Process for encapsulation of caplets in a capsule and solid dosage forms obtainable by such process

• US 6,245,350 B1
• Filed: 04/05/1996
• Issued: 06/12/2001
• Est. Priority Date: 12/16/1994
• Status: Expired due to Term

• Current Assignee: Capsugel Belgium NV (Lonza Group AG)
• Original Assignee: Warner-Lambert Company (Pfizer Inc.)
• Inventors: Maes, Paul, Scott, Robert, Amey, James, Cade, Dominique
• Primary Examiner(s): Spear, James M.
• Application Number:
  US08/628,823
• Time in Patent Office: 1,894 Days
• Field of Search: 424/451, 424/452, 424/453, 424/454, 424/456, 424/463, 424/457
• US Class Current: 424/456
• CPC Class Codes: A61J 3/07 into the form of capsules or similar small containers for oral use
• CPC Class Codes: A61J 3/071 into the form of telescopically engaged two-piece capsules
• CPC Class Codes: A61J 3/072 Sealing capsules, e.g. rendering them tamper-proof
• CPC Class Codes: A61K 9/2072 characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms A61K9/0004, A61K9/0056, A61K9/0065 take precedence
• CPC Class Codes: A61K 9/4808 characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release capsules filled with granules or microparticles A61K9/16; filled with microcapsules or coated microparticles A61K9/50; with mixture of different granules, microcapsules, (coated) microparticles A61K9/5084
• CPC Class Codes: A61K 9/4833 Encapsulating processes; Filling of capsules mechanical aspects A61J3/07

Abstract

A process for encapsulation of caplets in a capsule comprises the following steps: a. providing empty capsule parts; b. filling at least one of said capsule parts with one or more caplets; c. putting said capsule parts together; and d. treating the combined parts by cold shrinking. The solid dosage forms obtainable by such a process are tamper-proof in that they cannot be opened in a way to be reassembled without showing such opening process.

Claims

1. A process for the encapsulation of caplets in a capsule, comprising the following steps:

a. providing empty first and second capsule shell parts,

b. filling at least one of said capsule parts with one or more caplets, wherein the clearance between the capsule part and the caplet is in the range of from −

0.5-0.5 mm.,

c. putting said capsule parts together,

d. treating the combined capsule parts by cold shrinking,

wherein the empty capsule parts are either kept after production at humid conditions in the range of from about 40 to about 90% relative humidity to retain a moisture content in the range of from about 14 to about 19% by weight of the capsule shell or are re-humidified to said moisture content before feeding into a capsule filling machine and wherein the first capsule part is kept under humid conditions within the filling machine at said moisture content during rectifying and assembling with a caplet having a moisture content in the range of from about 0 to about 12% by weight the second capsule part is processed in the same manner, and the encapsulated dosage form is dried at a relative humidity in the range of from about 20 to about 40% and a temperature in the range of from about 15 to about 60 C.

2. The process according to claim 1 wherein the caplets comprise a compressed material.

3. The process according to claim 1 wherein the moisture content is in the range of from about 15 to about 18% by weight of the capsule shell by weight.

4. The process according to claim 3, wherein the moisture content is in the range of from about 16 to about 18% by weight.

5. The process according to claim 1, wherein the encapsulated dosage form is dried at a temperature in the range of from about 15 to about 40 C.

6. The process according to claim 5, wherein the encapsulated dosage form is dried at a temperature in the range of from about 18 to about 25 C.

7. The process according to claim 1, wherein the capsule parts are maintained at a relative humidity in the range of from about 60 to about 80% during the steps of feeding into a capsule filling machine, rectifying and assembling.

8. The process according to claim 7, wherein the moisture content of the capsule parts is in the range of from about 16 to about 18% by weight.

9. The process according to claim 1 wherein the moisture content of the caplet is in the range of from about 0 to about 6% by weight.

10. The process according to claim 1, wherein the moisture content of the caplet is in the range of from about 0 to about 3% by weight.

11. The process according to claim 1, wherein the caplet has conical ends.

14. The process according to claim 1, wherein after drying and shrinking of the capsule parts the encapsulated dosage form is film-coated.

15. Process according to claim 14, wherein the coating is enteric.

16. A solid dosage form obtainable according to the process of claim 1.

17. A solid dosage form according to claim 7, wherein the capsule part material comprises a hydrophilic polymer.

18. A solid dosage form according to claim 7, wherein the capsule part material is selected from the group consisting of gelatin, starch casein, chitosan, soya bean protein, safflower protein, alginates, gellan gum, carrageenan, xanthan gum, phthalated gelatin, succinated gelatin, cellulosephtalate-acetate, polyvinylacetate, hydroxypropyl methylcellulose, polycinylacetate-phthalate, polymerisates of acrylic or methacrylic esters and mixtures thereof.

19. A solid dosage form according to claim 17, wherein the capsule part material contains pharmaceutically acceptable plasticizers in the range of from about 0 to about 40% based upon the weight of the hydrophilic polymer.

20. A solid dosage form according to claim 19, wherein the plasticizer is selected from the group consisting of polyethylene glycol, glycerol, sorbitol, dioctyl-sodium sulfosuccinate, triethyl citrate, tributyl citrate, 1,2-propyleneglycol, mono-, di- or tri-acetates of glycerol and mixtures thereof.

21. A solid dosage form according to claim 17, wherein the capsule part material contains pharmaceutically acceptable lubricants in the range of from about 0 to about 10% based upon the weight of the hydrophilic polymer.

22. A solid dosage form according to claim 21, wherein the lubricant is selected from the group consisting of aluminumstearate, calciumstearate, magnesiumstearate, tinstearate, talc, sodium lauryl sulfate, lecithins, mineral oils, stearic acid or silicones and mixtures thereof.

23. A solid dosage form according to claim 17, wherein the capsule part material contains pharmaceutically acceptable coloring agents in the range of from about 0 to about 10% based upon the weight of the hydrophilic polymer.

24. A solid dosage form according to claim 23, wherein the coloring agent is selected from the group consisting of azoquinophthalone-, triphenylmethane-, xanthene-dyes, iron oxides or hydroxides, titanium dioxide or natural dyes and mixtures thereof.

25. A solid dosage form according to claim 23, wherein the coloring agent is selected from sunset yellow, allura red, amaranth, cochineal red, azogeranine, tartrazine, brilliant black, canthaxanthin, patent blue, fast green, brilliant blue, acid green, erythrosine, quinoline yellow, indigotine, curcumin or carbon black.

26. A solid dosage form according to claim 17, wherein the capsule part material contains pharmaceutically acceptable extenders in the range of from about 0 to about 95% based upon the weight of the hydrophilic polymer.

27. A solid dosage form according to claim 4, wherein the capsule part material contains an extender.

28. A solid dosage form according to claim 27, wherein the extender is selected from the group consisting of sunflower proteins, soy bean proteins, cotton seed proteins, peanut proteins, rape seed proteins, lactose, gum arabic, acrylates or methacrylates, cellulose acetyl phthalates, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulosephthalate, hydroxymethylcellulose, polyvinyl pyrrolidone, shellac, bentonite, polyvinyl-acetatephthalate, phthalated gelatin, succinated gelatin, agar agar, hydroxyalkylstarches and mixtures thereof.

29. A solid dosage form obtainable according to the process of claim 14.

30. A solid pharmaceutical dosage form obtainable according to the process of claim 15.

31. A solid pharmaceutical dosage form according to claim 14, comprising a coating selected from the group consisting of cellacephate, polyvinyl acetate phthalate, methacrylic acid polymers, hypromellose phthalate, hydroxyalkyl methyl cellulose phthalates and mixtures thereof.

32. A solid dosage form according to claim 7, wherein the first and second capsule parts have the same or different lengths.

33. A solid dosage form according to claim 7, wherein the first and second capsule parts have the same or different colors.

34. A solid dosage form according to claim 7, wherein the solid dosage form is banded at the contact area of the capsule parts.

35. A solid dosage form according to claim 7, wherein the solid dosage form is easily dividable at the contact area of the capsule parts.

36. A solid dosage form according to claim 2, wherein the caplet contained in the capsule has a preformed step or groove so that the solid dosage form may be dividing into separate portions.

37. A dosage form according to claim 7, wherein the caplet contained in the capsule is uncoated or coated with an acceptable coating for tablet processing.

38. A process according to claim 1, wherein an adhesive is sprayed onto the surface of the caplet and/or onto the inner surface of the capsule parts immediately before assembling.

39. A process according to claim 38, wherein the adhesive is tackidex or an aqueous gelatin solution.

40. A solid dosage form according to claim 16 comprising a pharmaceutically active composition.

41. A solid dosage form according to claim 16 comprising an agrochemically active composition.

42. A solid dosage form according to claim 16 comprising a foodstuff composition.

43. A solid dosage form according to claim 16 comprising a dyestuff composition.

44. A solid dosage form according to claim 40, wherein the caplet contained in the capsule is a pharmaceutical composition with an active substance selected from the group consisting of betamethasone, thioctic acid, sotalol, salbutamol, norfenefrine, silymarin, dihydroergotamine, buflomedil, etofibrate, indomethacin, oxazepam, acetyldigitoxins, piroxicam, haloperidol, isosorbide mononitrate, amitriptyline, diclofenac, nifedipine, verapamil, pyritinol, nitrendipine, doxycycline, bromhexine, methylprednisolone, clonidine, fenofibrate, allopurinol, pirenzepine, levothyroxine, tamoxifen, metildigoxin, o-(B-hydroxyethyl)-rutoside, propicillin, aciclovirmononitrate, paracetamolol, naftidrofuryl, pentoxifylline, propafenone, acebutolol, 1-thyroxin, tramadol, bromocriptine, loperamide, ketofinen, fenoterol, ca-dobesilate, propranolol, minocycline, nicergoline, ambroxol, metoprolol, B-sitosterin, enalaprilhydrogenmaleate, bezafibrate, isosorbide dinitrate, gallopamil, xantinolnicotinate, digitoxin, flunitrazepam, bencyclane, despanthenol, pindolol, lorazepam, diltiazem, piracetam, phenoxymethylpenicillin, furosemide, bromazepam, flunarizine, erythromycin, metoclopramide, acemetacin, ranitidine, biperiden, metamizol, doxepin, dipotassiumchlorazepat, tetrazepam, estramustinephosphate, terbutaline, captopril, maprotiline, prazosin, atenolol, glibenclamid, cefaclor, etilefrin, cimetidine, theophylline, hydromorphone, ibuprofen, primidone, clobazam, oxaceprol, medroxyprogesterone, flecainide, Mg-pyridoxal-5-phosphateglutaminate, hymechromone, etofyllineclofibrate, vincamine, cinnarizine, diazepam, ketoprofen, flupentixol, molsidomine, glibornuride, dimethindene, melperone, soquinolol, dihydrocodeine, clomethiazole, clemastine, glisoxepid, kallidinogenase, oxyfedrine, baclofen, carboxymethylcystsin, thioredoxin, betahistine, 1-tryptophan, myrtol, bromelain, prenylamine, salazosulfapyridine, astemizole, sulpiride, benzerazid, dibenzepin, acetylsalicylic acid, miconazole, nystatin, ketoconazole, sodium picosulfate, colestyramate, gemfibrozil, rifampin, fluocortolone, mexiletine, amoxicillin, terfenadine, mucopolysaccharidpolysulfuric acid, triazolam, mianserin, tiaprofensaure, ameziniummethylsulfate, mefloquine, probucol, quinidine, carbamazepine, Mg-1-aspartate, penbutolol, piretanide, amitriptyline, caproteron, sodium valproinate, mebeverine, bisacodyl, 5-amino-salicyclic acid, dihydralazine, magaldrate, phenprocoumon, amantadine, naproxen, carteolol, famotidine, methyldopa, auranofine, estriol, nadolol, levomepromazine, doxorubicin, medofenoxat, azathioprine, flutamide, norfloxacin, fendiline, prajmaliumbitartrate, aescin acromycin, anipamil, benzocaine, B-carotene, cloramphenicol, chlorodiazepoxid, chlormadinoneacetate, chlorothiazide, cinnarizine, clonazepam, codeine, dexamethasone, dicumarol, digoxin, drotaverine, gramicidine, griseofulvin, hexobarbital hydrochlorothiazide, hydrocortisone, hydroflumethiazide, ketoprofen, lonetil, medazepam, mefruside, methandrostenolone, sulfaperine, nalidixic acid, nitrazepam, nitrofurantoin, estradiol, papaverine, phenacetin, phenobarbital, phenylbutazone, phenytoin, prednisone, reserpine, spironolactine, streptomycin, sulfamethizole, sulfamethazine, sulfamethoxoazole, sulfamethoxydiazinon, sulfathiazole, sulfisoxazole, testosterone, tolazamide, tolbutamide, trimethoprim, tyrothricin or mixtures thereof.

45. A solid dosage form according to claim 15, wherein the shell halves do not completely cover the caplet.

46. A solid dosage form according to claim 45, wherein each of the shell halves and the caplet have different colors.

47. A solid dosage form according to claim 46, wherein the shell halves have the same color and the caplet has a different color.

12. A process for filling hard gelatin capsule comprising:

maintaining empty capsule bodies and caps or pre-assembled capsule bodies after production at humid conditions of about 40 to about 90% relative humidity to retain a moisture content of about 14 to about 19% by weight of the capsule shell or are re-humidified to said moisture content before feeding into a capsule filling machine;

maintaining the capsule body under humid conditions within the filling machine at said moisture content during rectifying and filling; and

maintaining the capsule cap under the same conditions until assembled with the body, and the encapsulated dosage form is dried at about 20 to about 40% relative humidity and a temperature of about 15 to about 60 C.

13. The process according to claim 12 wherein the moisture content is about 15 to about 18% by weight of the capsule shell.

48. The process according to claim 13, wherein the moisture content is about 16 to about 18%.

49. The process according to claim 12, wherein the encapsulated dosage form is dried at a temperature in the range of from about 15 to about 60 C.

50. The process according to claim 49, wherein the encapsulated dosage form is dried at a temperature in the range of from about 18 to about 25 C.