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

• US 6,080,426 A
• Filed: 01/11/1996
• Issued: 06/27/2000
• 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: Cade, Dominique, Maes, Paul, Scott, Robert, Amey, James
• Primary Examiner(s): Spear, James M.
• Application Number:
  US08/585,549
• Time in Patent Office: 1,629 Days
• Field of Search: 424/451, 424/453, 424/454, 424/456, 424/463, 424/452
• US Class Current: 424/456
• 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 9/4808 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

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 aprocess 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,

c. putting said capsule parts together,

wherein the empty capsule parts are either kept after production at humid conditions in the range of from about 40 to 90% relative humidity to retain a moisture content in the range of from about 16 to 18% by weight of the capsule 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. and wherein after drying and shrinking of the capsule parts the encapsulated dosage form is film-coated.

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

3. 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.

4. A process according to claim 3, wherein the adhesive is tackidex or an aqueous gelatin solution.

5. The process according to claim 1, wherein the encapsulated dosage form is dried at a temperature in the range of from about 18 to about 25 C.

6. 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.

7. A solid dosage form according to claim 6, wherein the caplet contained in the capsule is uncoated or coated with an acceptable coating for tablet processing.

8. 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.

9. 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.

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

11. The process according to claim 1, wherein the clearance between the capsule part and the caplet is in the range of from 0 to 0.5 mm.

12. Process according to claim 1, wherein the clearance between the capsule part and the caplet is in the range of from about 0 to -0.5 mm.

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

14. Process according to claim 1, wherein the coating is enteric.

15. A solid dosage form according to claim 13 comprising a pharmaceutically active composition.

16. A solid dosage form according to claim 13, comprising an agrochemically active composition.

17. A solid dosage form according to claim 6, wherein the capsule part material comprises a hydrophilic polymer.

18. A solid dosage form according to claim 6, 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, phtalated gelatin, succinated gelatin, cellulosephtalate-acetate, polyvinylacetate, hydroxypropyl methylcellulose, polyvinylacetate-phtalate, 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 aluminiumstearate, 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 azo-, quinophthalone-, 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 1, 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, soybean 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-acetatephtalate, phthalated gelatin, succinated gelatin, agar agar, hydroxyalkylstarches and mixtures thereof.

29. A solid dosage form according to claim 13 comprising a foodstuff composition.

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

31. A solid pharmaceutical dosage form according to claim 1, 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 6, wherein the first and second capsule parts have the same or different lengths.

33. A solid dosage form according to claim 6, wherein the first and second capsule parts have the same or different colors.

34. A solid dosage form according to claim 6, wherein the solid dosage form is banded at the contact area of the capsule parts.

35. A solid dosage form according to claim 6, 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.

38. A solid dosage form according to claim 15, 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, fenof allopurinol, pirenzepine, levothyroxine, tamoxif 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, dipotassium-chlorazepat, 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.

37. A solid dosage form according to claim l3 comprising a dyestuff composition.