Method for the preparation of an encapsulated medicament

A tamper-resistant, caplet like medicament that masks the taste of poor tasting drugs and possesses an improved lubricity for easier swallowing is produced by shrinking a gelatin-based capsule about a caplet-shaped tablet of the medicament at specific temperatures, pressure and relative humidity.

FIELD OF THE INVENTION 
The present invention is related to coated or encapsulated pharmaceuticals 
that can be administered in a caplet-type dosage form. A novel method for 
preparing gelatin coated pharmaceuticals and the caplets prepared thereby 
offers tamper-resistance protection and greater ease in swallowing so as 
to encourage better patient compliance. 
BACKGROUND OF INVENTION 
The use of hard gelatin capsules for the containment of pharmaceuticals in 
unit dosage forms has been known for years. As opposed to tablets wherein 
the medicament is itself compressed into an ovoid or elliptical cylinder 
and swallowed directly, solid gelatin capsules have been used to 
administer pharmaceuticals in many different forms such as powders, 
liquids, oils and the like. As opposed to tablets, capsules completely 
envelop the drug until it reaches the stomach wherein the gelatin coating 
is eventually dissolved thereby releasing the medicament for absorption 
into the bloodstream. This provides an additional benefit of not only 
taste-masking many otherwise bitter tasting or unpalatable pharmaceuticals 
but also provides a lubricious mouth-feel or texture to the surface of the 
medicament for easier swallowing and passage into the digestive system. 
Standard capsules known in the art are prepared by dipping rows of 
stainless steel pins into solutions of gelatin, starch gelatin or gelatin 
glycerin. The pins are removed from solution, the dipped portion dried and 
stripped off the pin. Both capsule halves are formed in this manner. One 
half is generally referred to as the capsule "body" while the half that 
fits over the open end of the first is referred to as the "cap". The cap 
is mated with the body by fitting over its open end. The capsules are 
generally sold in this assembled manner and the drug or medicament filled 
later. Commercially available capsule making machines are manufactured by 
Cherry-Burrell, Cedar Rapids, Iowa 52406 for example. 
A drawback in the use of hard gelatin capsules become frighteningly evident 
several years ago when several people died taking a well known, 
over-the-counter analgesic that had been laced with cyanide through 
tampering. The problem that exists in standard capsule technology of the 
art is that the two halves of a gelatin capsule can be pulled apart and 
the medicament exposed. Anything can be added or detracted from the 
composition at this point and the halves then compressed together to again 
form one whole capsule. Moreover, there is nothing that would indicate the 
composition inside the gelatin capsule had been changed so as to serve as 
a warning to any unsuspecting patient or consumer, i.e. there is no 
tamper-evident indication incorporated into most commercially available 
gelatin capsules. 
The cyanide tampering incidents forced many if not all prescription and 
over-the-counter pharmaceutical manufacturers to take additional packaging 
steps to insure that such tampering could not occur without it at least 
being noticed by the otherwise unsuspecting patient prior to a possibly 
fatal consumption. "Blister packs", safety sealed bottles and other forms 
of safety packaging rapidly appeared throughout the pharmaceutical 
industry in an effort to prevent any further tampering. Capsule products 
were withdrawn from the market altogether and in some cases were replaced 
by "caplets", solid oblong tablets comprised of the medicament and coated 
with a material such as cellulose, pectin, etc. The solid form of the drug 
not only protected against further tampering since the caplet would have 
to be broken apart in order to incorporate any additional ingredients and 
this lack of caplet integrity is easily discernible, but the coating also 
provides an ease in swallowing and protected some medicaments such as 
aspirin from causing stomach distress. 
However, all of these reactionary measures and their precautions have added 
additional expense to the manufacture and packaging of both prescription 
and over-the-counter drugs. U.S. Pat. No. 4,820,524 to Berta points out 
that beyond the additional cost factors of these precautions, consumer 
surveys suggest that the shiny, familiar capsule shape has a special 
appeal to patients as being easy to swallow. It is additionally theorized 
that consumers perceive capsuled medicaments as being more effective in 
light of the long term association of the capsule with many well known and 
well respected pharmaceutical companies and their products. This could 
possibly add an additional placebo factor to their actual effectiveness. 
There exists then, a very real need for truly tamper-resistant capsule or 
capsule-like encapsulating materials as carriers for pharmaceuticals and 
other medicaments. 
A number of references have coated pills or tablets by dipping them into 
gelatin solutions of one type or another. U.S. Pat. No. 599,865 to 
Richards discloses an apparatus for coating pills with gelatin whereby a 
bar is coated with an adhesive which holds the pills to be coated in 
place. The bar is then fitted over a second plate containing holes to 
which the affixed pills are aligned. The bar and plate, once joined, 
immerse half of the pill body into the gelatin. The bar and plate are then 
inverted whereby the other half is coated. Whereas the process may coat 
the pills with a material such as cellulose, starch, etc., there is no 
indication that a capsule-like appearance is achieved. Moreover, the 
process must be carried out manually and in no way could meet the 
production demands of today's world. 
Of particular interest is U.S. Pat. No. 4,820,520 to Berta wherein a solid 
medicament core such as a caplet is provided with a capsule-like coating 
by dipping first one end of the capsule into a gelatinous solution so as 
to cover one-half of the caplet. This is then dried and the other end is 
dipped into the solution so that both gelatinous "dips" over-lap at 
approximately the midway point of the longitudinal axis of the caplet. 
This over-lapping of the gelatin coats is perceived as the seam created 
when two solid gelatin capsule halves are joined in the traditional 
procedure known in the art. U.S. Pat. No. 4,867,983 also to Berta 
discloses the method whereby the caplet is coated with a first gelatinous 
core on one end followed by the coating of a second gelatinous core on the 
other end which is thicker than the first so as to simulate the 
interlocking halves of a hollow gelatin capsule. The dipping procedure 
however, must be precise and requires intricate processing and mechanical 
steps in order to guarantee a smooth gel coating about the caplet. Since 
two dipping steps are required, the likelihood of uneven coating about the 
caplet remains high and many caplets are not assured of consistency in 
capsule shape and size. 
It is an object of the present invention to provide a tamper-resistant 
pharmaceutical capsule whereby a medicament in the form of a caplet, is 
encapsulated with a solid gelatin capsule which is essentially tasteless 
and easy to swallow. 
It is a further object of the present invention to provide a method for 
encapsulating a medicament in the form of a caplet with a solid gelatin 
capsule by shrinking said capsule about said caplet with no space 
therebetween. 
It is yet a further object of the present invention to provide a 
capsule-like medicament wherein two solid gelatin capsule halves are fused 
about the caplet and cannot be removed without substantial damage thereto. 
It is yet a further object of the present invention to provide a method for 
the preparation of a tamper-resistant capsule about a solid medicament in 
the form of a caplet by shrinking said capsule at a specific temperature 
and relative humidity so as to insure uniform shrinkage and fusion of said 
capsule about said caplet. 
SUMMARY OF THE INVENTION 
The present invention presents a novel method for the encapsulation of a 
solid pharmaceutical or over-the-counter drug in a solid gelatin capsule 
so as to provide a tamper-resistant coating that has the additional 
advantages of ease in swallowing, taste masking and aesthetic 
desirability. The method requires the application of energy in the form of 
heat for a critical time at a constant relative humidity so as to insure 
uniform shrinkage of the capsule around the drug. The inner surface of the 
capsule bonds to the surface of the caplet while the two portions of the 
capsule halves that over lap bond to each other forming a contiguous and 
continuous intact coating about the drug. 
DETAILED DESCRIPTION OF THE INVENTION 
The present invention deals with the shrinking of solid, hard gelatin, 
starch, starch gelatin or gelatin glycerin capsules about a solid 
pharmaceutical or over-the-counter drug so as to provide several 
advantages over the uncoated caplets known in the art. For one, the 
gelatin capsules are tasteless so that by shrinking these capsules about 
an otherwise bad tasting drug, the patient's taste buds are insulated from 
the bad taste of the drug as it passes through the oral cavity. The 
capsule does not dissolve or disintegrate until it reaches the stomach and 
is well past the organoleptic sensory system. Secondly, the fused capsules 
provide a tamper-resistant feature to any drug so coated since any attempt 
to incorporate a foreign substance into one of the capsules of the present 
invention can only damage the integrity of the capsule which is readily 
noticed. The encapsulated pharmaceuticals and drugs of the present 
invention are slowly dissolved in the stomach due to the presence of the 
gelatin capsule and this reduces the likelihood of stomach distress 
associated with many of the analgesics such as aspirin. 
Moreover, the shiny aesthetic features of the capsule shaped medicament 
have been long associated with well known and trusted products of the 
pharmaceutical industry and it is believed that this association acts as 
additional psychological placebo factor in the drugs' actual effectiveness 
i.e., by encouraging better patient compliance. And finally, along these 
lines, the capsules inherently possess a certain ease in swallowing due to 
the lubricious nature of the gelatin coat and this can only serve to 
further encourage patient compliance. 
The core material can be any prescription pharmaceutical, over-the-counter 
drug, flavoring agent or sweetener so long as it can be compressed into a 
solid, oblong cylindrical form known in the industry as a caplet. Suitable 
medicaments may be antihypertensives, analgesics, antibiotics, 
anti-tussives antiarrythmics, antihistamines, antacids, decongestants, 
laxatives, vitamins, mineral supplements, mixtures thereof and the like. 
Whereas prescription pharmaceuticals and over-the-counter drugs comprise 
the preferred embodiments of the present invention, solid forms of 
sweeteners or flavoring agents may be so encapsulated so as to improve 
their stability or delay their release rates in certain environments. 
It has been determined that temperature, relative humidity and capsule 
moisture content are critical parameters in the shrinkage encapsulation 
process. Numerous capsule defects arise during the process of the present 
invention unless all of these parameters fall within specified ranges. 
Generally, these defects are attributable to one of the following. 
In one instance, air can become trapped inside the solid gelatin capsule 
during shrinkage which forms pockets or corrugations on the capsule 
surface, leaving an unsightly blemish that disrupts the integrity of the 
capsule and is commercially unacceptable. A second problem encountered is 
that of the short overlap defect whereby one-half of the solid gelatin 
capsule may shrink more than the other cap or body half resulting in no 
sectional overlap or a non-fused capsule at or about the midpoint of the 
longitudinal axis of the caplet. This enables one to pull the capsule 
apart and is obviously unacceptable. 
Another problem encountered is that the edges of the cap portion, which 
generally overlap a portion of the body thereby forming a collar about the 
mid-point of the longitudinal axis of the caplet, do not stick to the body 
but flange outward from the capsule after shrinkage. Generally, bonding of 
the capsule cap with the caplet has occurred but the flange is both 
unsightly and will interfere with proper swallowing of the medicament. 
For purposes of this invention, the term "hard gelatin" capsule is meant to 
include any conventional hard capsule which is capable of being shrunk, 
using the present inventive process. For example, capsules comprised of 
gelatin, starch, sugar gelatin, gelatin glycerin and mixtures thereof are 
useful in the practice of the present invention. 
Generally, the two capsule parts can be of identical or different colors, 
transparent or opaque. The hard gelatin capsules found to be of greatest 
value in the practice of the present invention are those registered under 
the trade name Supro C and are manufactured by the Capsugel Co. of 
Greenwood, S.C. Capsule size can be varied according to the dosage of the 
caplet to be coated. The moisture content of the hard gelatin capsules 
useful in the practice of the present invention can vary from about 13.0% 
to approximately 16.0% and preferably varies from about 14.0 to about 
15.0%. Table 1 below is indicative of the amount of water in each of five 
(5) representative capsule sizes useful in the practice of the present 
invention together with the capsule weight of the final product as 
dictated by the density of the core material. 
TABLE I 
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CONI-SNAP SUPRO .TM. 
CAPSULE WEIGHT CAITY MG 
CAP- 
SULE CAPSULE POWDER DOSE DENSITY 
SIZE VOLUME 0.6 g/cc 0.8 g/cc 
1.0 g/cc 
1.2 g/cc 
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A 0.68 408 544 680 816 
B 0.50 300 400 500 600 
C 0.37 222 296 370 444 
D 0.30 180 240 300 360 
E 0.21 126 168 210 252 
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The two halves of the hard gelatin capsules once selected according to the 
size of the caplet to be coated can be placed about the two ends of the 
caplet core either manually or mechanically by making minor modifications 
to any one of a number of commercially available machines known in the art 
such as capsule filling machines from Robert Bosch Corp., 121 Corporate 
Blvd., South Plainfield, N.J. and Zanasi Ima Group, Bologna, Italy. As 
mentioned previously, a critical element in the process of the present 
invention is the proper water content of the hard gelatin capsule that is 
used to shrink about the caplet medicament. If the moisture content of the 
capsule is too low, or if the gelatin film dries out, the capsule will not 
sufficiently shrink about the caplet upon the application of heat to be 
useful. If the moisture content on the other hand is too high, excessive 
shrinking occurs and the short overlap defect becomes prevalent. 
In order to overcome the moisture problem, the hard gelatin capsules can be 
heated in a sealed cavity or environmental chamber whose temperature and 
relative humidity are maintained at a constant. The climatic chamber 
allows the use of lower shrink temperatures than that of the sealed cavity 
and thereby generally gives better results. The relative humidity is kept 
sufficiently high, between approximately 50% and 90% and preferably 60% 
and 80% so as to prevent the capsules from drying out during shrinkage. 
Temperatures are best maintained from about 50.degree. C. to about 
100.degree. C. with a preferred range of from about 65.degree. C. to about 
75.degree. C. It was also found that the time in which the heat was 
applied played an important factor as short exposure times resulted in 
little or no shrinkage and bonding while too long an exposure resulted in 
excessive shrinkage and little to no overlap of the cap and body. 
Generally, the capsules can be heated from approximately 30 sec. to about 
600 sec., with a preferred range of from about 90 sec. to 360 sec.

The following examples are provided to better describe and define the 
process and capsules of the present invention. They are for illustrative 
purposes only and it is realized that minor variations or modifications 
can be made thereto and therefore these examples should not be regarded as 
limiting the spirit and scope of the claims that follow. 
EXAMPLE 1 
The two halves of the gelatin capsules can be placed about the medicament 
caplet core either manually or mechanically by one of any number of 
commercially available encapsulation machines known in the art. Using a 
Blue M humidity chamber, five (5) samples of six (6) caplets each were 
bonded using different temperature and humidity parameters for different 
exposure times. The caplets used were placebos manufactured by either 
Perrigo, Inc. or Bristol Myers and they were placed within Supro C 
transparent hard gelatin capsules. Table II shows the percentage of 
tablets exhibiting defects for each of the parameters tested. 
TABLE II 
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T (.degree.C.) 
% RH Exposure Time (sec.) 
% Defects 
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65 75 120 17 
68 70 180 7 
70 70 120 8 
72 70 120 3 
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Clearly, these ranges produced results which can be applied to large scale 
commercial applications.