Note: Descriptions are shown in the official language in which they were submitted.
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I =
PROCESS FOR ENCAPSULATION OF CAPLETS IN A CAPSULE
AND SOLID DOSAGE FORMS OBTAINABLE BY SUCH PROCESS
Field of the Invention
The present invention relates to a process for
5' encapsulation of caplets in a capsule and to solid dosage
forms obtainable by such a process, and more
particularly, to the manufacture of a tamper-proof
capsule containing.a pharmaceutically active composition.
Background of the Invention
Various oral medications have been manufactured in
the form of so called caplets, which can be swallowed by
patients during their regiment of taking medication.
Caplets, however, are not as easily swallowed by patients
as capsules having, for example, a gelatin coating.
Additionally, capsule coatings are desirable over caplets
since the coatings provide a neutral taste in contrast to
caplets per se which sometimes contain pharmaceutical
substances that taste, for example, bitter. Thus,
patients, in particular children, refuse to swallow such
caplets per se. Attempts have therefore been made to
encapsulate caplets in a capsule by means of a gelatin
cover.
U.S. Patent No. 4,867,983 to Berta describes a
method for double dipping gelatin coated caplets. The
method provides a procedure for coating solid cores, such
as caplets, with a first gelatinous coating on one end,
and then with a second gelatinous coating on the other
end which is thicker than the first, to simulate the
interlocking halves of a hollow capsule. The second,
thicker gelatinous coating can be provided with a single
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gelatin coating from a bath having a higher viscosity
than the bath used to provide the first gelatinous
coating. Alternatively, the second gelatinous coating
can be provided by double dipping to provide layers of
gelatinous material or gelatin. This known coating is
disadvantageous in that the gelatinous coating and the
color distribution is not uniformly distributed over the
caplets by this process. Moreover, an overlapping of the
different coatings results in color changes of the
coatings. Additionally, the dip margins obtained by the
known process tend not to be straight. Furthermore, the
coatings according to the above patent chip off under
stress if the coated caplets are stored under dry
conditions and/or high temperature. Finally, the dip
coating process of U.S. Patent No. 4,867,983 is time
consuming and expensive.
From U.S. Patent No. 5,081,822 to Boyd et al, an
automatic caplet filler is known for filling normal
gelatin capsules with caplets. The capsules formed by
this automatic caplet filler, however, are
disadvantageous in that they can be easily manipulated.
Sealing of the capsules has to be effected by means of an
additional gelatin strip or by gluing of the caplets in
the capsule with an adhesive, as e.g. described in U.S.
Patent No. 4,928,840 or European Patent Application No.
0435726. This further treatment of the capsules may have
the effect that substances other than the medication are
encapsulated in the capsule. If on one hand a
water-based adhesive is used for gluing the capsule
halves together, the capsule as well as the caplet may be
deformed. If on the other hand, an adhesive containing an
organic solvent is used, a brittleness of the capsule
will be the result. Finally, if the capsule halves are
connected with each other by means of a heat shrinking
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process, a visible gap will remain between the capsule
halves.
It is therefore the object of the present invention
to provide a method for encapsulating caplets in a
capsule in a tamper-proof form. It is yet another object
of the invention to provide a cost-effective process for
easily manufacturing tamper-proof solid dosage forms. It
is yet another object of the present invention to provide
a solid dosage form comprising a caplet covered by a
capsule. It is yet another object of the present
invention to provide a pharmaceutical dosage form having
a greater resistance to breaking than known products. A
further object of the present invention is to provide a
tamper-proof solid dosage form.
Summary of the Invention
According to a first aspect, the present invention
provides a process for encapsulation of a capiet in a
capsule by cold shrinking together capsule parts, which
are filled with a caplet. According to another aspect,
the present invention provides a solid dosage form
obtainable by such a process. The solid dosage form
according to the present invention is tamper-proof in
that the caplet contained in the capsule cannot be
removed from the capsule without destroying same.
The process according to the present invention
furthermore provides a capsule product comprising several
parts, which are combined with each other in a way that
no visible slits between the capsule parts are present
after the cold shrink procedure. The solid dosage forms
of the present invention have a completely smooth
surface, so that same can be swallowed easily by
patients.
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More specifically, a process for encapsulating
caplets in a capsule is provided, which 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 capsule parts by cold
shrinking.
Moreover, a solid dosage form comprising a caplet
and a capsule coating obtainable by such process is
described.
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.
I.) Moisture content of the capsule shells:
A specifically preferred process of the present
invention is carried out as follows. Empty capsule parts
are either kept after production at humid conditions of
to 90 %, particularly 60 to 80 %, relative humidity to
retain a moisture content of 14 to 19 %, preferred 15 to
18 % and more preferred 16 to 18 % by weight of the
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capsule shell 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 processed
in the same manner 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-phtalate,
polymerisates of acrylic or methacrylic esters or
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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 plasticizer 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
aluminiumstearate, 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
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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-acetatephtalate, 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 methyl 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.
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II. Capsule shell halves cover not completely the caplet:
A further aspect of the invention is to provide
encapsulated dosage forms in which the capsule shell
halves do not completely cover the whole caplet, which
means the caplet is longer than the two combined shell
halves. This will provide capsules with additional
advantageous features. If each of the capsule halves
have 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 obtaind, releasing
the medicament in the stomach first from the small
release band between the shell halves and later on from
the capsule openings.
III. Global concept of moisture control:
A further aspect of the invention is 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 like powders, pellets, liquids,
microcapsules, tablets etc. The preferred process in
this case is carried out as follows. Empty capsule
bodies and caps preferred assembled in a pre-lock state
are either kept after production at humid conditions of
40 to 90 %, particularly 60 to 80 %, relative humidity to
retain a moisture content of 14 to 19 %, preferred 15 to
18 % and more preferred 16 to 18 % by weight of the
capsule shell or are re-humidified to said moisture
before opening and sorting in the capsule filling
machine. Capsule bodies are then kept under humid
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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 rectifying and finally assembling
with the filled capsule bodies. Finally, the capsule is
dried at 20 to 40 % relative humidity and 15 to 60 C,
preferably 15 to 40 C, more preferably 18 to 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 betamethason,
thioctacid, sotalol, salbutamol, norfenefrin, silymarin,
dihydergotamin, buflomedil, etofibrat, indometacin,
oxazepam, acetyldigoxin, piroxicam, haloperidol,
isosorbide mononitrate, amitriptylin, diclofenac,
nifedipin, verapamil, pyritinol, nitrendipin, doxycyclin,
bromhexin, methylprednisolon, clonidin, fenofibrat,
allopurinol, pirenzepin, levothyroxin, tamoxifen,
metildigoxin, o-(a-hydroxyethyl)-rutoside, propicillin,
aciclovirmononitrat, paracetamol, naftidrofuryl,
pentoxifyllin, propafenon, acebutolol, 1-thyroxin,
tramadol, bromocriptin, loperamid, ketotifen, fenoterol,
ca-dobelisat, propranolol, minocyclin, nicergolin,
ambroxol, metoprolol, a-sitosterin,
enalaprilhydrogenmaleate, bezafibrat, isosorbide
dinitrate, gallopamil, xantinolnicotinat, digitoxin,
flunitrazepam, bencyclan, dexapanthenol, pindolol,
lorazepam, diltiazem, piracetam, phenoxymethylpenicillin,
furosemid, bromazepam, flunarizin, erythromycin,
metoclopramid, acemetacin, ranitidin, biperiden,
metamizol, doxepin, dipotassium-chlorazepat, tetrazepam,
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estramustinphosphate, terbutalin, captopril, maprotilin,
prazosin, atenolol, glibenclamid, cefaclor, etilefrin,
cimetidin, theophyllin, hydromorphon, ibuprofen,
primidon, clobazam, oxaceprol, medroxyprogesteron,
flecainid, Mg-pyridoxal-5-phosphateglutaminate,
hymechromon, etofyllinclofibrat, vincamin, cinnarizin,
diazepam, ketoprofen, flupentixol, molsidomin,
glibornurid, dimetinden, melperon, soquinolol,
dihydrocodein, clomethiazol, clemastin, glisoxepid,
kallidinogenase, oxyfedrin, baclofen,
carboxymethylcystsin, thioridacin, betahistin,
1-tryptophan, myrtol, bromelaine, prenylamin,
salazosulfapyridin, astemizol, sulpirid, benzerazid,
dibenzepin, acetylsalicylic acid, miconazol, nystatin,
ketoconazol, sodium picosulfate, colestyramin,
gemfibrocil, rifampicin, fluorcortolon, mexiletin,
amoxicillin, terfenadrin, mucopolysaccharidpolysulfuric
acid, triazolam, mianserin, tiaprofensaure,
amenziniummetilsulfate, mefloquin, probucol, quinidine,
carbamazepin, Mg-l-aspartate, penbutolol, piretanid,
amitriptylin, caproteron, sodium valproinate, mebeverin,
bisacodyl, 5-amino-salicyclic acid, dihydralazin,
magaldrat, phenprocoumon, amantadin, naproxen, carteolol,
famotidin, methyldopa, auranofin, estriol, nadolol,
levomepromazin, doxorubicin, medofenoxat, azathioprin,
flutamid, norfloxacin, fendilin, prajmaliumbitartrate,
aescin, acromycin, anipamil, benzocain, a-carotin,
cloramphenicol, chlorodiazepoxid, chlormadinonacetat,
clorothiazid, cinnarizin, clonazepam, codein,
dexamethason, dicumarol, digoxin, drotaverin, gramicidin,
griseofulvin, hexobarbital hydrochlorothiazide,
hydrocortison, hydroflumethiazid, ketoproten, lonetil,
medazepam, mefrusid, methandrostenolon, sulfaperin,
nalidixic acid, nitrazepam, nitrofurantoin, estradiol,
papaverin, phenacetin, phenobarbital, phenylbutazon,
phenytoin, prednison, reserpin, spironolacton,
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streptomycin, sulfamethazin, sulfamethizol,
sulfamethoxazol, sulfamethoxydiazin, sulfathiazol,
sulfisoxazol, testosteron, tolazamid, tolbutamid,
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.
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