MEDICAMENT MICROENCAPSULE DANS UNE MATRICE SUCREE

MICROENCAPSULATED MEDICAMENT IN SWEET MATRIX

Abrégé anglais

Abstract of the Disclosure
Any orally administrable medicament is prepared into a
dosage form which eliminates the unpleasant taste and mouth feel
of the medicament and is easily and pleasantly ingested even by
children, by microencapsulating the medicament and embedding the
microcapsules into a soft, sweet palatable matrix, such as
chocolate.

Revendications

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A dosage form for the oral administration to
human patients of a pharmaceutically active principle,
comprising:
a soft, sweet, palatable matrix which is
sufficiently soft to allow mastication thereof without
the necessity of substantial chewing, said matrix having
substantially homogeneously embedded therein
microcapsules of active principle, said microcapsules
having a diameter below about 300 microns, and being
present in said matrix in a quantity sufficient to
provide a unit dose of said active principle in each
bite-size unit of said matrix.
2. A dosage form in accordance with claim 1,
wherein said matrix is selected from the group
consisting of chocolate, fudge, mashmallow, peanut
butter, carob or solid yogurt.
3. A dosage form in accordance with claim 1,
wherein said matrix is one which has substantially the
same consistency as chocolate.
4. A doasage form in accordance with claim 3,
wherein said matrix is chocolate, carob or solid
yoghurt.
5. A dosage form in accordance with claim 3,
wherein said matrix is chocolate.
6. A dosage form in accordance with claim 5,
wherein said matrix is sweet chocolate or milk
chocolate.
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7. A dosage form in accordance with claim 1,
wherein said active principle is an anti-bacterial
agent, analgesic, anti-histamine, decongestant, anti-
inflammatory agent, anti-hypertensive agent, hypnotic,
sedative, tranquilizer, alkaloid, diuretic, vasodilator,
hormone or vitamin.
8. A dosage form in accordance with claim 1,
wherein said microcapsules of active principle have a
diameter of less than about 250 microns.
9. A dosage form in accordance with claim 1,
wherein said micro capsules of active principle have a
diameter of about 40-150 microns.
10. A dosage form in accordance with claim 1,
wherein the active principle is microencapsulated in a
material which prevents the active principle from coming
into contact with said matrix throughout production and
storage of the embedded matrix prior to use, is non-
toxic and harmless, and permits release of the active
principle in the stomach or gastro-intestinal tract
after ingestion.
11. A dosage form in accordance with claim 10,
wherein said encapsulation material is a sustained
release material.
12. A dosage form in accordance with claim 1,
wherein the active principle is encapsulated in a
material which prevents the active principle from coming
into contact with said matrix throughout production and
storage of the embedded matrix prior to use, is non-
toxic and harmless, and prevents release of the active
principle in the stomach but permits release of the
active principle in the intestinal tract after
ingestion.
12

13. A method for the production of a dosage form for
the oral administration of a pharmaceutically active principle,
comprising:
micro encapsulating the active principle into micro-
capsules of a size less than about 300 microns; and
substantially homogeneously embedding the micro-
encapsulated active principle in a soft, sweet, palatable
matrix which is sufficiently soft to allow mastication thereof
without the necessity of substantial chewing, said micro-
capsules being present in said matrix in a quantity sufficient
to provide a unit dose of said active principle in each bite-
size unit of said matrix.
14. In a dosage form for the administration of a
pharmaceutically active principle to a human patient, compris-
ing a matrix of chocolate having the active principle embedded
therein, the improvement whereby the palatability and flavor
of the combination is improved and any adverse effect of the
chocolate on the stability on the active principle is ameliora-
ted, wherein the active principle is in the form of micro-
capsules having a diameter of less than about 300 microns, said
microcapsules being substantially homogeneously embedded into
said chocolate in a quantity sufficient to provide a unit dose
of said active principle in each bite size unit of said choco-
late.
13

Description

95~5
MICROENCAPSULATFD MEDICAMENT It SWEPT matrix
.
Inventor: Aver Roman
Field of the Invention
The present invention relates to a manner in which medic
cements may be orally administered to children or others in a
pleasant manner in which the taste of the medicament is totally
hidden. More particularly, the present invention relates to a
medicament form for permitting such administration.
Background of the Invention
Oral medication is one of the most popular methods of
drug administration into the body because it enables self-medi-
cation of the patient. In this category, palatability is an
extremely important factor in formulating pharmaceutical forms.
Because of the strong unpleasant taste of many medicaments the
value of many drugs is substantially diminished. This is portico-
laxly common among children's medications, but is also true for
adults. In order to overcome these problems of unpleasant taste
and unpalatable taste, many flavorings have been employed with
pharmaceuticals. Thus, it is very common to administer many chit-
dryness drugs as flavored syrup. Unfortunately, flavoring merely
masks the unpleasant mouth taste but affects the palatability only
slightly. A number of medications have an especially bitter
taste, and even adults reluctantly take them. In many such cases
even syrups cannot mask the bitter taste, thus constituting a
difficult pharmaceutical problem.
Among the flavorings which have been used for the pun-
pose of misusing is chocolate. Examples of patents in which chock-
late is used in conjunction with medicaments, are U.S. patents
4,271,142 and 4,327,077 to Puglia et at, U.S. patent 3,697,641 to
Arenas, U.S. patent 199,139 to Clark, British patent 543,309 to
Evans and Australian patent 7310/32 -to Jones et at. Children's
vitamins encased in chocolate are also known and on the market,
hut in these products same of the vitamins are not sufficiently

395~
stable. Laxatives in chocolate are also well known. In all of
these, however, the unpleasant taste is merely masked and the
medicines still adversely affect the flavor of the chocolate and
the palatability of the medicine is not substantially improved.
Furthermore, stability problems caused by direct contact of the
drug with the chocolate can arise.
In order to permit the release of orally administered
drugs within selected portions of the alimentary canal, i.e. the
stomach or intestine, pills in which the medicaments are protected
with the desired coating have been developed. A more advanced
pharmaceutical form for this purpose is the micro encapsulated drug
where one tablet (or large capsule) contains a few hundred tiny
(approximately 0.5-0.8mm) capsules (called micro capsules) con-
twining the drug. The type of coating encapsulating the drug is
chosen according to the medication desired and the desired release
characteristics.
Summary of the Invention
It is an object of the present invention to provide a
new form of medication for oral administration.
It is another object of the present invention to provide
a new form of medicament for oral administration in which the
unpalatable taste end mouth feel of the medicament is totally
eliminated.
It is further object of the present invention to provide
a new form of medicament which is very palatable to children, as
well as to adults.
It is yet another object of the present invention to
provide a method for administering medicaments for children in a
manner which will be palatable to the child.
These and other objects are obtained in accordance with
the present invention by micro encapsulating the drug to be admix
sistered and embedding the micro capsules in a soft sweet palatable
matrix such as chocolate. The combination of encapsulation of the
drug and the use of the soft sweet matrix, such as chocolate,
achieves the goals of both preventing the unpleasant taste which
--2--

I
the drugs may possess and overcoming the palatability problem that
may arise when one tries to ingest the drug itself. The encapsul-
anion will prevent the unpleasant taste which many drugs possess
and the chocolate matrix will serve as a way to overcome the pate-
lability problem. Furthermore, the encapsulation will avoid the
medication giving an off-flavor to the chocolate itself, which
inevitably occurs when drugs are mixed directly with a chocolate
matrix without first being micro encapsulated and will avoid loss
of stability of the medicament ho eliminating direct contact of
the medicament with the chocolate.
This combination will totally eliminate the unpleasant
taste of the medicines and the patient will only taste the chock-
late or other soft sweet matrix. Obviously, this system is
superior to any other existing method.
Detailed Description of Preferred Embodiments
As the soft sweet matrix in accordance with the present
invention, there may be used any palatable foodstuff which can be
masticated without substantial chewing and easily swallowed, pro-
furl a confection which is sweet to the taste and will be
readily accepted by the child or adult. While chocolate is the
preferred matrix, it should be understood that other soft sweet
matrices such as fudge, marshmallows, peanut butter, carob, solid
yogurt, or even cookies of appropriate consistency may be used as
the matrix, alone or in combination with other matrices. The
matrix cannot be hard, such as a hard candy, because the heavy
pressure which would be involved in chewing such a matrix would
break the micro capsules and thus destroy the purpose of the
present invention. A soft chocolate, such as sweet or milk chock-
late, is ideal for this purpose as substantial chewing is not
required for complete mastication and the chocolate and embedded
micro capsules can be masticated and swallowed without breaking the
micro capsules.
The micro capsules should be of small size in order to
ensure easy and pleasant palatability. Thus, the size should be
less than 2mm diameter, preferably less than lam in diameter, and

I I
most preferably in the range of 10-100 microns. The smaller the
micro capsules, the less likely they are to be noticed by the
patient, and the more likely that the capsules will escape chewing
and essentially will be swallowed intact.
A very wide range of medicaments are suitable for inkwell-
soon in the micro capsules used in the present invention. Such
medicaments include antibiotics and other antibacterial agents,
analgesics, antihistamines, decongestants, anti-inflammatory
agents anti-hypertensive agents, hypnotics, sedatives, tranquil
livers, alkaloids, diuretics, vasodilators, hormones, vitamins or
any other medicament frequently used in oral dosage form. Those
with especially bitter taste, such as penicillin, are, of course,
particularly suited for use in the present invention.
Suitable antibiotics include penicillins, syphilis-
poring, tetracycline, chloramphenicol, streptomycins, and macro-
lids. Suitably fully synthetic anti-bacterial agents include
nitrofurantoin and the sulfonamides. Suitable anti-inflammatory
or analgesic agents include aspirin and acetaminophen. Suitable
psychotropic medicaments include -methyldopa and guanethidine.
Suitable diuretics include aminophyline and acetazolamide.
Antibacterial include benzylpenicillin, phenoxymethyl-
penicillin, ampicillin and its pivaloyloxymethyl or phthalyl
esters, amoxycillin, cloxicillin, dicloxicillin, flucloxicillin,
carbenicillin, propicillin, methicillin, cephalexin, seafloor-
iodine, cephaloglycine, cephalothin, tetracycline, oxytetracycline,
chlorotetracycline, novobiocin, neomycin, chloramphenicol, sulfa-
thiazole, sectional sulphathiazole, sulphadimidine, streptamycin,
erythromycin, fusidic acid, griseofulvin, kanamycin, lincomycin,
spiramycin, sulphamethoxy pyrideazine, sulphaphenazole, soullessly-
azosulphapyridine, sulphamethoxazole and trimethoprin.
Suitable vitamins or nutritional supplements include
thiamine, nicotinamide, ascorbic acid, pyridoxine, riboflavin,
tryptophan, pantothenates, glycerophosphates and mixtures of these
and other vitamins.
Other medicaments include alcofenac, theophylline, hex-
bending, xylamide, and 0-(4-methoxyphenylcarbomoyl)-3-diethyl-

585
aminopropiophenone oxide.
Normally any of the medicaments to be microencapsulatedmay be used as their conventional salts, hydrates or the like.
This list is not intended to be all inclusive as any
medicament which can be micro encapsulated may be administered in
the form of the present invention.
A broad range of encapsulating agents and methods of
encapsulation may also be used in the present invention. The only
limitations on the encapsulation material are that it must be such
that the active core material will not come into contact with the
chocolate, or other matrix, during production or storage, it must
be non-toxic and harmless, it must allow the core material to
become released in the stomach or gastrointestinal tract and it
must be compatible with the sweet matrix. Any capsule material
known to the art may be used in the present invention and any
method of micro encapsulation may be used. See, for example, the
methods of micro encapsulation discussed in Sparks, OR "Micro-
encapsulation", Kirk-Othmer Encyclopedia of Chemical Technology,
third edition, volume 15 (1981), pages 470-493. As is well known,
the micro encapsulation material may be chosen for sustained
release properties or for release in a preferred area of the elf-
Monterey canal (e.g., stomach or intestine). It is preferred that
a method be used such that as high a weight percent as possible of
the micro capsules be active material. For example, U.S. patent
4,016,254 teaches a method of micro encapsulation in which the
micro capsules have an average diameter of from 100u to 300u and
which comprise I to 99 9% of a medicament coated by 0.1~ to I
of a coaling agent. See also U.S. patent 3,119,742. Any such
micro encapsulation procedure known to the art or discovered by the
art in the future may be used to make the encapsulated medicarnent
for use in the present invention. The present invention does not
relate to techniques of micro encapsulation per so, but only to the
use of micro capsules of medicaments in a soft sweet matrix such as
chocolate.
The amount of micro capsules to be loaded into a single
dosage unit will depend upon the desired dosage of the particular

95~S
pharmaceutical being administered. For example, 200 my can easily
be formed into micro capsules and dispersed in a bite size unit
dosage of matrix in a manner which will be substantially undies-
cernible to those eating the matrix. The maximum loading of
micro capsules into the matrix will to a large extent be dependent
upon the size of the micro capsules, the smaller the micro capsules,
the larger the amount that can be loaded without being noticed
when the matrix is ingested. For very tiny micro capsules, for
example on the order of the size used in carbonless copy papers,
it is conceivable that amounts as high as 50%, or even more, could
be used without adversely affecting the consistency of the matrix.
For example, if the dosage morsel of chocolate is very small, a
unit dosage of medicament in very small micro capsules may be 500
my in 1 gram of chocolate. Such a heavy loading, however, would
not be preferred as substantial breakage of the micro capsules
during chewing would be nearly unavoidable. However, the loading
preferably should not exceed about ~5-30% of the weight of the
matrix and is most preferably less than 10%, depending on the
average dose of the particular medicament being administered and
the desired size of the dosage unit of matrix. A substantially
bite-size dosage of matrix will generally be about 1-15g, depend
ding on the density of the matrix.
When the matrix is chocolate, the microcapsu]es are
preferably added to the chocolate in the process of its original
production. For example, sweet chocolate and milk chocolate are
made by mixing cocoa butter, sugar, chocolate liquor and, for milk
chocolate, milk or milk solids. These are then refined to a fine
particle size and then subjected to couching. Couching is a
kneading process in which chocolate is slowly mixed, allowing
moisture and volatile acids to escape while smoothing the no-
mining chocolate paste. Couching temperatures for sweet chock-
late generally range from 55-85C and from ~5-55C for milk chock-
late. It is conventional to add flavors, emulsifiers, etc.
during conchinq. Thus, the most appropriate time to add the
micro capsules of the present invention in the chocolate production
is also during couching. Of course, care must be taken that surf-

Issued
fishnet mixing occurs to obtain a substantially homogeneous disk
tribution of micro capsules so that an accurate amount of medical
mint will be present in any given unit weight of chocolate.
Following couching, the product is standardized, them-
pored and molded in well known manners.
The micro capsules need not be added during couching, but
may be added at any appropriate step during the production of
chocolate, or may be added by taking completed chocolate, melting
it, adding the micro capsules, mixing to homogeneity, and then
again molding.
It should be understood that the manner of adding the
micro capsules to the chocolate or other soft sweet matrix is not
critical and any procedure can be used so long as a substantially
homogeneous distribution of micro capsules is obtained.
Example 1
The micro capsules used in this example are those of the
commercial drug "Contact", manufactured by Medley and James Labor-
tory (a Smith Kline Company). Each capsule contains 600 micro-
capsules, each of a diameter of about 0.5-0.8mm. The micro capsules
are prepared by pan-coating. Each capsule (i.e. 600 micro capsules)
contains 75 my phenylpropanolamine hydrochloride and 8 my color-
pheniramine Malta.
The 600 micro capsules of one Contact capsule were em-
bedded into chocolate by first heating a commercial chocolate
square to melting (50C) in an aluminum pan container, and then
adding and mixing the micro capsules until a homogeneous disk
tribution of the capsules in the chocolate matrix was achieved,
approximately 3 minutes. The chocolate was immediately cooled and
molded into a unit of approximately 32mm x 20mm x 9mm.
When this chocolate was chewed, no taste of the drug was
observed compared to a strong taste which was observed when the
capsules were chewed without the chocolate. In addition, there
was essentially no granular sensation upon chewing the chocolate
pieces.
A sample of this chocolate was stored over one month at
* trade mark

~39585
room temperature and then observed visually, and the stability of
the drug was analyzed by mass spectroscopy analysis. After one
month there was no change in the shape or number of the embedded
micro capsules, and 100% of them could be recovered from the chock-
late matrix. Mass spectrometic analysis of the embedded encamp-
sulfated drug showed it to be identical to a control sample (i.e.,
original micro capsules stored in commercial package). Thus, the
introduction of the micro capsules into the chocolate matrix did
not affect the stability or the chemical or physical state of the
drugs in the micro capsules.
example 2
The micro capsules used in this example were those of the
commercial drug "Sudafed, SPA.", manufactured by Burroughs Well-
come Co. Each capsule contains about 300 micro capsules (diameter
0.6-0.9 mm). Mach large capsule contains 120mg pseudoephedrine
hydrochloride. These micro capsules were embedded in a single
regular chocolate unit in the manner described in example 1. When
the chocolate tablet was chewed and swallowed, no unpleasant taste
of the drug was detected.
Example 3
Micro capsules of aspirin coated with a hydrolyzed pro-
loin (gelatin) with an average diameter of 1.7u to 2.0u, each
micro capsule comprising 99% aspirin, are prepared in the manner
set forth in example 59 of U.S. patent 4,016,254. 40.4g of such
micro capsules are added to 1 kg of milk chocolate during the
couching stage of the production thereof. After mixing to home-
junta, chocolate is standardized and tempered in a conventional
manner, and then poured into molds to produce units of approxi-
mutely 5g each. Each unit contains micro capsules which include
200mg of aspirin. The chocolate units may be chewed and swallowed
with no unpleasant taste of aspirin being detectable.
Example 4
Micro capsules of aspirin coated with hydroxyphenylmethyl
* Trade Mark

I
cellulose are prepared using the all-metal, conical IJni-Glatt 4"-
Wurster apparatus. The average size of aspirin micro capsules was
80-180u, in with each micro capsule comprising 93% aspirin and 7%
coating.
A similar coating, under the same conditions, was
carried out using cellulose acetylphthalate as coating material.
The above prepared micro capsules were embedded in chock-
late (loom encapsulated material per 1.5g chocolate) in the
manner described in example 1. When the chocolate tablet was
chewed and swallowed, no unpleasant taste of the drug was detect
ted.
Example 5
Acetaminophen was encapsulated in 2.4% ethyl cellulose
(Ethocel) and 1.0% hydroxypropylmethylcelluloe phthalate (HP 50).
This coating was perform on the Aromatic Starr fluidized bed
apparatus. The average size of the obtained micro capsules was 80-
120u. The micro capsules were embedded in chocolate (loom encamp-
sulfated material per 1.5g chocolate) in the matter described in
Example 1. When the chocolate tablet was chewed and swallowed, no
unpleasant taste of the drug was detected.
Example 6-13
The following drugs, each in encapsulated form with
diameter of about 500-600u, were embedded in 1.5g chocolate in
the unit dosages specified. In each case no unpleasant taste of
the drug was detected upon chewing and swallowing of the chocolate
formulation.
Example No Active Principle Unit Dosage
6 Theophylline 200 my
7 Chlorpromazine hydrochloride 75 my
8 Chlorpheniramine Malta 8 my
9 F.rythrornycin250 my
Ferrous sulfate heptahydrate 167 rung

~3~35
if Nitroglycerin 2.5 my
12 Papverine hydrochloride 150 my
13 Niacin 250 my
It will be obvious to those skilled in the art that
various changes may be made without departing from the scope of
the invention and the invention is not to be considered limited to
what is described in the specification.
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