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

United States Patent:  6,245,350

Assignee:  Warner-Lambert Company (Morris Plains, NJ)

Filed:  April 5, 1996

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.

DESCRIPTION OF PREFERRED EMBODIMENTS OF THE INVENTION

The capsule shell in which the caplet is to be enclosed preferably comprises two shell halves, a body portion and a cap portion. Other capsules comprising more than two parts are also possible. The capsule is typically a hollow shell of generally cylindrical shape having a diameter and length sufficient so that the caplet fits appropriately in the empty capsule. The clearance of the capsule shell and the caplet is preferably about +0.5 mm. According to a specifically preferred embodiment of the present invention, the clearance of the capsule shell and the caplet is in the range of from about 0 to about -0.5 mm, which means that the caplet is compressed in the capsule.

A specifically preferred process of the present invention is carried out as follows. Empty capsule parts are either kept after production at humid conditions in the range of from about 40 to about 90%, particularly from about 60 to about 80%, relative humidity to retain a moisture content of from about 14 to about 19% by weight of the capsule shell, preferably from about 15 to about 18% and more preferably from about 16 to 18%, or are re-humidified to said moisture content before feeding into a capsule filling machine.

The first capsule shell part is then 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.

A second or further capsule shell part is process in the same matter as the first one. Finally, 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, preferably from about 15 to about 40 C, more preferably from about 18 to about 25 C.

Caplets having a low moisture content of in the range of from about 0 to about 6% by weight, or more preferably of from about 0 to about 3% by weight, are especially suitable to be used in the process of the present invention. Conical ends of the caplet make the insertion of the caplet into one half of the capsule easier. After drying and shrinking the capsule parts together, the capsule can be further film coated, which coating may be enteric.

The capsule shell material can be a hydrophilic polymer, gelatin being the preferred choice. Other suitable capsule shell materials include starch, casein, chitosan, soya bean protein, safflower protein, alginates, gellan gum, carrageenan, xanthan gum, phtalated gelatin, succinated gelatin, cellulosephtalate-acetate, polyvinylacetate, hydroxypropyl methylcellulose, polyvinylacetate-phthalate, polymerisates of acrylic or methacrylic esters or mixtures thereof. The capsule shell material may furthermore contain from about 0 to about 40% pharmaceutically acceptable plasticizers based upon the weight of the hydrophilic polymer. The plasticizers which may be employed can be selected from polyethylene glycol, glycerol, sorbitol, dioctyl-sodium sulfosuccinate, triethyl citrate, tributyl citrate, 1,2-propyleneglycol, mono-, di, or tri-acetates of glycerol or mixtures thereof.

Additionally, the capsule shell material may contain pharmaceutically acceptable lubricants in the range of from about 0 to about 10% based upon the weight of the hydrophilic polymer. The lubricant may be selected from aluminumstearate, calciumstearate, magnesiumstearate, tinstearate talc, sodium lauryl sulfate, lecithins, mineral oils, stearic acid or silicones or mixtures thereof.

Moreover, the capsule shell material may contain pharmaceutically acceptable coloring agents in the range of from about 0 to about 10% based upon the weight of the hydrophilic polymer. The coloring agent may be selected from azo-quinophthalone-, triphenylmethane-, xanthene-dyes, iron oxides or hydroxides, titanium dioxide or natural dyes or mixtures thereof. Further suitable coloring agents are 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.

Furthermore, the capsule shell material may contain pharmaceutically acceptable extenders in the range of from about 0 to about 95% based upon the weight of the hydrophilic polymer. The extender may be selected from 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, polyvinylpyrrolidone, shellac, bentonite, polyvinyl-acetatephthalate, phthalated gelatin, succinated gelatin, agar agar, hydroxyalkylstarches or mixtures thereof.

The solid pharmaceutical dosage form according to the present invention also may comprise a coating selected from cellacephate, polyvinyl acetate phthalate, methacrylic acid polymers, hypromellose phthalate, hydroxyalkyl methy cellulose phthalates or mixtures thereof.

The capsule parts of the solid dosage form of the present invention may have the same or different lengths and/or the same or different color. In the contact area of the capsule parts, the solid dosage form may be banded or easily dividable. The caplet being contained in the capsule can have a preformed step or groove in the dividing position of the capsule. To furthermore improve the caplet which is contained in the capsule, the caplet can be coated with an acceptable coating for tablet processing. In some cases, uncoated caplets are, however, preferred. A better contact between the inner shells of the capsule parts and the caplets can be obtained by treating the inner shells and/or the surface of the caplet with an adhesive. A suitable technique to apply the adhesive is spraying same on the shells and caplets immediately before assembling same. Suitable adhesives are e.g. tackidex or an aqueous gelatin solution.

A further aspect of the present invention is to provide encapsulated dosage forms in which the capsule shell halves do not completely cover the entire caplet, which means the caplet is longer than the combined length of the shell halves. This will provide capsules with additional advantageous features. For example, if each of the capsule halves has a different color and the caplet has a third color, a three-colored capsule will be obtained, or, if the shell halves have the same color and the caplet has a different color, a color banded capsule will be obtained. A second optional feature may be obtained by use of enteric coated capsule shell halves. In such a case a capsule with delayed release will be obtained, releasing the medicament in the stomach first from the small release band between the shell halves and later from the capsule openings.

A further aspect of the invention is the use of the described moisture control and rehumidification on common encapsulation machines with all kinds of common hard gelatin capsule types. The inventive process gives much better filling results especially with filling machines in hot and dry areas for the encapsulation of all kinds of fillings such as powders, pellets, liquids, microcapsules, tablets, etc. The preferred process in this case is carried out as follows: Empty capsule bodies and the preferred capsules are assembled in a pre-lock state and are either kept after production at humid conditions of 40 to 90% humidity, preferably 60 to 80% relative humidity to retain a moisture content of about 14 to about 19%, preferably about 15 to about 18% and most preferably about 16% to about 18% by weight of the capsule shell or are rehumidified to said moisture before opening and sorting in the capsule filling machine. Capsule bodies are then kept under humid conditions within the filling machine at said moisture content during rectifying and filling with the desired product. In the same way, the capsule caps are kept at moisture content during the rectifying and finally assembling with the filled capsule bodies. Finally, the capsule is dried at 20 to 40% relative humidity and a temperature of about 15 to about 60 C, preferably about 15 to about 40 C and most preferably at about 18 to about 25 C.

The solid dosage form according to the present invention may, for example, comprise a pharmaceutically or agrochemically active composition. Furthermore comprised in the solid dosage form can, for example, be a foodstuff or a dyestuff composition. In case the solid dosage form of the present invention contains a pharmaceutical composition, the active substance of same can, for example, be selected from 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, depanthenol, 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.

The purpose of the above description is to illustrate some configurations and uses of the present invention, without implying any limitation. It will be apparent to those skilled in the art that various modifications and variations may be made in the process and product of the invention without departing from the spirit or scope of the invention.

Claim 1 of 50 Claims

We claim:

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.

____________________________________________
If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.