-infectives, antiviral agents, anticoagulants, antidepressants, antidiabetics, antiemetics, Intestinal regulating agent, antifungal agent, antispasmodic agent, appetite suppressant, bronchodilator, cardiovascular agent, central nervous system agent, central nervous system stimulant, decongestant, oral contraceptive, diuretic, expectorant, gastrointestinal, These include migraine drugs, motion sickness drugs, mucolytic agents, muscle relaxants, osteoporosis drugs, polydimethylsiloxane, respiratory drugs, hypnotic drugs, urological drugs and mixtures thereof.

  Suitable dental care agents include halitosis inhibitors, tooth whitening agents, antibacterial agents, tooth mineralizers, caries inhibitors, local anesthetics, mucosal protective agents and the like.

  Suitable flavoring agents include menthol, peppermint, mint flavor, fruit flavor, chocolate, vanilla, bubble gum flavor, coffee flavor, liqueur flavor and combinations.

  Examples of suitable gastrointestinal agents include antacids such as calcium carbonate, magnesium hydroxide, magnesium oxide, magnesium carbonate, aluminum hydroxide, sodium bicarbonate, dihydroxyaluminum sodium bicarbonate, and irritant laxatives such as bisacodyl and cascala. Sagrada, danslon, senna, phenolphthalein, aloe, castor oil, ricinoleic acid, dehydrocholic acid and mixtures thereof, H2 receptor antagonists such as famotadin, ranitidine, cimetadine, nizatidine ), As protopump inhibitors, for example omeprazole or lansoprazole, as gastrointestinal mucosa protective agents, for example, sucraflate and misoprostol, intestinal motility promoters For example, prucalopride, antibiotics for Helicobacter pylori, such as clarithromycin, amoxicillin, tetracycline and metronidazole, antidiarrheal agents such as difexilate and loperamide, glycopyrrolate, antiemetics For example, ondansetron and an analgesic include, for example, mesalamine.

  In one embodiment of the present invention, the active agent is bisacodyl, famotazine, ranicidine, cimetidine, plucaropride, difexilate hydrochloride, loperamide, lactase, mesalamine, bismuth, antacids and pharmaceutically acceptable salts, esters, isomers It may be selected from the group consisting of bodies and mixtures thereof.

  In another embodiment, the active agent is an analgesic, anti-inflammatory, antipyretic, such as a non-steroidal anti-inflammatory drug (NSAID) (such as a propionic acid derivative such as ibuprofen, naproxen, ketoprofen, etc., such as an acetic acid derivative such as Indomethacin, diclofenac, sulindac, tolmetin, etc., phenamic acid derivatives such as mefenamic acid, meclofenamic acid, flufenamic acid etc., biphenylcarboxylic acid derivatives such as diflunisal, flufenisal etc., and oxicam such as piroxicam ), Sudoxicam, isoxicam, meloxicam, etc.). In particularly preferred embodiments, the active agent is a propionic acid derivative NSAID such as ibuprofen, naproxen, flurbiprofen, fenbufen, fenoprofen, indoprofen, ketoprofen, fluprofen ( fluprofen), pirprofen, carprofen, oxaprozin, pranoprofen, suprofen and pharmaceutically acceptable salts, derivatives and combinations thereof. In another embodiment of the invention the active ingredient is 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, the active ingredient is pseudoephedrine, phenylpropanolamine, chlorpheniramine, dextromethorphan, diphenhydramine, astemizole, terfenadine, fexofenadine, loratadin, desloratadine (Desloratadine), doxilamine, norastemizole, cetirizine, mixtures thereof and pharmaceutically acceptable salts, isomers, and mixtures thereof. Good.

  Examples of suitable polydimethylsiloxanes are the polydimethylsiloxanes disclosed in US Pat. Nos. 4,906,478, 5,275,822 and 6,103,260. Such polydimethylsiloxanes include, but are not limited to, dimethicone and simethicone. The disclosures of each of these US patent specifications are incorporated by reference. As used herein, the term “simethicone” refers to a broader family with respect to polydimethylsiloxane, including but not limited to simethicone and dimethicone.

  The active ingredient or ingredients are present in the dosage form in a therapeutically effective amount, which can be obtained by oral administration to obtain a favorable therapeutic response and is readily determined by one skilled in the art. This is the amount. Determining such amounts requires consideration of the particular active ingredient being administered, the bioavailability characteristics of the active ingredient, usage, the age and weight of the patient, and other factors, as is known in the art. Typically, the dosage form comprises at least about 1%, preferably at least about 5%, such as at least about 25% by weight of a combination of one or more active ingredients. In a preferred embodiment, the core comprises a total of at least about 50% by weight of one or more active ingredients, such as at least about 70% by weight, for example at least about 80% by weight (based on the weight of the core).

  The active ingredient or ingredients may be present in the dosage form in any form. For example, the active ingredient can be dispersed at the molecular level in the dosage form, eg melted or dissolved, or can be in the form of particles, which can be coated or uncoated. Also good. When the active ingredient is in the form of particles, the particles (whether coated or not) typically have an average particle size of about 1 to 2,000 microns. In a preferred embodiment, such particles are crystals having an average particle size of about 1 to 300 microns. In another preferred embodiment, the particles are granules or pellets having an average particle size of about 50 to 2,000 microns, preferably about 50 to 1,000 microns, and most preferably about 100 to 800 microns.

  The core may be in any solid form. The core can be made by any suitable method, such as compression or molding. As used herein, the term “core” means a material that is at least partially surrounded or surrounded by another material. Preferably, the core is a self-contained unitary article, such as a tablet or capsule. Typically, the core consists of a solid, for example, the core is a composition based on compressed or molded tablets, hard or soft capsules, suppositories, or confectionery forms such as confectionery tablets, nougat, caramel, flux or fat. It is a thing. In certain other embodiments, the core or part thereof may be in semi-solid or liquid form in the final dosage form. For example, the core may consist of a liquid filled capsule or a semi-solid flux material. In embodiments where the core includes a flowable component, such as a plurality of granules or particles, or a liquid, the core preferably further includes an enclosing component, such as a capsule shell or coating, that contains the flowable material. In certain embodiments where the core has an enclosing component, the shell or shell portion of the present invention is in direct contact with the enclosing component of the core, which isolates the shell from the flowable component of the core.

In one embodiment, the core is a compressed tablet having a hardness of about 2 to about 30 kp / cm ² , such as about 6 to about 25 kp / cm ² . “Hardness” is used in the art to describe the diametrical fracture strength of a core or coated solid dosage form as measured by a conventional pharmaceutical hardness tester, eg, a Schleuniger Hardness Tester. It is a term that is used. In order to compare values between tablets of different sizes, it is necessary to normalize the fracture strength with respect to the fracture area. This normalized value expressed in kp / cm ² is sometimes referred to as tablet tensile strength. For a general description of tablet hardness testing, see Leiberman et al., “Pharmaceutical Dosage Forms-Tablets”, Volume 2, Second Edition, Marcel. Decker Incorporated (Marcel Dekker Inc.), 1999, p. 213-217, 327-329.

  The core may be one of a wide variety of shapes. For example, the core may be shaped as a polyhedron, such as a cube, pyramid, prism, or the like, or a spatial geometry with several uneven faces, eg, a cone, a truncated cone, a cylinder , Sphere, torus, etc. may be used. In certain embodiments, the core has one or more primary faces. For example, in embodiments where the core is a compressed tablet, the core surface typically has two opposing major faces formed by contact with the upper and lower punched faces in the compressor. In such embodiments, the core surface typically further comprises a “berry band” located between the two major faces and formed by contact with the die wall in the compressor. The core may consist of a multilayer tablet.

Examples of core shapes that can be adopted include the “The Elizabeth Companies Tablet Design Training Manual” as described below.
Tablet Design Training Manual) (Elizabeth Carbide Die Co., Inc.), p.7 (located in McKeesport, PA). (The tablet shape is the reverse of the shape of the compression tooling.) The contents of such non-patent literature are cited here as forming part of this specification. .
1. Shallow dent.
2. Standard dent.
3. Deep dent.
4). Extremely deep dent.
5. Modified ball dent.
6). Standard dent bisecting.
7). Standard dent double bisecting.
8). Standard dent European bisect.
9. Standard dent part bisecting.
10.2 double radius (radius).
11. Bevel and dent.
12 Flat plane.
13. Sloped edge with flat face (FFBE).
14 FFBE bisecto.
15. FFBE double bisecting.
16. ring.
17. dimple.
18. ellipse.
19. Oval shape.
20. Capsule shape.
21. Rectangle.
22. square.
23. triangle.
24. Hexagon.
25. pentagon.
26. Octagon.
27. Rhombus.
28. Arrow shape.
29. Bullet shape.
30. Shallow dent.
31. Standard dent.
32. Deep dent.
33. Extremely deep dent.
34. Modified ball dent.
35. Standard dent bisecting.
36. Standard dent double bisecting.
37. Standard dent European bisect.
38. Standard dent part bisecting.
39.2 double radius (radius).
40. Bevel and dent.
41. Flat plane.
42. Sloped edge with flat face (FFBE).
43. FFBE bisecto.
44. FFBE double bisecting.
45. ring.
46. dimple.
47. ellipse.
48. Oval shape.
49. Capsule shape.
50. Rectangle.
51. square.
52. triangle.
53. Hexagon.
54. pentagon.
55. Octagon.
56. Rhombus.
57. Arrow shape.
58. Bullet shape.
59. Barrel shape.
60. Half moon shape.
61. shield.
62. Heart shape.
63. Almond shape.
64. House / home plate.
65. parallelogram.
66. Trapezoid.
67.8 characters / barbell shape.
68. Bow tie shape.
69. Unequal triangle.

  The core typically contains various excipients depending on the active ingredient and the method for producing the core.

  In embodiments where the core is manufactured by compression, suitable excipients include fillers, binders, tablet disintegrants, lubricants, glidants, etc., as is known in the art. Can be mentioned. In embodiments where the core is made by compression and the core further provides controlled release of the active ingredients contained therein, such core preferably further comprises a release-adjustable compressible excipient.

  Suitable fillers used in making the core by compression include, for example, sugar (including dextrose, sucrose (sucrose), maltose and lactose), polydextrose, sugar alcohols (mannitol, sorbitol, maltitol ( water soluble compressible hydrocarbons such as maltitol, xylitol, erythritol), starch hydrolysates (including dextrin and maltodextrin), etc., such as microcrystalline cellulose or other cellulose derivatives Insoluble plastic defoaming materials such as brittle fracture materials that are not soluble in water, such as dicalcium phosphate, tricalcium phosphate, and mixtures thereof.

  Suitable binders used in making the core by compression include, for example, dry binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose and the like, for example, acacia, alginic acid, agar, guar gum, carob, carrageenan, Carboxymethyl cellulose, tara, gum arabic, tragacanth, pectin, xanthan, gellan, gelatin, maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan, inulin, pectin , Welan, rhamsan, zooglan, methylan, chitin, cyclodextrin, chitosan, polyvinylpyrrolidone, cellulose derivatives, sucrose, starch Liquid binder such as water-soluble polymers containing hydrophilic colloids such as N) such, derivatives and mixtures thereof.

  Suitable disintegrants used in making the core by compression include starch glycolate sodium, crosslinked polyvinylpyrrolidone, crosslinked carboxymethylcellulose, starch, microcrystalline cellulose and the like.

  Suitable lubricants used in making the core by compression include long chain fatty acids and their salts such as magnesium stearate and stearic acid, talc and wax.

  Suitable glidants used in making the core by compression include colloidal silicon dioxide and the like.

  In certain embodiments, the core or a portion thereof is known in the art, for example, in commonly assigned co-pending US patent application (unassigned) (Applicant Case Number: MCP321). It may include a controlled release excipient as disclosed, but this is optional. The disclosure of such US patent application is hereby incorporated by reference. Release-adjustable compressible excipients suitable for producing cores by compression include swellable and erodible hydrophilic substances, insoluble and edible substances, pH-dependent polymers, and the like.

  Pharmaceutically acceptable adjuvants suitable for producing the core by compression include preservatives, sweeteners such as aspartame, acesulfame potassium, sucralose, saccharin, flavor, Coloring agents, antioxidants, surfactants, wetting agents and the like and mixtures thereof can be mentioned.

  In embodiments where one or more cores are made by compression, drive lending (ie, direct compression methods) or wet granulation methods may be employed as is known in the art. In the drive lending (direct compression) method, one or more active ingredients are blended in a suitable blending machine rather than directly transferred to a compressor that pressurizes them into a tablet. In the wet granulation method, a solution or dispersion of one or more active ingredients, a suitable excipient and a liquid binder (for example, an aqueous cooked starch paste or a solution of polyvinyl pyrrolidone) is mixed. Grain. As a variant, a liquid binder may be included in the excipient and the mixture may be granulated with water or other suitable solvent. Equipment suitable for wet granulation is known in the art and includes such fluid beds as low shear, including planetary mixers, high shear mixers and rotating fluid beds. The resulting granulate is dried and optionally dry blended with other ingredients such as adjuvants and / or excipients such as lubricants, colorants and the like. In this case, the final dry blend is suitable for compression. Direct compression and wet granulation methods are known in the art, details of which are described in, for example, Lachman et al., “The Theory and Practice Pharmacy” of Industrial Pharmacy) ”, Chapter 11 (3rd edition, 1986).

  Dry blended or wet granulated powder mixtures are typically rotary compressors known in the art, such as Fette America, Inc., Rockaway, NJ, or Manesti Machines, Liverpool, UK. It is pressed into a tablet using a rotary compressor commercially available from LTD. In a rotary compressor, a weighed volume of powder is filled into a die cavity, and the die cavity is rotated from the filling position to the compaction position as part of the “die table”, at which the powder is It is pressed between the punch and the lower punch and sent to the protruding position, where the resulting tablet is pushed out of the die cavity by the lower punch and guided to the protruding chute by the fixed “take-off” bar.

  In one optional embodiment, the core may be made by the compression method and apparatus described on pages 16-27 of co-pending US patent application Ser. No. 09 / 966,509, such US patent. The disclosure content of the application is hereby incorporated by reference. Specifically, the core comprises a filling zone, insert, provided in a single device of a double row die structure as shown in FIG. 6 of US patent application Ser. No. 09 / 966,509. It is made using a rotary compression module consisting of a zone, a compression zone, an ejection zone and a purge zone. The dies of the compression module are preferably filled with the aid of a vacuum with the filter located in or near each die.

  The core produced by the compression method may be single layer or multilayer, for example, double layer, tablet.

  The density of the core is at least about 0.9 g / cc, such as at least about 1.0 g / cc. Exemplary cores include 385 mg compressed soft tablets with a volume of 0.4 cubic centimeters and 586 mg compressed tablets with a volume of about 0.5 cc.

  A shell surrounds the core. The shell is provided with one or more openings. The one or more openings serve as passages that allow the dosage form core to communicate with the outside. The opening may pass completely through the thickness of the shell and contact the core, or may only partially extend into the shell.

  The shell may be substantially integral or continuous except that an opening is provided, or the shell may consist of a number of parts, such as a first shell part and a second shell part. . In certain embodiments, the shell or shell portion is in direct contact with the core. In certain other embodiments, the shell or shell portion is substantially in contact with a sub-coating that substantially surrounds the core. In embodiments where the shell comprises first and second shell portions, at least the first shell portion is provided with an opening.

  In certain embodiments, the first shell portion and the second shell portion are compositionally different from each other. As used herein, the term “compositionally different” means having a characteristic that can be easily identified by qualitative or quantitative chemical analysis, physical inspection, or visual observation. For example, the first shell portion and the second shell portion may include different types of components or different levels of the same component, or the first shell portion and the second shell portion may be different from each other. It should have different physical or chemical properties, different functional properties, or be visually distinguishable. Examples of physical or chemical properties that may be different from each other include hydrophilicity, hydrophobicity, hygroscopicity, elasticity, plasticity, tensile strength, crystallinity and density. Examples of functional properties that may differ from each other include the dissolution rate and / or solubility of the material itself or the dissolution rate and / or solubility of the active ingredient from such material, the degradation rate of the material, and the permeability to the active ingredient And permeability to water or an aqueous medium. Examples of visual distinction include size, shape, topography or other geometric features, color, tint, opacity and gloss.

  In one embodiment, the dosage form of the invention comprises a) a core comprising the active ingredient, b) an optional subcoating that substantially covers the core, c) first and second located on the surface of the subcoating. A first shell portion having one or more openings, the first shell portion being easily soluble in gastrointestinal fluid. As used herein, the term “substantially covers” means that at least about 95% of the surface area of the core is covered by the subcoating.

  The use of subcoating is well known in the art and is disclosed, for example, in US Pat. No. 3,185,626, the disclosure of which is hereby incorporated by reference. Any composition suitable for film coating tablets can be used as the subcoating of the present invention. Examples of suitable subcoatings are U.S. Pat. Nos. 4,683,256, 4,543,370, 4,643,894, 4,828,841, Nos. 4,725,441, 4,802,924, 5,630,871 and 6,274,162, which are disclosed in U.S. Pat. The entire disclosure of is cited by reference. Additional suitable subcoatings include the following ingredients: cellulose ethers such as hydroxypropyl methylcellulose, hydroxypropyl cellulose and hydroxyethyl cellulose, polycarbohydrates such as xanthan gum, starch and maltodextrins, plasticizers such as Among glycerin, polyethylene glycol, propylene glycol, dibutyl sebacate, triethyl citrate, vegetable oils such as castor oil, surfactants such as polysorbate-80, sodium laurel sulfate, dioctyl sodium sulfosuccinate, polycarbohydrate, pigments and opacifiers Includes one or more.

  In one embodiment, the subcoating is about 2% to about 8%, such as about 4% to about 6% water soluble cellulose, as disclosed in detail in US Pat. No. 5,658,589. Contains ether and from about 0.1% to about 1% castor oil. The disclosure of this US patent is hereby incorporated by reference. In another embodiment, the subcoating comprises about 20% to about 50%, such as about 25% to about 40% HPMC, about 45% to about 75%, such as about 50% to about 70% maltodextrin and about 1% to about 10%, such as about 5% to about 10% PEG400.

  The dry subcoating is typically present in an amount of about 0% to about 5%, based on the dry weight of the core.

  FIG. 1 shows a dosage form 1 according to the invention having a shell 3 provided with a plurality of openings 2. The opening 2 is shaped as an elongated slit and does not extend completely through the shell 3 to the core (not shown) below the shell 3.

  FIG. 2 shows another dosage form of the present invention. The dosage form 1 has a core (not shown) covered with a shell made of a first shell portion 3a and a second shell portion 3b. The shell portion 3a has a plurality of openings 2a and 2b. The opening 2a has a dimple shape, and the opening 2b has a character shape.

  FIG. 3 shows another dosage form of the present invention. The dosage form 1 has a core (not shown) covered with a shell 3, and the shell 3 has openings 2a and 2b. The opening 2a has a circular hole shape, and the opening 2b has a character shape.

  FIG. 4 shows another dosage form of the present invention. The dosage form 1 has a core 4 surrounded by a shell 3 having an opening 2. The core 4 is partially visible at the bottom of each opening 2 in the shell 3.

  FIG. 5 shows another dosage form of the present invention. The dosage form 1 has a football-shaped core (not shown) covered by a shell consisting of a first shell portion 3a and a second shell portion 3b. The first shell portion 3 a has a plurality of small round openings 2.

  Each opening is a dimension of about 0.1% to about 100% of the diameter of the dosage form or any dimension (eg, diameter, length or width) of the main face of the dosage form, eg, length, width or diameter It is good to have. The diameter or width of each opening is preferably from about 0.5% to about 5% of the diameter of the dosage form or any dimension (eg, diameter, length or width) of the main face of the dosage form. In certain embodiments, the diameter or width of the opening may be from about 200 to about 2,000 microns. The length of the opening may be from about 1% to about 100% of the diameter of the dosage form or the diameter of the main face of the dosage form. In certain embodiments, the major face length or diameter of the dosage form is from about 10,000 to about 20,000 microns. In one particular embodiment, the opening length is from about 100 to about 20,000 microns. The depth of the opening is typically about 75% to about 100% of the thickness of the shell at the location of the opening. In certain embodiments, the thickness of the shell at the location of the opening is typically from about 20 to about 800 microns, such as from about 100 to about 400 microns. In one particular embodiment, the depth of the opening is from about 75 to about 400 microns. Where multiple openings are provided, these openings are typically spaced from one another by at least about 1/2 times the smallest dimension of the smallest opening, for example at least about 1 time. Yes. The openings may be of various shapes, for example as shown in FIG. 6, or may be arranged in a wide variety of patterns, and may be of approximately the same or different dimensions from one another. .

  In one embodiment, the size of the openings is small enough to prevent the core from being tasted, but the number of openings is high enough to allow communication between some of the core surface area and the exterior of the dosage form. .

  The shell thickness at various locations may be measured, for example, using a model XL 30 ESEM LaB6, an environmental scanning electron microscope of Phillips Electronic Instruments Company, Mahwah, Wisconsin. Shell thickness is measured at six different points on a single dosage form. Relative standard deviation (RSD) is calculated as the sample standard deviation, divided by the mean value and multiplied by 100 as known in the art (ie, RSD is the standard deviation expressed as a percentage of the mean value). Is). Shell thickness RSD provides an indication of shell thickness variation on a single dosage form. In certain optional embodiments of the invention, the relative standard deviation of the shell thickness is about 40% or less, such as about 30% or less, or about 20% or less.

  The dosage form of the present invention allows for immediate release of one or more active ingredients contained therein. One or more active ingredients may be found in the core, shell, or portion thereof, or combinations thereof. In one embodiment, at least one active ingredient is in the core.

  In embodiments where it is desirable to absorb the active ingredient into the animal's systemic circulation, the active ingredient or ingredients are preferably soluble upon contact with a fluid, such as water, gastric fluid, intestinal fluid, and the like. In one embodiment, the dissolution characteristics of the at least one active ingredient meet USP specifications for immediate release tablets containing the active ingredient. For example, in the case of acetaminophen tablets, according to USP24 regulations, at pH 5.8 phosphate buffer, at least 80% of acetaminophen contained in the dosage form using USP device 2 (paddle) at 50 rpm. In the case of ibuprofen tablets, according to USP24 regulations, a phosphate buffer of pH 7.2 is included in the dosage form using USP device 2 (paddle) at 50 rpm. At least 80% of the ibuprofen being released is released within 60 minutes after administration. See USP24 2000 version 19-20 and page 856 (1999) for this. In another embodiment, at least about 70% of the active ingredient can be detected in a suitable dissolution medium after about 60 minutes of stirring at appropriate conditions.

  Thus, the shell or part of it is easily dissolved in the gastrointestinal fluid. In a preferred embodiment where the shell consists of first and second shell portions, at least the first shell portion is provided with an opening, which first shell portion is readily soluble in gastrointestinal fluid. In such an embodiment, such a shell or shell portion is preferably 900 ml water or 0.1 N HCl, or a 37 ° C. phosphate buffer with stirring at 50 or 100 rpm by a USP type 2 dissolution apparatus (paddle method). Will break or dissolve within 30 minutes.

  The shell or shell portion is preferably made of a material that exhibits rapid dissolution in gastrointestinal fluid. For example, such a shell or shell portion comprises a readily soluble material selected from water soluble or water swellable film formers, water soluble or water swellable thickeners, crystalline or amorphous hydrocarbons. In certain such embodiments, suitable water soluble or water swellable film formers include water swellable cellulose derivatives, thermoplastic starches, polyalkalene glycols, polyalkalene oxides, amorphous sugar glasses and these It may be selected from a combination. In certain other such embodiments, suitable film formers are selected from film-forming water-soluble polymers, such as water-soluble vinyl polymers, water-soluble polycarbohydrates, water-soluble copolymers, film-forming proteins, and combinations thereof. It may have been made. In certain other such embodiments, suitable thickeners may be selected from gelling polymers or hydrocolloids, gelling starches and crystalline carbohydrates. In certain other such embodiments, suitable non-crystalline carbohydrates may be selected from polydextrose, starch hydrolysates, and non-crystalline sugar alcohols. In one embodiment, the shell is preferably at least about 50%, preferably at least about 50% of a material selected from film formers, gelling polymers, low melting hydrophobic materials, amorphous sugars or sugar alcohols and mixtures thereof. 80%, most preferably at least about 90%. In another embodiment, the shell is at least about 50%, preferably at least about 80%, most preferably at least about 90% of a material selected from film formers, gelling polymers, low melting hydrophobic materials and mixtures thereof. % Is included.

  In another specific embodiment, the shell comprises at least 50% or less crystalline sugar, preferably about 25% or less, most preferably about 5% or less.

  In another embodiment, the dosage form is substantially free of charge control agent (ie, less than 1 wt%, preferably about 0.1 wt% or less, based on the shell weight). As used herein, the term “charge control agent” means a material having a charge control function, for example, a material used for electrostatic coating of a coating on a substrate. Examples of such charge control agents include metal salicylates such as zinc salicylate, magnesium salicylate and calcium salicylate, quaternary ammonium salts, benzalkonium chloride, benzethonium chloride, trimethyltetradecylammonium bromide (cetrimide) and cyclodextrins and their addition Including things.

  In certain optional embodiments, the shell itself or the outer coating applied thereto may contain the active ingredient. In one particular embodiment, such active ingredients are released immediately from the dosage form upon contact with a suitable liquid medium. In another embodiment, the shell consists of a first shell portion and a second shell portion. An outer coating is located on the second shell portion, and an opening is provided in the first shell portion. The active ingredient may be released immediately or in a controlled manner, e.g. in a sustained manner, in a long time manner, in an extended manner or in a delayed manner, e.g. in a pulsatile manner or repeated In some ways, it may be released from the dosage form upon contact with a suitable liquid medium. In embodiments where the active ingredient is released immediately from the outer coating, the outer coating is also preferably readily soluble in the gastrointestinal fluid as described above.

  The shell can be applied to the core by any suitable method, such as spraying, dipping, dressing or molding. Suitable spray coating methods are, for example, U.S. Pat. Nos. 3,185,626, 4,683,256, 4,543,370, 4,643,894, Nos. 4,828,841, 4,725,441, 4,802,924, 5,630,871 and 6,274,162 The entire disclosure of these US patent specifications is hereby incorporated by reference. Suitable dipping methods are described in U.S. Pat. Nos. 4,820,524, 5,538,125, 5,228,916, 5,436,026, 679,406, the entire disclosures of which are hereby incorporated by reference. Suitable makeup methods are described in US Pat. Nos. 5,146,730 and 5,459,983. Suitable molding methods are described herein.

  In certain optional embodiments of the invention, the core, shell, or both are made by molding. Specifically, the core, shell, or both can be made by a molding method using a solvent or a molding method without using a solvent. In such embodiments, the core or shell is made of a flowable material that optionally includes an active ingredient. The flowable material may be any edible material that is flowable at a temperature of about 37 ° C. to about 250 ° C. and capable of forming a solid, semi-solid, or gel at a temperature of about −10 ° C. to about 35 ° C. The flowable material, when in a fluid or fluid state, may include a decomposed, dispersed or molten component and optionally a solvent, such as water, an organic solvent, or combinations thereof. The solvent should be one that can be partially or substantially removed by drying.

  In one embodiment, a solvent-based or solvent-free molding process is thermoset molding using the method and apparatus described on pages 57-63 of co-pending US patent application Ser. No. 09 / 966,450. The disclosures of such US patent application specifications are hereby incorporated by reference. In this embodiment, the core or shell is formed by injecting a flowable form into the molding chamber. The flowable material preferably comprises a thermosetting material at a temperature above its melting point but below the decomposition temperature of the active ingredient contained therein. The starting material is cooled and solidified in a molding chamber into a shaped form (ie, having a mold shape).

  According to this method, the flowable material may have solid particles suspended in a molten matrix, such as a polymer matrix. The flowable material may be in a completely molten or paste state. The flowable material may consist of solid particles dispersed in a fluid carrier. Alternatively, the flowable material may be made by dissolving a solid in a solvent and then evaporating the solvent after the molding process.

  In another embodiment, molding with or without solvent is performed using a method and apparatus described on pages 27-51 of pending US patent application Ser. No. 09 / 966,497. It is performed by a cycle molding method. The disclosure of such US patent application is incorporated by reference. Thermal cycle molding is performed by injecting a flowable material into a heated molding chamber. The flowable material includes the active ingredient and the thermosetting material at a temperature higher than its melting point but lower than the decomposition temperature of the active ingredient. The flowable material is cooled and solidified in the molding chamber to form a shape (ie, having a mold shape).

  In the thermal cycle molding method and apparatus of US patent application Ser. No. 09 / 966,497, a thermal cycle molding module having the overall shape shown in FIG. 3 is used. The thermal cycle molding module 200 has a rotor 202 around which a plurality of mold units 204 are arranged. The thermal cycle molding module has a reservoir 206 (see FIG. 4) that holds a flowable material. In addition, the thermal cycle molding module includes a temperature control system that quickly heats and cools the mold unit. 55 and 56 show a temperature control system 600. FIG.

  The mold unit has a central mold assembly 212, an upper mold assembly 214, and a lower mold assembly 210, as shown in FIGS. For example, a mold cavity having the shape of a core or a shell surrounding one or more cores is formed. When the rotor 202 rotates, the opposed center mold assembly and upper mold assembly or the opposed center mold assembly and lower mold assembly are closed. The flowable material heated to flow in the reservoir 206 is injected into the resulting mold cavity. Next, the flowable material is cured by reducing the temperature of the flowable material. The mold assembly opens and ejects the final product.

  In one optional embodiment of the present invention, the shell is applied to the dosage form using a general type thermal cycle molding apparatus as shown in FIGS. 28A-28C of co-pending US patent application Ser. No. 09 / 966,497. . The thermal cycle molding apparatus includes a rotatable central mold assembly 212, a lower mold assembly 210, and an upper mold assembly 214. The core is continuously supplied to the mold assembly. The shell flowable material heated to flow in the reservoir 206 is injected into a mold cavity formed by a closed mold assembly holding the core. Next, the temperature of the shell flowable material is decreased and allowed to cure around the core. The mold assembly opens and ejects the final dosage form. The shell coating is performed in two stages and each half of the dosage form is coated separately by rotation of the central mold assembly as shown in the flow diagram of FIG. 28B of co-pending US patent application Ser. No. 09 / 966,939. To do.

  In one embodiment, the core is manufactured using the compression module described on pages 16-27 of co-pending US patent application Ser. No. 09 / 966,509, and the thermal cycle molding module as described above is used. And attach the shell to the core. The core may be transferred from the compression module to the thermal cycle molding module using a transfer device such as described in US patent application Ser. No. 09 / 966,414, pages 51-57, such US patent. The disclosure of the application specification is hereby incorporated by reference. Such a transfer device may have the structure shown at 300 in FIG. 3 of co-pending US patent application Ser. No. 09 / 966,939. This transfer device has a plurality of transfer units 304 that are cantilevered to a belt 312 as shown in FIGS. 68 and 69 of co-pending US patent application Ser. No. 09 / 966,939. The transfer device rotates and operates in synchronism with the compression module and the thermal cycle molding module to which it is coupled. The transfer unit 304 has a retainer 330 that holds the core as it moves around the transfer device.

  Suitable thermoplastic materials used in or as the flowable material are generally water-soluble polymers that are linear, not cross-linked, and not strongly hydrogen bonded to adjacent polymer chains. Both water insoluble polymers are mentioned. The thermoplastic material may be a single material or a mixture of such a material and a solvent or plasticizer. Examples of suitable thermoplastic materials include water-swellable cellulose derivatives, water-insoluble cellulose derivatives, thermoplastic vinyl polymers, thermoplastic starch, thermoplastic polyalkalene glycol, thermoplastic polyalkalene oxide and amorphous sugar glass. And materials comprising these derivatives, copolymers and combinations. Examples of suitable thermoplastic water-swellable cellulose derivatives include hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), methylcellulose (MC) and these with water or other suitable solvent and / or plasticizer The combination of is mentioned. Examples of suitable thermoplastic water-insoluble cellulose derivatives include cellulose acetate (CA), ethyl cellulose (EC), cellulose acetate butyrate (CAB), cellulose propionate and suitable organic solvents and / or plasticizers. These combinations are mentioned. Examples of suitable thermoplastic vinyl polymers include polyvinyl alcohol (PVA) and polyvinyl pyrrolidone (PVP). Examples of suitable thermoplastic starches are disclosed, for example, in US Pat. No. 5,427,614. An example of a suitable thermoplastic polyalkalene glycol is polyethylene glycol. Examples of suitable thermoplastic polyalkalene oxides include polyethylene oxide having a molecular weight of about 100,000 to about 900,000 daltons. Other suitable thermoplastic materials include, for example, sugars in the form of amorphous glass used to make hard candy forms.

  It should be noted that when used to make a shell, the flowable material must be a material that dissolves easily in the gastrointestinal fluid as described above.

  In embodiments in which the shell is made using a solvent-free molding process, the shell typically comprises at least about 30% by weight, eg, at least about 45% by weight of a thermoreversible carrier. The shell may further comprise up to a total of up to about 30% by weight of various plasticizers, adjuvants and excipients, although this is optional.

  In embodiments in which the shell is made using a solvent-based molding process, the shell is typically at least about 10 wt%, such as at least about 12 wt%, at least about 15 wt%, at least about 20 wt%, or at least About 25% by weight of a film former. Again, the shell may further include up to a total of up to about 30% by weight of various plasticizers, adjuvants, and excipients, although this is optional.

  The total weight of the shell is preferably from about 20% to about 400% of the total weight of the core. In embodiments in which the shell is made by a solvent-free molding process, the total shell weight is typically about 50% to about 400%, such as about 75% to about 400%, or about 100% of the total weight of the core. % To about 200%. In embodiments in which the shell is made by a solvent-based molding process, the total shell weight is typically about 20% to about 100% of the total core weight.

  In embodiments in which the shell is applied to the core by a molding process, at least a portion of the shell surrounds the core such that the inner surface of the shell is applied substantially conformally on the outer surface of the core. As used herein, the term “substantially conformally” has peaks and valleys or depressions and protrusions where the inner surface of the shell corresponds substantially oppositely to the peaks and valleys of the outer surface of the core. Means that. In certain such embodiments, the indentations and protrusions are typically unidimensional lengths of 10 microns or more, such as 20 microns or more and about 30,000 microns or less, preferably about 2,000 microns or less. , Having a width, height or depth.

  In embodiments using a solvent-free molding process, the flowable material may include a thermoreversible carrier. Suitable thermoreversible carriers used in making the core, shell or both by molding are typically thermoplastic materials having a melting point of about 110 ° C. or less, more preferably from about 20 ° C. to about 100 ° C. is there. Examples of suitable thermoreversible carriers for solventless molding processes include thermoplastic polyalkalene glycols, thermoplastic polyalkalene oxides, low melting point hydrophobic materials, thermoplastic polymers, thermoplastic starches, and the like. . Preferred thermoreversible carriers include polyethylene glycol and polyethylene oxide. The thermoplastic polyalkylene glycol used as the thermoreversible carrier includes polyethylene glycol having a molecular weight of about 100 to about 20,000, such as about 100 to about 8,000 daltons. Suitable thermoplastic polyalkalene oxides include polyethylene oxide having a molecular weight of about 100,000 to about 900,000 daltons. Suitable low melting point hydrophobic materials used as thermoreversible carriers include fats, fatty acid esters, phospholipids, solid waxes at room temperature, fat-containing mixtures such as chocolate and the like. Examples of suitable fats include hydrogenated vegetable oils such as cocoa butter, hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenated sunflower oil, hydrogenated soybean oil, free fatty acids and salts thereof. Examples of suitable fatty acid esters include sucrose fatty acid esters, monoglycerides, diglycerides, triglycerides, glyceryl behenate, glyceryl palmitostearate, glyceryl monostearate, glyceryl tristearate, glyceryl trilaurate, glyceryl myristate, Glyco Wax -932, lauroyl macrogol-32 glyceride and stearoyl macrogol-32 glyceride. Examples of suitable phospholipids (phospholipids) include phosphotidyl choline, phosphotidyl selenium, phosphotidyl enositol and phosphotidine acid. Examples of suitable waxes that are solid at room temperature include carnauba wax, whale wax, beeswax, candelilla wax, shellac wax, microcrystalline wax and paraffin wax. Suitable thermoplastic polymers for use as thermoreversible carriers include thermoplastic water swellable cellulose derivatives, thermoplastic water insoluble polymers, thermoplastic vinyl polymers, thermoplastic starch, thermoplastic resins and combinations thereof. Suitable thermoplastic water-swellable cellulose derivatives include hydroxypropyl methylcellulose (HPMC), methylcellulose (MC), carboxymethylcellulose (CMC), crosslinked hydroxypropylcellulose, hydroxypropylcellulose (HPC), hydroxybutylcellulose (HBC), Examples include hydroxyethyl cellulose (HEC), hydroxypropyl ethyl cellulose, hydroxypropyl butyl cellulose, hydroxypropyl ethyl cellulose and their salts, derivatives, copolymers and combinations. Suitable thermoplastic water-insoluble polymers include ethyl cellulose, polyvinyl alcohol, polyvinyl acetate, polycaprolactone, cellulose acetate and derivatives thereof, acrylates, methacrylates, acrylic acid copolymers and the like, and derivatives, copolymers and combinations thereof. Suitable thermoplastic vinyl polymers include polyvinyl acetate, polyvinyl alcohol, and polyvinyl pyrrolidone (PVP). Examples of suitable thermoplastic starches used as thermoreversible carriers are disclosed, for example, in US Pat. No. 5,427,614. Examples of suitable thermoplastic resins used as thermoreversible carriers include dammer, mastics, pine ani, shellac, sandalac and pine glycerol esters. In one embodiment, the thermoreversible carrier for producing the core by a molding process is selected from polyalkylene glycols, polyalkali oxides, and combinations thereof.

  In embodiments where the shell has an active ingredient that provides immediate release from the dosage form, the shell is preferably made by a molding process that does not use a solvent. In such embodiments, a thermoreversible carrier is used in the flowable material to produce the shell, and such thermoreversible carrier preferably has an average molecular weight of about 1,450 to about 20,000. Selected from polyethylene glycol, polyethylene oxide having an average molecular weight of about 100,000 to about 900,000, and the like.

  In a preferred embodiment of the present invention, the shell is applied to the core by a decorative method. In a decorative method, a cast film is applied to both sides of a core, i.e., a compressed tablet, using a rotating die and sealed together in an essentially edge-to-edge manner with a sealing line extending around the core at the desired location. To do. The dies are positioned so that the surfaces are in abutting relationship with each other, thereby forming a nip between the dies. Each of the dies has a series of matching recesses provided on its circumferential surface. As the die rotates, the films are joined together and fused at the nip between the dies, where a pair of mating recesses form a pocket through which the core is dropped by the metering mechanism. As the die continues to rotate, the core pushes the film into the recesses in the die so that the core is tightly surrounded by the film and draped while the film continues to be joined around the core by the die. Simultaneously with the fusion of the film around the core, the dressed core is clipped from the film by a rotating die, which then leaves the film in the form of individual dressed dosage forms.

  Useful dressing methods and devices are described, for example, in US Pat. Nos. 5,146,730 (hereinafter “the '730”) and US Pat. No. 5,459,983. The disclosure of the patent specification is hereby incorporated by reference. With reference to the '730 patent specification and in particular with reference to FIG. 13, cast films 36, 37 are formed on the rotary casting drums 42, 43 and cooled with a coolant. The film is fed through a series of rotating drums to the drum dies 38, 39, which rotate in synchronization with each other. The dies 38, 39 are arranged symmetrically with respect to each other around the functional center plane 54 of the entire dressing device. Films 36 and 37 contact each other at the nip between dies 38 and 39. Here, a coating is applied to the core, and the two films are sealed together and cut.

More specifically, when the films 36 and 37 converge and are squeezed together, a web is formed. The films are self-attaching to each other. The web with the dressed core exits between the dies 38, 39 and then passes between a pair of squeeze rolls. The web is stretched and the decorated core itself separates itself and falls into the product receptacle 65.
Referring to FIG. 20 of the '730 patent specification, each die 38, 39 has a plurality of recesses 108 that cooperate with corresponding recesses in the other die. These cavity cavities are shaped to receive a single core. The cavities are constituted by ribs 109 that close together to cut the laid core from the web. The teeth 115 provided at the edges of the dies 38 and 39 grip the films 36 and 37.

  The veneered core should be washed and dried, and optionally further processed as desired.

  In another embodiment, the shell is again applied to the core by a decorative method, but the films used to form the shell each have a distinct portion, eg, a stripe, visually. The film is deposited by the makeup method described in the commonly assigned co-pending U.S. patent application (application number not granted; applicant case numbers: MCP301 and MCP316). Referring generally to FIGS. 9-11 of such U.S. Patent Application, the film casting apparatus 30 used in this makeup method has a casting drum 34, the outer surface 36 of which is in contact therewith. The coating material is cooled to at least partially solidify. A multi-chamber slit extruder 38 deposits the film on the casting drum 34. The extruder 38 has partitions 58, 60, 62 that divide into four chambers 64, 66, 68, 70 in the interior 44. Each of the chambers 64, 66, 68, 70 may contain a different coating material, ie a different color coating material. Each partition has a tapered blade edge 94, 96, 98 that controls the flow of coating material onto the casting drum 34. The coating material is supplied to the chamber from, for example, feeder pipes 72 and 74. An open slit 78 is provided at the bottom of the slit extruder 38. The slit 78 communicates with the chambers 64, 66, 68 and 70. The slit extruder is heated to heat the coating material to a fluid state, which is between about 40 ° C. and 250 ° C., depending on the material.

  Referring to FIGS. 14-16 of the MCP 301 application, the visually distinct parts are substantially the same as those described in US Pat. Nos. 5,146,730 and 5,459,983. It is preferable to use a makeup hooking device 102 used for a cast film provided with Specifically, the cast films 32, 32 'are continuously moved by a series of rollers 106, 108, 110, 106', 108 ', 110' toward a series of cooperating rotating dies 112, 112 '. These rotating dies are positioned symmetrically on each side of the central symmetry plane 104 of the device 102. The rotary dies 112, 112 'rotate about their respective rotational axes AR, AR', thereby forming a nip therebetween. The nip between the rotating dies 112 and 112 'is located in the above-described central symmetry plane 104, and the striped films 32 and 32' are passed therethrough.

  The dressing device 102 further includes a core dispensing means 118, which holds the core 10 for one time and dispenses them into the nip in a timed manner. The core dispensing means 118 is also aligned with the central symmetry plane 104. When the core 10 enters the nip, the core dispensing means 118 dispenses the core 10 in a state in which each core 10 is directed so as to simultaneously contact the contact surfaces 32a and 32a 'of the striped films 32 and 32' where the cores are converged. The lateral symmetry plane 16 is located in the central symmetry plane 104 of the decorative device 102, and the color transition portions 92a and 92a 'of the films 32 and 32' are located in the conjugate symmetry plane 18 of the core 10. To do. Next, the films 32 and 32 ′ are stretched symmetrically around opposite sides of each core 10.

  FIG. 15 of the MCP 301 patent application shows the color transitions 92a, 92b between the striped films 32, 32 'and between the films 32, 32' when the core 10 enters the nip between the dies 112, 112 '. , 92c, 92a ′, 92b ′, 92c ′. The color transition portions 92 a, 92 b, 92 c, 92 a ′, 92 b ′, 92 c ′ are all aligned with the conjugate symmetry plane 16 of the corresponding core 10.

  Furthermore, the dressing device 102 preferably has alignment means 120 to ensure that the colored stripes (not shown) of the films 32, 32 'are correctly aligned with each other before passing between the rotating dies 112, 112'. (Schematically shown in FIG. 14 of the MCP301 patent application). The alignment means 120 also ensures that the position of the dispensed core 10 is correct with respect to the color transitions 92a, 92b, 92c, 92a ', 92b', 92c 'and thus the resulting product 122. The transitions between the colors are correctly aligned with each other and the conjugate symmetry plane 18 of each core 10.

  An enlarged schematic perspective view of the drum-like rotating dies 112, 112 'is provided in FIG. 16 of the MCP301 patent application. The rotating dies 112, 112 'are substantially identical to each other, and each die has an outer circumferential surface 124, 124' provided with a series of recesses 126, 126 '. The recesses 126 and 126 'are arranged such that their lengths 130 and 130' are aligned parallel to the rotation axes AR and AR 'of the respective rotary dies 112 and 112'. Each recess 126 in one die 112 cooperates with a corresponding recess 126 'in the other die 112'. In addition, the number of recesses 126, 126 'arranged in a row is the number of stripes 84, 86, 88, 90, 84', 86 of the striped films 32, 32 'passing between the dies 112, 112', respectively. It is necessary to match the number of color transition portions 92a, 92b, 92c, 92a ', 92b' and 92c 'between', 88 'and 90'.

  The direction of the films 32 and 32 'when the striped films 32 and 32' pass between the rotating dies 112 and 112 'is, for example, that the red stripes 84 and 88 of one film 32 are the other film 32'. The red stripes 84 ′, 88 ′ match each other, and the yellow stripes 86, 90, 86 ′, 90 ′ of each film 32, 32 ′ match each other in the same way. Using the alignment means 120 of the dressing device 102 can facilitate the orientation of the films 32 and 32 'so as to improve the alignment and alignment of the color transition portions of each film.

  When the rotary dies 112 and 112 'rotate, the core 10 is dispensed into the nip between the dies 112 and 112' so that the length of the core is aligned parallel to the rotation axes AR and AR 'of the dies 112 and 112'. The cores are oriented so that each core 10 is correctly aligned so that it is received between a pair of cooperating recesses 126, 126 '. The rotating dies 112, 112 ′ continue to rotate so that the films 32, 32 ′ are sealed together by the raised rims 128, 128 ′ of the recesses 126, 126 ′ that cooperate around the core 10, thereby A film seam 134 is formed that is located in the plane of symmetry 16. The raised rims 128, 128 ′ also cut the bonded film 32, 32 ′ at the film seam 134 around each dressed core 10, thereby binding the dressed core product 122. Separate from films 32 and 32 '.

  The produced film seam 134 may have film edges that abut each other. It is also possible to provide a film seam 134 where the cut edge of one film 32 slightly overlaps the cut edge of the other film 32 'by an amount approximately equal to the thickness of the films 32, 32'. Alternatively, the film seam 134 is positioned so that the cut edges of the films 32, 32 'are aligned with each other around the core 10 but slightly spaced by a distance approximately equal to the thickness of the films 32, 32'. You may form.

  If aesthetically desired, the films 32, 32 ′ may be aligned such that the resulting product 122 has a film seam 134, in which case one color 32 stripe on one film 32 ( For example, the red stripe 84) (or visual distinguishing means) abuts or overlaps another color stripe (eg, yellow stripe 90 ') (or visual distinguishing means) on the other film 32'. To form a product 122 having a “checkerboard pattern”, ie, four alternating quadrants of red and yellow (or other visual distinction means). ing.

  FIGS. 17-19 of the MCP301 patent application specification show another film casting apparatus 136 used in the makeup method. Another film casting device 136 has film receiving means, such as a conventional metal casting belt 140, which has two rotating drums for receiving the film 138 cast thereon. 142 and 144. The rotating drums 142 and 144 rotate, thereby causing the casting belt 140 to move in the directions indicated by arrows J and K. A warming plate 148 may be positioned adjacent to the casting belt 140 to warm the casting belt 140 prior to casting the film on the casting belt 140. After casting the film on the casting belt 140, a cooling plate 150 is positioned adjacent to the casting belt 140 to cool the casting belt 140.

  Another film casting apparatus 136 further comprises film placement means, such as a reciprocating multi-chamber slit extruder 146, for placing the film 138 semi-continuously on the casting belt 138. As with the slit extruder 38 described above, the reciprocating slit extruder 146 includes an internal partition 152, which forms internal chambers 158, 160, 162, 164 that house and hold visually distinct coating materials 166, 168. 154, 156. A slit 170 is also provided, through which the coating material 166, 168 exits the chambers 158, 160, 162, 164 and flows onto the casting belt 140, thereby forming a striped film 138.

  The reciprocating slit extruder 146 provides supply means, such as feeder pipes 182 and 184, and coating materials from the chambers 158, 160, 162 and 164 for supplying the coating materials 166 and 168 to each of the chambers 158, 160, 162 and 164. It further comprises flow control means for controlling the flow from 166, 168, for example a slidable gate 180. The internal partitions 152, 154, 156 of the reciprocating slit extruder 146 have stripe control means, such as tapered blade edges, for controlling the flow of coating material 166, 168 exiting the chambers 158, 160, 162, 164, respectively. . One of the notable differences between the slit extruder 38 described above and the reciprocating slit extruder 146 of the present invention is that the reciprocating slit extruder 146 is indicated by the arrow M in FIG. 18 of the MCP301 patent application. It is connected to a conventional motor so as to reciprocate in the direction.

  Initially, feeder pipes 182 and 184 supply two colors, for example, red and yellow coating materials 166 and 168, respectively, to alternating chambers 158, 160, 162 and 164 of reciprocating slit extruder 146, respectively. Within the chambers 158, 160, 162, 164, the coating material 166, 168 becomes or is maintained as a liquid and fluid. The cooling plate 150 at least partially solidifies the coating materials 166 and 168 when in physical contact with the surface of the casting belt 140 to form a laterally striped film 138.

  After the coating materials 166, 168, the heating plate 148 and the cooling plate 150 achieve their desired temperatures, a portion 198 of the casting belt 140 is warmed by the heating plate 148 and then the rotating drums 142, 144. Is advanced to a position below the reciprocating slit extruder 146. Next, the slidable gate 180 is moved to a position where the slit 170 is opened to a desired thickness with respect to the striped film 138. While the rotating drums 142, 144 and the casting belt 140 are stationary, the coating material 166, 168 flows out of the chambers 158, 160, 162, 164, along the tapered blade edge (not shown), and slits. Flowing through 170 onto the heated portion 198 of the casting belt 140, the casting belt 140 maintains the coating material 166, 168 in a substantially liquid, fluid state for a short period of time.

  Simultaneously with the flow of the coating material 166, 168 onto the casting belt 140, the reciprocating slit extruder 146 is moved from the first position 194 to the second position 196 where it is temporarily stopped. As soon as the reciprocating slit extruder 146 reaches its second position 196, the slidable gate 180 is moved to the closed position, thereby closing the slit 170 and temporarily stopping the flow of the coating material 166, 168; As a result, the film segment 200 is formed. The film segment 200 has red stripes 172 and 176 and yellow stripes 174 and 178 that are alternately directed laterally, and straight and consistent color transitions 186, 188, and 190 are provided therebetween. .

  Next, the casting belt 140 is moved by the rotating drums 142 and 144 to move the film segment 200 so that the newly heated portion of the casting belt 140 is positioned below the reciprocating slit extruder 140. The first film segment 200 is cooled, while the second film segment is cast on the casting belt 140.

  If it is desired to cast the next film segment, the reciprocating slit extruder 146 is now in its second position 196 and the slidable gate with the casting belt 140 held stationary. 180 is again moved to a position where slit 170 is opened by an amount equal to the desired thickness for striped film 138. As the coating material 166, 168 flows out of the casting belt 140, the reciprocating slit extruder 146 is returned from its second position 196 to its first position 194 where it is temporarily stopped again. When the coating material 166, 168 is cast on the casting belt 140, the first edge of the new film segment meets and bonds with the second edge 204 of the first film segment 200. After the reciprocating slit extruder 146 returns to its first position 194, the slidable gate 180 is moved again to its closed position, thereby closing the slit 170 and temporarily flowing the coating material 166, 168. , So that a new film segment bonded to the first film segment 200 is formed.

  The above-described method steps are carried out continuously and repeatedly, resulting in a film casting process that produces a continuous ribbon of film 138 that is semi-continuous and laterally striped. The laterally striped film 138 is continuously removed from the casting belt 140 by a scraper or other device and then fed into the rotating die dressing device 102, thereby dressing the core 10 as described above. However, because another film casting device 136 produces a film 138 with stripes oriented in the lateral direction, the rotating dies 208, 208 'have recesses 210, 210', these recesses being The length is directed to align perpendicular to the direction of rotation of each rotating die. In addition, the core dispensing means used in conjunction therewith each core 10 end first in the nip between the dies 208, 208 ', i.e. the end 12 of each core 10 as the core 10 enters the nip. , 14 are oriented and dispensed simultaneously in contact with the converging films 138, 138 '.

  FIGS. 22-30 of the MCP301 U.S. Patent Application Specification relate to another makeup device for producing a film having a visually distinct portion, which device has another film casting device 136 as described above. ing. A two-color product is manufactured by feeding a film with a stripe in the transverse direction into a separate dressing device together with the core. And having a film seam located on a different reference surface than the reference surface.

  Another makeup device includes a conveyor system 220 that is paired with a series of horizontally oriented rollers 222 for supporting and carrying a laterally striped film 138. It has rollers 224, 226, 228. A core dispensing means 230 is positioned over the conveyor system 220 and the film 138 for the purpose of dispensing the core 10 onto the film 138 in the required orientation with respect to the color transitions 186, 188, 190. The core dispensing means 230 has slat feeders 234, 236 that direct the core as desired for correct positioning on the film 138. The core dispensing means 230 further includes a core positioning slat 238 and a core plunger 240 positioned on the positioning slat 238.

  The core 10 is sent from the hopper 232 through the slat feeders 234 and 236 to the positioning slat 238. Cores 10 ′, 10 ″, 10 ″ ″ are aligned with end 12 and end 14 abutted so that each core is moved along positioning slat 238 substantially continuously by the core located behind it. . When the core 10 'is pushed over the support rails 248, 250 so that it is no longer supported, and the position of the color transition 186 of the film 138 is located within the conjugate symmetry plane 18' of the core 10 ', the alignment means 242 issues a signal to the motor, which moves the plunger 240 up and down until the core 10 'contacts the film 138 and rests on it. When the plunger 240 reaches its uppermost position, the plunger stops briefly until the next core 10 "moves past the support rails 248, 250 contained in the positioning slats 238. As long as 10 is sent and passed through the positioning slats 238, it is repeated continuously.

  The starting portion of the conveyor system 220, that is, the portion located between another film casting device 136 and a short distance on the opposite side of the core positioning slat 238, consists of horizontally oriented rollers 222. ing. The film 138 is moved by the roller 222 oriented horizontally along this starting portion. The remaining portion of the conveyor system 220 located between the short distance located beyond the positioning slats 238 and the rotating dies 260, 262 is comprised of pairs of rollers 224, 226, 228. As schematically shown in FIG. 26 of the MCP301 patent application, the individual rollers of a series of pairs of rollers 224, 226, 228 are positioned with respect to successive pairs of rollers 224, 226, 228. Starting near 238, it gradually and sequentially turns upward from the horizontal plane in approximately 10 ° increments. Thus, as the film 138 approaches the rotary dies 260, 262, the film 138 is folded longitudinally around the core 10.

  The rotating dies 260, 262 rotate to cooperate with each other, thereby forming a nip therebetween, and the core 10 and film 138 are fed into this nip. Similarly, each of the dies 260, 262 has recesses 282, 284 arranged in a row on the surface of each die 260, 262 in a circumferential direction. Each of the recesses 282 and 284 has a raised rim that seals and cuts the bonded film 138 around the core 10, thereby filing the core 10. However, the rotary dies 260, 262 are directed to rotate in a horizontal plane, not in the vertical plane as in the rotary dies 112, 112 ', 208, 208' described above. However, when the cores 10 are fed into the nip, the film 138 is folded around these cores and partially bonded. Further, the partially-decorated core 10 is fed continuously, ie one by one, into the nip between the dies 260, 262.

  The shell can also be applied to the core using a vacuum forming device. Common assignee's co-pending U.S. patent application (application number not assigned; applicant case numbers: MCP301 and MCP316) discloses such a device.

  Referring to FIGS. 31-44 of the MCP301 patent application, a vacuum forming apparatus 292 includes a first plurality of individual porous surface plates 294, a first conveyor system 296, and a second conveyor system 298. ing. The first and second conveyor systems 296, 298 are arranged in series with each other to form a single path, and the porous platen 294 is moved semi-continuously along this single path. The first and second conveyor systems 296, 298 include a conventional vacuum source that applies a vacuum to each of the porous platens 294 while moving them along the vacuum forming apparatus.

  The vacuum forming apparatus 292 includes a second plurality of individual porous surface plates 304 and a third conveyor system 306 that moves the porous surface plate 304 along a second path indicated by an arrow GG in FIG. In addition. The third conveyor system 306 is positioned between the first conveyor system 296 and the second conveyor system 298.

  A rotation mechanism 308 is also positioned between the first conveyor system 296 and the second conveyor system 298. The rotating mechanism 308 simultaneously holds two of the surface plates, that is, the surface plate 294 and the surface plate 304 corresponding thereto, and rotates them together so that the surface plate 304 is first turned upside down. It will be positioned on the bottom.

  Each porous surface plate 294, 304 has at least one recess 310, 312 sized and configured to receive the core 10 to be dressed temporarily but closely.

  Using various combinations of surface plates and laterally and longitudinally striped films, multicolor cosmetic products having color transitions oriented in a wide variety of ways can be obtained. However, in a specific vacuum forming apparatus, the orientations of all the concave portions 310 and 312 of the surface plates 294 and 304 must be in the longitudinal direction, or, as a modification, all the concave portions 310 of the surface plates 294 and 304. , 312 must be lateral (or aligned with the direction of the stripes in the film).

  The vacuum forming device 292 further includes a first pair of rollers 338 and 340 to which a film 342 is attached. The first pair of rollers 338 and 340 are positioned proximate to the first conveyor system 296 such that the first film 342 is suspended over the first plurality of porous surface plates 294. ing. A second pair of rollers 344, 346 having a second film 348 deposited thereon is positioned proximate to the second conveyor system 298, and the second film 348 is also a first plurality of porous. It can be hung on the surface plate 294.

  The vacuum forming device 292 is provided in the vicinity of the first conveyor system 296, and the first film 342 is correctly positioned with respect to the core 10 positioned in the recess 310 of the porous surface plate 294. An alignment device 350 is further provided. A second alignment device 352 is provided in close proximity to the second conveyor system 298 and is located on the partially-decorated core 10 positioned within the recess 310 of another porous surface plate 294. In contrast, the second film 348 is correctly positioned.

  The vacuum forming device 292 further includes a first ring press 354 and a first film cutter 356 that are positioned proximate to the first conveyor system 296 and move in a reciprocating manner. In addition, a second ring press 358 and a second film cutter 360 are positioned proximate to the second conveyor system 298. Each of the first and second ring presses 354 and 358 has an open shape as viewed from above, for example, an O shape or an oval shape, and passages 362 and 364 are formed therethrough, respectively. . Each of the ring presses 354, 358 has contact edges 366, 368 configured to contact the first and second films 342, 348, respectively, without damaging them. The ring presses 354 and 358 are sized and shaped such that the contact edges 366 and 368 respectively enclose and surround the core 10.

  The first and second film cutters 356, 360 each have a recess 370, 372 sized and configured to receive a portion of the partially-decorated core 10 already coated with a film coating. Yes. The first film cutter 356 is oriented to face the porous platen 294 located below it, while the second film cutter 360 faces the porous platen 304 located below it. Oriented. The first and second film cutters 356, 360 also reciprocate.

  The first film 342 is attached to and stretched between a first pair of rollers 338, 340 such that one side of the first film 342 is connected to the first conveyor system 296 and a first plurality of rollers. The other side is positioned between the first ring press 354 and the first film cutter 356. Similarly, the second film 348 is attached to and stretched between a second pair of rollers 344 and 346 such that one side of the second film 348 is connected to the second conveyor system 298 and the second conveyor system 298. The other side is positioned between the second ring press 360 and the second film cutter 362.

  First of all, the first, second and third conveyor systems 296, 298, 306 are activated so that the porous surface plates 294, 304 are moved by arrows EE, FF, GG in FIG. 31 of the MCP301 patent application. Move each in the indicated direction. The first conveyor system 296 moves one of the porous surface plates 294 to a position just before the first station 378. The core 10 is placed in the recess of this porous surface plate 294 and held firmly in the recess 310 by the vacuum described above, and this vacuum is applied by the first vacuum source 300 to all other surfaces on the surface plate 294 and conveyor 298. Work continuously on things.

  Next, the surface plate 294 is moved to the first station 378 by the first conveyor system 296. The movement of the surface plate 294 temporarily stops when the first alignment device 350 confirms that the core 10 has been correctly positioned. While the surface plate 294 is momentarily stopped, warm air is blown into the first ring press 354, thereby softening the first film 342 into a formable state. Next, the first ring press 354 is moved, and the contact edge 366 of the first ring press 354 presses the first film 342 against the work surface 314 of the surface plate 294 to contact the upper half of the core 10.

  At the same time, the heated first film 342 is attracted to the core 10 by the above-described vacuum, so that it matches the shape of the upper half of the core 10. Thereafter, the first ring press 354 is retracted, and the surface plate 294 is moved to the second station 380, where it is temporarily stopped. While the surface plate 294 and the core 10 are temporarily stopped, the cool air is blown to the first film 342 and the core 10, thereby cooling the first film 342, so that the upper half of the core 10 is shaped. Mold to match.

  36-44 of the MCP301 patent application, after a sufficient time has passed to cool the first film 342 and mold it onto the core 10, the platen 294 and partially makeup The hung core 10 is moved a predetermined distance to the third station 382 of the vacuum forming device 292 by the first conveyor system 296, temporarily stopped there, and the partially hung core 10 is moved into the recess 370 and Align with the cutting edge 374 of the first film cutter 356. Moving the first film cutter 356 eventually causes the partially-decorated core 10 to be snugly received in the recess 370 and a tapered cutting edge 374 around the periphery of the partially-decorated core 10. The first film 342 is brought into close contact with the first film 342 and cut. Next, the first film cutter 356 is moved away from the surface plate 294.

  Next, the surface plate 294 and the partially-decorated core 10 are moved to the fourth or rotating station 384 of the vacuum forming device 292, again again temporarily stopped, and then partially-decorated. The core 10 is transferred to one of the surface plates 304 as follows. The third conveyor system 306 moves one of the platens 304 to a fixed position at the rotation station 384 and moves it against the platen 294 carrying the partially dressed core 10. Turn upside down. After the platen 294 is moved a predetermined distance and the partially-decorated core 10 is aligned with the inverted recess 312 of the platen 304, the first conveyor system 296 is partially veneered with the platen 294. The core 10 is temporarily stopped at the rotation station 384. Next, the surface plate 304 is moved toward the partially-decorated core 10, and finally the partially-decorated core 10 is held in both the recesses 310, 312 of the surface plates 294, 304. (As shown in FIGS. 31 and 40 of the MCP301 patent application). The vacuum applied to the porous surface plate 294 is interrupted, and the surface plates 294 and 304 are rotated with the partially covered core 10 positioned between them, and then the core 10 is held. The surface plate 294 is turned upside down, and the surface plate 304 is moved to a position where the left side is up. Now, the upside-down surface plate 294 is then moved away from the surface plate 304 with the right side up, and this is moved to one of the surface plates 304 that moves along the path indicated by the arrow GG in FIG. 31 of the MCP 301 patent application. Become. The platen 304 with the right side up is then moved onto the second conveyor system 298, which is a portion of the platen that moves along the path indicated by arrows EE, FF in FIG. 31 of the MCP301 patent application. It becomes one of 294. Next, a vacuum is applied to the partially dressed core 10, thereby bringing the partially dressed core 10 into the recess 310 of the platen 294 now moving on the second conveyor system 298. It is stored and held so that the uncovered portion of the core 10 that is partially covered is exposed.

  The platen 294 and the partially-decorated core 10 are moved to the fifth station 386 of the vacuum forming device 292 by the second conveyor system 298. The movement of the surface plate 294 temporarily stops when it is confirmed that the core 10 partially covered by the second alignment device 352 is correctly positioned with respect to the second film 248. While the surface plate 294 is momentarily stopped, warm air is blown into the second ring press 358, thereby softening the second film 348 into a formable state. Next, the second ring press 358 is moved so that the contact edge 368 of the second ring press 358 presses the second film 348 against the work surface 314 of the surface plate 294, and the partially-decorated core 10. Touch the exposed part.

  The heated second film 248 is attracted to the core 10 by the vacuum applied by the second vacuum source 302 so that the second film 248 conforms to the shape of the upper half of the core 10. After that, the second ring press 358 is retracted, and the surface plate 294 with the decorative core 10 held in the recess 10 is now moved to the sixth station 388, where it is temporarily stopped. Of note, as shown in FIG. 42 of the MCP 301 patent application, the second film 348 partially overlaps the cut edge of the first film 342 already applied to the core 10. . While the surface plate 294 and the core 10 are temporarily stopped, the cool air is blown to the second film 348 and the core 10, thereby cooling the second film 348 so that the shape matches the core 10. To form.

  After sufficient time has passed to cool the second film 348 and mold it onto the core 10, the surface plate 294 and the partially dressed core 10 are vacuum formed by the second conveyor system 298. The device 292 is moved a predetermined distance to the seventh station 390, where it is temporarily stopped, so that the decorated core 10 is aligned with the recess 372 and the cutting edge 376 of the second film cutter 360. When the second film cutter 360 is moved, the decorative core 10 is finally received in the recess 372 and the cutting edge 376 is exactly second around the periphery of the decorative core 10. 248 comes into contact with and cuts. Next, the second film cutter 360 is moved away from the surface plate 294.

  The platen 294 and the fully dressed core 10 are moved away from the seventh station 390 by the second conveyor system 298. After the platen 294 and the dressed core 10 pass over the seventh station 390, the vacuum applied to the platen 294 is stopped, thereby releasing the dressed product 404 from the recess 310.

  As a modification, a platen provided with concave portions each surrounded by a raised cut raised portion that can cleanly cut the first and second films 342 and 348 may be used. As a modification, instead of first placing the core 10 into the recess 310 of the first platen 294, the first film 342 is laid over the entire first platen, and then the hot air is applied to the first platen 294. The film 342 is sprayed to soften it into a formable state. Next, a vacuum is applied through the surface plate to draw the first film 342 into the recess and match it with the shape of the recess. Thereafter, the core 10 is disposed in the recess 310, and cold air is blown onto the surface plate 294, the first film 342, and the core to form the first film 342 in the same shape as the core 10. Next, the second film 348 is placed on the surface plate on the top of the core 10, and warm air is blown onto the second film 348 to soften it into a formable state. Next, another platen is moved to bring it into contact with the second film 348, pressing the second film 348 against the core 10 and the first platen 294, thereby causing the second film 348 to move to the core 10. Match the contour. Next, cold air is blown onto the second film 348, thereby forming the second film 348 on the core 10. Finally, the raised cut edge of the recess cuts both the first and second films 342, 348, thereby releasing the dressed product.

  It should be noted that the temperature ranges of hot and cold air and the vacuum pressure range belong to the ordinary knowledge of those skilled in the art.

  In embodiments in which the shell is applied to the core by spraying, dipping, dressing or molding methods, the shell is preferably applied to the core in the form of a flowable material. The flowable material may include dissolved, dispersed or molten components, and may further include a solvent or fluid carrier component that can be optionally removed during processing, for example, by drying. Whether or not is arbitrary. Regardless of the method by which the shell is applied, the finished shell, and thus the flowable material for making the shell, preferably comprises a film former. Optionally, the shell or readily soluble shell portion of the present invention may further comprise one or more thickeners and various adjuvants and / or excipients known in the art.

  Film formers known in the art are suitable for use in flowable materials. Examples of suitable film forming agents 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 former may be selected from cellulose acetate, B-type ammonio methacrylate copolymer, shellac, hydroxypropyl methylcellulose, polyethylene oxide and combinations thereof.

  Suitable film-forming water-soluble polymers include water-soluble vinyl polymers such as polyvinyl alcohol (PVA), water-soluble polycarbohydrates such as hydroxypropyl starch, hydroxyethyl starch, pullulan, methylethyl starch, carboxymethyl starch, alpha Starch, film-forming modified starch, water-swellable cellulose derivatives such as hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), methylcellulose (MC), hydroxyethylmethylcellulose (HEMC), hydroxybutylmethylcellulose (HBMC), hydroxy Ethyl ethyl cellulose (HEEC), hydroxyethyl hydroxypropyl methyl cellulose (HEMPMC), water-soluble copolymers such as Acrylic acid, methacrylate ester copolymers, polyvinyl alcohol, polyethylene glycol copolymers, polyethylene oxide, polyvinyl pyrrolidone copolymers and derivatives and combinations thereof.

  Suitable film-forming proteins may be natural or chemically modified, such as gelatin, whey protein, myofibrillar protein, coagulant protein such as albumin , Casein, casein salt, casein isolate, soy protein, soy protein isolate, zein and their polymers, derivatives and mixtures.

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

  Suitable film-forming pH-dependent polymers include intestinal 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 acetate phthalate, acetaldehyde dimethyl cellulose acetate, intestinal acrylate derivatives, such as polymers based on polymethacrylates, such as those marketed under the trade name EUDRAGIT S from Rohm Pharma Gesellshaft Mitt Beschlenktel Huffung Poly (methacrylic acid, methyl methacrylate) 1: 2, Rohm Pharma Gesellshaft Mitt Besch Examples include poly (methacrylic acid, methyl methacrylate) 1: 1 and the like, as well as derivatives, salts, copolymers and combinations thereof, commercially available from Lenckel Huffung under the trade name EUDRAGIT L.

  One suitable hydroxypropylmethylcellulose formulation used as a thermoplastic film-forming water soluble polymer is “HPMC 2910”, which has a degree of substitution of about 1.9 and a degree of hydroxypropyl molar substitution of 0.23. A cellulose ether containing from about 29% to about 30% methoxyl groups and from about 7% to about 12% hydroxylpropyl groups, based on the total weight of the formulation. HPMC 2910 is commercially available from Dow Chemical Company under the registered trade name “METHOCEL E. METHOCEL E5”, which is a grade of HPMC 2910 suitable for use in the present invention and is 20 ° C. in 2% aqueous solution. Having a viscosity of about 4-6 cps (4-6 millipascal seconds) as measured by an Ubbelohde viscometer. Similarly, METHOCEL E6 is another grade of HPMC 2910 suitable for use in the present invention and is about 5-7 cps (5-7 mm) as measured by a Ubbelohde viscometer in a 2% aqueous solution at 20 ° C. Pascal second). METHOCEL E15 is another grade of HPMC 2910 suitable for use in the present invention, having a viscosity of about 15,000 cps (15 millipascal second) as measured by a Ubbelohde viscometer in a 2% aqueous solution at 20 ° C. is doing. As used herein, the term “degree of substitution” refers to the average number of substituents attached to the anhydroglucose ring, and “hydroxypropyl molar substitution” refers to the number of hydroxypropyls per mol of hydroglucose. It means the number of moles.

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

  The term “modified starch” as used herein is modified by crosslinking, chemically modified for improved stability or performance optimization, or improved dissolution properties or performance optimization. Therefore, it means starch that has been physically modified. Examples of chemically modified starches are well known in the art and typically include chemical modifications to replace some of the hydroxy groups with either ester or ether groups. Processed starch. As used herein, crosslinking may occur in the modified starch when two hydroxy groups on adjacent starch molecules are chemically bonded. As used herein, the terms “pregelatinized starch” or “instantized starch” refer to modified starches (starch) that have been previously wetted and then dried to improve their cold water solubility. Suitable modified starches are available from several suppliers, such as A.I. E. Commercially available from Stanley Manufacturing Company and National Starch and Chemical Company. One suitable film-forming modified starch includes pregelatinized waxy corn derivative starches and their derivatives commercially available under the trade names “PURITY GUM” and “FILMSET” from National Starch and Chemical Company, Copolymers and mixtures are mentioned. Such waxy corn starch typically comprises from about 0% to about 18% amylose and from about 100% to about 88% amylopectin, based on the total weight of the starch.

  Another suitable film-forming modified starch includes hydroxypropylated starch, in which some of the hydroxy groups of the starch are etherified with hydroxypropyl groups, usually by treatment with propylene oxide. ing. An example of a suitable hydroxypropyl starch with film-forming properties is commercially available from Grain Processing Company under the trade name “PURE-COTE B790”.

  Tapioca dextrin suitable for use as a film-forming agent includes tapioca dextrin and its derivatives commercially available under the trade names “CRYSTAL GUM” or “K-4484” from National Starch and Chemical Company, such as National -Modified food starch derived from tapioca and its copolymers and mixtures marketed under the trade name "PURITY GUM 40" from Starch and Chemical Company.

  Thickeners known in the art are suitable for use in the flowable material of the present invention. Examples of such thickeners include hydrocolloids (also referred to herein as gelling polymers), clays, gelling starches and crystalline carbohydrates and their derivatives, copolymers and mixtures, It is not limited to these.

  Examples of hydrocolloids (also referred to herein as gelling polymers) include, for example, alginic acid, agar, guar gum, locust bean, carrageen, cod, gum arabic, tragacanth, pectin, xanthan, gellan, maltodextrin Galactomannan, pstran, laminarin, scleroglucan, gum arabic, inulin, pectin, welan, ramsan, zoolan, methylan, chitin, cyclodextrin, chitosan. Examples of suitable clays include smectites such as bentonite, kaolin, laponite, magnesium trisilicate, magnesium aluminum silicate, and derivatives and mixtures thereof. Examples of suitable gelling starches include, but are not limited to, acid hydrolytic starches, and derivatives and mixtures thereof. Additional suitable thickening hydrocolloids are used to make low moisture polymer solutions, such as a mixture of gelatin and other hydrocolloids with a maximum water content of about 30%, such as “gummi” dragees. Such mixtures are mentioned.

  Additional suitable thickeners include crystalline carbohydrates and the like and derivatives and combinations thereof. Suitable crystalline carbohydrates include monosaccharides and oligosaccharides. Among monosaccharides, in addition to aldohexoses, eg D and L isomers of allose, altrose, glucose, manose, gulose, idose, galactose, talose and ketohexose, eg D and L isomers of fructose and their hydrogenated analogues Solulose such as glucitol (sorbitol) and mannitol are preferred. Among the oligosaccharides, 1,2-disaccharide sucrose and trehalose, 1,4-disaccharide maltose, lactose, cellobiose, 1,6-disaccharide gentiobiose, melibiose and trisaccharide raffinose are isomaltulose and its hydrogenated analog Preferred with the isomerized form of sucrose known as isomalt. Other hydrogenated forms of reduced disaccharides such as maltose and lactose such as maltitol and lactitol are also preferred. In addition, hydrogenated forms of aldopentose, such as hydrogenated forms of D and L ribose, arabinose, xylose and lyxose and aldohexose, such as D and L erythrose and trerose are preferred, exemplified by xylitol and erythritol, respectively. .

  In one embodiment of the invention, the flowable material comprises gelatin as a gelling polymer. Gelatin is a natural thermogelling polymer. This is a tasteless colorless mixture of albinic class derived proteins that normally dissolve in warm water. Two types of gelatin, type A and type B, are usually used. Type A gelatin is a derivative of an acid-treated raw material. Type B gelatin is a derivative of an alkali-treated raw material. Gelatin moisture and bloom strength, composition and original gelatin treatment conditions determine its transition temperature between liquid and solid. Bloom is a standard measure of gelatin gel strength and is roughly correlated with molecular weight. Bloom is defined as the weight (in grams) required to move a 0.5 inch diameter plastic plunger 4 mm into a 6.67% gelatin gel held at 10 ° C. for 17 hours. In a preferred embodiment, the flowable material is an aqueous solution consisting of 20% 275 bloom pork skin gelatin, 20% 250 bloom bone gelatin and about 60% water.

  Suitable xanthan gums include C.I. P. Examples are those marketed by the Kelco Company under the trade names “KELTROL 1000”, “XANTROL 180” or “K9B310”.

  Suitable clays include sectites such as bentonite, kaolin, laponite, magnesium trisilicate, magnesium aluminum silicate, and derivatives and mixtures thereof.

  The term “acid hydrolytic starch” as used herein is a type of modified starch that results from treating a starch suspension with dilute acid at a temperature below the gelatinization temperature of the starch. During acid hydrolysis, the granular form of the starch is maintained in the starch suspension and is terminated by neutralization, filtration and drying once the desired degree of water dissolution is reached. As a result, the average molecular size of the starch polymer is reduced. Acid hydrolyzed starch (which is also referred to as “dilute boiling starch”) tends to exhibit a much lower high temperature viscosity and stronger gelling tendency on cooling than the same natural starch.

  As used herein, “gelled starch” refers to a starch that forms a gel when mixed with water and heated to a temperature sufficient to form a solution and cooled to a temperature below the gelling temperature of the starch. Is mentioned. Examples of gelled starches are acid hydrolyzed starches available under the trade name “PURE-SET B950”, for example from Grain Processing Corporation, eg available under the trade name “PURE-GEL B990” from Grain Processing Corporation. Examples include, but are not limited to, hydroxypropyl distarch phosphate and mixtures thereof.

  Suitable low melting point hydrophobic materials include fats, fatty acid esters, phospholipids and waxes. Examples of suitable fats include hydrogenated vegetable oils such as cocoa butter, hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenated sunflower oil and hydrogenated soybean oil, free fatty acids and salts thereof. Examples of suitable fatty acid esters include monoglycerides, diglycerides, triglycerides, glyceryl behenate, glyceryl palmitostearate, glyceryl monostearate, glyceryl tristearate, glyceryl trilaurate, glyceryl myristate, Glyco Wax-932, lauroyl Macrogol-32 glycerides and stearoyl macrogol-32 glycerides. Examples of suitable phospholipids (phospholipids) include phosphotidyl choline, phosphotidyl selenium, phosphotidyl enositol and phosphotidine acid. Examples of suitable waxes that are solid at room temperature include carnauba wax, whale wax, beeswax, candelilla wax, shellac wax, microcrystalline wax and paraffin wax, fat-containing mixtures such as chocolate and the like.

  Suitable amorphous carbohydrates include amorphous sugars such as polydextrose, starch hydrolysates such as glucose syrup, corn syrup, high fructose corn syrup, amorphous sugar alcohols such as maltitol syrup.

  Suitable solvents optionally used as components of the flowable material include water, polar organic solvents such as methanol, ethanol, isopropanol, acetone and the like, nonpolar organic solvents such as methylene chloride and mixtures thereof.

  A flowable material for making a shell by spraying, dipping, dressing or molding may optionally include an auxiliary agent or excipient that accounts for up to about 30% based on the weight of the flowable material. Examples of suitable adjuvants or excipients include plasticizers, anti-sticking agents, wetting agents, surfactants, defoaming agents, coloring agents, flavoring agents, sweeteners, opacifiers and the like. Suitable plasticizers for making cores, shells or parts thereof by molding include polyethylene glycol, glycerin, sorbitol, triethyl citrate, tributyl citrate, dibutyl sebacate, vegetable oils such as castor oil, surfactants such as polysorbate Sodium laurel sulfate, dioctyl sodium sulfosuccinate, propylene glycol, glycerol monoacetate, glycerol diacetate, glycerol triacetate, natural gum, triacetin, acetyltributyl citrate, diethyl oxalate, diethyl malate, diethyl fumarate, diethyl malonate , Dioctyl phthalate, dibutyl succinate, glycerol ribribylate, hydrogenated castor oil, fatty acids, substituted triglycerides, glycerides, etc. And mixtures thereof. In one embodiment, the plasticizer is triethyl citrate. In certain embodiments, the shell is substantially free of plasticizer, i.e., the plasticizer content is about 1% or less, such as about 0.01% or less.

  The opening may be provided in the shell in some way. In the pharmaceutical and other technical fields, various methods for forming openings or holes in a coating are known, and any of these can be used. As will be appreciated by those skilled in the art, various methods of forming the opening are suitable for combination with various methods of manufacturing dosage forms and / or various methods of attaching a shell thereto. The method of forming the opening will also depend on the properties and composition of the shell and, if provided, the properties and composition of the outer coating. To some extent, depending on the method used to adhere the shell to the core, the opening can be formed in the shell of the present invention in any of several different steps of the method. In the case of an embodiment in which the shell is attached to the core by a decorative method, during the production of the casting film, after the casting film is formed but before the film is attached to the core, during the application of the film to the core Alternatively, the opening can be formed after the film is deposited on the core. In the case of the embodiment in which the shell is applied to the core by dipping, transfer, spraying or molding, the opening is formed in the shell material during or after the shell is applied to the core. be able to.

  For example, to form an opening, shell evaporation, sand blasting, grinding, arc evaporation, dielectric breakdown, ion beam sputtering, ultrasonic abrasive machining, cavitation fluid jet or laser evaporation by erosion, melting or water jet erosion can be used. The ablative method used can be used. Mechanical methods, such as punching, drilling, slitting, drilling, drilling, dipping after masking, or vacuum removal can be used to form the openings. To form the opening, chemical means such as acid reaction, base reaction, solvent washing, acid etching with masking, photoetching with masking, anisotropic wet chemical etching, isotropic wet chemical etching, non-wetting Hydrophobic or burn-in mask effects can be used, for example, by printing dots of material on a roller. Methods of applying heat to form the opening, such as melting with a high temperature iron, laser processing, arc evaporation, ultrasonic melting or cavitation, microwave heating, high energy methods such as plasma methods, infrared selective polymer curing, Alternatively, induction heating using an iron additive can be used. Finally, an additive method is used to form the opening, such as painting, dipping, solvent washing, woven fabric, wrapping the core with a strand or ribbon, masking material, and removing the masking material by solvent or hydrophobic incompatibility Spray coating, spraying through a masking sheet, the use of ribbon-like materials or the deposition of yarns or webs in a shell, or mats may be used.

  In one embodiment of the present invention, as described above, the shell is attached to the core by thermal cycle molding, and the opening is formed through one or more protrusions provided on the inner surface of at least one of the mold assemblies. To do. Each protrusion, adjusted to the desired dimensional shape, masks a narrow location on the underlying core, leaving an opening in the shell at the location of the protrusion. The mold assembly may have a plurality of protrusions that form a plurality of corresponding openings in the shell. Protrusions may be placed on only one part of the mold assembly, for example on the inner surface of the upper mold assembly, or only partly, i.e. in a quarter of the inner surface of one mold assembly as desired. Good. Or you may arrange | position a protrusion so that a pattern, a symbol, a word, etc. may be formed in a shell.

  In another embodiment of the invention, a visually uniform film or co-assignment of common assignees as described in US Pat. Nos. 5,146,730 and 5,459,983. The shell is attached to the core with a cosmetic hook using a film having a visually distinct portion as described in US patent application (No application number assigned; Applicant Case Number: MCP301 and MCP316) . In any case, the cast film used in the makeup application process is perforated before, during or after the application of the application method.

  In one embodiment where the shell is attached to the core by a decorative hook, using a casting surface with a suitable shape or surface pattern, such as a chilled film forming roll (the outer surface 36 of the casting drum 34 of the MCP301 patent application). The openings may be formed during the formation of the cast film by a mechanical method of casting the openings into the film. Suitable surface patterns include surfaces with protrusions that are so high that the casting film does not surround the protrusions, and thus the cooled film will later have openings. FIG. 7 shows such a forming roll with a surface 1020 with a suitable surface pattern that creates voids, slits or open areas in the film. The film reaches the die roll 1040 where the opening is already provided.

  In a second embodiment, where the shell is attached to the core by a decorative hook, after forming the cast film and before its application to the core, the opening is mechanically perforated or punched into the cast film. Also good. For example, FIGS. 8 and 9 show a punching device 1030 provided between the forming roll 1010 and the die roll 1040. The perforating apparatus perforates or punches openings in the formed film. In another such embodiment utilizing a vacuum forming method in which the shell is applied to the core by a decorative hook, the film is formed into a vacuum formed plate (ie, a plurality of porous surface plates 294 as described in the MCP301 patent application). ) Forming the core into a cavity shape for placement in the recess, and then forming the opening before inserting the core. In one such specific embodiment, the shaped film with the recesses is removed from the forming plate (ie, the plurality of porous surface plates 294) and travels to the perforator. In another specific embodiment, the shaped film with recesses remains in contact with the forming plate (ie, the plurality of porous surface plates 294), and the opening is appropriately abraded prior to core insertion. The film is formed by the active method. One ablative method that is particularly suitable for this application is to “bake” the openings into the formed film with the desired shape, size and pattern using a laser.

  Another particular embodiment is shown in FIG. 10 in which the opening is formed in the shell prior to its application to the core by means of a decorative hook. This method uses a capsule shell (gelatin, starch, cellulose ether, or other suitable material known in the art and described herein) that lays the core of the dosage form. The capsule shell is formed in two portions 1210 by dipping a steel pin in a shell material solution in fluid form as is known in the art. The shell material is then solidified on the steel pin. Prior to removing the solidified capsule shell from the forming pin, the openings are formed in the capsule shell by baking to the desired size, shape and pattern using suitable means, such as a laser. Next, for example, half of the capsule shell is used in U.S. Pat. Nos. 5,415,868, 6,126,767, 5,464,631, and 5,460,824. No. 5,317,849, No. 5,511,361, No. 5,609,010, No. 5,795,588, No. 6,080,426 As disclosed in International Publication No. WO 97/37629, the capsule shell 1210 is applied to the core 1220 by shrink fitting onto a compressed tablet as known in the art. Dosage form 1230 is manufactured.

  In the third embodiment, the opening may be formed in the shell while the shell is attached to the core. In such embodiments, the shell can be applied to the core by any suitable method, such as dressing, dipping, transferring, spraying or molding.

  For example, in one embodiment in which the shell is applied by a decorative hook, the surface of the rotating die 1040 may have voids, slits or open areas in the shell by drilling, punching or punching when casting the cast film on the core. It has a suitable surface pattern to be formed.

  An example of a method for forming an opening in a shell during the deposition of the shell onto the core by the dipping method is shown in FIG. In this method, during immersion, the core is held by a holder 1310 with one or more, preferably a plurality of masking pins 1320, which hold the core and define areas that are not covered by the shell. Mask it. The shape, size, and arrangement state of the masking pin 1320 determine the shape, size, and pattern of the opening provided in the shell.

  Another example of a method for forming an opening in a shell during the application of the shell to the core by an immersion method is shown in FIG. In this case, the core is immersed in the foam shell material 1420. Bubbles in the foam will result in a finished solidified shell opening 1430. In a similar embodiment, the core is simultaneously formed in the shell coating by dipping the solid wax in the film-forming shell material into a non-pareil suspension. A non-pareil is applied to the core along with the shell material. Next, the shell material is solidified. Next, heat is applied to melt the non-pareils in the wax, and the wax will later be formed in the shell with non-pareil dimensions. In another embodiment, the core is immersed in a fluid material that reacts and solidifies upon activation by ultraviolet light, light or heat, such as a polymer. In this method, a highly specific or targeted energy source, such as a laser, is used to selectively solidify the portion of the shell that is intended to remain on the tablet. After this treatment, the remaining fluid is drained or washed away. In a similar embodiment, the core surface may be coated with powder, after which the powder can be partially selectively melted using a laser, and later the powder where the opening did not dissolve in the desired location. Remains. The rest of the material remains in powder form and is dropped.

  An example of a preferred method of forming openings in the shell during the deposition of the shell onto the core by a transfer method similar to printing is shown in FIG. The surface of the transfer plate 1510 has a sculpture image having peaks and valleys. A shell material is applied to the surface of the transfer plate 1510 in the form of a fluid, and the shell material selectively fills the valleys but does not cover the peaks. A “print pad” applicator 1520 picks up shell material from the transfer plate 1510 in a pattern of images and deposits or transfers the shell material in a desired pattern onto the surface of the core. The transfer plate provides the advantage that the pattern can be applied indirectly to the dosage form. Another suitable method of selectively applying the shell material to the core is by powder coating, such as electrostatic coating as disclosed in WO 01/57144. Another suitable method for selectively applying the shell material to the core is by ink jet printing as described in such patent literature.

  In the fourth embodiment, the opening is preferably formed in the shell after the shell is attached to the core. One such embodiment is shown in FIG. In this case, the core 1610 has a protrusion 1620 and the shell 1630 is applied to surround the entire core, and then the protrusion is ground and removed, for example, by a pair of rotating grinding wheels 1640 to expose the uncoated core. (Ie, the opening 1650 is formed). In yet another example, the shell is applied to the core as a multi-layer of film, for example, with a decorative hook. Next, the region of the film is selectively burned off with a laser to form an opening having a desired pattern and any desired depth on the shell surface. In another such embodiment, the shell is deposited using a sintering process. A powdered shell material is applied to the core surface, and then heat is applied to partially but not completely melt the powder particles to form a porous shell surface.

  Other preferred methods of forming openings in the shell after deposition of the shell to the core use mechanical methods such as stamping, drilling, drilling, hot knife, melting. One such mechanical method is shown in FIG. FIG. 15A illustrates the use of a hot pin or knife that melts and / or drills an opening in the shell. FIG. 15B shows a method of drilling the opening into the shell. The fused or perforated tip shown in FIG. 15 may form the surface (or “working end”) of the punching mechanism or roller mechanism.

  Another suitable mechanical method includes punching the opening into the molded shell as shown in FIG. In this particular embodiment, the stamped shell material remains in the cavity formed by the punch, but a portion of the core surface is exposed as part of the interior of the cavity. Other methods for forming openings in the shell after deposition of the shell onto the core include ablative methods such as sand / grit blasting, grinding, arc evaporation, dielectric breakdown, ion beam sputtering, ultrasonic abrasive machining, cavitation Fluid jet or laser evaporation, chemical methods, selectively applied acid or base reactions, chemical photo-etching, thermal methods such as using hot pins, laser processing, arc evaporation, ultrasonic melting or cavitation, microwave heating, etc. It is done. With these methods, the shell material can be selectively removed after first masking the areas of the shell that are intended to remain intact, but this is optional.

  As will be appreciated, there are many more suitable methods for forming openings in the shell of the present invention, such methods not specifically illustrated herein, but ablative, mechanical, chemical Examples include, but are not limited to, methods that fall within a broad category of thermal or addition.

  For example, the film sheet may be subjected to a mechanical process such as punching, drilling, slitting, drilling or drilling after it leaves the film casting apparatus but before it is fed into the dressing apparatus. The above opening can be formed. For example, slits can be formed in cast or extruded films by ablative methods, mechanical methods, chemical methods, thermal methods or additive methods.

  The following non-limiting examples further illustrate the present invention.

Example
Part A: Preparation of compressed tablet core A compressed tablet core containing 500 mg of acetaminophen as the active ingredient is made from the following ingredients.
Ingredient mg / core -Activities and excipients Acetaminophen, USP 500.0
Powdered cellulose, NF 40.0
Pregelatinized starch, NF 10.0
Starch glycolate sodium ester, NF 10.0
II. -Granulating agent Starch, NF 40.0
Purified water: USP Sufficient amount III. -Dry additive Magnesium stearate, NF 3.2
Total amount 603.2

  Part I activity and excipients are weighed in the proportions provided and added to the bowl of a fluid bed granulator, such as an AEROMATIC brand granulator. A granulating agent (Part II) is prepared by adding purified water to a processing tank containing about 15 grams of water per 1 gram of starch NF. The starch is mixed slowly and the mixture is heated until the temperature reaches about 82 ° C to about 84 ° C. The granulating agent is sprayed onto the powder while the Part I ingredients are in a heated fluidized state and the inlet air temperature is from about 75 ° C to about 85 ° C. After all of the granulation agent has been sprayed, the granulated powder is dried to a moisture state of about 1.4% to 1.9% as determined by loss on drying using, for example, a COMPUTRAC brand analyzer. The dried granulate is then screened using, for example, GLATT QUICK brand sieve stator number 3, screen number 1.5 mm, 1,000 RPM. The screened dry granulation is then blended with the Part III powder using a suitable mixer, such as a twin shell, ribbon or planetary mixer. The finished blend is then loaded into the hopper of a rotating tablet machine and compressed into a tablet using a round, deep concave tool having a diameter of 7/16 inch (11.11 mm). The resulting tablet core has an average thickness of about 0.3 inches (7.62 mm). The resulting tablet core has an average hardness of about 10 Kp. The average weight of the tablet core is about 603.2 mg.

Part B: Preparation of shell material as casting film for dressing First cast film based on gelatin for dressing the core of Part A (thickness is about 0.02 inch (0 508 mm) is prepared from the following ingredients:
Gelatin (150 bloom) 45%
Glycerin 6% Sorbitol 2%
Water 45%
Colorant 2%

  The colorant is mixed with water to form a uniform solution. Add the dry gelatin granules to the colorant solution and mix for about 1 minute to completely wet the gelatin granules. The gelatin slurry is placed in a water bath and heated to 55 ° C. to melt and decompose the gelatin. Next, glycerin and sorbitol are mixed into this. The final solution is degassed by maintaining at 55 ° C. for about 10 hours. The solution is then agitated at low speed until uniform (about 5-15 minutes) and transferred to a jacketed feed tank equipped with a propeller-type electric mixer. During use, the gelatin solution is kept at 55 ° C. with continuous mixing to form a cast film for making the first shell portion of the present invention. The gelatin solution is then poured onto a casting drum (molding roll 1010) and the surface of the casting drum is cooled to a temperature of about 25 ° C. to form a casting film.

  A cast film having substantially the same thickness but mainly comprising a second gelatin of the second color is prepared by the method described above.

  Next, the cooled first cast film is supplied between two rolls constituting the perforating apparatus (1030), and the perforating apparatus punches and forms an opening in the formed film. The openings are round and 750 microns in diameter, with seven such openings arranged in a group and one central opening surrounded by six peripheral openings. A group of seven openings is provided in the film at intervals corresponding to the cavities of the die roll 1040. A cooled second cast film is fed between two rolls having a smooth surface, thus leaving a continuous state without openings.

  The first perforated film and the second non-perforated film are then fed between the die roll 1040 of the dressing device together with the tablet core of Part A. The first and second films are pressed in contact with the tablet core and each other at an interface that forms a seam around the belly band of the compressed tablet core. The resulting dosage form has a first color first shell portion provided with an opening and a second color second shell portion substantially free of an opening.

It is a figure which shows the dosage form of this invention. It is a figure which shows the dosage form of this invention. It is a figure which shows the dosage form of this invention. It is a figure which shows the dosage form of this invention. It is a figure which shows the dosage form of this invention. It is a figure which shows the various opening part of this invention. It is a figure which shows the method of manufacturing the dosage form of this invention using a makeup | decoration method. FIG. 3 shows another method for producing the dosage form of the present invention using a makeup method. FIG. 6 shows yet another method for producing the dosage form of the present invention using a makeup method. It is a figure which shows the method of manufacturing the dosage form of this invention with the capsule with an opening part by a makeup | decoration method. It is a figure which shows the method of manufacturing the dosage form of this invention using an immersion method. FIG. 6 shows another method of manufacturing the dosage form of the present invention using the dipping method. It is a figure which shows the method of manufacturing the dosage form of this invention using a transcription | transfer method. FIG. 4 is a diagram showing a method of making an opening in a shell of a dosage form of the present invention using a grinding means. FIG. 6 shows a method for making an opening in the shell of the dosage form of the present invention using a hot pin. FIG. 3 is a diagram showing a method of making an opening in a shell of a dosage form of the present invention using a punching means.

Claims (31)

  A dosage form comprising at least one active ingredient having a core and a shell surrounding at least a portion of the core, the density of the core being at least about 0.9 g / cc, the shell having one or more openings A dosage form characterized in that the shell is easily dissolved in the gastrointestinal fluid and the dosage form allows an immediate release of at least one active ingredient upon contact with the liquid medium.   The dosage form according to claim 1, wherein the shell has a plurality of openings.   The dosage form of claim 1, wherein the one or more openings are in contact with the core.   The dosage form according to claim 2, wherein the plurality of openings are in contact with the core.   The dosage form of claim 1, wherein the core comprises at least one active ingredient.   The dosage form of claim 1, wherein the shell comprises at least one active ingredient.   7. Dosage form according to claim 5 or 6, characterized in that the dosage form allows an immediate release of at least one active ingredient contained in the core.   The dosage form of claim 1, wherein the core comprises a compressed tablet. The hardness of the compressed tablets, the dosage form according to claim 1, characterized in that about 2 to about 30 kp / cm ^2.   The dosage form of claim 1, wherein the shell is applied to the core by dipping.   The dosage form of claim 1, wherein the shell is applied to the core by molding.   The dosage form according to claim 1, wherein the shell is applied to the core by a decorative hook.   The dosage form of claim 1, further comprising an outer coating covering at least a portion of the shell.   13. The dosage form according to claim 12, wherein the outer coating comprises at least one active ingredient.   The dosage form of claim 12, wherein the outer coating covers at least a portion of the opening.   13. The dosage form of claim 12, wherein the outer coating dissolves easily in gastrointestinal fluid.   The dosage form according to claim 1, wherein the shell comprises a film-forming agent.   18. The dosage form according to claim 17, wherein the film forming agent comprises gelatin.   The dosage form of claim 1, wherein the average thickness of the shell is from about 100 to about 400 microns.   The dosage form of claim 1, wherein the relative standard deviation of the shell thickness of the dosage form is about 30% or less.   The dosage form of claim 1, wherein the shell comprises no more than about 50% crystalline carbohydrates.   The dosage form according to claim 1, wherein the dosage form is substantially free of a charge control agent.   The dosage form of claim 1, wherein the shell comprises a first shell portion and a second shell portion that are compositionally different from each other.   24. The dosage form of claim 23, wherein the first shell portion and the second shell portion are different in appearance.   The dosage form of claim 23, wherein the first shell portion and the second shell portion are joined together at an interface.   24. A dosage form according to claim 23, wherein the first shell portion is provided with one or more openings, and the second shell portion is substantially free of openings.   The dosage form of claim 23, wherein the first and second shell portions are in direct contact with the core.   24. A dosage form according to claim 1 or 23, wherein the core is substantially surrounded by a subcoating.   The dosage form of claim 28, wherein the first and second shell portions are in direct contact with the sub-coating.   24. The dosage form of claim 1 or 23, wherein the diameter or width of the one or more openings is from about 200 to about 2,000 microns. A dosage form comprising a core with an outer surface and a shell with an outer surface and an inner surface, wherein at least a portion of the shell is positioned substantially conformally on the outer surface of the core. Surrounding the core, at least a portion of the shell is provided with one or more openings, one or more of the openings having a diameter or width of about 200 to about 2,000 microns and at least one of the shell The part dissolves easily in the gastrointestinal fluid, the average thickness of the shell is from about 100 to about 400 microns, the shell contains no more than about 50% crystalline sugar, and the dosage form is substantially charge controlled A dosage form characterized in that it contains no agent and allows the immediate release of at least one active ingredient upon contact with a liquid medium.

Images