The present invention relates to novel liquid oral suspensions incorporated within a soft gelatin capsule comprised of a bitter or bad-tasting pharmaceutical active (such as antihistamines, decongestants and the like) which is dispersed within an adsorbate comprised of magnesium trisilicate, silicon dioxide or mixture thereof. The adsorbate is dispersed within an aqueous or non-aqueous carrier base and combined with other flavors, sweeteners, emulsifiers and the like. The adsorbate not only taste-masks the active but also insures that is evenly dispersed through the liquid suspension so that a uniform dosage rate is readily achievable. The encapsulation of the adsorbate within a gelatin capsule makes administration easier for children andmore convenient. The capsule also affords the adsorbate suspension greater shelf life.

FIELD OF THE INVENTION 
The present invention relates generally to pharmaceutical delivery systems 
for the oral administration of therapeutic drugs. More specifically, the 
invention relates to delivery systems for the oral administration of 
bitter or otherwise unpleasant tasting drugs in a manner that is more 
palatable and less objectionable to young children and some older patients 
as well. 
BACKGROUND OF THE INVENTION 
There are many means in which therapeutic agents can be administered to a 
patient such a intravenous, intramuscular or intraperitoneal injections, 
naso-gastric tubes, transdermal patches and the like. Oral delivery 
systems have proven to be the easiest means for drug administration when 
the active can be absorbed into the digestive system as the tablet or oral 
suspension containing the drug of interest can be simply placed in the 
mouth and swallowed with or without water. Oral delivery also provides a 
relatively fast and efficient means to get the drug absorbed into the 
digestive system and dissolved into the bloodstream where the active drug 
is delivered to wherever necessary. 
There have been numerous pharmaceutical vehicles developed over the years 
for the oral administration of drugs and therapeutic agents. Oral delivery 
systems have consisted of solid tablets that must be swallowed whole; 
solid tablets that dissolve in water and are then consumed; confectionery 
delivery systems in which the pharmaceutical agent is provided in a 
flavored, pleasant-tasting vehicle which is either chewed and ingested or 
is allowed to dissolve slowly in the mouth. The drug may also be dissolved 
and suspended in a liquid vehicle such as a flavored cough syrup which is 
easily swallowed. 
One of the drawbacks to oral delivery systems however, is the situation 
wherein the drug to be administered is bitter, bad-tasting, odorous or in 
some manner organoleptically unpleasant. Many efforts have been made in 
the past to "taste mask" these compounds either through elaborate flavor 
and/or sweetener delivery systems, adsorption of the drug within another 
material or by encapsulation with a polymer, fat, carbohydrate or other 
like material. These taste-masking methods basically prevent the bitter 
tasting components of the drug from contacting the taste-buds during oral 
ingestion yet break down and release the active upon dissolution in the 
stomach. However, each of these methods also have their own drawbacks and 
the search remains for a fast-acting, non-offensive easily administrable 
oral drug delivery system. 
U.S. Pat. No. 4,632,821 to Peters et al. discloses a medicament adsorbate 
in which a pharmaceutical such as an anti-tussive, antihistamine, 
decongestant and the like is adsorbed onto magnesium trisilicate particles 
having a flake-like structure and a surface area of at least 400 m.sup.2 
/g. Whereas a number of pharmaceutical compositions are listed as being 
useful in the practice of the present invention, decongestants are the 
active of choice and are preferably formulated as a chewing gum or 
lozenge. 
U.S. Pat. No. 4,647,459 also to Peters et al. discloses and claims a 
confectionery composition in which a pharmaceutical active is dispersed 
within a magnesium trisilicate adsorbate. The adsorbate is incorporated in 
a lozenge, tablet, toffee or nougat in an amount of from about 1.0% t 20% 
by weight. 
U.S. Pat. No. 5,112,604 to Beurline et al. discloses an oral pharmaceutical 
liquid suspension comprised of theophylline as the active agent, silicon 
dioxide, a wetting agent and a hydrocolloid gum. The gum and silicon 
dioxide act to suspend the agent evenly throughout the liquid thereby 
insuring uniform dose dispersions. Whereas theophylline is the primary 
drug of interest anti-inflammatories, analgesics, antihistamines and 
others are also listed as suitable for use with the invention. 
U.S. Pat. No. 4,650,663 also to Peters et al. discloses the preparation of 
an oral pharmaceutical delivery system in which an unpleasant tasting 
anti-tussive such as noscapine, carbetapentane citrate or clophedianol 
hydrochloride is adsorbed onto magnesium silicate flakes and incorporated 
into a chewable tablet or lozenge. The adsorbate allegedly masks the 
bitter taste to an almost negligible level to encourage better patient 
compliance. 
U.K. Patent 1,388,786 assigned to the Schereer Corporation discloses an 
integral solid dosage carrier for pharmaceutical agents consisting of a 
gel-lattice structure that has been extruded into conventional 
configurations. The gel lattice consists of water-soluble colloidal 
hydrates such as gelatin, derivatives. The drug of interest is dissolved 
and mixed in the hydrate which is in liquid form. A plasticizer such as 
glycerin or triethyl citrate is then added which causes the gel lattice to 
form. Since it is relatively rigid containing from only 15%-20% water, no 
outer coating is needed for the dosage forms to retain their form and 
solubility over time. 
It is an object of the present invention to provide a novel, oral delivery 
system that is chewable for rapid release of the active yet is pleasant 
tasting even when bitter tasting or otherwise unpalatable drug actives are 
involved. The drug is dispersed within an oral suspension comprising a 
medicament adsorbate and is then incorporated within a gelatin capsule. 
The soft, chewable capsules will encourage better patient compliance in 
difficult patients such as young children who are hesitant to swallow 
pills, caplets or capsules. The dosage form also provides excellent 
stability for the drug for extended longer term shelf life. 
SUMMARY OF THE INVENTION 
A novel pharmaceutical delivery system is comprised of a chewy, soft 
gelatin capsule within which a drug adsorbate is dispersed in a solid or 
liquid fill material. The drug is absorbed onto flake-like particles of an 
adsorbate such as magnesium trisilicate, silicate dioxide or preferably a 
mixture of both. The fill material of the capsule within which the 
adsorbate is dispersed is comprised of flavors, sweeteners, corn syrup, 
solvents and other food-grade excipient that assist in the stabilizing and 
taste-masking of bitter tasting drugs. 
DETAILED DESCRIPTION OF THE INVENTION 
Chewable tablets and capsules are highly valuable forms of oral 
pharmaceutical delivery systems in both the prescription and over the 
counter markets due to the convenience of their administration; i.e., no 
water is necessary. However, the bitter or unpalatable tastes of most 
drugs has severely limited their acceptance in these markets. The present 
invention seeks to overcome these limitations by affording a chewable 
gelatin capsule in which the bitter taste of the drug has been masked 
through the use of a drug adsorbate disposed therein together with other 
pleasant tasting syrup carriers, flavors, sweeteners and the like. 
The adsorbate suspension technology of the present invention that is 
incorporated within the gelatin capsule is comprised of a pharmaceutical 
active adsorbed onto a magnesium trisilicate microgranule or agglomerate. 
The drug/adsorbate composition is dispersed in an aqueous or non-aqueous 
carrier solvent which is then injected into a chewable gelatin capsule so 
the drug can be ingested and readily adsorbed into the patient's stomach 
for quick relief. With magnesium trisilicate adsorbate technology, the 
present invention can provide chewable encapsulated liquid suspensions 
that would otherwise be bitter tasting, with superior taste to other drug 
delivery systems known in the art. Moreover, despite the presence of the 
solid adsorbate, there is no gritty texture due to the preparation of the 
adsorbate in a very small particle size. The gelatin capsules known in the 
art generally must be swallowed whole which again is a problem for 
children, the elderly and others who have difficulty in swallowing. 
Magnesium trisilicate (Mg(O.sub.3 S).sub.3) is a fine, white odorless and 
tasteless powder that is a well known adsorbent, antioxidant and antacid. 
The compound is an excellent adsorbate carrier for pharmaceutical agents 
as it can form flake-like lattice structures with many interstitial spaces 
that provides a large surface area for maximum drug loading. When 
solubilized in an aqueous-solution containing the drug of interest, the 
flakes can then be precipitated as masses with the drug adsorbed within 
the interstitial crevices between the individual flakes. The drug 
adsorbate is then mixed within the carrier fill which is encapsulated by 
the soft gelatin capsule. 
Silicon dioxide, (SiO).sub.2) or silica is a second substance useful as the 
adsorbate for the active agent in the practice of the present invention. A 
colorless crystalline powder, it also may be precipitated from solution as 
clumped flakes with interstitial spaces in which the active pharmaceutical 
is trapped and adsorbed. Preferably, the adsorbate used in the practice of 
the present invention is comprised of a mixture of both magnesium 
trisilicate and silicon dioxide in a 1:1 ratio. 
The pharmaceutical agent useful in the delivery system of the present 
invention could conceivably be any active drug capable of delivery by oral 
administration. For example, suitable pharmaceuticals might include 
anti-tussives, antacids, analgesics, antihistamines, anti-arrythimics, 
decongestants, anti-inflammatory agents, central nervous system drugs, 
diuretics, antidiarrheal compounds, steroids, antibiotics, 
chemotherapeutic agents, neoplastic agents, antiparasitic agents and the 
like. The only criteria as to whether the drug would be useful in the 
chewable delivery system is whether it can provide its therapeutic effect 
after ingestion and absorbation and its compatibility with the filler 
material and chewable gelatin shell. Other criteria to consider is the 
drug's dissolution rate and shelf life stability. 
Conceivably the, the specific therapeutic agent useful in the practice of 
the present invention can be any one of the many pharmaceutical agents 
that may be delivered orally, ingested, and then absorbed through the 
digestive tract and into the bloodstream. Preferably however, the drug 
active is both water soluble and one of the many unpleasant tasting drugs 
currently available on the Rx and over the counter market. Pharmaceutical 
actives of this type include antitussive compounds such as 
dextromethorphan, detromethorphan hydrobromide, noscapine, carbetapentane 
citrate, chlorphedianol hydrochloride and the like; sedating 
antihistamines include chlorphenramine, phenidamine, doxylamine, 
phenylOxamine, diphenhydramine, promethazine and triprolidine, 
hydroxyzine, meclinzine, cyproheptadine, azatadine their salts and 
mixtures thereof. Suitable non-sedating antihistamines include 
fexofenadine, terfenadine, astemizole, loratadine and cetirizine, while 
suitable decongestants include phenylephrine, phenylpropanolamine, 
pseudoephedrine, ephedrine, theirs salts and mixtures thereof. 
Nonsteroidal anti-inflammatory agents (NSAIDS) may also be incorporated in 
the absorbate compositions of the present invention. Suitable NSAIDS 
include ibuprofen, ketoprofen, acetylsalicylic acid, ketoprofen, aproxen, 
naprosyn, meclomen, indomethicin and mixtures thereof. Suitable analgesics 
include acetaminophine. H.sup.2 -antagonists useful in the composition of 
the present invention include famotidine, ranitidine, cimetidine and 
mixtures thereof. 
Useful antibiotics, antibacterials and bactericidals include erythromycin, 
cephalosporin, tetracyclines, penicillin, amoxycillin, clathromycin and 
mixtures thereof. Useful anti-convulsants include phenyltoin and 
thosuximide. 
The wide variety of pharmaceuticals useful herein include their acid 
addition salts. Both organic and inorganic salts may be used and exemplary 
acid salts include the hydrochloride, hydrobromide, orthophosphate, 
benzoate, maleate, tartrate, succinate, citrate, salicylate sulfate, 
acetate and mixtures thereof. 
The pharmaceutical or therapeutic agent is preferably first dissolved in 
water or some other organic solvent for those drugs which are not water 
soluble. Depending on the dosage desired, and the type of drug involved, 
the drug is added in an amount of from 0.5% to about 25% w/w of the 
absorbate. Once complete dissolution of the active has occurred, the 
solution is added to the absorbate in amounts of from about 0.1 to about 
3.0 mls. per gram of absorbate. The preferred absorbate for the use in the 
practice of the present invention is magnesium trisilicate (2MgO.sub.3 
SiO.sub.2 H.sub.2 O) or silicon dioxide (SiO.sub.2) and most preferably a 
combination of the two. The magnesium trisilicate and silicon dioxide are 
very fine, white, odorless powders with flake-like structures with 
multiple interstitial spaces. 
Once the pharmaceutical solution is prepared, it is added to the magnesium 
trisilicate/silicon dioxide powder and a slurry is prepared as the 
absorbate and drug are combined. The absorbate/drug carrier agent is then 
dispersed into a non-aqueous or aqueous base using a moderate to high 
sheer mixer. 
Suitable non-aqueous bases may be selected from the group comprising 
vegetable oils and fats, animal fat, mineral oils, paraffin and wax, 
natural fatty acids any edible oil, glycerin, sugar and mixtures thereof. 
Suitable aqueous-based solvents include water with a second excipient 
comprised of sorbitol, glycerine, corn syrup, sugar, alcohols and mixtures 
thereof. 
Again, the amount of pharmaceutical active incorporated into the 
magnesium/silicate will vary depending on the target dosage and the type 
of drug to be taste masked. Generally, the active will be mixed in amounts 
of from 0.2 grams to about 0.3 grams per gram of absorbate. The amount of 
active absorbate per volume of liquid carrier will also vary but generally 
may be from about 1.0% to about 15% active/adsorbate based on the total 
weight percent (wt %) of the liquid formulation. 
The filler composition that carries the adsorbate within the soft chewable 
shell is comprised of flavors, sweeteners, colorants, solvents, 
preservatives, polyethylene glycol, corn syrup, emulsifiers, 
gums/thickeners, oils and fat fillers and other insoluble or soluble 
excipients. The specific components of each genus can be readily 
ascertained by those skilled in the art. Flavor and component 
compatibility are perhaps the major criteria in the excipient selection. 
In formulating the final suspension product, additional excipients such as 
flavoring agents, preservatives, gums/thickeners, sweeteners, coloring 
agents, emulsifiers, fillers, oils and fats and the like may be added to 
the encapsulated oral suspension to further improve the taste and 
palatability thereof during chewing. These can be added in varying amounts 
as is known in the art and as desired according to the formulation. 
Generally, a standard liquid will be comprised of the following components 
in their respective amounts, based on the total weight percent of the 
liquid suspension. 
______________________________________ 
Compositions Percentage 
______________________________________ 
Drug adsorbate 1.00-15.00% 
Sorbitol 5.00-90.00% 
Water 10.00-80.00% 
Preservatives 0.01-1.00% 
Glycerin 5.00-30.00% 
Gums/thickeners 0.500-5.00% 
Flavors 0.500-4.00% 
Buffers 0.500-5.00% 
______________________________________ 
In order to prepare the adsorbate suspensions incorporated in the gelatin 
capsule of the present invention, generally a wet granulation methodology 
is employed as is known in the art. If magnesium trisilicate is used as 
the sole adsorbate carrier, it is important to maintain the pH of the 
process and that of the product as well at a pH of about 8.5 in order to 
maintain the stability of the trisilicate. If silicon dioxide is employed 
as the sole adsorbate, pH is of no consequence, but again, this is not 
preferred. Most preferably a combination of the two is employed wherein pH 
will not be a major factor of concern. Nevertheless, maintaining a pH as 
close to 8.5 as possible will produce a better final product. 
The soft chewable capsules of the present invention are generally comprised 
of plasticized gelatin or a pharmaceutically acceptable polymer. The 
capsule itself is a one-piece, sealed construction enclosing the 
components therein. Soft capsules are generally used for encapsulating a 
fluid carrier, a semi-fluid carrier or both. The difficulty in using 
gelatin as the drug matrix shell is the inherent and marked affinity of 
the gelatin capsules for water. Usually, special considerations must be 
taken to keep the water content of the filler material below a critical 
minimum, otherwise the carrier medium may be adsorbed into the gelatin 
shell resulting in its degradation and breakdown. 
The gelatin capsules are generally comprised of natural or synthetic 
polymers as is known in the art. Natural gelatin, pectin, casein, 
collagen, protein, modified starches, polyvinyl pyrolidone and the like 
are all capsule components well-known in the art. Gelatin is the 
composition of choice and may be combined with stabilizers, plasticizers 
and coloring agents as is known in the art. Specific capsules useful in 
the practice of the present invention and methods for their preparation 
are described in U.S. Pat. Nos. 4,325,761 and 4,281,763 to Pace, 4,532,126 
to Ebert et al. and 4,780,316 to Brox et al., all of which are 
incorporated by reference. 
The filler materials described above may therefore be dispersed in a water 
immiscible solvent or oil as a carrier medium within the shell. This will 
also serve as the carrier medium within which the drug adsorbate is 
dispersed prior to encapsulation. 
The gelatin capsule itself is generally ovoid in shape and can be sized 
according to the potency of the drug and dosage. Other shapes can be 
utilized according to individual preference although ovoid is generally 
preferred. Gelatin encapsulation methodologies are well-known in the art, 
and large scale commercial means are described in U.S. Pat. No. 4,922,682 
to Tart et al., U.S. Pat. No. 4,997,359 to Lebrun and Re 33,251 to Wittmer 
et al., all which are also incorporated by reference. 
The following examples are provided to set forth and disclose particular 
ways of practicing and preparing the novel compositions of the present 
invention. The are for illustrative purposes only however, and it is 
understood that minor changes and variations can be made which are not 
fully contemplated herein. It is to be understood that to the extent any 
such changes or alterations do not materially affect the final product or 
process, they are to be considering as falling within the spirit and scope 
of the invention as recited by the claims that follow.

EXAMPLE I 
The following ingredients were collected in their respective amounts in 
order to prepare the adsorbate suspension of the present invention 
containing a decongestant/antihistamine dual active therapeutic 
formulation. 
______________________________________ 
Ingredient Percent Wt/Liter 
______________________________________ 
1. POLOXAMER 407 .3000 3.0000 GM 
2. POLYETHYLENE GLYCOL 20.0000 200.0000 GM 
1450 NP 
3. 15% PSEUDOPHENDRINE 4.00 40.00 
HYDROCHLORIDE Adsorbate 
4. 12% DIPHENYDRAMINE 2.08 20.83 
HYDROCHLORIDE Adsorbate 
5. SODIUM BENZOATE NF .4000 4.0000 GM 
6. SODIUM PHOSPHATE .02 2.00 
7. SODIUM CITRATE .1000 1.0000 GM 
GRANULAR USP 
8. SODIUM CHLORIDE USP .1000 1.0000 GM 
GRANULAR (IRON FREE) 
9. SODIUM SACCHARIN USP .1000 1.0000 GM 
GRANULAR 
10. SORBITOL SOLUTION USP 
60.0000 600.0000 GM 
11. GLYCERIN USP SPECIAL 5.0000 50.0000 GM 
12. MONO AMMONIUM .0080 .0800 GM 
GLYCYRRHIZINATE 
13. SODIUM CARBOXYMETHYL .2000 2.0000 GM 
CELLULOSE USP TYPE 
14. 1 RASPBERRY CHERRY FLAVOR 
ART. NV-17688 (INC) 
15. 2 D & C RED NO. 33 .0005 .0050 GM 
16. 3 FD & C RED NO. 40 .0050 .0500 GM 
17. XANTHAN GUM 0.8 8.0 
18. WATER PURIFIED USP 100.0000 1.0000 L 
______________________________________ 
The diphenhydramine hydrochloride/pseudoephedrine hydrochloride adsorbate 
suspension was then prepared as follows. Water (150 ml) was heated in a 
container with a mixer to 45.degree. C. The Poloxamer 407 was added and 
mixed until fully dissolved. The polyethylene glycol was then added and 
the solution mixed for 30 minutes maintaining the temperature at 
45.degree. C. A pseudoephedrine hydrochloride adsorbate was previously 
prepared comprising 15 wt % pseudophendrine HCl, 50 wt % magnesium 
trisilicate and 35 wt % silicon dioxide. Similarly, a diphenhydramine HCl 
adsorbate was prepared comprising 12.0 wt % diphenhydramine HCl and 88.0 
wt % magnesium trisilicate. Each were then encapsulated within a standard 
gelatin capsule as is known in the art. 
EXAMPLE II 
______________________________________ 
Weight 
Ingredient Percent gms/kilo 
______________________________________ 
1. Diphenhydramine - HCl/Magnesium trisili- 
3.36 33.60 
cate 
2. Sorbitol (70% Solution) 
43.07 430.07 
3. Xylitol (60% Solution) 43.07 430.07 
4. Xanthan Gum .35 3.5 
5. Sodium Carboxymethyl Cellulose 
.15 1.5 
6. Glycerin .10 100.0 
______________________________________ 
The sorbitol was first mixed with the xylitol to a homogenous blend. to 
this was added the drug adsorbate followed by further mixing at moderate 
speed. In a separate container, the sodium carboxymethyl cellulose, 
glycerin and xanthan gum were mixed well and the two containers were then 
combined. The suspension was mixed until a smooth, substantially uniform 
viscous liquid was obtained. A phosphate buffer was added (optional) to 
raise to pH to about 8.5. The pH was recorded to be 8.38 while the 
viscosity measured 6750 cps. The suspension was then injected into soft, 
chewable gelatin capsules as is known in the art. The adsorbate suspension 
capsules proved stable for extended periods at room temperature, and 
30.degree. C., 40.degree. C. and 50.degree. C.