Pleasant-tasting aqueous liquid composition of a bitter-tasting drug

A liquid pharmaceutical composition is contemplated that comprises a pharmaceutically effective amount of a bitter tasting drug dissolved or dispersed in an aqueous medium that is free of ethanol. That aqueous medium consists essentially of water, about 5 to about 30 weight percent polyvinylpyrrolidone, about 45 to about 55 weight percent of a C.sub.3 -C.sub.6 polyol, about 0.01 to about 0.5 weight percent ammonium glycyrrhizinate and one or more flavorants. The liquid composition is transparent and has a pleasant taste.

TECHNICAL FIELD 
This present invention relates to a liquid drug composition, and more 
particularly to a pleasant-tasting aqueous liquid pharmaceutical 
composition that contains an otherwise bitter-tasting drug. 
BACKGROUND ART 
Many useful, effective drugs have a bitter taste when dissolved in liquid 
form or even when administered as pills or tablets. Exemplary of such 
drugs are acetaminophen, terfenadine, guaifenesin, trimethoprim, 
prednisolone, ibuprofen, prednisolone sodium phosphate, methacholine, 
neostigmine, epinephrine, albuterol, pseudoephedrine hydrochloride, 
diphenhydramine, chlorpheniramine maleate, phenothiazine, chlorpromazine, 
chlordiazepoxide, amitriptyline, barbiturates, diphenylhydantoin, 
caffeine, morphine, demerol, codeine, lomotil, lidocaine, salicylic acid, 
sulfonamides, chloroquine and penicillins. These and other bitter-tasting 
drugs are consequently usually formatted for oral administration as coated 
pills or tablets or as a powder or prills within a capsule so that the 
bitter-tasting medicament does not contact the tongue during oral 
administration. 
Although provision in an above coated tablet or pill form or within a 
capsule overcomes the problem of offensive taste for several valuable 
medicaments for most of the adult population that uses those drugs, many 
adults and many children have difficulty swallowing the pills or tablets 
or cannot swallow them, and thereby do not benefit from those drugs. 
Recently issued U.S. Pat. No. 5,455,049 illustrates one technique that was 
successful in overcoming the bitter taste problem associated with orally 
administered terfenadine. 
The disclosure that follows illustrates another, more general solution to 
both of the problems of bitter taste and oral administration of a solid 
dosage form such as a pill or capsule that is applicable to adults and 
children that have difficulty swallowing or cannot swallow pills, capsules 
and the like, as well as an alternative delivery mode for the general 
population. 
BRIEF SUMMARY OF THE INVENTION 
A transparent liquid pharmaceutical composition is contemplated by the 
present invention. That composition comprises a pharmaceutically effective 
amount of a bitter-tasting drug that is dissolved or dispersed in an 
aqueous medium that is free of ethanol. That aqueous medium consists 
essentially of water, about 5 to about 30 weight percent 
polyvinylpyrrolidone (PVP), about 45 to about 55 weight percent of a 
C.sub.3 -C.sub.6 polyol, about 0.01 to about 0.5 weight percent ammonium 
glycyrrhizinate and one or more flavorants. The aqueous liquid composition 
is transparent and has a pleasant taste; i.e., it is free from having a 
bitter taste that would otherwise be associated with the bitter-tasting 
drug. 
In preferred practice, the drug is present in an amount of about 0.5 to 
about 5 weight percent and the ammonium glycyrrhizinate is present in a 
weight ratio relative to the drug of about 1:50 to about 1:10. More 
preferably, the PVP is present at about 7 to about 15 weight percent, the 
drug at about one to about 3 weight percent, with the glycyrrhizinate 
present at the before-noted weight ratio to the drug, and most preferably 
at a weight ratio to the drug of about 1:20. 
The present invention has several benefits and advantages. 
One benefit is that a contemplated composition has a pleasant taste that 
permits it to be administered to children without the usually observed 
reluctance of children to take the bitter-tasting drug. 
An advantage of the invention is that the bitter drug-containing 
composition is provided as a liquid to that it can be taken by those 
persons that have difficulty swallowing or cannot swallow usual solid 
forms of the drug such as a pill, tablet or capsule. 
Another benefit of the invention is that a contemplated composition is free 
of ethanol so that it can be taken by children to whom an 
ethanol-containing pharmaceutical composition would normally not be given. 
Another advantage of the invention is that a contemplated composition is 
transparent, homogeneously dispersed and non-settling so that one need not 
resuspend the medication within the composition prior to each 
administration and each dose contains a desired amount of the medicament. 
Still further benefits and advantages of the invention will be apparent to 
those skilled in the art from the disclosure that follows. 
DETAILED DESCRIPTION OF THE INVENTION 
The present invention contemplates a liquid pharmaceutical composition that 
contains a normally bitter-tasting drug as active ingredient. A 
contemplated composition nonetheless has at least a pleasant taste if not 
a good taste. 
The otherwise or normally bitter-tasting drug is dissolved or dispersed in 
an aqueous medium that is transparent. That is, the composition of drug 
and ingredients other than the flavorant, even if not forming a true 
solution, is not cloudy or milky in the aqueous medium. It is presently 
not known if the aqueous medium containing the drug and other ingredients 
is a true solution or a non-settling dispersion, but that composition 
containing its various constituents discussed hereinafter is transparent 
as would be a true solution or a colloidal dispersion. 
A contemplated pharmaceutical composition is free of ethanol (ethyl 
alcohol). Ethanol is often used in aqueous medicinal compositions as a 
solvent for the active medicament. However, because of its potential 
effects upon children, ethanol is not utilized in a contemplated 
composition, or if used is present in an amount of about one percent by 
volume or less. 
A contemplated composition is referred to as having an aqueous medium in 
that water is present as a major ingredient. 
A pharmaceutically effective amount of a bitter-tasting drug is also 
present in a contemplated composition as the active ingredient. Exemplary 
bitter-tasting drugs include acetaminophen, terfenadine, guaifenesin, 
trimethoprim, prednisolone, ibuprofen, prednisolone sodium phosphate, 
methacholine, neostigmine, epinephrine, albuterol, pseudoephedrine 
hydrochloride, diphenhydramine, chlorpheniramine maleate, phenothiazine, 
chlorpromazine, chlordiazepoxide, amitriptyline, barbiturates, 
diphenylhydantoin, caffeine, morphine, demerol, codeine, lomotil, 
lidocaine, salicylic acid, sulfonamides, chloroquine and penicillins. The 
determination of a bitter taste is carried out by standard, well-known 
practices, and is a characteristic often listed along with a description 
of the drug in texts such as The Merck Index, 11th ed., S. Budavari et al. 
eds., Merck & Co., Inc., Rahway, N.J. (1989) and Remington's 
Pharmaceutical Sciences, 18th ed., A. Gennaro ed., Mack Publishing Co., 
Easton, Pa. (1990). 
A pharmaceutically effective amount of a bitter-tasting drug is a 
concentration of the drug, which when present in a predetermined volume of 
the composition, provides a therapeutic dosage. It should be apparent that 
a pharmaceutically effective amount of a bitter-tasting drug is or can be 
different for each drug. In addition, that amount can also differ for the 
same drug where compositions formulated for children and adults are 
contemplated. 
Therapeutic dosages of a contemplated bitter-tasting drug are well-known 
and are available from the above-noted texts as well as from the 
Physicians' Desk Reference, Medical Economics Company, Inc., Oradell, N.J. 
or Goodman and Gilman's The Pharmacological Basis of Therapeutics, 8th 
ed., Gilman et al. eds, McGraw Hill, Inc., New York, N.Y. (1993). 
Exemplary therapeutic dosages and therapeutically effective amounts of 
exemplary bitter-tasting drugs are provided hereinafter. 
Exemplary amounts of active bitter-tasting drug are present at about 0.1 to 
about 10 weight percent, and preferably at about 0.5 to about 5 weight 
percent of the completed composition. The bitter-tasting drug is more 
preferably present at about one to about 3 weight percent of the completed 
composition. 
In addition to the water and bitter-tasting drug, a contemplated 
composition also contains about 5 to about 30 weight percent 
polyvinylpyrrolidone, (PVP) and preferably about 7 to about 15 weight 
percent PVP. PVP is commercially available from a number of suppliers 
under a number of designations. The PVPs sold under the Trademark 
KOLLIDON.RTM. K25, K30 and K90 having weight-average molecular weights of 
28,000-34,000, 44,000-54,000 and 1,000,000-1,500,000, respectively, are 
preferred for use here, with the K25 and K30 being most preferred. 
PVP is dissolved or dispersed in the water of the aqueous medium and serves 
to assist in dissolving or dispersing the bitter-tasting drug in that 
medium, as well as masking the flavor of the bitter-tasting drug. The 
disclosures of Volker Buhler's book, Kollidon, BASF Aktiengesellshaft, 
Ludwigshafen, Germany (1992) teach the use of PVP as both a solubilization 
aid for several drugs as well as for masking the bitter taste of 
acetaminophen. An exemplary formulation for an oral PVP- and 
acetaminophen-containing composition is provided at page 113, Table 81 of 
the above Buhler text, but to the inventors' knowledge, no commercial 
liquid product takes advantage of that combination of ingredients and 
effects, indicating that those debittering effects are insufficient to 
provide a useful product. 
A contemplated composition also contains about 45 to about 55 weight 
percent (as solids or non-volatile liquids) of a C.sub.3 -C.sub.6 polyol. 
Exemplary C.sub.3 -C.sub.6 polyols include propylene glycol, glycerin 
(glycerol), threose, threitol, erythrose, erythritol, ribose, arabinose, 
lyxose, sorbitol, sorbose, glucose, mannose, galactose, xylose, fructose 
and the like. 
A C.sub.3 -C.sub.6 polyol serves the dual function of being a solvent for 
the system as well as being a bitter flavor masking agent. In one 
preferred embodiment, a mixture of two or more C.sub.3 -C.sub.6 polyols is 
utilized. Such a preferred mixture utilizes a C.sub.3 polyol such as 
glycerin or 1,3-propanediol (propylene glycol) and one or more C.sub.6 
polyols such as maltitol NF (a starch hydrolyzate containing about 75 
weight percent dry solids of which at least about 50 percent is D-maltitol 
and about 15 percent or less is D-sorbitol and is available under the mark 
LYCASIN.TM. from Roquette Corp., Gurnee, Ill., fructose such as that 
available under the mark KRYSTAR.TM., from A. E. Staley Mfg. Co., Decatur, 
Ill. that is sold as an aqueous liquid about 77 weight percent of which is 
fructose, as well as sugars such as glucose, xylitol and the like. It is 
noted that each maltitol molecule is composed of a plurality of C.sub.6 
polyols linked together and so is deemed to be a C.sub.3 -C.sub.6 polyol 
as is sucrose. This mixture, when utilized, is typically present at a 
ratio weight of 1:4 to about 3:5, C.sub.3 to C.sub.6 polyol, as 
non-volatiles. In another preferred embodiment, polyols other than a 
C.sub.6 polyol constitute less than about 5 weight percent of the total 
composition. 
Surprisingly, the use of the above C.sub.3 -C.sub.6 polyols together with 
the PVP is not sufficient to suitably mask the bitter taste of the 
bitter-tasting drug. This fact remains even when further sweeteners such 
as sodium saccharin USP present at 0.05-2 weight percent or aspartame 
present at about 0.1 to about 2 weight percent and further flavorants are 
admixed with the composition. A further debittering agent is still 
required to be present. 
That further debittering agent is found to be ammonium glycyrrhizinate that 
can be present at about 0.01 to about 0.5 weight percent as ammonium 
glycyrrhizinate itself. The ammonium glycyrrhizinate is present at a 
weight ratio to the otherwise bitter-tasting drug of about 1:50 to about 
1:10, and most preferably at weight ratio of about 1:20 ammonium 
glycyrrhizinate to drug. 
Ammonium glycyrrhizinate is available as a 10 weight percent solution in 
glycerin or propylene glycol from MacAndrews & Forbes Company of Camden 
N.J. under the name MAGNASWEET.RTM. MM110 or MM115, and also as a white, 
amorphous powder as MM150. Ammonium glycyrrhizinate is the monoammonium 
salt of a triterpenoid saponin that consists of an aglycone of 
glycyrrhetic acid and a sugar moiety of two glucuronic acid units linked 
to each other. This material is said by its manufacturer to be about 50 to 
about 100 times sweeter than sucrose, and is known to be useful in masking 
bitterness. 
Although ammonium glycyrrhizinate is a known bitterness-masking agent as is 
PVP, neither material alone or with the before-discussed sweeteners and 
flavorants is sufficient to mask the bitter taste of a contemplated 
bitter-tasting drug. Rather, PVP and ammonium glycyrrhizinate appear to 
potentiate each other to provide the desired bitterness-masking effect. 
The mechanism by which the bitterness-masking is achieved is unknown. 
However, without wishing to be bound by theory, it is believed that a 
complex is formed between the PVP, drug and ammonium glycyrrhizinate, 
particularly because so little of the glycyrrhizinate is present. 
The before-mentioned Buhler, Kollidon, BASF Aktiengsellshaft, Ludwigshafen, 
Germany (1992) book teaches that PVP forms complexes with aromatic 
compounds, particularly those drugs also having hydrophilic groups that 
can form hydrogen bonds such as carboxyl, hydroxyl and amine groups. See 
also, Horn et al., J. Pharm. Sci., 71:1021-126 (1982). The contemplated 
bitter-tasting drugs have one or more rings, most of which are aromatic, 
and so it is thought that PVP forms a complex with the bitter-tasting 
drug. Table 20 at page 40 of Buhler's book lists interaction constants for 
several such complexes, although no such interaction constant could be 
determined for trimethoprim, which is quite useful here. See also, Horn et 
al., J. Pharm. Sci., 71:1021-1026 (1982). 
Ammonium glycyrrhizinate contains no aromaticity, but has several 
hydrophilic groups such as hydroxyls and carboxyl groups and a hydrophobic 
aglycone portion that can be solvated by the PVP polymeric backbone. It is 
consequently believed that the three components form a presently undefined 
complex in the aqueous medium, and that that complex acts to shield taste 
buds from the bitterness inherently present in the bitter-tasting drug. 
As was noted previously, a contemplated composition can also contain 
additional sweeteners, and flavorants, as well as colorants and 
thickeners. Flavorants such as bubble gum and chocolate flavors can 
provide opacity or translucency to a contemplated composition, while the 
composition other than the flavorant is transparent. Exemplary thickeners 
include sodium alginate, gelatin or a polyalkylene oxide such as the 
polyoxyethylene-polyoxypropylene-polyethylene terpolymer available under 
the name PLURONIC.RTM. F68 having an average of 75 polymerized ethylene 
oxide units on either side of 30 polymerized propylene oxide units, F-87 
having 62 polymerized ethylene oxide units on either side of 39 
polymerized propylene oxide units, or F-88 having an average of about 97 
polymerized ethylene oxide groups on either side of about 39 polymerized 
propylene oxide groups that are available from BASF, Mount Olive, N.J. 
Conventional preservatives such as sodium benzoate NF, methylparaben NF 
and propylparaben NF can be and preferably are also present. A 
contemplated aqueous liquid pharmaceutical composition has a viscosity of 
25.degree. C. between that of water and about that of corn syrup at 
25.degree. C. 
A contemplated composition has a final pH value of about 2 to about 8, and 
preferably about 3 to about 5, and more preferably about 3.5 to about 4.5. 
Sodium hydroxide (1N) and hydrochloric acid (10N) or citric acid and 
sodium citrate are typically used for pH value adjustments and 
maintenance. 
A contemplated aqueous liquid pharmaceutical composition is readily 
prepared. Thus, in an exemplary procedure where a C.sub.3 polyol is 
utilized, a solution or dispersion of about 30 weight percent PVP is 
prepared in water. About one part bitter-tasting drug is slurried with 
about 5 parts by weight C.sub.3 polyol (glycerin or propylene glycol or 
both). The two compositions are admixed and heated to a temperature of 
about 45.degree. C. with continued agitation. Agitation is continued at 
that temperature until a clear, non-settling solution or dispersion is 
formed, which generally takes about 30 minutes. Where no or less than 5 
weight percent C.sub.3 polyol is used, the bitter-tasting drug is admixed 
directly with the aqueous PVP. 
The aqueous composition so formed is cooled at a temperature below about 
30.degree. C. and the ammonium glycyrrhizinate, other C.sub.3 -C.sub.3 
polyols, flavorants, colorant if used and remaining ingredients are 
admixed until a homogenous composition is obtained. These additions are 
typically carried out serially, with admixture to homogeneity between each 
admixture. The pH value is thereafter adjusted as required. The examples 
that follow illustrate these procedures more fully.

BEST MODE FOR CARRYING OUT THE INVENTION 
EXAMPLE 1 
Guaifenesin-Containing Syrup 
A liquid anti-tussive composition was prepared containing the following 
ingredients and their amounts. 
______________________________________ 
Ingredient Amount 
______________________________________ 
Guaifenesin, USP 2.0 g 
Polyvinylpyrrolidone 7.5 g 
(PVP;K25) 
Glycerin, USP 10.0 g 
Purified Water, USP 25.0 mL 
Sodium Benzoate, NF 0.15 g 
Saccharin Sodium, USP 0.50 g 
Monoammonium 1.0 g 
Glycyrrhizinate (10%).sup.1 
Citric Acid 0.25 g 
anhydrous, USP 
Sodium Citrate, USP 0.384 g 
Sodium Alginate, USP 0.2 g 
Maltitol Syrup, NF 20.0 g 
(75%) solids) 
Flavors and Colorants q.s. 
Liquid Fructose q.s. 
(77.0-77.5% solids) 
100.0 mL 
______________________________________ 
.sup.1 A 10% solids solution in glycerin or propylene glycol from 
MacAndrews & Forbes Co. 
The PVP was dissolved or dispersed in 25 mL of purified water. The sodium 
alginate was added to that composition and the resulting admixture mixed 
until homogeneity to form Phase A. 
The guaifenesin and glycerin were mixed to form a smooth slurry as Phase B. 
Phase A was then added to Phase B with constant stirring. This admixture 
was heated to a temperature of 45.degree. C. and that temperature was 
maintained for about 30 minutes with mixing to form Phase C as a 
transparent composition. Phase C was then cooled to a temperature below 
30.degree. C. 
The citric acid and sodium citrate were dissolved in 5 mL of water to form 
Phase D. The sodium benzoate and sodium saccharin were similarly dissolved 
in another 5 mL of water to form Phase E. 
Phase D was admixed with Phase C and mixed for about 5 minutes to obtain 
homogeneity. Phase E was then similarly admixed with that homogeneous 
composition to form Phase F. 
The maltitol was similarly admixed with Phase F to form Phase G to which 
the ammonium glycyrrhizinate was added with another about 5 minutes mixing 
time being used. The flavors and colorants were then admixed, with a 
mixing time of about 5 minutes, followed by addition of a sufficient 
amount of liquid fructose to make the desired volume and mixing to 
homogeneity. The pH value was thereafter adjusted to be between 4 and 5 
using a citric acid or sodium citrate solution. This composition provides 
100 mg of guaifenesin per 5 mL (teaspoon). 
Four differently flavored and colored clear syrups were prepared using the 
before-described ingredients. Those syrups were orange/vanilla-flavored 
colorless, vanilla-flavored colorless, chocolate-flavored brown, and 
gum-fruit-flavored red syrups. The bitter guaifenesin taste was well 
masked in each syrup. 
EXAMPLE 2 
Comparative Taste Study 
A flavor acceptance study was conducted using a composition of Example 1 
colored red and flavored with gum-fruit and a commercially available 
guaifenesin-containing composition sold under the mark ROBITUSSIN.RTM.. 
Eighty-one children aged between 3 and 6 years (33 boys and 48 girls) were 
enrolled in the study. 
More specifically, the study followed a two-way crossover design, with all 
subjects evaluating both products at one-half teaspoon for each product. 
The two products were evaluated on a single study day. The sequence of 
products was randomized among subjects. All enrolled subjects completed 
all aspects of the study protocol. There were no adverse events reported. 
The primary analysis of the ordinal taste scores (1=disliked a lot, 
2=disliked a little, 3=just OK, 4=liked a little, 5=liked a lot) was an 
analysis of variance including factors for dosing sequence, subject within 
sequence, dose order and product. The effect of sequence was tested using 
subject (sequence) for error and was not significant. Dose order and 
product effects were tested against the residual error variance. All tests 
were performed at the 5% level. A secondary analysis tested product 
preferences using the Sign Test. 
The results showed a statistically significant preference (p=0.013) for a 
syrup of Example 1 (mean=3.42.+-.1.52) compared to ROBITUSSIN.RTM. 
(mean=2.86.+-.1.63) based on the primary analysis of the children's 
ordinal ratings of the flavor. In the secondary analysis, 59.3 percent of 
children (48/81) stated a preference of the syrup of Example 1 compared to 
ROBITUSSIN.RTM. (33/81), showing a trend in support of the primary 
results. 
The analysis of variance showed no statistically significant effect of 
sequence. Dose order, however, did show a statistically significant effect 
(p=0.004) on flavor scores: the second product tasted tended to be rated 
higher than the first. Thus, mean flavor scores.+-.standard deviations 
were 3.03.+-.1.56 for the composition of Example 1 when tested first and 
3.80.+-.1.38 when tested second for an overall score of 3.42.+-.1.52. The 
commercial ROBITUSSIN.RTM. product exhibited scores of 2.61.+-.1.70 and 
3.13.+-.1.54 when tested first and second, respectively, and an overall 
score of 2.86.+-.1.63. 
EXAMPLE 3 
Trimethoprim Oral Liquid #1 
An oral liquid pharmaceutical composition was prepared utilizing the 
following ingredients in the following amounts. 
______________________________________ 
Ingredient Amount 
______________________________________ 
Trimethoprim, USP 5 kg 
Polyvinylpyrrolidone, 50 kg 
USP (PVP;K25) 
Glycerin, USP 25 kg 
Propylene Glycol, USP 52.5 kg 
Purified Water, USP 125 kg 
Methylparaben, NF 500 g 
Propylparaben, NF 250 g 
Sodium Benzoate, NF 500 g 
Saccharin Sodium, USP 5 kg 
Monoammonium 20 kg 
Glycyrrhizinate (10% 
solids).sup.1 
Sorbitol Solution, USP 65 kg 
Hydrochloric Acid, NF 1.25 L 
Sodium Hydroxide, USP q.s. 
(1N) 
Hydrochloric Acid, USP q.s. 
(10N) 
Maltitol Solution, NF 50 kg 
(75%) solids) 
Bubblegum Flavor 2.5 kg 
Liquid Fructose q.s. 
(77.0-77.5% solids) 
500 L 
______________________________________ 
.sup.1 A 10% solids solution in glycerin or propylene glycol from 
MacAndrews & Forbes Co. 
Here, 110 kg of the purified water was acidified with 1.25 liters of HCl to 
which the trimethoprim was added and mixed until dissolved. The PVP was 
admixed with agitation and the agitation continued until a homogeneous, 
clear composition was obtained. Most of the propylene glycol (40 kg) was 
admixed to homogeneity, followed by admixture of the glycerin. The 
resulting admixture was heated to a temperature of 45.degree. C. and 
maintained of that temperature with constant mixing for about 10 minutes 
to form Phase A. 
The parabens were dissolved in the remaining 12.5 kg of propylene glycol to 
form Phase B. The sodium benzoate and sodium saccharin were dissolved in 
15 kg of purified water to form Phase C. 
The maltitol was admixed with Phase A for about 5 minutes, at which time 
the sorbitol was added followed by another about 5 minutes of stirring to 
form Phase D. Phase B was admixed with Phase D followed by about 5 minutes 
of stirring to form Phase E, to which Phase C was added and mixed for 
about 5 minutes to form Phase F. The ammonium glycyrrhizinate was admixed 
with Phase F followed by about 5 minutes of stirring to form Phase G to 
which the bubblegum flavor was added and stirred to homogeneity. The 
volume was made up to 500 liters with the liquid fructose, and the 
resulting composition was stirred to homogeneity. The pH value of the 
composition was thereafter adjusted with sodium hydroxide and/or 
hydrochloric acid as required to provide a pH value of 3.5 to 4.5. 
The resulting liquid pharmaceutical composition did not have the bitter 
taste usually associated with trimethoprim, and provided trimethoprim in 
an amount of 50 mg/teaspoon (50 mg/5 mL). 
EXAMPLE 4 
Trimethoprim Oral Liquid #2 
A second trimethoprim-containing oral liquid pharmaceutical composition was 
prepared that contained less than 5 weight percent C.sub.3 polyol; i.e., 
only the C.sub.3 polyol contributed by an ammonium glycyrrhizinate 
solution. That composition had the following ingredients present in the 
following amounts. 
______________________________________ 
Ingredient Amount 
______________________________________ 
Trimethoprim, USP 1.0 g 
Polyvinylpyrrolidone, 15.0 g 
USP (PVP;K25) 
Purified Water, USP 25 mL 
Sodium Benzoate, NF 0.15 g 
Saccharin Sodium, USP 1.0 g 
Monoammonium 4.0 g 
Glycyrrhizinate (10% 
solids).sup.1 
Hydrochloric Acid, NF 0.25 mL 
Sodium Hydroxide, USP q.s. 
(1N) 
Hydrochloric Acid, USP q.s. 
(10N) 
Maltitol Solution, NF 10 g 
(75%) solids) 
Flavorant q.s. 
Colorant q.s. 
Liquid Fructose q.s. 
(77.0-77.5% solids) 
100.0 mL 
______________________________________ 
.sup.1 A 10% solids solution in glycerin or propylene glycol from 
MacAndrews & Forbes Co. 
For this preparation, the purified water was acidified with the 0.25 mL of 
hydrochloric acid. The trimethoprim was added to the acidified water with 
stirring over about 5 minutes. The PVP was then added with stirring to 
homogeneity for about 10 minutes, followed by admixture of the maltitol 
and stirring for a further 5 minutes time period. The resulting admixture 
was then heated to a temperature of 45.degree.-60.degree. C. and 
maintained at that temperature with continued mixing until the composition 
clarified and no particles could be seen. The heating was then stopped, 
the composition cooled to below 30.degree. C., and ammonium 
glycyrrhizinate was added. The composition was then mixed for about 5 
minutes to form Phase A. 
The sodium benzoate and sodium saccharin were dissolved in about 30 g of 
liquid fructose to form Phase B. Phase B was added to Phase A, and the 
resulting composition was mixed for about 5 minutes, after which the 
flavorant and colorant were added with another 5 minutes of mixing. The pH 
value was adjusted to 3.5-4.5, the composition was made up to a final 
volume of 100 mL using liquid fructose, and the resulting composition was 
stirred for another 5 minutes to form the trimethoprim-containing oral 
liquid pharmaceutical composition. That composition was homogeneous and 
clear, and exhibited a pleasant taste, particularly as compared to the 
usually bitter taste of trimethoprim, and provided 50 mg of trimethoprim/5 
mL of composition. 
The foregoing description and the examples are intended as illustrative and 
are not to be taken as limiting. Still other variations within the spirit 
and scope of this invention are possible and will readily present 
themselves to those skilled in the art.