Tastemasked liquid pharmaceutical delivery system

A substantially tasteless liquid phramaceutical delivery system containing an active material and a high osmolarity aqueous system comprising (i) water; (ii) about 20% to about 45% by weight sugar derivative; (iii) about 10% to about 15% by weight hydrogenated maltose syrup; and (iv) about 0% to about 35% by weight polyhydroxy alcohol.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
This invention relates to substantially tastemasked liquid pharmaceutical 
delivery systems and to methods for making the same. More particularly, 
the invention relates to tastemasking the noxious, bitter tastes 
associated with bad tasting drugs for use in a liquid delivery systems to 
prepare pleasant tasting orally administered compositions. 
2. Description of the Prior Art 
Oral pharmaceutical formulations are administered to patients in many 
forms, such as liquid solutions, emulsions or suspensions, as well as in 
solid forms such as capsules or tablets. Preparations administered in 
tablet or capsule form are usually intended to be swallowed whole. 
Therefore, the often disagreeable taste of the active ingredient need not 
be taken into account in formulating the medicine, except as a means to 
prevent the taste from being apparent during the short time that the 
medicine is in the mouth. Such means may include forming the active into a 
matrix preparation, the use of capsules or simply compressing a tablet 
firmly so that it will not begin to disintegrate during the short time 
that it is intended to be in the mouth. 
In some preparations, the unpleasant tasting particles are coated with 
water-soluble and/or water-insoluble coating agents, film forming 
polymers, water-swelling agents and acid soluble agents. 
In contrast, liquid preparations or preparations in the form of solutions 
or suspensions are used to tastemask bitter tasting drugs by use of 
sucrose sweetening agents and/or flavoring agents. These formulations are 
advantageous for administration to children and the elderly. Such 
formulations have high patient compliance and are easily taken. Such 
formulations are generally prepared using an organic solvent system and 
may even contain high amounts of ethyl alcohol, i.e., around 8%. Some of 
the foregoing procedures are described in the following patents. 
U.S. Pat. No. 2,954,322 to Heilig, et al. discloses a tablet intended for 
oral administration wherein the whole tablet is coated with a mixture of 
shellac and polyvinylpyrrolidone. It is intended that the tablet be 
swallowed whole and that the coating will disintegrate in the stomach to 
release the active medicament. 
U.S. Pat. No. 3,133,863 to Tansey, et al. discloses a method for forming 
granules of medicament that can be compressed into tablet form, wherein 
the granules include various polymers dispersed throughout the granules. 
One embodiment comprises acetaminophen mixed with PVP and methyl 
cellulose. 
U.S. Pat. No. 3,420,931 to Daum, et al. discloses sugar-coated 
pharmaceutical preparations ("Dragees") coated with a mixture of sugar and 
a vinyl polymer such as PVP. The coating may also contain cellulose 
derivatives. 
U.S. Pat. No. 3,458,622 to Hill discloses a controlled release tablet 
wherein the active medicament is contained in a core comprising a matrix 
of a mixture of PVP and a carboxyvinyl (polyacrylic acid) hydrophilic 
polymer. 
U.S. Pat. No. 4,252,786 to Weiss, et al. discloses a controlled release 
tablet similar to that of Hill, wherein the core containing the active 
medicament is coated with a relatively insoluble, water permeable, 
rupturable film comprising a combination of hydrophobic and hydrophilic 
polymers. Cellulose acetate is disclosed as one of the hydrophobic 
polymers. The tablets of Weiss, et al. and Hill are intended to be 
swallowed whole. 
U.S. Pat. No. 4,415,547 to Yu, et al. discloses sustained release 
pharmaceutical tablets consisting essentially of drug pellets encapsulated 
with a water-soluble film-forming substance and a water-insoluble 
film-forming substance. The materials are blended and compressed into 
tablet form with a compressible tableting mixture. 
U.S. Pat. No. 4,059,416 to Cherukuri, et al. discloses a process for 
preparing a zinc compound delivery system comprised of a zinc core 
material coated with a first hydrophilic coating comprising a hydrocolloid 
material and a second hydrophobic coating selected from the group 
consisting of fats, waxes and mixtures thereof. The delivery system masks 
the bitter flavor characteristic of zinc compounds. 
U.S. Pat. No. 5,085,868 to Mattsson, et al. discloses a liquid dosage form 
for oral administration of a pharmaceutically active substance 
characterized in that it includes an encapsulated or embedded 
pharmaceutically active substance in a pharmaceutically acceptable 
non-aqueous liquid. More particularly Mattsson, et al. provide a liquid 
delivery system for active compounds which have an unpleasant taste which 
prevents the active compound from degrading in the liquid medium. The 
mechanism behind this phenomenon is described as first the application of 
a liquid carrier in which the active compound is not soluble or soluble to 
a very low extent and secondly the fact that the active compound is 
microencapsulated or embedded in a micromatrix structure to delay release 
of the active compound from the matrices or microcapsules in an aqueous 
media. The combination of these two factors is a solid ground for 
obtaining the above-mentioned properties. 
In contrast, U.S. Pat. No. 3,879,511 to Goodhart, et al. discloses use of a 
vegetable oil vehicle to suspend a coated unpleasant tasting drug. The 
suspension is alleged to be stable, palatable and therapeutically active. 
Unlike the prior art, the present invention is directed to the discovery of 
an aqueous based liquid delivery system that can be used to orally 
administer the active component and which achieves a good balance of 
tastemasking for both water-soluble and water-insoluble active components. 
SUMMARY OF THE INVENTION 
This invention relates to a substantially tasteless liquid pharmaceutical 
delivery system, comprising: (a) an active material and (b) a high 
osmolarity aqueous system comprising: (i) water; (ii) about 20% to about 
45% by weight sugar derivative; (iii) about 10% to about 15% by weight 
hydrogenated maltose syrup; and (iv) about 0% to about 35% by weight 
polyhydroxy alcohol. 
An alternative embodiment involves use of an active material which is a 
drug selected from the group consisting of analgesics, 
anti-inflammatories, antihistamines, antitussives, expectorants, 
decongestants, narcotics, antibiotics, bronchodilators, cardiovasculars, 
central nervous system drugs, minerals, vitamins, metal salts and mixtures 
thereof disbursed within the delivery system. 
A further embodiment of the invention involves a process for preparing a 
substantially tasteless liquid pharmaceutical delivery system, comprising 
a) preparing an aqueous phase containing: (i) water; (ii) about 20% to 
about 45% by weight sugar derivative; and (iii) about 10% to about 15% by 
weight hydrogenated maltose syrup; b) blending the aqueous phase to form a 
high osmolarity homogenous mixture of components; c) adding the active 
material to water and about 0% to about 35% by weight polyhydroxy alcohol; 
d) uniformly dispersing the active material within the water to obtain a 
smooth dispersion or dissolution to form an active phase; and e) blending 
the aqueous phase a) with the active phase d) to form a substantially 
tasteless liquid pharmaceutical delivery system and recovering the same. 
DETAILED DESCRIPTION OF THE INVENTION 
The present invention involves the preparation of a liquid tastemasked 
system by dispersing the active material in a high osmolarity aqueous 
solution. In this manner a substantially tasteless liquid pharmaceutical 
delivery system is formed which comprises: (a) an active material; and (b) 
a high osmolarity aqueous system comprising: (i) water; (ii) about 20% to 
about 45% by weight sugar derivative; (iii) about 10% to about 15% by 
weight hydrogenated maltose syrup; and (iv) about 0% to about 35% by 
weight polyhydroxy alcohol. 
The active materials or drug(s) may be described as a single drug entity or 
a combination of entities. The term "drug" includes without limitations, 
medicaments, vitamins, mineral supplements and other chemical or 
biological substances intended for use in the treatment, prevention, 
diagnosis, cure or mitigation of disease or illness, or substances which 
affect the structure or function of the body. 
Suitable categories of drugs that may be employed in the instant system may 
vary widely and generally represent any stable water-soluble or 
water-insoluble drug compound and combination thereof. Illustrative 
categories and specific examples include: (a) antitussives, such as 
dextromethorphan, dextromethorphan hydrobromide, noscapine, carbetapentane 
citrate and chlophedianol hydrochloride; (b) antihistamines, such as 
chlorpheniramine maleate, phenindamine tartrate, pyrilamine maleate, 
doxylamine succinate and phenyltoloxamine citrate; (c) decongestants, such 
as phenylephrine hydrochloride, phenylpropanolamine hydrochloride, 
pseudoephedrine hydrochloride, ephedrine; (d) various alkaloids, such as 
codeine phosphate, codeine sulfate and morphine; (e) mineral supplements 
such as potassium chloride, zinc chloride and calcium carbonates, 
magnesium oxide and other alkali metal and alkaline earth metal salts; (f) 
laxatives, vitamins and antacids; (g) ion exchange resins such as 
cholestyramine; (h) anti-cholesterolemic and anti-lipid agents; (i) 
antiarrhythmics such as N-acetylprocainamide; (j) antipyretics and 
analgesics such as acetaminophen, aspirin and ibuprofen; (k) appetite 
suppressants such as phenylpropanolamine hydrochloride or caffeine; and 
(l) expectorants such as guaifenesin. 
Additional useful active medicaments include anti-inflammatory substances, 
coronary dilators, cerebral dilators, peripheral vasodilators, 
anti-infectives, psychotropics, antimanics, stimulants, laxatives, 
gastro-intestinal sedatives, antidiarrheal preparations, anti-anginal 
drugs, vasodialators, anti-arrythmics, antihypertensive drugs, 
vasoconstrictors and migraine treatments, antibiotics, tranquilizers, 
antipsychotics, antitumor drugs, anticoagulants an antithrombotic drugs, 
hypnotics, sedatives, anti-emetics, anti-nauseants, anti-consulsants, 
neuromuscular drugs, hyper- and hypo-glycaemic agents, thyroid and 
antithyroid preparations, diuretics, antispasmodics, uterine relaxants, 
antiobesity drugs, anabolic drugs, erythropoietic drugs, antiasthmatics, 
cough suppressants (anti-tussives), mucolytics, anti-uricemic drugs and 
the like. 
Mixtures of the drugs and medicaments may also be used. 
Particular unpleasant tasting drugs include pyridonecarboxylic acid 
antibacterial agents whose degree of unpleasantness is said to be 
strongest, such as 
5-amino-1-cyclopropyl-6,8-difluoro-7-(cis-3,5-dimethyl-1-piperazinyl)-1,4- 
dihydro-4-(oxoquinoline-3-carboxylic acid, Enoxacin, Pipemidic acid, 
Ciprofloxacin, Ofloxacin and Pefloxacin; antiepileptic drugs such as 
zonisamide; macrolide antibiotics such as Erythromycin; beta-lactam 
antibiotics such as penicillins or cephalosporins; psychotropic drugs such 
as Chlorpromazine; drugs such as Sulpyrine; and antiulcer drugs such as 
Cimetidine. An exemplary decongestant is pseudoephedrine hydrochloride and 
mineral would be zinc salts. 
The drugs are used in amounts that are therapeutically effective. While the 
effective amount of a drug will depend on the drug used, amounts of drug 
from about 0.01% to about 5% have been easily incorporated into the 
present system while achieving bitter taste masking. Amounts above about 
5% may result in the lose of tasteless properties. 
According to the present inventive subject matter, the tastemasking of 
bitter or unpleasant liquid preparations is accomplished by causing a 
hyperosmotic condition in the pharmaceutical preparation. In this way, it 
is believed that when the pharmaceutical preparation is administered 
orally a temporary condition occurs wherein water moves from the taste 
receptors on the tongue to the liquid in the mouth. The flow of water in 
this direction is believed to then impede the diffusion of the bitter or 
otherwise unpleasant particles contained within the pharmaceutical 
preparation towards those taste receptors. The resulting effect occurs for 
a sufficient time to allow passage of the bad tasting materials past the 
receptors before the perception of bad taste can occur. 
It should be pointed out that tastemasking of liquid pharmaceuticals has 
been historically difficult to accomplish for two major reasons: 1) The 
bad tasting components are usually in solution, so coating technologies 
are not applicable; and 2) since the bad tasting components are usually in 
solution as molecules, rapid diffusion to taste receptors occurs. The 
present effect of using water flux in the opposite direction from the 
physiological taste receptors overcomes the difficulty in tastemasking 
liquid pharmaceutical preparations heretofore observed. It should be noted 
that the concept of high osmolarity to overcome bad taste can also be 
applied to dry powder/granule formulations for reconstitution with water. 
The present formulation must contain at least two distinct phases which are 
prepared separately and then blended together. One phase, the aqueous 
phase, contains the osmolarity modifying agents whereas the other phase, 
the active phase, contains the active material in solubilizing or 
suspension amounts of water and optional amounts of an organic solvent and 
additional osmolarity modifying agents. Each phase is designed to be 
aqueous based and when combined make up the aqueous system. 
The aqueous phase contains three components; water, a sugar derivative and 
a hydrogenated maltose syrup. The water can be added either directly in 
the amount desired or is preferably added through solutions of the 
remaining components. The water is generally present in amounts of about 
12% to about 30% and preferably about 15% to about 25% by weight of the 
final system. 
The sugar derivative may be selected from a wide variety of sources and is 
preferably sorbitol, mannitol, xylitol and mixtures thereof. It is 
generally employed in amounts of about 25% to about 45% and preferably 
from about 30% to about 40% by weight of the final system. While other 
carbohydrate sources may be used in addition to these particular sugar 
derivatives, such other materials would be generally added for sweetness 
rather than as an osmolarity modifier. The sugar derivatives are also 
preferably added in solution form, such as a sorbitol solution which 
normally contains about 30% water by weight. 
Another component of the aqueous phase is a hydrogenated maltose syrup. 
This component, like the sugar derivative, is used to control the 
solutions osmolarity. The hydrogenated maltose syrup may be derived from 
high maltose syrups and generally contains about 25% water by weight. A 
particularly preferred source is Lycasin.RTM., a sugarless sweetener from 
Roquette Corporation and described in U.S. Pat. No. 4,279,931. 
The hydrogenated maltose syrup is generally added in amounts of about 10% 
to about 15% by weight and preferably from about 11% to about 14% by 
weight of the final system. 
The aqueous phase is prepared by blending the water, sugar derivative, 
preferably as a sorbitol solution and hydrogenated maltose syrup together 
in sufficient amounts until the phase has an osmolarity measurement of 
from about 1500 to about 5000 and preferably about 2000 to about 4000 
mOsm/liter (miliosmoles/liter water). 
In addition to the foregoing components the aqueous phase may contain 
buffers, such as sodium citrate and sodium gluconate to maintain the pH of 
the system. pH values from about 3.0 to about 8.5 have been found 
effective in the present delivery systems. Acidifiers, such as citric 
acid, may also be added when desirable, depending on the drug used, 
solubility conditions and so forth. 
In addition to the aqueous phase the system must contain an active phase 
which contains the active material (pharmaceutical drug) and a solvent 
system. The present delivery system is aqueous based, and as such can be 
easily used with all water-soluble active material. When water-insoluble 
active materials are to be used in the liquid pharmaceutical delivery 
systems an optional cosolvent is employed, such as propylene glycol. The 
propylene glycol must be a non-toxic grade of material and be 
pharmaceutically acceptable. When a cosolvent system is used, water and 
propylene glycol are generally employed in amounts of about 1 to 2 parts 
by weight to about 1 to 1 part by weight, respectively. 
The active phase is prepared by simply blending the active material into 
the water or cosolvent system. Once blended, a homogenous solution or 
dispersion is formed which can be added to the aqueous phase to form the 
final product. Optionally, osmolarity modifying agents may be used in the 
active phase and when used are present in amounts of about 10 to about 
3500 mOsm/liter, and preferably about 100 to about 2500 mOsm/liter. 
Besides the active phase and the aqueous phase, it is beneficial to employ 
a preservative phase with the present formulations. Well known 
preservatives are used for this purpose, such as methyl paraben and propyl 
paraben, in a solvent system comprising a polyhydroxy alcohol. Preferred 
polyhydroxy alcohols are propylene glycol or glycerin systems. The 
solvent, when present, is generally used in amounts up to 35% by weight 
and preferably about 15% to about 30% by weight of the final system. The 
preservatives are used in amounts of about 0.01% to about 1.0% by weight 
and preferably 0.1 to 0.5% by weight of the final system. The preservative 
phase may be prepared by blending the preservative into the solvent and 
then blending the resulting solution into a mixture containing the active 
phase and aqueous phase. The preservative phase may contain osmolarity 
modifying agents in the amount of about 500 to about 2500 mOsm/liter. 
A particularly preferred process for preparing the present formulation 
comprises: a) preparing an aqueous phase containing: (i) water; (ii) about 
20% to about 45% by weight sugar derivative; and (iii) about 10% to about 
15% by weight hydrogenated maltose syrup; b) blending the aqueous phase to 
form a high osmolarity homogenous mixture of components; c) adding the 
active material to water and about 0% to about 35% by weight polyhydroxy 
alcohol; d) uniformly dispersing the active material within the water to 
obtain a smooth dispersion or dissolution to form an active phase; and e) 
blending the aqueous phase a) with the active phase d) to form a 
substantially tasteless liquid pharmaceutical delivery system and 
recovering the same. The final system has an osmolarity measurement of 
from about 4000 to about 9000 and preferably about 5000 to about 7000 
mOsm/liter (miliosmoles/liter water). Osmolarity values below 4000 are not 
effective to mask the bitter taste of most active material. Amounts above 
9000 are too difficult to process as a liquid system. 
The delivery system may contain additional ingredients, herein referred to 
as excipients or additives. Exemplary excipients include well known 
components, but are not limited to sweetening agents, colorants, 
surfactants, flavors, fragrances, pH modifiers, bulking agents, acidifiers 
and mixtures thereof which components may be used in amounts up to about 
50% and preferable from about 0.01% to about 25% by weight of the delivery 
system. 
The term "excipients" as used herein means substances and materials 
generally used in the drug or food industry which do not alter the 
character and function of the active component of the delivery system. 
Flavors which may optionally be added to the delivery system, are those 
well known in the pharmaceutical art. For example, synthetic flavor oils, 
and/or oils from plants, leaves, flowers, fruits and so forth, and 
combinations thereof are useful. 
Representative flavor oils include spearmint oil, peppermint oil, cinnamon 
oil, and oil of wintergreen (methylsalicylate). Also useful are 
artificial, natural or synthetic fruit flavors such as citrus oils 
including lemon, orange, grape, lime, and grapefruit, and fruit essences 
including apple, strawberry, cherry, pineapple and so forth. 
The amount of flavoring agent employed is normally a matter of preference 
subject to such factors as flavor type, base type and strength desired. In 
general, amounts of about 0.05% to about 5.0% by weight of the final 
product are useful with amounts of about 0.3% to about 1.5% being 
preferred and about 0.8% to about 1.2% being most preferred. 
The delivery system may contain an additional sweetening agent. Sweetening 
agents may be selected from a wide range of materials such as 
water-soluble sweetening agents, water-soluble artificial sweeteners, and 
dipeptide based sweeteners, including mixtures thereof. Without being 
limited to particular sweeteners, representative illustrations encompass: 
A. Water soluble sweetening agents such as monosaccharides, disaccharides 
and polysaccharides such as xylose, ribose, glucose, mannose, galactose, 
fructose, dextrose, sucrose, sugar, maltose, partially hydrolyzed starch, 
or corn syrup solids and sugar alcohols such as sorbitol, xylitol, 
mannitol and mixtures thereof. 
B. Water-soluble artificial sweeteners such as the soluble saccharin salts, 
i.e., sodium or calcium saccharin salts, cyclamate salts, acesulfam-K and 
the like, and the free acid form of saccharin. 
C. Dipeptide based sweeteners such as L-aspartyl L-phenylalanine methyl 
ester and materials described in U.S. Pat. No. 3,492,131 and the like. 
The excipients are added to the delivery system at anytime during 
processing. It should be recognized that certain excipients should be 
added prior to, during or after the active phase is blended into the 
aqueous phase in order to achieve uniform distribution of the ingredients. 
Preferably, excipients in liquid form are added before the active phase 
whereas powdered excipients may be added before or after the active phase 
is blended into the aqueous phase. 
Since tastemasking is a key feature of the invention, use of the inventive 
liquid systems as a solid system is contemplated, but-not generally 
preferred. In such solid systems, the product would be taken orally and be 
expected to be retained in the mouth for significant amounts of time to be 
solubilized and swallowed. Alternatively, the system may be previously 
disbursed in water to obtain the desired osmolarity and then swallowed. 
The following examples are illustrative of preferred embodiments of the 
invention and are not to be construed as limiting the invention thereto. 
All percentages are based on the percent by weight of the delivery system 
unless otherwise indicated and all totals equal 100% by weight.

EXAMPLE 1 
This example describes the production of a tastemasked antihistamine liquid 
formulation. 
The mixture was prepared by the following procedure to include the 
components listed in Table 1. 
Three separate solutions are made then mixed together as follows: 
I) Water Sodium Gluconate Sodium Saccharin Citric Acid Color Maltitol 
Solution Sorbitol Solution 
II) Propylene Glycol Methylparaben Propylparaben Magnasweet #180 
III) Water Diphenhydramine Hydrochloride Propylene Glycol 
Solution III would then be added with mixing to Solution I. 
Solution II would then be added with mixing to the first mixture. 
Flavor would be added last and the product recovered. 
This formulation represents 67.5 grams of dissolved material in 100 grams 
of solution resulting in a high osmolarity formulation of approximately 
6500 mOsm/liter. 
When the formulation was subjected to a multiple member test panel, the 
product did not exhibit any bitter taste sensation. 
TABLE I 
______________________________________ 
INGREDIENT % WEIGHT/WEIGHT 
______________________________________ 
Diphenhydramine Hydrochloride, USP 
0.2111 
Purified Water, USP 16.4624 
Sorbitol Solution, USP 
41.8179 
Maltitol Solution 13.9287 
Propylene Glycol, USP 
25.8670 
Sodium Gluconate, USP 
0.1857 
Citric Acid, USP 0.2111 
Saccharin Sodium, USP 
0.1013 
Magnasweet 180 0.0422 
Methylparaben, NF 0.0844 
Propylparaben, NF 0.0152 
Color 0.0177 
Flavor 1.0553 
100.0000 
______________________________________ 
EXAMPLE 2 
This example describes the production of a taste-masked cough/cold liquid 
containing a decongestant, cough suppressant and antihistamine. The 
formation was prepared by the following procedure to include the 
components listed in Table II. 
Make three separate solutions containing the following ingredients: 
I) Water Sodium Gluconate Sodium Citrate Sodium Saccharin Citric Acid Color 
Maltitol Solution Sorbitol Solution 
II) Propylene Glycol Methylparaben Propylparaben Magnasweet #180 
III) Water Pseudoephedrine Hydrochloride Dextromethorphan Hydrobromide 
Chlorpheniramine Maleate 
Solution III is then added with mixing to Solution I. 
Solution II is then added with mixing to the first mixture. 
Flavor is added last and the product recovered. 
This formulation represents 66.9 grams of dissolved material in 100 grams 
of solution resulting in a high osmolarity of approximately 5500 
mOsm/liter. 
When the formulation was tested by a multiple member test panel, the 
product did not exhibit any bitter taste sensations. 
TABLE II 
______________________________________ 
INGREDIENT % WEIGHT/WEIGHT 
______________________________________ 
Pseudoephedrine Hydrochloride, USP 
0.2451 
Dextromethorphan Hydrobromide, USP 
0.1225 
Chlorpheniramine Maleate, USP 
0.0163 
Purified Water, USP 12.8624 
Sorbitol Solution, USP 
52.7602 
Maltitol Sollution 17.5867 
Propylene Glycol, USP 
15.6117 
Sodium Gluconate, USP 
0.1634 
Citric Acid, USP 0.1225 
Sodium Citrate, USP 0.0817 
Saccharin Sodium, USP 
0.0980 
Magnasweet 180 0.0817 
Methylparaben, NF 0.0735 
Propylparaben, NF 0.0082 
Color 0.0027 
Flavor 0.1634 
100.0000 
______________________________________ 
The invention being thus described, it will be obvious that the same may be 
varied in many ways. Such variations are not to be regarded as a departure 
from the spirit and scope of the invention and all such modifications are 
intended to be included within the scope of the following claims.