CN1684671A - Immediate release dosage form comprising shell having openings therein - Google Patents

Abstract

The invention provides an immediate release dosage form having a solid core and a shell readily soluble in gastrointestinal fluids. The dosage form also comprises one or more openings in the shell.

Description

The immediate release dosage form that includes the shell of opening

The cross-reference of related application

The present patent application is the PCT/US02/31129 of JIUYUE in 2002 submission on the 28th; The PCT/US02/31117 of JIUYUE in 2002 submission on the 28th; The PCT/US02/31062 of JIUYUE in 2002 submission on the 28th; The PCT/US02/31024 of JIUYUE in 2002 submission on the 28th; The part continuation application of the PCT of the PCT/US02/31163 that submitted in 28th with JIUYUE in 2002.Above-mentioned each PCT application is the USSN09/966 of calendar year 2001 JIUYUE submission on the 28th, 939; The USSN09/966 of calendar year 2001 JIUYUE submission on the 28th, 509; The USSN 09/967,414 of calendar year 2001 JIUYUE submission on the 28th; The USSN09/966 of calendar year 2001 JIUYUE submission on the 28th, 497; The calendar year 2001 USSN09/967 that submits to of JIUYUE 28 days, 414 and the USSN09/966 that submitted in 28th of (calendar year 2001) JIUYUE, 450 part continuation application fits into this paper as a reference in all above-mentioned applications.

Technical field

The present invention relates to provide the dosage form that active component is promptly discharged.This dosage form comprises the solid piece heart and the shell that surrounds the sheet heart.This shell has one or more openings.

Technical background

Known some contain the dosage form of hole or relief.For example, " osmotic pumps " dosage form that is used to use pharmacy activity component known in the art.They comprise the semipermeable wall round storage place that contains medicine usually.This wall is permeable to the process of external liquid, is impervious to the process of medicine, and has the passage of the semipermeable wall of passing to be used for transmitting medicine from osmosis system.For example, U.S. Patent No. 4,576,604 disclose the permeability apparatus that comprises the medicine compartment, and this compartment is surrounded by channelled wall (coating).What this wall can comprise medicine promptly releases dosage, and interior medicine compartment can comprise the sustained-release dosage of medicine.

U.S. Patent No. 4,449,983 disclose another permeability apparatus, and this device comprises two two kinds of medicines of settling respectively that separately discharge from device.This device comprises two compartments, and one of every kind of medicine is separated by spacer.Each compartment has the hole with the device external communications.

U.S. Patent No. 3,823,816 disclose a kind of water miscible packing, and its form is the hard-shell capsule of filling powder, granule or the like.This capsule is foraminous, and the hole is covered by water solublity barrier thin film.This thin film is than capsule water solublity more, so when packing contact water, this thin film come the exposed content thing to dissolve and/or discharge by the hole, and capsule is complete than the first dissolving of capsule.

U.S. Patent No. 5,256,444 relate to the dosage form that contains the intaglio of one or more restricted areas on the surface.This dosage form is coated with emulsion polymer spraying bag.When placing environment for use, discharge on the latex coating recyclability ground in restricted area, makes the sheet heart tablet of coating quilt have predetermined hole, and this hole is exposed in the environment for use separating part on sheet heart surface.

A kind of known method of dosage form of preparation gelatine glaze is undertaken by the coating process, and wherein two separating films being made by the gelatin material are applied to the opposite side of tablet by a pair of rotation mould, as U.S. Patent No. 5,146,730 and 5,459,983 is disclosed.As U.S. Patent No. 5,146,730 and 5,459, the 983 disclosed thin film formulations that are used to produce gelcaps and geltabs by coating method preparation comprise the gelatin goods based on water usually, these goods have an appointment 45% gelatin and about 9% plasticizer (glycerol and/or sorbitol) (by weight).Glycerol and sorbitol can be used as the independent use of plasticizer or unite use mutually.In addition, other sugar and polyol can be used as additive and plasticizer.If anti-refractive gelatine glaze medicinal tablet is the finished product that needs, then plasticizer and the gelatin ratio in gelatin formulation should be in about 1: 5 scope.

Another kind is gone up the principle that the conventional method that forms shell (or coating) is WO 01/57144 a disclosed use electrostatic precipitation formation coating at the sheet heart (or substrate).Preferably, at least one mixes one or more " charge control agents " in the sheet heart or the shell, as metal salicylate salt, and for example zinc salicylate, magnesium salicylate and calcium salicylate; Quaternary amine, benzalkonium chloride, benzethonium chloride, Tetradonium Bromide (cetyl ammonium bromide); With cyclodextrin and adduct thereof, their amount accounts for about 1% to about 10% of shell weight.

Now the applicant to find a kind of can be release dosage form with what make around the shell of the sheet heart by the solid piece heart, wherein the density of the sheet heart is at least about 0.9g/cc.This shell comprises one or more openings and is dissolved in the gastro-intestinal Fluid easily.It is preferable that this shell is applied to the sheet heart by coating method.

Brief summary of the invention

The invention provides the dosage form that comprises at least a active component, wherein comprise the sheet heart and with around the shell of the sheet heart, wherein the density of the sheet heart is at least about 0.9g/cc, shell comprises one or more openings, shell is dissolved in the gastro-intestinal Fluid easily, and dosage form provides at least a active component of releasing when contact has the dosage form of liquid medium.

The present invention also provides a kind of sheet heart and the dosage form that the shell of outer surface and inner surface is arranged that includes outer surface, wherein at least a portion shell holds the sheet heart and makes the inner surface of shell reside on the outer surface of the sheet heart unanimous on the wholely, at least a portion shell comprises one or more openings, about 200 microns to about 2000 microns of the diameter of one or more openings or width, at least a portion shell is dissolved in the gastro-intestinal Fluid easily, about 100 microns to about 400 microns of the scope of shell average thickness, shell comprises the crystallizable sugar at least about 50%, this dosage form does not have charge control agent substantially, and dosage form provides at least a active component of releasing when contact has the dosage form of liquid medium.

Brief description of drawings

Fig. 1-5 shows according to dosage form of the present invention.

Fig. 6 shows according to various openings of the present invention.

Fig. 7 shows and uses coating method to produce the method for dosage form of the present invention.

Fig. 8 shows and uses coating method to produce the another kind of method of dosage form of the present invention.

Fig. 9 shows and uses coating method to produce the further method of dosage form of the present invention.

Figure 10 shows the method for coating method with the capsule manufacture dosage form of the present invention that contains opening of using.

Figure 11 shows and uses dipping method to produce the method for dosage form of the present invention.

Figure 12 shows and uses dipping method to produce the another kind of method of dosage form of the present invention.

Figure 13 shows and uses conversion method to produce the method for dosage form of the present invention.

Figure 14 shows that the use milling device prepares the method for dosage form shell of the present invention upper shed.

Figure 15 shows that the hot pin of use prepares the method for dosage form shell of the present invention upper shed.

Figure 16 shows that the use decompressor prepares the method for dosage form shell of the present invention upper shed.

The detailed description of invention

Term used herein " formulation " can be used for design and comprises some composition of concrete scheduled volume (dosage), any solid, semisolid or the fluid composition that transmit such as the active component of hereinafter definition. Suitable formulation can be drug delivery system pharmaceutically, comprise Orally administered, contain that clothes are used, rectal administration, part or mucous membrane transmission, or subcutaneous implantation, or other implant transmission systems; Or for the composition that transmits mineral matter, vitamin and other nutriment, oral care formulations, edible spices etc. It is better that formulation of the present invention is considered to solid, but they can comprise liquid or semi-solid components. In a better especially embodiment, this formulation is to transmit the oral delivery system of active constituents of medicine in the human gastrointestinal tract.

Being used for suitable active component of the present invention comprises such as medicine, mineral matter, vitamin or other nutrition qualities, oral care formulations, edible spices and their mixture. Suitable medicine comprises that analgesia medicine, antiphlogistic, Antiarthritic medicine, arcotic, anti-histamine medicine, antitussive, antibiotic, anti-infectious agent, disease-resistant poison, anti-coagulants, antidepressants, antidiabetic, town tell medicine, anti-inflatable medicine, antimycotic medicine, antispasmodic, appetite inhibitor, bronchodilators, cardiovascular preparation, central nervous system preparation, central nervous system excitant, alleviate congested agent, oral contraceptive, diuretics, expectorant, gastrointestinal agent, antimigraine preparation, the sick product of cinetosis, mucus dissolving medicine, muscle lax agent, osteoporosis preparation, dimethyl silicone polymer, breathing preparation, help the preparation of sleeping, urethra preparation and their mixture.

Suitable oral care formulations comprises breath freshener, brightener for tooth, antimicrobial, dental mineralization agent, dental caries inhibitor, local anesthetic, mucosa protective agent or the like.

Suitable flavorant comprises menthol, Oleum menthae, mint flavouring, fruit flavor, chocolate, Rhizoma et radix valerianae, bubble gum flavor, coffee flavour, liqueur spice and compositions or the like.

The example of suitable gastrointestinal agent comprises antacid such as calcium carbonate, magnesium hydroxide, magnesium oxide, magnesium carbonate, aluminium hydroxide, sodium bicarbonate, dihydroxy aluminum sodium carbonate; Zest laxative such as bisacodyl, Sacred bark, dihydro-anthraquinone, Folium Sennae, phenolphthalein, Aloe, Oleum Ricini, castor oil acid and deoxycholic acid and their mixture; Bisfentidine such as famotidine, ranitidine, cimetidine, nizatidine; Proton pump inhibitor such as omeprazole or lansoprazole; Gastrointestinal tract cell protective agent such as sucralfate and misoprostol; Gastrointestinal tract is actuated medicine such as general card Billy, at antibiotic such as clarithromycin, amoxicillin, tetracycline and the metronidazole of helicobacter pylori; Diarrhea such as diphenoxylate and loperamide; The sugar pyrroles; Anti-emetic such as ondansetron; Analgesic such as U.S. salad are bright.

In one embodiment of the invention, active component can be selected from that bisacodyl, famotidine, ranitidine, cimetidine, general card Billy, diphenoxylate, loperamide, Lactose enzyme, U.S. salad are bright, bismuth, antacid and pharmaceutically acceptable salt, ester, isomer and their mixture.

In another embodiment, active component can be selected from analgesic, antiinflammatory and antipyretic, as nonsteroidal anti inflammatory medicine (NSAIDs), comprises propanoic derivatives, as ibuprofen, naproxen, ketoprofen or the like; Acetic acid derivative is as indomethacin, diclofenac, sulindac, Tolmetin or the like; Fenamic acid derivative, as mefenamic acid, meclofenamic acid, flufenamic acid or the like; The xenyl carboxylic acid derivates, as diflunisal, flufenisal, or the like; With former times health class preparation, as piroxicam, sudoxicam, isoxicam, meloxicam or the like.In a preferable embodiment, active component can be selected from propanoic derivatives NSAID, as ibuprofen, naproxen, flurbiprofen, fenbufen, fenoprofen, indoprofen, ketoprofen, fluprofen, pirprofen, carprofen, Ao Shapu piperazine, pranoprofen, suprofen and pharmaceutically acceptable salt, derivant and their compositions.In a preferable embodiment of the present invention, active component can be selected from acceptable salt in acetaminophen, aspirin, ibuprofen, naproxen, ketoprofen, flurbiprofen, diclofenac, cyclobenzaprine, meloxicam, rofecoxib, celecoxib and the pharmacy, ester, isomer and their mixture.

In another embodiment of the invention, active component can be selected from isoephedrine, cathine, chlorphenamine, dextromethorphan, diphenhydramine, Chinese mugwort department imidazoles, terfenadine, Fu Kefende, loratadine, Desloratadine, cetirizine, their mixture and pharmaceutically acceptable salt, ester, isomer and their mixture.

The example of suitable polydimethylsiloxane includes but not limited to dimethicone and dimethicone, by United States Patent (USP) 4,906,478; 5,275,822; With 6,103,260 is open, fits into this paper in each file as a reference.Term used herein " dimethicone " refers to the big class of polydimethylsiloxane, includes but not limited to dimethicone and dimethicone.

Effectively have one or more active component in the dosage form of therapeutic dose, this is measured and produces required therapeutic response when oral, and can easily be determined by those skilled in the art.As known in the art, be to determine this amount, must consider the given activity composition used, the bioavailability feature of this active component, dosage, patient's age and body weight and other factors.Usually, dosage form comprises one or more active component at least about 1% percentage by weight of compositions, comprises the preferable at least about 5% percentage by weight of compositions, for example comprises at least 25% percentage by weight of compositions.In a preferable embodiment, the sheet pericardium contains altogether at least about 50% percentage by weight, as at least about 70% percentage by weight, promptly at least about one or more active component of 80% percentage by weight (based on the weight of the sheet heart).

One or more active component in this dosage form can be any forms.For example, active component can disperse at molecular level, as melting or dissolving, and in dosage form, or form that can microgranule, but this microgranule also coating or coating not.If active component is through particulate form, the about usually 1-2000 micron of particle mean size of microgranule (coating or not coating).In a preferable embodiment, this microgranule is the crystal of the about 1-300 micron of particle mean size.In another preferable embodiment, this microgranule is the granule and the piller of the about 50-2000 micron of particle mean size, and about 50-1000 micron is preferable, and about 100-800 micron is better.

The sheet heart can be any solid form.The sheet heart can pass through prepared by any suitable process, comprises for example compacting or molding." the sheet heart " used herein is meant that a kind of material sealed by other materials at least in part or center on.This sheet heart is that self comprises one matter, and is preferable as tablet or capsule.Usually the sheet pericardium contains solid, and for example, the sheet heart can be the tablet of compacting or molding, hard or soft capsule, suppository, or confection form such as lozenge, nougat, caramel, side's dawn sugar or fat are basic compositions.In certain other embodiments, the part of the sheet heart or the sheet heart can be semisolid or the liquid form in the dosage form of finishing.For example, the sheet heart can comprise liquid-filled capsule, or semisolid side's dawn sugar substance.Contain the composition that can flow at the sheet pericardium, in the embodiment as many granules or microgranule or liquid, the sheet heart comprises in addition seals composition, and it is preferable to be used to hold stream material as capsule shells or coating.Contain in some particular of sealing composition at the sheet pericardium, the part of shell of the present invention or shell directly contacts with the composition of sealing of the sheet heart, and the composition of sealing of the sheet heart separates the flowed composition of shell with the sheet heart.

In one embodiment, the sheet heart is the tablet of compacting, its hardness about 2 to about 30kp/cm ², 6 arrive 25kp/cm approximately according to appointment ²Term " hardness " is to be used for describing the sheet heart or coated solid dosage form in this area to learn the hardness checkout equipment with conventional thing, the diameter breakdown strength of measuring as the Schleuniger hardness-testing device.For the value of more different big or small tablets, breakdown strength must standardization to destroyed area.This standardized value is with kp/cm ²Expression sometimes is called as the tablet tensile strength in this area.The visible Leiberman of general discussion of tablet hardness test etc., " medicine cuts open type one tablet " (Pharmaceutical Dosage Forms-Tablets), the 2nd volume, the 2nd edition., Marcel Dekker Inc., 1990,213-217,327-329 page or leaf.

The sheet heart can have a kind of in the various difformities.For example, the shape of the sheet heart can be a polyhedron, as cube, pyramid, prism or the like; The geometry that nonplanar spatial shape maybe can be arranged is as cone, truncated cone body, cylinder, spheroid, torus body or the like.In certain embodiments, the sheet heart has one or more main faces.For example, be in the embodiment of tablet of compacting at the sheet heart, sheet heart surface has two relative main usually, they be in the press up and down the contact of punch press face form.In this embodiment, sheet heart surface also comprises " bellyband " between two main faces usually, and it is contact formation with mold walls in the press.The sheet heart also can comprise multilayer tablet.

Adoptable exemplary heart shape comprises (the Elizabeth Carbide Die Co. by " Elizabeth company tablet design training manual " (TheElizabeth Companies Tablet Design Training Manual), Inc..) the 7th page of (McKeesport, Pa.) figure of tablet made of (this paper quotes as a reference) operated pressing tool shape of describing, (figure of tablet is just in time opposite with the shape of operated pressing tool) specific as follows:

1. scrobicula face

2. standard concave

3. dark concave surface

4. special dark concave surface

5. modify the ball impression face

6. standard concave is divided equally

7. standard concave is two divides equally

8. standard concave Europe is divided equally

9. standard concave is partly divided equally

10. two arcs

11. inclined-plane and concave surface

12. plane

13. the plane is to hypotenuse (F.F.B.E.)

14.F.F.B.E. divide equally

15.F.F.B.E. two dividing equally

16. annular

17. scrobicula

18. it is oval

19. it is avette

20. cryptomere

21. rectangle

22. square

23. triangle

24. hexagon

25. pentagon

26. octagon

27. rhombus

28. arrow-shaped

29. it is bullet-shaped

30. scrobicula face

31. standard concave

32. dark concave surface

33. special dark concave surface

34. modify the ball impression face

35. standard concave is divided equally

Divide equally 36. standard concave is two

37. standard concave Europe is divided equally

38. standard concave is partly divided equally

39. two arcs

40. inclined-plane and concave surface

41. plane

42. the plane is to hypotenuse (F.F.B.E.)

43.F.F.B.E. divide equally

44.F.F.B.E. two dividing equally

45. annular

46. scrobicula

47. it is oval

48. it is avette

49. cryptomere

50. rectangle

51. square

52. triangle

53. hexagon

54. pentagon

55. octagon

56. rhombus

57. arrow-shaped

58. it is bullet-shaped

59. tubular

60. semilune

61. peltate

62. it is heart-shaped

63. Semen Armeniacae Amarum shape

64. domestic dish type

65. parallelogram

66. it is trapezoidal

67. Fig. 8/barbell shape

68. string tie shape

69. scalene triangle

The sheet heart comprises active component and multiple excipient usually, depends on its preparation method.

In the embodiment of the sheet heart by the drawing method preparation, suitable excipient comprises filler known in the art, binding agent, disintegrating agent, lubricant, fluidizer or the like.The active component for preparing by drawing method and it is comprised at the sheet heart improves in the embodiment of release in addition, and it is preferable that this sheet heart further comprises the compressible excipient that improves release.

The suitable filler that is used for preparing by drawing method the sheet heart comprises water-soluble compressibility carbohydrate such as sugar, comprises glucose, sucrose, maltose and lactose; Sugar alcohols comprises mannitol, sorbitol, maltose alcohol, xylitol; Glucidtemns comprises dextrin and maltodextrin or the like; The insoluble plastic deformation material of water is as microcrystalline Cellulose or other cellulose derivatives; Water-insoluble non-plastic fracture material is as dicalcium phosphate, tricalcium phosphate or the like and their mixture.

The suitable bonding for preparing the sheet heart by drawing method comprises dry adhesives such as polyvinylpyrrolidone, hydroxypropyl methylcellulose or the like; Wet binder such as water soluble (CO) polymers comprise aqueous colloid such as acacin, alginate, agar, guar gum, carob, carrageenin, carboxymethyl cellulose, tara gum, arabic gum, tragacanth, pectin, xanthan gum, gellan gum, gelatin, maltodextrin, galactomannan, pustulan, laminarin, small pieces heart bacterium glucosan, inulin, whelan, rhamsan, zooglan, methylan, chitin, cyclodextrin, chitosan, polyvinylpyrrolidone, cellulose, sucrose, starch or the like; With derivant and their mixture.

The suitable disintegrants for preparing the sheet heart by drawing method comprises primojel, crospolyvinylpyrrolidone, cross-linked carboxymethyl cellulose, starch, microcrystalline Cellulose or the like.

Be used for comprising long-chain fatty acid and their salt, as magnesium stearate and stearic acid, Talcum, glyceride and wax by the examples of suitable lubricants that drawing method prepares the sheet heart.

The suitable fluidizer that is used for preparing by drawing method the sheet heart comprises silica sol or the like.

In certain embodiment, the part of this sheet heart or the sheet heart can randomly comprise release known in the art and improve excipient, as common transfer, U.S. Patent application No.___________[MCP 321 undetermined] disclosed content, the disclosure reference in content is incorporated into this.But the suitable release improvement compression excipients for preparing the sheet heart by drawing method comprises that inflatable easy erosion hydrophilic substance, insoluble Edible material, pH rely on polymer or the like.

Prepare the suitable pharmaceutically acceptable adjuvant of the sheet heart by drawing method, comprise antiseptic, high intensity sweetner such as aspartame, acesulfame-K, sucralose and glucide; Correctives, coloring agent, antioxidant, surfactant, wetting agent or the like and their mixture.

Preparing by drawing method in the embodiment of the one or more hearts, can use dry blending known in the art (i.e. directly compacting), or wet granulation.In dry blending (i.e. directly compacting) method, one or more active component, are directly transferred to subsequently and are pressed into tablet in the press in suitable stirrer for mixing with excipient.In wet granulation, one or more active component, suitable excipient, and the solution of wet binder (as the decocting in water gelatinized corn starch, or polyvinylpyrrolidonesolution solution) or dispersion liquid is mixed and granulating.Alternatively in excipient, can comprise dry adhesives, and mixture can with water or other suitable solvent granulating.The suitable device that is used for wet granulation is known in the art, comprises low the shearing, as planetary-type mixer; High-shear mixer; And fluid bed, comprise rotating fluidized bed.The particulate matter that produces is dried, can be randomly and other composition dry mixed, and as adjuvant and/or excipient for example lubricant, coloring agent or the like.Final drying is mixed and is fit to compacting.Directly the method for compacting and wet granulation is known in the art, and is described in detail, for example, Lachman etc., " theory and practice of industrial pharmacy (The Theory and Practice of Industrial Pharmacy) ", Chapter 11 (the 3rd edition, 1986).

The powder mixture of dry blending or wet granulation usually uses rotation press known in the art to be pressed into tablet, for example can be from Fette America Inc., and Rockaway, NJ, perhaps Manesty Machines LTD, Liverpool, UK buys.In the rotation press, the powder that measures volume is loaded in the mold cavities, mold cavities rotates to the compacting position as the part of " mould platform " from the filling position, powder is being suppressed between the punch press up and down there, and forwarding the discharge position to, the following punch press release of the tablet of generation quilt from mold cavities and " shifting out " bar that is fixed are directed in the drain tank.

In an optional embodiments, the sheet heart can pass through U.S. Patent application No.09/966 undetermined, and 509, described drawing method of 16-27 page or leaf and equipment prepare, and the disclosure file content is with reference to being incorporated into this.Concrete is, the sheet heart is to use rotation compacting cabin preparation, this rotation compacting cabin comprises the filling area, inserts district, blanketed zone, discharge area and cleaning area, and they are at U.S. Patent application No.09/966, in the individual equipment with double form structure that shows among Fig. 6 of 509.The mould in this compacting cabin uses vacuum to support filling, in each mould or near have filter preferable.

The sheet heart of compacting preparation can be single or multiple lift, for example bilayer tablet.

The density of the sheet heart is at least about 0.9g/cc, as at least about 1.0g/cc.Sheet pericardium as demonstration is drawn together 385mg, and volume is the film agent of 0.4 cubic centimetre compacting, and 586mg, and volume is the tablet of the compacting of about 0.5cc.

Shell is round the sheet heart.Shell comprises one or more openings.One or more openings provide passage to getting in touch between the outside of the sheet heart and dosage form.These openings can pass through the thickness contact chip heart of shell fully, or just part is passed through shell.

Except opening wherein, shell can be homogeneous and successive basically, and perhaps shell can comprise a plurality of parts, as first shell part and the second shell part.In certain embodiments, shell or shell part directly contacts with the sheet heart.In certain other embodiments, shell or shell part is directly to contact with the sub-coating that holds the sheet heart substantially.Comprise in the embodiment of first shell part and second shell part at shell, at least the first shell partly comprises opening.

In certain embodiments, first shell part is different with second shell part on forming.Term used herein " different on forming " refers to have the feature of distinguishing easily on qualitative and quantitative chemical analysis, physical testing or visual observation.For example, first shell part and second shell part can comprise different compositions, or the identical component of varying level, or first shell part partly can have different physics or chemical characteristic with second shell, different functional characteristics, or difference is visually arranged.The different physics or the example of chemical characteristic comprise hydrophilic, hydrophobicity, hygroscopicity, elasticity, plasticity, tensile strength, crystallinity and density.The example of different functional characteristics comprises material itself or the wherein dissolution rate and/or the degree of active component, and the speed of substance decomposition is to the permeability of active component, to permeability of water or aqueous medium or the like.Visually the example of Qu Fening comprises size, shape, topological structure or other geometric features, color, colourity, opacity and gloss.

In one embodiment, dosage form of the present invention comprises: the sheet heart that a) contains active component; B) the optional sub-coating of the basic emulsion sheet heart; And c) comprise the shell that resides in lip-deep first and second shells part of sub-coating, first shell partly comprises one or more openings, and first shell part is dissolved in the gastro-intestinal Fluid easily." the basic covering " used herein refers to that the surface area at least about 95% of the sheet heart is covered by sub-coating.

The use of sub-coating is well known in the art, and is disclosed in, for example, U.S. Patent No. 3,185,626, this paper is with reference to being incorporated into this.Any compositions that is fit to film coating tablet can be used as sub-coating of the present invention.The example of suitable sub-coating is in U.S. Patent No. 4,683, and open in 256,4,543,370,4,643,894,4,828,841,4,725,441,4,802,924,5,630,871 and 6,274,462, full content is with reference to being incorporated into this.Suitable sub-coating in addition comprises one or more in the following ingredients: cellulose ether such as hydroxypropyl methylcellulose, hydroxypropyl cellulose and hydroxyethyl-cellulose; Poly-carbohydrate such as xanthan gum, starch and maltodextrin; Plasticizer comprises for example glycerol, Polyethylene Glycol, propylene glycol, dibutyl sebacate, triethyl group citrate, vegetable oil such as Oleum Ricini, surfactant such as polysorbate-80, sodium lauryl sulfate and dioctyl sodium sulfosuccinate; Poly carbohydrate, pigment and opacifier.

In one embodiment, sub-coating comprises about 2% to about 8%, 4% to about 6% water-soluble cellulose ether and about 0.1% to about 1% Oleum Ricini according to appointment, and as U.S. Patent No. 5,658,589 is disclosed in detail, and the full content reference is incorporated into this.In another embodiment, sub-coating comprises about 20% to about 50%, according to appointment 25% to about 40% HPMC and about 45% arrive about 75%, the maltodextrin as from about 50% to about 70%; With about 1% to about 10%, 5% to about 10% PEG 400 according to appointment.

The amount of exsiccant sub-coating is usually to exist based on the about 0-5 weight of the dry weight of sheet heart %.

Fig. 1 has shown the dosage form of the present invention 1 of the shell 3 that includes many openings 2.The shape of opening 2 does not extend through whole path (not shown) that shell 3 arrives under the shell 3 as extended breach.

Fig. 2 has shown another dosage form of the present invention.Dosage form 1 comprises the sheet heart (not shown) of the cover housing of being made up of the first shell part 3a and the second shell part 3b.Shell part 3a comprises many opening 2a, 2b.Opening 2a is a shallow concave shape, and opening 2b is a letter shapes.

Fig. 3 has illustrated another dosage form of the present invention.Dosage form 1 comprises the sheet heart (not shown) that is covered by shell 3, and this shell comprises opening 2a, 2b.Opening 2a is the circular hole shape, and opening 2b is a letter shapes.

Fig. 4 shows another dosage form of the present invention.Dosage form 1 includes the sheet heart 4 that the shell 3 of opening 2 centers on.The bases part of the sheet heart 4 each opening 2 on shell as seen.

Fig. 5 shows another dosage form of the present invention.Dosage form 1 includes the sheet heart (not shown) of the football-shaped that the shell of the first shell part 3a and the second shell part 3b covers.The first shell part 3a comprises many little, circle opening 2.

Each opening has size, as, length, width or diameter, scope the dosage form diameter about 0.1% to about 100%, or the virtually any size of dosage form interarea (as diameter, length or width).The diameter of each opening or width are virtually any size (as diameter, length or width) about 0.5% to about 5% preferable of dosage form diameter or dosage form interarea.In certain embodiments, the scope of the diameter of opening or width is at about 200 to about 2000 microns.The length range of opening is from about 1% to about 100% of dosage form diameter or dosage form interarea diameter.In a certain particular, the length of dosage form interarea or diameter are about 10,000 to about 20,000 microns.In a particular, the length of opening is from about 100 to about 20,000 microns.The degree of depth of opening is generally the sheet heart thickness of about 75% to about 100% opening.In certain embodiments, the scope of the thickness of the shell of opening is generally about 20 to about 800 microns, 100 to about 400 microns according to appointment.In a particular, the length of opening is about 75 to about 400 microns.If many openings are arranged, their mutual intervals are about 0.5 times of minimum opening diameter at least usually, as at least about 1 times.Opening can have many shapes, or is arranged to many different patterns, and similar or different sizes is arranged, as shown in Figure 6.

In one embodiment, the size of opening is small enough to make the sheet heart not tasted, and number of openings is even as big as to providing contact between the surface area of the certain percentage of the sheet heart and the dosage form outside.

Can use microscope to measure the thickness of the shell of different parts, for example, environmental scanning electron microscope, XL 30ESEM LaB6 type, Philips Electronic Instruments Company, Mahwah, WI.6 different parts are measured thickness of the shell on single dosage form.(that is, RSD represents with the percentage ratio of standard deviation and meansigma methods) as known in the art, sample standard deviation multiply by 100 divided by meansigma methods, calculates relative standard deviation (RSD).The RSD of thickness of the shell provides the index of thickness of the shell variation on the single dosage form.In some optional embodiment of the present invention, it is about 40% that the relative standard deviation of thickness of the shell is less than, as be less than approximately 30%, or is less than about 20%.

Dosage form of the present invention provides promptly to release and comprises wherein one or more active component.One or more active component can be found in the sheet heart, shell or their part or compositions.In one embodiment, sheet comprises a kind of active component in the heart at least.

In active component need be absorbed into embodiment in the system circulation of animal, one or more active component can dissolve preferable when contact liq such as water, gastric juice, intestinal juice or the like.In one embodiment, the dissolution characteristics of at least a active component reaches the specification requirement of USP to the immediate-release tablet formulations that contains active component.For example, the acetyl aminophenol tablet, USP24 specifically specifies in the phosphate buffer of PH5.8, use USP device 2 (stirring paddles) at 50rpm, after administration, have at least 80% the acetyl aminophenol that comprises in the dosage form to be released in 30 minutes, and Genpril, USP24 specifically specifies in the phosphate buffer of PH7.2, use USP device 2 (stirring paddles) under 50rpm, after administration, have at least 80% the ibuprofen that comprises in the dosage form to be released in 60 minutes.See USP24,2000 editions, 19-20 and 856 pages (1999).In another embodiment, under appropriate condition, stir after 60 minutes, in suitable dissolution medium, can detect active component at least about 70%.

Therefore, the part of shell or shell is dissolved in the gastro-intestinal Fluid easily.Comprise in the preferable embodiment of first shell part and second shell part at shell, at least the first shell part wherein comprises opening, and is dissolved in the gastro-intestinal Fluid easily.In this embodiment, this shell and shell part 37 ℃ with USP2 type dissolver (stirring paddle method) with 50 or 100rpm be stirred in implosion in 30 minutes or be dissolved in 900ml water or 0.1N HCl, perhaps preferable in the phosphate buffer.

Shell or shell partly are included in and show in the gastro-intestinal Fluid that rapidly-soluble material is preferable.For example, this shell or shell part can comprise and is selected from water solublity or hydroexpansivity film former, the ease of solubility material of water solublity or hydroexpansivity thickening agent, crystallization and non-crystallizable carbohydrates.In certain embodiments, suitable water solublity or hydroexpansivity film former can be selected from hydroexpansivity cellulose derivative, thermoplastic starch, poly alkylene glycol (polyalkylene glycols), polyalkylene oxides and amorphous sugar glass, and their compositions.In certain other embodiments, suitable film former can be selected from thin film formation water-soluble polymer for example water-soluble ethylene polymer, water solublity poly carbohydrate and water solubility copolymer; Thin film forms albumen and their compositions.In certain other embodiments, suitable thickening can be selected from gelatinate polymer or hydrocolloid; Gelling starch, and crystalline carbohydrate.In certain other embodiments, suitable non-crystallizable carbohydrates can be selected from poly dextrose, glucidtemns and non-crystallizable sugar-alcohols.In one embodiment, it is about 50% that shell comprises at least, preferred about 80%, and most preferably from about 90% material is selected from film former, gelatinate polymer, low melting point hydrophobic substance, non-crystallizable sugars or sugar alcohol, and their mixture.In another embodiment, shell comprises at least about 50%, preferably at least about 80%, most preferably is selected from film former, gelatinate polymer, low melting point hydrophobic substance and their mixture at least about 90% material.

In another special embodiment, shell comprises less than about 50%, preferably less than about 25%, most preferably less than about 5% crystal sugar.

In another embodiment, dosage form does not have the charge control agent of (that is, based on shell weight, less than 1 weight %, preferably less than about 0.1 weight %) fully.Term used herein " charge control agent " refers to have electric charge control function, as is used for the material of electrostatic precipitation coating on substrate.This charge control agent comprises metal salicylate salt, for example zinc salicylate, magnesium salicylate and calcium salicylate; Quaternary ammonium salt, benzalkonium chloride, benzethonium chloride, Tetradonium Bromide (cetyl ammonium bromide); With cyclodextrin and adduct thereof.

In some optional embodiment, shell itself or outer coating thereon can comprise active component.In a particular, this active component is released from dosage form when dosage form contacts suitable liquid medium.In another embodiment, shell comprises first shell part and the second shell part.On second shell part outer coating is arranged, and first shell part comprises opening therein.When the suitable liquid medium of contact, the release of active component or promptly releasing, or with controlled release, as continue, prolongation, extension form, or, from dosage form, discharge as pulsation or repeat function form to postpone.In the embodiment that active component is promptly released from outer coating, outer coating also is dissolved in the gastro-intestinal Fluid preferable as mentioned above easily.

Shell can be administered to sheet in the heart with any suitable method, for example by spraying, dipping, coating or molding.The description of suitable spray coating method sees, as, U.S. Patent No. 3,185,626,4,683,256,4,543,370,4,643,894,4,828,841,4,725,441,4,802,924,5,630,871 and 6,274,162, all open files are with reference to being incorporated into this.U.S. Patent No. 4,802,524,5,538,125 are seen in the description of suitable dipping method; 5,228,916; 5,436,026; 5,679,406, all open file is with reference to being incorporated into this.U.S. Patent No. 5,146 is seen in the description of suitable coating method, 730 and 5,459,983.Suitable molding methods sees that this paper describes.

In some optional embodiment of the present invention, the sheet heart, shell or the two prepare by molding methods.Particularly, the sheet heart, shell or the two can prepare by molding or the solvent-free molding based on solvent.In this embodiment, the sheet heart or shell are made by the stream material that can randomly comprise active component.Stream material can be that the temperature between about 37 ℃ to 250 ℃ can mobile any edible material, and is solid, semisolid, maybe can forms the material of gel in the temperature between-10 ℃ to about 35 ℃ approximately.When in liquid or flow regime, stream material can comprise the component of dissolved, dispersive or thawing and randomly comprise solvent for example water or organic solvent, or their compositions.Can or remove fully by part by dry solvent.

In one embodiment, undertaken by the thermocoagulation molding based on the molding or the solvent-free molding of solvent, the method and apparatus of use is seen U.S. Patent application No.09/966 undetermined, 450, the 57-63 pages or leaves, and open file is with reference to being incorporated into this.In this embodiment, form the sheet heart or shell by injecting the molding chamber to liquid form.Stream material comprises that temperature surpasses its melting temperature but to be lower than the thermocoagulation material of decomposition temperature of its any active component that comprises preferable.Initial substance is cooled in the molding chamber and is solidified into the form (that is the shape that mould, is arranged) of shape.

According to this method, stream material can comprise and is suspended in thawing substrate, for example the solid particle in the polymeric matrix.Stream material can be melted or be the form of paste fully.Stream material can comprise the active component that is dissolved in the thawing material.Stream material can comprise the solid particle that is dispersed in the liquid-carrier.Alternatively, stream material can be made by dissolved solid in solvent, and solvent is evaporated after molding step subsequently.

In another embodiment, undertaken by the thermal cycle molding based on the molding or the solvent-free molding of solvent, the method and apparatus of use is seen U.S. Patent application No.09/966 undetermined, 497, the 27-51 pages or leaves, and open file is with reference to being incorporated into this.The thermal cycle molding is to be undertaken by the molding chamber of stream material being injected heating.Stream material can comprise that active component and temperature surpass the solidification temperature of thermoplastic but the thermoplastic that is lower than the decomposition temperature of active component.Stream material is cooled in the molding chamber and is solidified into the form (that is the shape that mould, is arranged) of shape.

U.S. Patent application No.09/966 undetermined, in the 497 thermal cycle molding methods and equipment that use, the overall configuration of thermal cycle molding chamber sees that Fig. 3 shows.Thermal cycle molding chamber 200 comprises rotor 202, many mould units 204 in its disposed about.Thermal cycle molding chamber comprises that storage place 206 (see figure 4)s hold stream material.In addition, thermal cycle molding chamber is equipped with temperature control system and is come Fast Heating and cooling frame subunit.Figure 55 and 66 has shown temperature control system 600.

Mould unit can comprise center die sub-component 212, last mold assemblies 214 and following mold assemblies 210, and shown in Figure 26-28, pairing forms has the mold cavities of required form, as the sheet heart or around the shape of the shell of the one or more hearts.When rotor 202 rotations, relative center is closed with last mold assemblies or relative center and following mold assemblies.Stream material is heated to flow regime in storage place 206, is injected in the mold cavities of formation.The temperature of stream material is lowered by subsequently, makes the stream material sclerosis.The product of finishing is opened and ejected to mold assemblies.

In optional embodiment of the present invention, use the U.S. Patent application No.09/966 undetermined shown in Figure 28 A-C, 497 comprise rotatable center die sub-component 212, and the thermal cycle mold apparatus of the universal models of low mold assemblies 210 and high mold assemblies 214 is applied to dosage form with shell.The sheet heart is added to mold assemblies continuously.The shell stream material is heated to flow regime in storage place 206, is injected in the closed mold cavities that forms of the mold assemblies of holding the sheet heart.The temperature of shell stream material is lowered by subsequently, makes it round the sheet cardiosclerosis.The dosage form of finishing is opened and ejected to mold assemblies.The shell coating carries out with two steps, and each half dosage form such as U.S. Patent application No.09/966 undetermined shown in Figure 28 B flow chart of 939, are distinguished coating by the rotation of center die sub-component.

In one embodiment, U.S. Patent application No.09/966 undetermined, the compacting cabin in 509, the 16-27 pages or leaves can be used for making the sheet heart, and shell can use above-mentioned thermal cycle molding chamber to apply the sheet heart.Can use as U.S. Patent application No.09/966, the described transfer device of 414, the 51-57 pages or leaves (disclosure is with reference to being incorporated into this) is transferred to thermal cycle molding chamber with the sheet heart from the compacting cabin.This transfer device can have U.S. Patent application No.09/966 undetermined, the structure shown in 300 among Fig. 3 of 939.It comprises and manyly is connected to the transfer device 304 of driving-belt 312 with cantilevered fashion, as U.S. Patent application No.09/966 undetermined, shown in Figure 68 of 939 and 69.Rotation synchronously of compacting cabin that transfer device is connected with it and thermal cycle molding chamber and operation.Transfer device 304 comprises localizer 330, holds the sheet heart when the sheet heart moves with transfer device.

Comprise water solublity and water insoluble polymer in stream material or as the suitable thermoplastic that stream material uses, they are normally linear, are not crosslinked, near the polymer chain hydrogen is not connected in consumingly yet.Thermoplastic can be an one matter, also can be the mixture of material and solvent or plasticizer.The example of suitable thermoplastic comprises that those comprise hydroexpansivity cellulose derivative, water-insoluble cellulose derivative, thermoplastic ethylene's polymer, thermoplastic starch, thermoplastic poly aklylene glycol, thermoplastic poly alkylene oxide and amorphous sugar glass or the like, and the material of their derivant, copolymer and compositions.The example of suitable thermoplasticity hydroexpansivity cellulose derivative comprises hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), methylcellulose (MC), and the compositions of they and water or other suitable solvents and/or plasticizer.The example of suitable thermoplasticity water-insoluble cellulose derivatives comprises cellulose acetate (CA), ethyl cellulose (EC), acetylbutyrylcellulose (CAB), cellulose propionate, and the compositions of they and appropriate organic solvent and/or plasticizer.The example of suitable thermoplastic ethylene's polymer comprises polyvinyl alcohol (PVA) and polyvinylpyrrolidone (PVP).The example of suitable thermoplastic starch is seen U.S. Patent No. 5,427,614 disclosed examples.The example of suitable thermoplastic poly aklylene glycol comprises Polyethylene Glycol.The example of suitable thermoplastic poly alkylene oxide comprises that molecular weight is in about 100,000 to about 900,000 daltonian poly(ethylene oxide).Other suitable thermoplastics comprise the sugar as the amorphous glass form that is used to make the boiled goods form.

Should be pointed out that when being used to prepare shell stream material must be the aforesaid material that is dissolved in easily in the gastro-intestinal Fluid.

Using solvent-free molding methods to prepare in the embodiment of shell, shell comprises the about 30 weight % that account for hot reversible barrier weight at least usually, as at least about 45 weight %.Shell randomly further comprises up to about various plasticizers, adjuvant and the excipient of 30 weight %.

Prepare in the embodiment of shell based on the solvent molding methods using, shell comprises usually at least about 10 weight %, as at least about 12 weight % or at least about 15 weight % or at least about 20 weight % or at least about the film former of 25 weight %.Shell also randomly comprises up to about various plasticizers, adjuvant and the excipient of 30 weight %.

The gross weight of shell be the sheet heart gross weight about 20 weight % to about 400 weight % preferable.Using solvent-free molding methods to prepare in the embodiment of shell, the gross weight of shell is about 50-400 weight % of the gross weight of the sheet heart normally, 75-400 weight %, or about 100-200 weight % according to appointment.Prepare in the embodiment of shell based on the solvent molding methods in use, the gross weight of shell is the about 100 weight % of about 20-of the gross weight of the sheet heart normally.

Using molding shell to be applied in the embodiment of the sheet heart, the part of shell holds the sheet heart at least, makes the inner surface of shell basically conformally on the outer surface of the sheet heart.Term used herein " basically conformally " refers to that the peak of inner surface of shell is mutually not compound basically with the Feng Hegu of the outer surface of the sheet heart with projection with paddy or depression.In certain embodiments, the depression and the length of projection or deeply dimensionally usually greater than 10 microns, for example greater than 20 microns with less than about 30,000 microns, less than about 2000 microns preferable.

In the embodiment of using solvent-free molding, stream material can comprise hot reversible carrier.Be used to prepare the sheet heart, shell or the suitable hot reversible carrier of the two normally fusing point be lower than about 110 ℃ thermoplastic, fusing point about 20 and about 100 ℃ between better.The example that is used for the hot reversible carrier of solvent-free molding comprises thermoplastic poly aklylene glycol, thermoplastic polyalkylene oxides (polyalkalene oxide), low melting point lyophobic dust, thermoplastic polymer, thermoplastic starch or the like.The example of preferable hot reversible carrier comprises Polyethylene Glycol and poly(ethylene oxide).Suitable thermoplastic poly aklylene glycol as hot reversible carrier comprises molecular weight about 100 to about 20,000 daltonian Polyethylene Glycol, as molecular weight at about 100 to about 8,000 daltonian Polyethylene Glycol.Suitable thermoplastic poly alkylene oxide comprises that molecular weight is in about 100,000 to about 900,000 daltonian poly(ethylene oxide).Suitable low melting point lyophobic dust as hot reversible carrier comprises it at room temperature being solid fat, fatty acid ester, phospholipid and wax, comprises the mixture such as the chocolate of fat; Or the like.The example of suitable fat comprises for example cocoa butter of hydrogenated vegetable oil, hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenation Oleum helianthi and oil with hydrogenated soybean; With free fatty and their salt.The example of suitable fatty acids ester comprises sucrose fatty acid ester, monoglyceride, double glyceride, triglyceride, Glyceryl Behenate, Palmic acid tristerin, glyceryl monostearate, glyceryl tristearate, trilaurin, myristin, Glyco Wax-932, dodecanoyl Polyethylene Glycol-32 glyceride and stearoyl Polyethylene Glycol-32 glyceride.The example of suitable phospholipid comprises phosphatidylcholine, Phosphatidylserine, the pure and mild phospholipid phosphonic acids of phosphatidyl-4 (phosphatidic acid).It is that solid wax comprises Brazil wax, spermaceti, Cera Flava, wax rhimba wax, shellac wax, microwax and paraffin that the example of suitable wax is included in room temperature.Suitable thermoplastic polymer as hot reversible carrier comprises thermoplasticity water expansion cellulose derivant, the water insoluble polymer of thermoplasticity, thermoplastic ethylene's polymer, thermoplastic starch and thermoplastic resin, reaches their compositions.The example of suitable thermoplasticity hydroexpansivity cellulose derivative comprises hydroxypropyl methylcellulose (HPMC), methylcellulose (MC), carboxymethyl cellulose (CMC), crosslinked hydroxypropyl cellulose, hydroxypropyl cellulose (HPC), hydroxybutyl cellulose (HBC), hydroxyethyl-cellulose (HEC), cellulose, hydroxypropyl butyl cellulose, cellulose and their salt, derivant, copolymer and compositions.Suitable thermoplasticity water-insoluble polymer comprise ethyl cellulose, polyvinyl alcohol, polyvinyl acetate, polycaprolactone, cellulose acetate and derivant thereof, acrylate, methacrylate, acrylic copolymer, or the like with their derivant, copolymer and compositions.Suitable thermoplastic ethylene's polymer comprises polyethylene acetic acid, polyvinyl alcohol and polyvinylpyrrolidone (PVP).Suitable thermoplastic starch as hot reversible carrier is seen U.S. Patent No. 5,427,614 disclosed examples.The glyceride that comprises dammar, olibanoresin, Colophonium, Lac, sandarac and Colophonium as the suitable thermoplastic resin of hot reversible carrier.In one embodiment, be used for being selected from poly alkylene glycol, polyalkylene oxides and their compositions by the hot reversible carrier of the molding manufacturing sheet heart.

Comprise in the embodiment of the active component that can promptly release from dosage form at shell, shell prepares preferable by solvent-free molding.Be used for making the embodiment of the stream material of shell at the reversible carrier of heat, the reversible carrier of described heat is preferably selected from the Polyethylene Glycol of weight average molecular weight about 1450 to about 20000, the poly(ethylene oxide) of weight average molecular weight about 100,000 to about 900,000, or the like.

In the preferable embodiment of the present invention, shell is applied to the sheet heart by coating.In coating method, the thin film that makes is applied to the opposite of the sheet heart with the rotation mould, i.e. Ya Zhi tablet, and be enclosed in together needing the position to center on the blockade line that the sheet heart extends with basic edge-to-edge's form.Mould is positioned in the position of the surface relation of adjoining each other, therefore therebetween formation folder.Each mould has a series of recesses that match at its circumferential surface.When mould rotates, connect in the folder of thin film between mould and fusion, the recess of pair of matched forms bag, and the sheet heart falls into bag by metering feeding mechanism.When mould continued rotation, the sheet heart promoted the inside of thin film recess in the mould, and in the time of when thin film continues to be connected to the sheet heart by mould near, the sheet heart is nearby encapsulated and coating safely.When thin film merged near the sheet heart, the mould that the sheet heart of coating is rotated scaled off from the thin film folder, so it separates from thin film with the dosage form of independent coating.

Useful coating method and equipment are for example being described in the U.S. Patent No. 5,146,730 and 5,459,983, and the disclosure file references are incorporated into this.With reference to " particularly 730 patents and Figure 13, the refrigerative plastic casting film 36 of the agent that is cooled and 37 forms on rotational casting drum 42 and 43.Thin film is fed to bulging original mold 38 and 39 of phase mutually synchronization rotation by a series of going barrels.Mould 38 and 39 is configured in around the function central plane 54 of whole coating equipment symmetrically.Thin film 36 and 37 is in contact with one another on the folder between mould 38 and 39.At this place, sheet heart coating, two thin film are closed in together and downcut.

Concrete is to produce net when thin film 36 and 37 is concentrated and is pressed together.Self adheres to each other thin film.After appearing between mould 38 and 39, the net that contains the coated tablet heart passes through between a pair of calendering roller 63.Net is trailed, and the sheet heart of coating self separates and falls into product container 65.

With reference to the Figure 20 of " 730 patent ", each mould 38,39 has many recesses 108, cooperatively interacts with corresponding recess in other moulds.The chamber of these recesses is made into to accept the shape of the single heart.The chamber is limited by rib 109, and the closed mutually sheet heart with coating of rib 109 downcuts from net.Tusk 115 at mould 38,39 edges clips thin film 36,37.

The sheet heart of coating can wash and be dry, can randomly further handle on demand.

In another embodiment, shell is administered to sheet in the heart once more by coating, but be used to make shell thin film each comprise visually differentiable part, for example striped.Thin film is used by coating method, as common transfer, and U.S. Patent application No.___________[MCP 301 and MCP316 undetermined] described content.Common reference Fig. 9-11 wherein, the film casting equipment 30 that is used for this coating method comprises casting drum 34, and partly solidified at least coating substance is cooled when its outer surface 36 of contact.Multicell breach extruder 38 places thin film on the casting drum 34.Extruder 38 comprises the separator 58,60,62 that inside 44 is divided into four chambers 64,66,68,70.Chamber 64,66,68,70 each can be included in visually different coating substance, i.e. the coating substance of different color.Each separator has the sword limit 94,96,98 of taper to control coating substance to flow on the casting drum 34.Coating substance is provided to the chamber from for example feed pipe 72,74.Breach 78 is positioned at the bottom of breach extruder 38.Breach 78 has been communicated with each chamber 64,66,68,70.The breach extruder is heated to and makes coating substance become flow regime, and this depends on the material that scope is about 40 to 250 ℃.

With reference to [MCP 301] _ _ _ _ _ _ _ _ _ _ Figure 14-16 of application, can with U.S. Patent No. 5,146,730 and 5,459,983 description similarly visually can be distinguished the coating equipment 102 that uses together of plastic casting film of part.Particularly, plastic casting film 32,32 ' moves with conitnuous forms, by a series of cylinders 106,108,110,106 ', 108 ', 110 ' shifts to a pair of cooperative rotation mould 112 and 112 ', and mould 112 and 112 ' symmetrical placement are on the both sides on the symmetrical centre plane 104 of equipment 102.According to their rotating shaft AR, AR ' rotates rotation mould 112 and 112 ' respectively, therefore therebetween formation folder.Folder between the rotation mould 112 and 112 ' is positioned at aforesaid symmetrical centre plane 104, striped thin film 32,32 ' is arranged through this place.

Coating equipment 102 also comprises sheet heart dispersal device 118, and it can hold the supply of the sheet heart 10 and with the timing form they is distributed to folder.Sheet heart dispersal device 118 is also arranged with symmetrical centre plane 104.Sheet heart dispersal device 118 orientations make the sheet heart 10 sheet heart 10 when entering folder contact set striped thin film 32 simultaneously with each sheet heart 10 of dispersion, 32 ' contact surface, symmetric transverse plane 16 is positioned at the symmetrical centre plane 104 of coating equipment 102, thin film 32,32 ' color conversion 92a, 92a ' lay respectively at the symmetrical conjugate planes 18 of the sheet heart 10.Thin film 32 then, and 32 ' extends around the opposite of each sheet heart 10 symmetrically.

With reference to [MCP 301] _ _ _ _ _ _ _ _ _ _ Figure 15 of application is presented at the sheet heart 10 and enters mould 112, the folder between 112 ' and with respect to the color conversion 92a of each thin film 32,32 ', 92b, 92c, 92a ', 92b ', the correct position of 92c '.All color conversion 92a, 92b, 92c, 92a ', 92b ', 92c ' are arranged in the symmetrical conjugate planes 16 of the respective flap heart 10.

And, coating equipment 102 preferably comprise LD device 120 ([MCP 301] _ _ _ _ _ _ _ _ _ Figure 14 of application schematically shows) correctly be arranged in rotation mould 112 mutually with the colour play (not shown) that guarantees thin film 32,32 ', before the passage between 112 '.LD device 120 guarantees that also the position of the dispersible tablet heart 10 is with respect to color conversion 92a, 92b, 92c, 92a ', 92b ', 92c ' are suitable, make the color conversion that generates on the product 122 can suitably mate each other and the suitable symmetrical conjugate planes 18 that cooperate each sheet heart 10.

[MCP 301] _ _ _ _ _ _ _ _ _ _ Figure 16 of application provides the amplification perspective illustration of bulging sample rotation mould 112,112 '.Rotation mould 112,112 ' is basic identical each other, and each has a series of recess 126,126 ' external peripheral surface 124,124 '.The arrangement of each recess 126,126 ' makes its length 130,130 ' be parallel to rotate mould 112 separately, 112 ' rotating shaft AR, AR '.Each recess 126 matches with respective notches 126 ' on another mould 112 ' on mould 112.In addition, recess 126,126 ' row's quantity should be respectively with through mould 112, the striped 84,86 on the striped thin film 32,32 ' between 112 ', 88,90,84 ', 86 ', the color conversion 92a between 88 ', 90 ', 92b, 92c, 92a ', 92b ', the quantity of 92c ' is corresponding.

Through rotation mould 112, the location of the striped thin film 32,32 ' between 112 ' is, for example, the red streak 84,88 of thin film 32 and the red streak of other thin film 32 ' 84 ', 88 ' coupling, thin film 32,32 ' yellow cord 86,90 mates similarly mutually with 86 ', 90 ' respectively.The LD device 120 of coating equipment 102 can be used for promoting thin film 32,32 ' location, make each thin film color conversion coupling and arrange to improve.

When rotation mould 112, during 112 ' rotation, the sheet heart 10 is dispersed to mould 112, folder between 112 ', make they along with mould 112,112 ' rotating shaft AR, the length orientation that AR ' is arranged in parallel, and therefore each sheet heart 10 can correctly be arranged between 126 ' at a pair of synergistic recess 126.Rotation mould 112,112 ' continues rotation, thin film 32, and 32 ' passes through raised brim 128, the 128 ' sealing mutually of synergistic recess 126,126 ', therefore is positioned at the thin film seam 134 on the symmetric transverse plane 16 of the sheet heart 10 around 10 formation of the sheet heart.In thin film seam 134 around each coated tablet heart 10, raised brim 128,128 ' also cuts adherent thin film 32, therefore disengages the sheet heart product 122 of coating from adherent thin film 32,32 '.

The thin film seam 134 that produces can comprise the film edge of adjacency.The cut edge of the slight overlapping other thin film 32 ' in cut edge of thin film 32 in the also possible thin film seam 134, its amount approximates thin film 32,32 ' thickness greatly.Alternatively, the formation of thin film seam 134 makes thin film 32, and arrange mutually around the sheet heart 10 32 ' cut edge, but keep at a certain distance away a little, approximates thin film 32 greatly, 32 ' thickness.

If aesthetic requirement is arranged, thin film 32,32 ' arrangement makes the product 122 that produces that thin film seam 134 be arranged, wherein a kind of colour play of thin film 32 (for example, red streak 84) a kind of colour play (for example, yellow cord 90 ') of (or visually difference) and another thin film 32 ' (or visually difference) near or overlapping, be formed with the product 122 of " checkerboard pattern ", that is, red and yellow mutual four quadrants (or other visual difference) are arranged.

With reference to [MCP 301] _ _ _ _ _ _ _ _ _ Figure 17-19 of application shows the selectable film casting equipment 136 can be used for coating processing.Selectable film casting equipment 136 comprises the thin film receiving device, and as the metal casting band 140 of routine, it is contained on two going barrels 142,144 that are used to be accepted thereon the thin film 138 that casting becomes.Going barrel 142,144 rotation, thus make casting be with 140 to move along arrow J and K indicated direction.Heating plate 148 can place near casting is with 140 to be with 140 with warm casting before the plastic casting film thereon.Cooler pan 150 can place near casting and be with 140 with cooling casting band 140 after the plastic casting film thereon.

Selectable equipment for making film 136 further comprises film deposition apparatus, as reciprocal multicell breach extruder 146, is with deposit film 138 on 138 in semicontinuous mode in casting.With breach extruder 38 discussed above, separator 152,154,156 in back and forth breach extruder 146 comprises forms inner room 158,160,162,164 and holds visually different coating substance 166,168 therein.It also provides breach 170, is with on 140 by its coating substance 166,168 delivery chamber 158,160,162,164 and to casting, thereby produce striped thin film 138 is arranged.

Back and forth multicell breach extruder 146 also comprises feeding mechanism, as feed pipe 182,184 coating substance 166,168 is provided to chamber 158,160, each chamber of 162,164, and volume control device are as control coating substance 166,168 from the chamber 158,160,162,164 mobile sliding door.Back and forth separator 152,154,156 has the striped control device in each of multicell breach extruder 146, as taper sword limit, with flowing of control coating substance 166,168, withdraws from chamber 158,160,162,164.Notable difference between above-mentioned breach extruder 38 and the present reciprocal breach extruder 146 is that reciprocal breach extruder 146 is connected to conventional motor, makes its move back and forth according to the arrow M indicated direction of Figure 18 of [MCP 301] application.

At the beginning, feed pipe 182,184 is with two kinds of colors, as being the alternately chamber 158,160,162,164 that redness and xanchromatic coating substance 166,168 are provided to reciprocal breach extruder 146 respectively respectively.In the chamber in 158,160,162,164, coating substance 166,168 becomes liquid and can flow or keep liquid and can flow.When 140 surfaces were with in coating substance 166,168 physics contact casting, the partly solidified at least coating substance 166,168 of cooler pan 150 formed horizontal stripe thin film 138.

After coating substance 166,168, heating plate 148 and cooler pan 150 obtained temperature that they need, casting was heated dish 148 heating and brings up to position below the reciprocal breach extruder 146 by going barrel 142,144 subsequently with a part 198 of 140.Sliding door 180 moves to the position subsequently, opens the thickness that breach 170 needs to striped thin film 138.When going barrel 142,144 and casting when being with 140 to keep static, coating substance 166,168 delivery chamber 158,160,162,164, along taper sword limit (not shown), through breach 170 and to casting with on 140 the heating part 198, keeping coating substance 166,168 momently is being the flow regime of liquid substantially.

Coating substance 166,168 flow to casting with 140 on the time, back and forth breach extruder 146 moves to second position 196 from first position 194, it is supspended there.Back and forth breach extruder 146 1 arrives second position 196, and sliding door 180 just moves to the closed position, thereby has blocked breach 70 and supspended flowing of coating substance 166,168, and the result forms thin film fragment 200.Thin film fragment 200 has alternative horizontal red streak 172,176 and yellow cord 174,178, and the color conversion 186,188,190 of direct sum unanimity wherein.

Then, casting is with 140 to move by going barrel 142,144, makes the thin film fragment move, and casting is with 140 the new heating part position below reciprocal breach extruder 146.Be with when casting on 140 in casting when the second thin film fragment, the first film fragment 200 is cooled.

When needing subsequently thin film fragment of casting, be in second position 196 now at reciprocal breach extruder 146, casting is with 140 to keep static, and sliding door 180 moves to the position once more, opens breach 170, and amount is to equal the thickness that striped thin film 138 needs.Flow out to casting at coating substance 166,168 and be with on 140, back and forth breach extruder 146 is moved back into its first position 194 from second position 196, and it is supspended once more there.Be placed in casting when being with on 140 at coating substance 166,168, new segmental first edge of thin film contacts also bonding with second edge 204 of the first film part 200.After back and forth breach extruder 146 was got back to its first position 194, sliding door 180 moved to the closed position once more, thereby blocked breach 70 and supspend flowing of coating substance 166,168, and the result has produced and the first film fragment 200 adherent new thin film fragments.

The aforesaid course of processing is continued to repeat, and forms semi-continuous film casting process, produces the continuous band of horizontal stripe thin film 138.Horizontal stripe thin film 138 is with 140 to continue mobile and be added to rotation mould coating equipment 102 subsequently to be used for the coated tablet heart 10 as stated above by scraper or other devices from casting.But, because selectable film casting equipment 136 produces the thin film 138 that travers are arranged, rotation mould 208,208 ' has recess 210,210 ', recess 210,210 ' orientation makes their length and the rotating shaft arranged vertical of their rotation moulds separately.In addition, the sheet heart allocation device that herein uses is located and is disperseed the end of each sheet heart 10 at first to arrive mould 208, the folder between 208 ', that is, enter when folder, make the end 12 of each capsule sheet 10 at the sheet heart 10, thin film 138,138 ' is concentrated in a contact simultaneously in 14.

Reference [MCP 301] _ _ _ _ _ _ _ _ _ _ Figure 22-30 of application relates in preparation the selectable coating equipment of the thin film of different piece visually, and this equipment comprises above-mentioned selectable film casting equipment 136.The travers thin film is added in the selectable coating equipment along the sheet heart produces double-colored product, and this travers thin film each have part only to center on the thin film seam of the sheet heart, and this thin film is positioned on the plane of reference different with the plane of reference of the color conversion of product.

Selectable coating equipment comprises transfer system 220, and this transfer system comprises the cylinder 222 of a series of horizontal directions and several to cylinder 224,226, and 228 to support and to transmit Cross slat thin film 138.Sheet heart dispersal device 230 is positioned at and transmits on transfer system 220 and the thin film 138 with color conversion 186,188, and the 190 direction dispersible tablet hearts 10 that need are to thin film 138.Sheet heart dispersal device 230 comprises lath feeder 234,236, and it is by the requirement spacer heart that correctly navigates on the thin film 138.Sheet heart dispersal device 230 further comprises sheet heart location lath 238 and is positioned at sheet on the lath 238 of the location plug 240 of being indecisive and changeable.

The sheet heart 10 is charging in 232 from hopper, by lath feeder 234,236 to location lath 238.The sheet heart 10 ', 10 ", 10 " ' arrangement be straight, terminal 12 pairs of ends 14, so the sheet heart of each sheet heart and its back moves along locating lath 238 with successive substantially form.When the sheet heart 10 ' is pushed above guide rail support 248, therefore 250 also no longer support, when the position of the color conversion 186 of thin film 138 is positioned at the symmetrical conjugate planes 18 ' of the sheet heart 10 ', LD device 242 signals to motor, and motor starting piston 240 high and lows motion contacts and rests on the thin film 138 until the sheet heart 10 '.When piston 240 arrives its highest positions, it temporarily stops until the next sheet heart 10 " be moved beyond the guide rail support 248,250 that is included in the lath 238 of location.As long as the sheet heart 10 is fed and move aforesaid process and carry out with regard to continuing repeatedly by location lath 238.

The beginning part of transfer system 220, that is, localized part between the short spacing that can select on lath 238 opposites, the film casting equipment 136 and sheet heart location comprises horizontal direction cylinder 222.Thin film 138 is moved along the beginning part by horizontal direction cylinder 222.All the other positions of transfer system 220 are positioned between the short spacing and rotation mould 260,262 through location lath 238, comprise several to cylinder 224,226,228.Diagram as Figure 26 of [MCP 301] application shows that several to cylinder 224,226 continuously, 228 independent cylinder upwards rotates gradually and continuously from horizontal plane, and each is continuously to cylinder 224,226, and 228 from beginning to increase about 10 degree near location lath 238.Correspondingly, along with thin film 138 approaching rotation moulds 260,262, thin film 138 is longitudinal folding near the sheet heart 10.

260,262 rotations of rotation mould and the formation folder therebetween of cooperating with each other add the sheet heart 10 and thin film 138 therein.Similarly, each has recess 282,284 in the mould 260,262, arranges circumferentially on each mould 260,262 surface.Each is useful on recess 282,284 along near the sealing sheet heart 10 and cuts the edge that the height of adherent thin film 138 rise, thus the coated tablet heart 10.But rotation mould 260,262 is directed and makes them be rotatable in a horizontal plane, rather than the rotation mould of discussing in the past 112,112 ', 208, and 208 ' rotates in vertical plane.And, when the sheet heart 10 is added in the folder, thin film 138 be folded and near the sheet heart part bonding.And the sheet heart of part coating promptly, is added in the folder between the mould 260,262 one by one by continuous feed.

Shell also vacuum available formation device is applied to the sheet heart.Common U.S. Patent application No.[MCP 301 and the MCP306 undetermined that transfers the possession of] _ _ _ _ _ _ _ _ _ this equipment disclosed.

With reference to [MCP 301] _ _ _ _ _ _ _ _ _ _ _ Figure 31-44 of application, vacuum forms device 292 and comprises that first most porous pressing plate 294, the first transfer systems 296 separately and second transmit transfer system 298.First and second transfer systems 296,298 are by mutual serial ordering, thus the single passage that formation porous pressing plate 294 moves with semicontinuous form.When equipment moves, first and second transfer systems 296,298 have conventional vacuum source vacuum are applied to each porous pressing plate 294.

Vacuum forms device 292 and further comprises second most porous pressing plates 304 separately and move the 3rd transfer system 306 of porous pressing plate 294 along second channel, sees shown in Figure 31 arrow G G.The 3rd transfer system 306 is positioned between first and second transfer systems 296,298.

Rotating machinery device 308 also is positioned between first and second transfer systems 296,298.Rotating machinery device 308 holds two pressing plates together simultaneously, that is, a pressing plate 294 and corresponding pressing plate 304, they rotate together, make beginning be reversed and place on the bottom at the pressing plate 304 at top.

Each porous pressing plate 294,304 has a recess 210,312 at least respectively, its size and shape be fit to temporarily but snugly acceptance therein treat the sheet heart of coating.

It is possible that use has the various combination of the pressing plate of horizontal and vertical striped thin film to obtain to have versicolor coated product in many different modes.But, in a special vacuum forming device, all pressing plates 294, the direction of 304 recess 310,312 must be longitudinally, or alternatively, the direction of the recess 310,312 in all pressing plates 294,304 must be horizontal (or the direction of striped is arranged on opposite and the thin film).

Vacuum forms device 292 and further includes thin film 342 first pair of cylinder 338,340 placed on it.First pair of cylinder 338,340 is positioned near first transfer system 296, makes the first film 342 be suspended from first most porous pressing plates 294.Thin film 348 second pair of cylinder 344,346 position placed on it are arranged near second transfer system 298, make second thin film 348 also be suspended from first most porous pressing plates 294.

Vacuum forms device 292 and also comprises first LD device 350 that is positioned near first transfer system 296, correctly to settle the first film 342 with respect to the sheet heart 10 in the recess 310 of porous pressing plate 294.Second LD device 352 is positioned near second transfer system 298, correctly to settle second thin film 348 with respect to the part coated tablet heart 10 in the recess 310 of another porous pressing plate 294.

Vacuum forms device 292 and also comprises first annular press 354 and the first film cutting machine 356 that is positioned near first transfer system 296 and complex form motion in the past.In addition, the position of the second annular press 358 and second film cutter 360 is near second transfer system 298.Each has open configuration the first and second annular press 354,358, is O shape or ellipse as seeing from above, makes by wherein forming passage 362,364 respectively.Each also has engagement edge 366,368 respectively in the annular press 354,358, and installation is used for contacting respectively first and second thin film 342,348 and does not destroy them.Each annular press 354,358 is dimensioned and formalizes, like this engagement edge 366, the 368 qualifications sheet heart 10 wherein.

Each has recess 370,372 respectively first and second film cutters 356,360, and its size and shape are adapted at wherein accepting having the part of the part coated tablet heart 10 that film coating is applied thereto.The first film cutting machine 356 is directed the porous pressing plate 294 that is positioned under it to face, and second film cutter 360 is directed the porous pressing plate 304 that is positioned under it to face.First and second film cutters 356,360 also move back and forth.

The first film 342 be installed on first pair of cylinder 338,340 and between extend, make the first film 342 be positioned at first transfer system 296 and first most porous pressing plates 294 on one side, the first annular press 354 and the first film cutting machine 356 are at another side.Similarly, second thin film is mounted second pair of cylinder 344, on 346 and between extend, make second thin film 348 be positioned at second transfer system 298 and first most porous pressing plates 294 on one side, the second annular press 360 and second film cutter 362 are at another side.

At the beginning, first, second and the 3rd transfer system 296,298,306 setting in motions, thereby make porous pressing plate 294,304 by [MCP 301] _ _ _ _ _ _ _ _ _ _ the arrow E E of Figure 31 of application, FF, GG indicated direction motion respectively.First transfer system 296 makes porous pressing plate 294 move to the directly position before first stop 378.The sheet heart 10 is placed in the recess 310 of this porous pressing plate 294 and by vacuum mentioned above and firmly is contained in the recess 310, and this vacuum is continuously applied every other porous pressing plate on porous pressing plate 294 and the transfer system 298 by first vacuum source 300.

Moved to first stop 378 with rear fender 294 by first transfer system 296.When first LD device 350 determined that the sheet heart 10 is correctly settled, the motion of pressing plate 294 was supspended.Temporary transient when static when pressing plate 294, blow hot-air through the first annular press 354, thereby but softening the first film 342 to shaped state.The first annular press 354 moves subsequently, makes the engagement edge 366 of the annular press 354 of winning oppress the first film 342 and contact with the first half of the sheet heart 10 on the working surface of pressing plate 294.

By vacuum mentioned above, the first film of heating is pulled on the sheet heart 10 simultaneously and therefore makes the shape of the first half that meets the sheet heart 10.After this, first annular press 354 withdrawals, pressing plate 294 moves to second station 380, and it temporarily stops there.When pressing plate 294 and the sheet heart 10 are temporarily static, cold air blows on the first film 342 and the sheet heart 10, therefore the first film 342 that meets of the first half of cooling and molding and the sheet heart 10.

With reference to [MCP 301] _ _ _ _ _ _ _ _ _ _ _ application Figure 36-44, the first film 342 on the sheet heart 10 by cooling and molding after the enough time, the sheet heart 10 of pressing plate 294 and part coating is moved to vacuum by first transfer system 296 according to predetermined distance and forms the 3rd station 382 of device 292 and supspend there and make the part coated tablet heart 10 and the cut edge 374 of recess 370 and the first film cutting machine 356 arrange.The first film cutting machine 356 is moved until the part coated tablet heart 10 and is received in the recess 370 by applying, and taper-cut edge 374 contacts and be close to the girth cutting the first film 342 of the part coated tablet heart 10.The first film cutting machine 356 is removed from pressing plate 294 subsequently.

The pressing plate 294 and the part coated tablet heart 10 are moved to vacuum subsequently and form the 4th of device 292, or rotation, stands 384 also to supspend once more, so the part coated tablet heart 10 is as mentioned below, are transferred to a pressing plate 304.The 3rd transfer system 306 moves a pressing plate 304 in turning base 384 positions, makes that it is reversed positions with respect to the pressing plate 294 that carries the part coated tablet heart 10 thereon.After pressing plate 294 moves by predetermined distance, make the arrangement of recesses of the part coated tablet heart 10 and the pressing plate of putting upside down 304, first transfer system 296 holds pressing plate 294, and the part coated tablet heart 10 is temporarily static at turning base 384.With rear fender 304 to the part coated tablet heart 10 move in the part coated tablet heart 10 is accommodated in the recess 310,312 of pressing plate 294,304 (as [MCP 301] _ _ _ _ _ _ _ Figure 31 and 40 of application shown in).The vacuum that puts on porous pressing plate 294 is interrupted, pressing plate 294,304 and 10 rotations of the part coated tablet heart therebetween, and the pressing plate 294 that wherein holds the sheet heart 10 is reversed, and pressing plate 304 moves to position up, right side.The pressing plate put upside down 294 now from the right side up pressing plate 304 remove, make a pressing plate 304 along [MCP 301] _ _ _ _ _ _ _ _ _ approach shown in the arrow G G of Figure 31 of application moves.Then right side pressing plate 304 up moves on second transfer system 298, makes the arrow E E of a pressing plate 294 along Figure 31 of [MCP 301] application, and the approach shown in the FF moves.Then, apply vacuum to the part coated tablet heart 10, thus in the recess 310 of pressing plate 294 the holding portion coated tablet heart 10, move on pressing plate 294 present second transfer systems 298, make the unmasked portion of the sheet heart 10 of part coating expose.

The pressing plate 294 and the part coated tablet heart 10 are moved to the 5th station 386 that vacuum forms device 292 by second transfer system 298.When second LD device, the 352 determining section coated tablet hearts 10 were correctly located with respect to second thin film 248, the motion of pressing plate 294 was supspended.When pressing plate 294 temporary transient when static, but hot-air is blown into softening second thin film 348 to shaped state by the second ring-type press 358.The second ring-type press 358 moves and makes the engagement edge 368 of the second ring-type press 358 contact on the working surface 314 of pressing plate 294 and oppress second thin film 348 and contact with the unmasked portion of the part coated tablet heart 10 subsequently.

By the vacuum that second vacuum source 302 provides, second thin film 248 of heating is pulled on the sheet heart 10 subsequently, therefore the unmasked portion of second thin film 248 and the sheet heart 10.After this, second annular press 358 withdrawals move to the 6th station 388 by vacuum with the pressing plate 294 that the coated tablet heart 10 is contained in the recess 310, and temporarily stop there.Should be noted that as [MCP 301] _ _ _ _ _ _ _ _ _ _ _ application shown in Figure 42, second thin film 348 be applied in thin unconcerned 342 the cut edge of first on the sheet heart 10 and overlapped.Temporary transient when static when pressing plate 294 and the sheet heart 10, cold air blows on second thin film 248 and the sheet heart 10, thereby makes 348 coolings of second thin film and make it consistent with the sheet heart 10 moldings.

Second thin film 348 is at cooling and molding after the enough time on the sheet heart 10, the pressing plate 294 and the coated tablet heart 10 are moved to the 7th station 390 of vacuum formation device 292 by second transfer system 298 by predetermined distance and supspend there, make the coated tablet heart 10 and the cut edge 376 of the recess 372 and second film cutter 360 arrange.Second film cutter 360 is moved until the coated tablet heart 10 and is received in the recess 372 by next to the shin, and cut edge 376 contact and the girth of being close to the coated tablet heart cut second thin film 248.Second film cutter 360 is removed from pressing plate 294 subsequently.

The pressing plate 294 and the complete coated tablet heart 10 are shifted out from the 7th station 390 by second transfer system 298.After pressing plate 294 and the coated tablet heart 10 were through the 7th station 390, the vacuum that is applied to pressing plate 294 was ended, thereby disengages coated product 404 from recess 310.

Alternatively, can use and have the height that can clearly be cut first and second thin film 342,348 and play the recess pressing plate that the cut edge limits.Alternatively, replace at first capsule sheet 10 being placed the recess 310 of first pressing plate 294, the first film 342 can be placed on first pressing plate, but warm air can blow to and it softened become shaped state subsequently.Subsequently, can apply vacuum through pressing plate conforms to so that the first film 342 is moved to recess and made it.After this, the sheet heart 10 can be placed in the recess 310, and cold air blows to pressing plate 294, the first film 342 and sheet in the heart, makes the first film 342 consistent with the sheet heart 10 moldings.Second thin film 348 can be placed on the pressing plate subsequently, and on the sheet heart 10, but warm air blows to and it softened become shaped state.Another pressing plate moves then and contacts with second thin film 348, tightly suppresses the sheet heart 10 and first pressing plate 294 with second thin film 348, and second thin film 348 is conformed to the profile of the sheet heart.Cold air blows on second thin film 348 subsequently, thus on capsule sheet 10 molding second thin film 348.At last, first and second thin film 342,348 can be cut in the cut edge that the height of recess rises, thereby disengage coated product.

It should be noted, the temperature range of hot cold air, and the vacuum pressure scope is known to the those skilled in the art.

At shell is to be applied in the sheet embodiment in the heart by spraying, anxiety, coating or molding, and it is preferable that shell is applied to the sheet heart with the stream material form.Stream material can comprise dissolving, disperses or melt composition, randomly can randomly be removed the solvent of liquid-carrier composition in the course of processing, for example by dry.No matter use which kind of method, the shell of finishing and correspondingly prepare the stream material of shell, it is preferable to comprise film former.Randomly, shell of the present invention and Yi Rong shell part can further comprise one or more thickening agents known in the art and various adjuvant and/or excipient.

Any film former known in the art is suitable for stream material.The example of suitable film former includes, but not limited to thin film and forms water-soluble polymer, thin film formation protein, thin film formation insoluble in water polymer and thin film formation pH dependence polymer.In one embodiment, film former can be selected from cellulose acetate, ammonio methacrylate copolymer type B, Lac, hydroxypropyl methylcellulose and poly(ethylene oxide) and their compositions.

Suitable thin film forms water-soluble polymer and comprises water-soluble ethylene based polyalcohol such as polyvinyl alcohol (PVA); Water-soluble poly carbohydrate such as hydroxypropyl starch, hetastarch, amylopectin sugar, the first and second basic starch, carboxymethyl starch, starch,pregelatinized and thin film form modified starch; Hydroexpansivity cellulose derivative such as hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), methylcellulose (MC), hydroxyl second methylcellulose (HMEC), hydroxyl fourth methylcellulose (HBMC), hydroxyl second ethyl cellulose (HEEC), hydroxyl second hydroxypropyl methylcellulose (HEMPMC); Water solubility copolymer such as methacrylic acid and methacrylate copolymer, polyvinyl alcohol and ethylene glycol copolymer, poly(ethylene oxide) and polyvinylpyrrolidone copolymer; With their derivant and compositions.

It can be natural or chemical modification that suitable thin film forms protein, and comprise gelatin, myofibrillar protein, solidifiable albumen such as albumin, casein, caseinate and casein separator, lactalbumin, soybean protein and soy protein isolate, zein, reach their polymer, derivant and mixture.

The water insoluble polymer of suitable thin film comprises for example ethyl cellulose, polyvinyl alcohol, polyethylene acetate, polycaprolactone, cellulose acetate and derivant thereof, acrylates, methacrylate, acrylic copolymer; Or the like and their derivant, copolymer and compositions.

Suitable thin film forms pH dependence polymer and comprises the intestinal cellulose derivative, as phthalic acid hydroxypropyl methylcellulose, succinic acid acetic acid hydroxypropyl methylcellulose, cellulose acetate phthalate, natural resin, as Lac and zein; Intestinal acetic acid derivative such as phthalic acid polyvinyl acetate, cellulose acetate phthalate, acetaldehyde acetic acid dimethyl cellulose; Commercially produced product polymer (the methacrylic acid that provides with trade name EUDRAGIT S with intestinal acrylic acid derivative such as polymethylacrylic acid based polyalcohol such as RohmPharma GmbH, the methyl acrylate) poly-(methacrylic acid of commercially produced product that 1: 2 and Rohm Pharma Gmbh provide with trade name EUDRAGIT L; Methacrylate) 1: 1, or the like and their derivant, salt, copolymer and compositions.

A kind of suitable hydroxypropyl methylcellulose chemical compound as thermoplastic film formation water-soluble polymer is " HPMC2910 ", the degree of exchange of its cellulose ether about 1.9, the mole degree of exchange of hydroxypropyl is 0.23, based on the gross weight of chemical compound, this chemical compound contains have an appointment 29% to about 30% methoxy group and about 7% to 12% hydroxypropyl group.The commercially produced product of HPMC2910 is provided by Dow Chemical Company, its trade name METHOCEL E.METHOCEL E 5 is ranks that are applicable to HPMC2910 of the present invention, at 20 ℃, determines its viscosity about 4 to 6cps (4 to 6 bold and unconstrained Pascal/second) with the Ubbelohde viscometer in 2% the aqueous solution.Similarly, METHOCEL E 6 is applicable to another rank of HPMC2910 of the present invention, at 20 ℃, determines its viscosity about 5 to 7cps (5 to 7 bold and unconstrained Pascal/second) with the Ubbelohde viscometer in 2% the aqueous solution.METHOCEL E 15 is applicable to another rank of HPMC2910 of the present invention, at 20 ℃, determines the about 15000cps of its viscosity (15 bold and unconstrained Pascal/second) with the Ubbelohde viscometer in 2% the aqueous solution." degree of exchange " used herein refers to be attached to the average number of the displacement group on the anhydroglucose ring, and " hydroxypropyl mole degree of exchange " refers to the molal quantity of every mole of anhydroglucose hydroxypropyl.

A kind of suitable polyvinyl alcohol and ethylene glycol copolymer are the commercialization goods that BASF Corporation provides, trade name KOLLICOAT IR.

" modified starch " used herein is included as and improves stability or optimize performance and crosslinked, the starch of chemical modification, or for improving dissolubility property or optimizing the starch of performance physical modification.The example of converted starch is well known in the art and generally includes the starch that is substituted some hydroxyls by chemical treatment with ester or ether group.Used herein crosslinked can be to take place in the chemical banded modified starch at two oh groups of adjacent starch molecule." starch,pregelatinized " used herein or " instant starch " have referred to humidifying in advance, and subsequent drying is to increase the modified starch of cold water solubility.Suitable modified starch can be buied from many suppliers, for example, and A.E.StaleyManufacturing Company and National Starch ﹠amp; Chemical Company.A kind of suitable modified starch comprises the wax shape corn derivatized starch of pregelization, and this starch is by National Starch ﹠amp; ChemicalCompany is with trade name PURITY GUM and FILMSET provides and their derivant, copolymer and mixture.Above-mentioned waxy corn starch comprises usually, based on this starch gross weight, and about 0% to about 18% amylose and about 100% to about 82% amylopectin.

Other suitable thin film form modified starches and comprise hydroxypropyl acidify starch, wherein some hydroxyls of starch with the hydroxypropyl etherificate, handle by the propylene oxide thing usually.An example with suitable hydroxypropyl starch of thin film formation characteristic is the product that Grain Processing Company provides with trade name PURE-COTE B790.

Suitable Maninot esculenta crantz. dextrin as film former comprises National Starch ﹠amp; The material that Chemical Company provides with trade name CRYSTAL GUM or K-4484 and the derivant of this material are as the modified food starch derived from tapioca, and this starch is by National Starch ﹠amp; Chemical provides with trade name PURITY GUM 40, and the copolymer of this material and mixture.

Any thickening agent of knowing in this area can be used for stream material of the present invention.The example of this thickening agent includes but not limited to hydrocolloid (also referring to the gelling compound herein), clay, gelatinized starch and crystallizable carbohydrate and their derivant, copolymer and compositions.

The example of suitable hydrocolloid (also referring to gel polymer herein) such as alginate, agar, guar gum, carob, carrageenin, tara gum, arabic gum, tragacanth, pectin, xanthan gum, gellan gum, maltodextrin, galactomannan, pustulan, laminarin, scleroglycan, inulin, pectin, whelan, rhamsan, zooglan, methylan, chitin, cyclodextrin, chitosan.The example of suitable clay comprises terre verte such as bentonite, Kaolin and laponite; Magnesium trisilicate, Magnesiumaluminumsilicate, or the like and their derivant and mixture.The example of suitable gelatinized starch comprises acid hydrolyzed starches and their derivant and mixture.Suitable in addition viscous water colloid comprises the mixture of low humidity polymer solution such as gelatin and other hydrocolloids, and the water content of this mixture is up to about 30%, as is used for making " gummi " confection form.

Suitable thickening comprises crystallizable carbohydrate in addition, or the like and their derivant and compositions.Suitable crystallizable carbohydrate comprises monosaccharide and oligosaccharide.In monosaccharide, as aldohexose, D and L isomer as allose, A Zhuo hexose, glucose, mannose, gulose, idose, galactose, talose and ketohexose, as the D and the L isomer of fructose, sorbose and their hydrogenated analogs, preferable as glucitol (Sorbitol) and mannitol.In oligosaccharide, 1,2-disaccharide sucrose and trehalose, 1,4-disaccharide maltose, lactose, and cellobiose, with 1,6-disaccharide gentiobiose and 6-(.alpha.-D-galactosido)-D-glucose. and trisaccharide melitriose and the sucrose isomerization form and the different Fructus Hordei Germinatus of hydrogenated analogs thereof that are called isomaltulose are preferable.Other hydrogenated forms of reduction disaccharide (as maltose and lactose), as, maltose alcohol and lactose also are preferable.In addition, the hydrogenated form of aldopentose: as the hydrogenated form of D and L sheet heart sugar, arabinose, xylose and lyxose and aldotetrose: as D and L erythrose and threose is preferable, and is example with xylitol and erythritol respectively.

In one embodiment of the invention, stream material comprises gelatin as gel polymer.Gelatin is a kind of natural hot glue cohesion compound.It is the colorless and odorless mixture that dissolves in the albumin class derived protein of warm water usually.Normally used gelatin has two types-A type and Type B.A type gelatin is the derivant of acid treatment raw material.The Type B gelatin is the derivant of alkali-treated raw materials.The moisture of gelatin, and Bloom intensity, composition and original gelatin processing conditions have determined its inversion temperature between liquid and solid.Bloom is the gauge of gelatin gel body intensity, and it and molecular weight have rough relation.It is unit of weight that Bloom is defined as with the gram, is used for measuring that to reach mobile diameter in 17 hours the 6.67% gelatin gel body be plastic piston 4 millimeters required power of half inch keeping 10 ℃.In a preferred embodiment, stream material is the pigskin gelatin that comprises 20%275 Bloom, the water of the bone gelatin of 20%250 Bloom and about 60% water.

Suitable xanthan gum comprises that by C.P.Kelco Company with trade name KELTROL 1000, XANTROL 180, or the material that provides of K9B310.

Suitable clay comprises terre verte such as bentonite, Kaolin and laponite; Magnesium trisilicate, Magnesiumaluminumsilicate, or the like and their derivant and mixture.

" acid hydrolyzed starches " used herein is a class modified starch that produces at the Temperature Treatment starch suspension that is lower than starch gelling application point by dilute acid.In acid hydrolysis, the particle form of starch maintains in the starch suspension, in case reach the hydrolysis degree that needs, hydrolysis stops by neutralization, filtration and drying.As a result, the mean molecule of starch polymer size descends.Acid hydrolyzed starches (being also referred to as " rare cooking starch ") is compared with identical native starch and is more prone to gel when having tended to lower thermoviscosity and cooling.

" gelatinized starch " used herein comprise with water combination and be heated to the temperature that is enough to form solution, thereby form gel when being cooled to be lower than the temperature of starch gelling application point.The example of gelatinized starch includes, but not limited to the product that acid hydrolyzed starches such as Grain Processing Corporation provide with trade name PURE-SET B950; Product that two starch phosphate hydroxypropyl acrylates such as Grain Processing Corporation provide with trade name PURE-GEL B990 and their mixture.

Suitable eutectic hydrophobic substance comprises fat, fatty acid ester, phospholipid and wax.The example of suitable fat comprises hydrogenated vegetable oil for example cocoa butter, hydrogenated palm kernel oil, cotmar, hydrogenation Oleum helianthi and oil with hydrogenated soybean, free fatty and their salt.The example of suitable fatty acids ester comprises sucrose fatty acid ester, monoglyceride, double glyceride, triglyceride, Glyceryl Behenate, Palmic acid tristerin, glyceryl monostearate, glyceryl tristearate, trilaurin, myristin, Glyco Wax-932, dodecanoyl Polyethylene Glycol-32 glyceride and stearoyl Polyethylene Glycol-32 glyceride.The example of suitable phospholipid comprises phosphatidylcholine, Phosphatidylserine, phosphatidylinositols and phospholipid phosphonic acids.The example of suitable wax comprises Brazil wax, spermaceti, Cera Flava, wax rhimba wax, shellac wax, microwax and paraffin; Fatty mixture such as chocolate, or the like.

Suitable non-crystallizable carbohydrates comprises non-crystallizable sugars such as poly dextrose and starch hydrolysate, as dextrose syrup, corn syrup and high-fructose corn syrup; With non-crystallizable sugar-alcohols such as maltitol syrup.

The suitable solvent that randomly is used as the composition of stream material comprises water, polar organic solvent such as methanol, ethanol, isopropyl alcohol, acetone or the like; With non-polar organic solvent such as dichloromethane or the like; With their mixture.

Be used to spray, flood, be coated with the stream material that sugar-coat or molding prepare shell and can randomly comprise adjuvant or excipient, can comprise nearly about 30 weight % of stream material.The suitable adjuvant or the example of excipient comprise plasticizer, antitack agent, wetting agent, surfactant, defoamer, coloring agent, correctives, sweeting agent, opacifier or the like.The suitable manufacturing methods of making the sheet heart, shell and their part by molding includes but not limited to Polyethylene Glycol; Propylene glycol; Glycerol; Sorbitol; Triethyl citrate; Tributyl citrate; Dibutyl sebacate; Vegetable oil such as Oleum Ricini, vegetable oil, olive oil and Oleum sesami; Surfactant such as polysorbate, dodecanol sodium sulfate, and dioctyl sodium sulfosuccinate; The glycerol monoacetate; The glycerol diacetate; The glycerol triacetate; Natural gum; Triacetin; Citric acid acetyl tributyl; Diethyl oxalate salt; The diethyl malate; The diethyl fumarate; Diethylmalonate; The dioctyl phthalic acid; The dibutyl succinate; Glycerol three butyrates; Castor oil hydrogenated; Fatty acid; The triglyceride and the glyceride that replace; Or the like and/or their mixture.In one embodiment, plasticizer is a triethyl citrate.In certain embodiments, shell does not have plasticizer basically, that is, comprise less than about 1%, that is to say to be less than about 0.01% plasticizer.

Opening can prepare in shell in any form.Known to many methods in manufacturing opening and hole were pharmacy and other field in coating, wherein any method can be used.It will be appreciated by those skilled in the art that the distinct methods of making opening can be used in combination with the distinct methods of making dosage form and/or be applied on the shell.The method of making opening also depends on the character and the compositions of shell, also has the situation of outer coating if any.Opening can any several different steps in procedure of processing of the present invention form in shell, depends in part on shell is applied to sheet step in the heart.Be applied to sheet embodiment in the heart for shell by being coated with sugar-coat, opening can form during plastic casting film forms, and form the back at plastic casting film but before thin film is applied to the sheet heart, be applied to sheet between heart stage at thin film, or after thin film is applied to the sheet heart.For by dipping, shift, spraying or molding be applied to the embodiment of the sheet heart with shell, opening can be applied to sheet between heart stage at shell, or forms in shell material after shell is applied to the sheet heart.

For example, the ablation method to the erosion of shell, thawing or evaporation uses by water jet erosion, blasting treatment, mills, arc evaporation, dielectric breakdown, ion beam sputtering, ultrasound wave attrition process, cavitation corrosion fluid jet or laser evaporation prepare opening.Machining is as at dipping, or punching press, the perforation of vacuum after removing, cuts, pinks, holes, shelters and can be used to prepare opening.Chemical method, shelter acid etching, tool as acid reaction, alkali reaction, solvent clean, tool and shelter photoetch, anisotropy wet chemical etching, isotropism wet chemical etching, hydrophobic interaction and the point of non-humidifying material for example is imprinted on the cylinder, or the heating opacifying effect can be used for preparing opening.Relate to the method that heat is used, as melting with fomentation bucket, Laser Processing, arc evaporation, ultrasound wave thawing or cavitation erosion, microwave heating, high-energy method such as plasma method, infrared ray selective polymerisation thing is handled, or can be used for preparing opening with the iron-containing additive eddy-current heating.At last, adding method such as painted, dipping, solvent clean, with woven material, line and the band coated tablet heart, remove masking material with the masking material spray coating and by solvent or hydrophobic incompatibility, spray by masking sheet, materials used band in shell, or assemble line or net or pad also can be used for preparing opening.

In one embodiment of the invention, shell is applied to sheet in the heart by thermal cycle molding as indicated above, and opening forms by the one or more projections on the inner surface of at least one mold assemblies.Each projection, shape and size are adjusted on demand, and the little position of having sheltered the lower panel heart has stayed opening at the position of projection in shell.Mold assemblies can comprise many projections and form many corresponding openings in shell.Projection can be positioned at the inner surface that has only a mold assemblies, promptly goes up mold assemblies, or only is positioned at a part, promptly is positioned at a quadrant of the inner surface of a mold assemblies on demand.Perhaps projection can arrange to form pattern, symbol, word or the like in shell.

In another embodiment of the invention, use as U.S. Patent No. 5,146,730 and 5,459, the thin film of 983 described homogeneities visually, or common U.S. Patent application No.__________[MCP 301 undetermined and the MCP3 16 that transfers the possession of] _ _ _ _ _ _ _ _ _ _ _ _ _ in the thin film of different piece is visually arranged, by coating shell is applied to the sheet heart.In each case, the plastic casting film that is used for coating steps coating cross the Cheng Qian, during or be perforated later on.

In one embodiment, shell is applied to the sheet heart by coating, the formation of opening can be at the mo(U)ld face by use suitable shape or quality, as freezing thin film form reel ([MCP 301] _ _ _ _ _ _ _ _ _ application in the outer surface 36 of casting mold drum 34), during the plastic casting film that opening is casted into the mechanical means in the shell forms.Suitable quality comprises that the sufficiently high surface of projection makes the thin film of pouring into can not seal projection, therefore stays opening in refrigerative thin film.Fig. 7 has shown the formation cylinder 1010 on the surface 1020 that the suitable quality that produces space, crack or open area in thin film is arranged.This thin film has comprised opening when arriving the dyeing cylinder.

In second embodiment, its mesochite is applied to the sheet heart by coating, opening can be after thin film forms and thin film apply and use before the sheet heart in casting film machinery and pink or punching press.For example, Fig. 8 and 9 shows at the perforating apparatus 1030 that forms between cylinder 1010 and the dyeing cylinder 1040.This perforating apparatus is pinked opening or be stamped in the thin film of formation.In another embodiment, use vacuum formation method to be applied to the sheet heart by coating, thin film forms plate (promptly in vacuum, as [MCP 301] _ _ _ _ _ _ _ _ _ _ the many porous pressing plates 294 described in the application) the hole shape vacuum that goes up to settle the sheet heart in recess forms, formed in the past inserting the sheet heart with after-opening.In a particular, jagged formed film removes from forming on the plate (that is, many porous pressing plates 294), and runs to perforating apparatus.In another embodiment, jagged formed film keeps in touch with forming plate (that is, many porous pressing plates 294), forms opening therein by suitable ablation method before the sheet heart inserts.A kind of specially suitable ablation method uses laser " burning " on demand shape, size and pattern formation opening on the thin film that forms among the application.

Another particular, its split shed formed in shell before shell is applied to the sheet heart by the coating form, as shown in figure 10.This method uses capsule shells (comprise gelatin, starch, cellulose ether, or other materials known in the art and described herein) to come the sheet heart of coated dosage form.Capsule shells is to form with two parts 1210 by draw point is flooded the back in the shell material solution of liquid form known in the art.Shell material solidifies on draw point subsequently.Before solidified capsule shells removes from the formation draw point, suitable method, for example laser is used to as required size, shape and pattern burning opening on capsule shells.With the rear panel heart 1220 usefulness methods known in the art coating capsule shells 1210, as U.S. Patent No. 5,415,868,6,126,767,5,464,631,5,460,824,5,317,849,5,511,361,5,609,010,5,795,588, with 6,080,426 and PCT application No.WO97/37629 described on compressed tablets shrink-fit half and half capsule shells, to produce dosage form 1230 of the present invention.

In the 3rd embodiment, opening can be applied to sheet at shell and form between heart stage.In this embodiment, shell can be applied to the sheet heart by any suitable method, as coating, dipping, transfer, spraying or molding.

For example, be applied to by coating in the sheet embodiment in the heart at shell, the surface of rotation mould 1040 have the sheet heart during by the casting film coating by perforation, pink or punching press can produce the suitable quality of space, crack or open area.

Figure 11 show by dipping method shell be applied to the sheet heart during in shell, form the example of the method for opening.In the method, during dipping the sheet heart is held by container 1310, and container 1310 is equipped with one or more pins 1320 of sheltering, and many to shelter pin 1320 preferable, shelters pin 1320 and holds the sheet heart and cover and do not need the zone that covered by shell.Shelter shape, the size of pin 1320 and arrange shape, size and the pattern that determines the shell split shed.Figure 12 show by dipping method shell be applied to the sheet heart during in shell, form another example of the method for opening.Wherein the sheet heart is immersed in the foamy heartwood material 1420.Bubble in the foam becomes opening 1430 in the solidifying shell of finishing.In similar embodiment, during applying, shell produces opening by solid wax sugar spheroidal particle (non-pareils) suspension that the sheet heart is impregnated in the thin film formation shell matter.This sugar spheroidal particle places sheet in the heart with shell matter.Shell material is with after fixing.Secondly, wax sugar spheroidal particle is melted in heating, stays wax sugar spheroidal particle size and shaped aperture in shell.In another embodiment, the sheet heart is impregnated in the liquid substance, reaction and cure polymer when activating down as passing through ultraviolet radiation, light or heat.In the method, high special or targeting energy source such as laser be used to selectivity and solidify and want the shell part that keeps on the tablet.After this is handled, the liquid that stays or be drained or washed off.In similar embodiment, sheet heart surface is coated with powder by bag, can use laser selective to melt the powder part later on, not melting the position that powder is stayed needs opening.The material that stays is still powder and is shrugged off.

Figure 13 show by similar printing transfer method with shell be applied to sheet in the heart during form a preferred approach of opening.The image of peak and paddy is carved with on transfer blade 1510 surfaces.Shell material is applied to transfer blade 1510 surfaces with liquid form, and selectivity is filled to paddy place but does not cover the peak." printing blanket " application apparatus 1520 is picked up the shell material of vivid pattern and is placed from transfer blade 1510, or shifts the shell material that needs in the pattern to sheet heart surface.The advantage of transfer blade is the non-dosage form that is applied directly to of pattern.It is by the powder coating that another shell material selectivity prints to sheet suitable method in the heart, as PCT application No.WO 01/57144 disclosed electrostatic precipitation.It is the ink-jet printing that passes through described in open source literature that another shell material selectivity prints to sheet suitable method in the heart.

In the 4th embodiment, be applied to the sheet heart at shell and can in shell, form with after-opening.Figure 14 shows this embodiment.Wherein, the sheet heart 1610 has projection 1620, and shell 1630 is used to be worn away with rearward projection around the whole heart, exposes the uncoated tablets heart (promptly producing opening 1650) as being ground off by a pair of spin finishing wheel 1640.In another embodiment, shell is applied to the sheet heart with the form (as coating) of plural layers.With the zone of rear film by the laser selective burning-off to form opening with the pattern of needs and the degree of depth of any needs on the shell surface.In another embodiment, sintering method is used to settle shell.Powdered shell material is sintered to sheet heart surface, with part, rather than all merges the powder microgranule with post-heating, produces porous shell surface.Shell be sintered to other preferred approach that sheet forms opening after in the heart comprise mechanical means such as punching press, perforation, boring, earnestly, melt.A kind of mechanical means shows shown in Figure 15 A of Figure 15 and uses hot pin or cutter to melt and/or pierce through opening to sheet in the heart.Figure 15 B is presented at and bores opening in the shell.Thawing that Figure 15 shows or puncture top form press, or the surface of cylinder machinery (or " commercial terminal "), and another suitable mechanical method comprises as shown in figure 16 opening is stamped in the shell of formation.In this particular, the shell material of going out is retained in the chamber of punching press generation, but the part on sheet heart surface exposes the part of coelosis inside.Be sintered at shell that but the system of selection that sheet forms opening after in the heart comprises ablation method such as blasting treatment, mills, arc evaporation, dielectric breakdown, ion beam sputtering, ultrasound wave attrition process, cavitation corrosion fluid jet, laser evaporation; Chemical method such as selectivity are used acid or alkali reaction, chemical light etching; Relate to the method that heat is used, as with hot pin, Laser Processing, arc evaporation, ultrasound wave thawing or cavitation erosion, microwave heating or the like.These methods can randomly be used at first sheltering and optionally remove shell material after wanting to keep int shell zone.

Should understand many other methods, include but not limited to those melt, the method for the big apoplexy due to endogenous wind of machinery, chemistry, heat treatment or additive method, though this paper is for example not special, can be fit to form the opening of shell of the present invention.

For example, after leaving film casting equipment but before being fed to coating equipment, diaphragm can be with mechanical treatment such as punching press, perforation, crack, penetrate or hole to form one or more openings on diaphragm.For example, by melt, machinery, chemistry, heat treatment or additive method, the crack can form on casting mold or outstanding thin film.

Following non-limiting examples further specifies the present invention.

Embodiment

A part: the preparation of the compressed tablets sheet heart

The compressed tablets sheet heart comprises the 500mg acetyl aminophenol as active component, prepares with following ingredients:

Composition	The Mg/ sheet heart
		I.-active component and excipient
Acetyl aminophenol, USP	????500.0
		Powderd cellulose, NF	????40.0
Pregelatinized starch, NF	????10.0
		The hydroxyacetic acid sodium cellulosate, NF	????10.0
The II.-granulating agent
		Starch, NF	????40.0
Purified water, USP	In right amount
		The III.-dry additive
Magnesium stearate, NF	????3.2
		Amount to	????603.2

The active component of part I and excipient are weighed according to the ratio that provides and are added to fluidized bed granulator, in the bowl as AEROMATIC board granulating machine.Granulating agent (part II) is by being added to purified water in the treatment box with the every gram starch of about 15 gram water NF.Starch slowly mixes, and mixture is heated until temperature and reaches about 82 to 84 ℃.75 to 85 ℃ of the fluid state of heating and Inside Air Temperatures, granulating agent is sprayed on the powder at the composition of part I.After all granulating agents were sprayed, it is about 1.4 to 1.9% that granulous powder is dried to moisture, and its drying loss for example uses COMPUTRAC board analyser to determine.Dried granules is sieved subsequently, for example, uses GLATT QUICK board sieve stator No.3, sieve No.1.5mm, 1,000RPM.Screening and dried granules subsequently with the powder of part III with suitable mixer such as bivalve, banding pattern or planet mixer.The mixture of finishing is loaded into rotary tablet machine subsequently and uses the dark recessed instrument of circle of 7/16 inch of diameter to be pressed into tablet.The average thickness of the tablet heart that produces is about 0.3 inch.The average hardness of the tablet heart that produces is about 10Kp.The average weight of the tablet heart is about 603.2mg.

B part: as the preparation of the shell material of the plastic casting film that is used for coating

Be used for the first gelatin-based plastic casting film of the sheet heart of coating A part, thickness prepares with following ingredients in about 0.02 inch scope:

Gelatin (150 Bloom)	????45％
		Glycerol	????6％
Sorbitol	????2％
		Water	????45％
Coloring agent	????2％

Coloring agent mixes with water to form homogeneity solution.Exsiccant gelatin particle is added into colourant solution, mixes about 1 minute with complete humidifying gelatin particle.Gelatin is stuck with paste and is placed water-bath and be heated to 55 ℃ to melt and the dissolving gelatin.Glycerol and sorbitol mix subsequently therein.Final solution be maintained at 55 ℃ about 10 hours with degasification.Solution mixes under low speed until homogeneous (about 5 to 15 minutes), and transfers to the interlayer charging box that propeller-type electricity blender is housed.During being used for being formed for making first shell of the present invention casting film partly, gelatin solution remains on 55 ℃ to be continued to mix.Gelatin solution is introduced in the casting mold drum (forming cylinder 1010) subsequently, its surface be cooled to about 25 ℃ to form plastic casting film.

Prepare the second gelatin-based plastic casting film that similar thickness is arranged but second kind of color arranged according to the method described above.

Refrigerative first plastic casting film is fed between two cylinders that comprise punching machine (1030) subsequently, and this device is at the thin film that opening is stamped into formation.Opening is round, 750 microns of diameters, and with 7 groups of arrangements, a central opening is surrounded by 6 peripheral openings.7 groups of openings separate in thin film sometimes, and are corresponding with the chamber in the dyeing cylinder 1040.Refrigerative second casting film is fed between two cylinders of smooth surface, thereby keeps not having continuously opening therein.

Next, the first film of perforation and imperforated second thin film are fed between the dyeing cylinder 1040 of coating device together with the tablet heart of A part.First and second thin film contact compacting with the tablet heart, and compacting mutually, form around the seam of the abdomen shape band of the compressed tablets sheet heart at interface.The dosage form that produces has the first shell part of first color, opening is wherein arranged and the second shell part of second color is arranged, and does not wherein have opening substantially.

Claims (31)

1. dosage form that comprises at least a active component, comprise the sheet heart and the shell that centers at least a portion sheet heart, wherein the density of the sheet heart is at least about 0.9g/cc, shell comprises one or more openings, shell is dissolved in the gastro-intestinal Fluid easily, and this dosage form is released at least a active component with the contacting of its liquid medium the time.

2. dosage form as claimed in claim 1 is characterized in that shell comprises many openings.

3. dosage form as claimed in claim 1 is characterized in that, one or more opening contact chip hearts.

4. dosage form as claimed in claim 2 is characterized in that, many opening contact chip hearts are arranged.

5. dosage form as claimed in claim 1 is characterized in that the sheet pericardium contains at least a active component.

6. dosage form as claimed in claim 1 is characterized in that shell comprises at least a active component.

7. as claim 5 or 6 described dosage forms, it is characterized in that this dosage form provides and promptly releases at least a active component that sheet comprises in the heart.

8. dosage form as claimed in claim 1 is characterized in that the sheet heart is a compressed tablet.

9. dosage form as claimed in claim 1 is characterized in that, the hardness of compressed tablet about 2 to 30kp/cm ²

10. dosage form as claimed in claim 1 is characterized in that shell is applied to the sheet heart by dipping.

11. dosage form as claimed in claim 1 is characterized in that, shell is applied to the sheet heart by molding.

12. dosage form as claimed in claim 1 is characterized in that, shell is applied to the sheet heart by coating.

13. dosage form as claimed in claim 1 further comprises the outer coating that covers at least a portion shell.

14. dosage form as claimed in claim 12 is characterized in that, outer coating comprises at least a active component.

15. dosage form as claimed in claim 12 is characterized in that, outer coating covers at least a portion opening.

16. dosage form as claimed in claim 12 is characterized in that, outer coating is dissolved in the gastro-intestinal Fluid easily.

17. dosage form as claimed in claim 1 is characterized in that shell comprises film former.

18. dosage form as claimed in claim 17 is characterized in that film former comprises gelatin.

19. dosage form as claimed in claim 1 is characterized in that, average thickness of the shell arrives about 400 micrometer ranges about 100.

20. dosage form as claimed in claim 1 is characterized in that, the relative standard deviation of the thickness of the shell of dosage form is less than about 30%.

21. dosage form as claimed in claim 1 is characterized in that, shell comprises and is less than about 50% crystalline carbohydrate.

22. dosage form as claimed in claim 1 is characterized in that, dosage form does not have charge control agent substantially.

23. dosage form as claimed in claim 1 is characterized in that, shell is included in to form goes up the first and second different shell parts.

24. dosage form as claimed in claim 23 is characterized in that, first and second shells part is visually different.

25. dosage form as claimed in claim 23 is characterized in that, first and second shells part connects on the interface.

26. dosage form as claimed in claim 23 is characterized in that, first shell partly comprises one or more openings, and second shell part does not have opening basically.

27. dosage form as claimed in claim 23 is characterized in that, first and second shells part directly contacts with the sheet heart.

28., it is characterized in that the sheet heart is surrounded by sub-coating substantially as claim 1 or 23 described dosage forms.

29. dosage form as claimed in claim 28 is characterized in that, first and second shells part directly contacts with described sub-coating.

30., it is characterized in that the diameter of one or more openings or width about 200 is to about 2000 microns as claim 1 or 23 described dosage forms.

31. sheet heart and the dosage form that the shell of outer surface and inner surface is arranged that includes outer surface, wherein at least a portion shell surrounds the sheet heart, reside on the sheet heart outer surface with making shell inner surface basically identical, at least a portion shell comprises one or more openings, about 200 microns to about 2000 microns of the diameter of one or more openings or width, at least a portion shell is dissolved in the gastro-intestinal Fluid easily, about 100 microns to about 400 microns of the scope of shell average thickness, shell comprises the crystal sugar at least about 50%, this dosage form does not have charge control agent substantially, releases at least a active component when this dosage form contact liq medium.

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