Documenti di Didattica
Documenti di Professioni
Documenti di Cultura
18654A1
(19) United States
(12) Patent Application Publication (10) Pub. No.: US 2003/0118654A1
B. Santos et al. (43) Pub. Date: Jun. 26, 2003
(54) TASTE MASKEDAQUEOUS LIQUID Publication Classification
PHARMACEUTICAL COMPOSITION
(51) Int. Cl." ....................... A61K 3.1/545; A61K 31/43;
(76) Inventors: Joyce Bedelia B. Santos, Mandaluyong A61K 31/522; A61K 31/495;
City (PH); Rita Josefina M. Santos, A61K 31/485; A61K 31/473
Quezon City (PH); Kennie U. Dee, (52) U.S. Cl. .................... 424/486; 514/282; 514/263.34;
Quezon City (PH) 514/649; 514/200; 514/192;
514/255.04; 514/290; 514/629
Correspondence Address:
BROWN & MICHAELS, PC (57) ABSTRACT
400 M & T BANK BUILDING
118 NORTH TOGA ST A Substantially taste masked liquid pharmaceutical compo
ITHACA, NY 14850 (US) Sition containing a pharmaceutically effective amount of an
unpleasant tasting drug dissolved or dispersed in an aqueous
(21) Appl. No.: 10/017,697 excipient base, Said excipient base comprising polyvinyl
pyrrollidone and/or copolyVidone, and high molecular
(22) Filed: Dec. 7, 2001 weight polyethylene glycol.
US 2003/0118654 A1 Jun. 26, 2003
TASTE MASKEDAQUEOUS LIQUID 0008. Several other approaches have been pursued to
PHARMACEUTICAL COMPOSITION address the unpleasant taste of a drug in a liquid format. U.S.
Pat. No. 5,730,997 illustrates the use of a hyperosmotic
BACKGROUND OF THE INVENTION liquid using a Sugar derivative and maltose Syrup for taste
masking. U.S. Pat. No. 5,154,926 claims reduction of the
0001) 1. Field of the Invention bitter taste of acetaminophen Syrup by using a water-Soluble
0002 The present invention relates to a liquid drug macromolecule with a polyhydric alcohol and/or polymer of
composition, and more particularly to a Substantially taste a polyhydric alcohol of MW 300-400. U.S. Pat. Nos. 5,763,
masked aqueous liquid pharmaceutical composition that 449 and 5,962,461 teach the use of a combination of
contains an otherwise unpleasant tasting drug. poVidone, C3-C6 polyol and ammonium glycyrrhizinate for
0003 2. Description of Related Art taste masking. EP application 1025858 A1 discloses relief of
bitterneSS of basic drugs by combining propylene glycol
0004. The most convenient and commonly employed with poVidone and/or copolyVidone.
route of drug delivery has been by oral ingestion, either in 0009. The disclosure that follows illustrates another,
liquid or Solid formats. The unpalatable taste of most drugs more general Solution to the problem of bad taste in liquid
is generally not a problem with Solid dosage formats, which compositions containing either dissolved or dispersed drugs.
are intended to be Swallowed whole. In the case of capsules,
the hard gelatin shell prevents the drug from being tasted SUMMARY OF THE INVENTION
during the short transit time in the mouth. Tablets, on the
other hand, can be coated with Sugar or film forming 0010. The present invention provides a taste masked oral
polymers for tastemasking. liquid composition comprising at least one therapeutically
effective amount of a bitter-tasting drug. The drug is dis
0005. Many children and some adults however have Solved or dispersed in an aqueous taste masking excipient
difficulty Swallowing Solid dosage formats, and in this case, base comprising a high molecular weight (MW) polyethyl
the drug is given in liquid form, either as Syrup or Suspen ene glycol, a polyvinyl pyrrollidone and/or copolyVidone.
Sion. Most drugs however are bitter, and this can lead to poor The taste masked liquid composition has Substantially
patient compliance. Because the threshold for bitterneSS is reduced bitter taste and aftertaste.
low, only a very Small amount of dissolved drug is needed
for perception of bitterneSS. 0011. In preferred embodiments of the invention, the oral
pharmaceutical liquid composition comprises about 0.1 to
0006 The prior art has shown extensive use of one or a about 10 weight percent of at least one bitter-tasting drug
combination of different flavoring methodologies to mask wherein the bitter-tasting drug is an aromatic compound
the bitter taste of drugs. For example, a flavor can be with hydrophilic groups that can form hydrogen bonds Such
Selected that complements the taste of the preparation, or a as hydroxyl, carboxylic or amine groups, about 0.5 to about
flavor with a longer intensity and Stronger taste than the drug 10 weight percent of polyvinyl pyrrolidone and/or copoly
can be used. High levels of Sweetening agents are often used vidone; about 0.05 to about 10 weight percent polyethylene
to overwhelm bitterness with Sweetness. The taste buds may glycol of MW 4000-6000; about 30-90% of a sweetening
also be anesthetized by menthol or mint flavors. These composition; about 0 to 0.4% of a Viscosity-building agent;
approaches are generally not very effective in masking the about 0-20% of a polyhydric alcohol, and 0.1-0.5% of a
taste of a bitter drug, and a flavoring System that works with flavoring agent. The liquid composition is adjusted to a pH
one drug usually does not apply to another drug. between 2.5 to 8.
0007. The prior art also indicates that taste masking could
also be achieved by increasing the Viscosity of liquid prepa DETAILED DESCRIPTION OF THE
rations. Various combinations of Viscosity modifiers for taste INVENTION
masking exist in the patent literature. For example, U.S. Pat. 0012. The present invention contemplates a taste masked
No. 5,616,621 provides taste masked liquid preparations by liquid composition where the liquid composition is a Syrup,
increasing the Viscosity with a combination of polyethylene a ready-to-use Suspension, or extemporaneously prepared
glycol and sodium carboxymethylcellulose; U.S. Pat. No. liquid Syrup or Suspension Such as, for example, dry powder
5,658,919 discloses taste masking of acetaminophen SuS for reconstitution with water, liquid concentrate for dilution,
pension using a Suspending System consisting of Xanthan dispersible tablet or capsule. In the case of extemporane
gum and a mixture of cellulosic polymers. The increase in ously prepared Syrup or Suspension, the concentration of
Viscosity is assumed to limit the contact of the drug with the ingredients are based on the reconstituted product.
tongue, presumably by Slowing down Salivary water uptake
into the Viscous liquid medicament, which can lead to 0013 The liquid pharmaceutical composition of the
dilution and dissolution of the ingested medication. This present invention contains at least one normally bitter tasting
approach is only moderately Successful in reducing bitter drug as active ingredient. The bitter-tasting drugs are present
neSS especially at high drug loading. While bitterneSS may at therapeutically effective amounts in the dosage form.
be reduced at the onset, bitter aftertaste becomes prominent These amounts differ depending on the drug and prescribed
after Swallowing because thick preparations are more diffi dosage regimens. For instance, liquid preparations intended
cult to wash down thus leaving behind Some residual Viscous for infants generally contain high drug concentrations to
liquid medicament in the mouth after Swallowing. This bitter enable Small doses and reduced dosing frequency. The
aftertaste is more prominent with water intake due to the amount of drug in the composition is from about 0.02 to
reduction in Viscosity and dilution of the residual liquid about 15 percent by weight, preferably from about 0.1 to
medicament and Subsequent dissolution of the drug in the about 10 percent by weight of the total composition. In the
mouth. case of dry powder for reconstitution with water, the drug
US 2003/0118654 A1 Jun. 26, 2003
may be present as uncoated or coated particles. Coated drug done is a copolymer of vinyl pyrrollidone and Vinyl acetate
particles are not usually perfectly Sealed. After reconstitu available from BASF under the Tradename KOLLIDON VA
tion, Some amount of drug can leach out through the coating 64. In the present invention, water-soluble PVPs, water
into the liquid phase during Storage, which can result in insoluble PVPs, and copolyvidone may be used either singly
Some bitterneSS in the product. or in combination.
0.014 Bitter tasting drugs that may be used with the liquid 0019. The disclosure of Volker Buhler's book, Kollidon,
composition are aromatic compounds with hydrophilic BASF Aktiengesellshaft, Ludwigshafen, Germany (1992)
groups that can form hydrogen bonds Such as hydroxyl, teaches the use of PVP as both a solubilization aid for
carboxylic or amine groups. These drugs may be Selected Several drugs as well as for Specifically masking the bitter
from but not limited to the group consisting of analgesics, taste of acetaminophen. This book teaches that PVP forms
decongestants, antituSSives, expectorants, antihistamines, complexes with aromatic compounds particularly those with
mucolytics, laxatives, vasodilators, anti-arrhythmics, anti hydrophilic groups that can form hydrogen bonds Such as
diarrhea drugs, anti-hypertensives, antibiotics, narcotics, hydroxyl, carboxyl, and amine groupS. See also Horn et al.,
bronchodilators, anti-inflammatory drugs, cardiovascular J. Pharm. Sci., 71:1021-126 (1982). It is thought that PVP
drugs, tranquilizers, antipsychotics, antitumor drugs, Seda forms a complex with acetaminophen reducing its bitter
tives, antiemetics, anti-nauseants, anti-convulsant, neuro taste. An exemplary formulation for an oral liquid PVP- and
muscular drugs, hypoglycemic agents, diuretics, antispas acetaminophen Syrup composition is provided in page 113,
modics, uterine relaxants, antiobesity drugs, antianginal Table 81 of the above Bihler's text. This formulation
drugs, and antiviral drugs. Combinations of these drugs can contains 5 weight percent of fully dissolved acetaminophen
also be used. and 20 weight percent Kollidon K25.
0.015 Particular unpleasant tasting drugs include but are 0020 Consistent with Bihler's disclosure, we have found
not limited to acetaminophen, ibuprofen, phenylpropanola that the addition of PVP improves the taste of an acetami
mine hydrochloride, pseudoephedrine hydrochloride, phe nophen Suspension. The bitterneSS reduction however is still
nylephrine hydrochloride, diphenhydramine hydrochloride, not significant to eliminate the bitterneSS especially the bitter
guaifenesin, dextromethorphan hydrobromide, chlorphe aftertaste.
niramine maleate, brompheniramine maleate, terfenadine, 0021 We have now surprisingly found that the bitterness
loratadine, descarboethoxyloratadine, brom hexine hydro of an acetaminophen Suspension especially the bitter after
chloride, ambroXol hydrochloride, Salbutamol Sulphate, taste can be significantly improved by using a high molecu
amoxicillin, amplicillin, cloxacillin, flucloxacillin, cephal lar weight polyethylene glycol (PEG) with PVP and/or
exin, and combinations thereof. copolyVidone. This despite the fact that polyethylene glycol
0016 One embodiment of the present invention contains is known to increase the Solubility of acetaminophen.
acetaminophen from about 1 to about 15 weight percent, 0022. Thus, the amount of dissolved acetaminophen
preferably from about 2 to about 10 weight percent of total would have been theoretically higher when polyethylene
composition. A Second embodiment of the invention con glycol is used with PVP and/or copolyvidone in an acetami
tains guaifenesin from about 0.5 to about 10 weight percent, nophen Suspension, which in turn should have increased the
preferably from about 1 to about 5 weight percent of total bitterneSS, and yet on contrary, Significant reduction in
composition. If Suspensions of these drugs are to be pre
pared, the drug should preferably be micronized with more bitterneSS especially on the bitter aftertaste was achieved.
than 80% of the particles having a particle Size less than or The improvement is more prominent when water intake
equal to 10 microns and not more than 15% having particle follows Swallowing of the medication.
sizes greater than or equal to 50 microns. 0023 The molecular weight of polyethylene glycol is
0.017. In the present invention, the normally bitter drug is critical to its contribution to taste masking when combined
dissolved or dispersed in an aqueous taste masking excipient with PVP and/or copolyvidone. Liquid polyethylene glycol
base comprising a polyvinyl pyrrolidone and/or copolyvi with MW 400-600 has no effect on tastemasking, only the
done, and a high MW polyethylene glycol. The taste masked semisolid/solid polyethylene glycol of MWe 900 works.
liquid composition has Substantially reduced bitter taste and The higher the molecular weight, the lower the level of
aftertaste. polyethylene glycol required. The preferred polyethylene
glycol molecular weight is about 2000 to about 8000, more
0.018. A contemplated composition contains about 0.1 to preferably the molecular weight is about 4000 to about 6000.
about 30 weight percent polyvinyl pyrrolidone (PVP) and/or The amount of polyethylene glycol is from about 0.01 to
copolyvidone, preferably about 0.5 to about 10 weight about 25 weight percent, preferably from about 0.05 to about
percent, more preferably about 1 to about 7 weight percent 10 weight percent, and more preferably from about 0.1 to
of total composition. The PVP can either be water-soluble or about 5 weight percent. We have also Surprisingly found that
water-insoluble. PVP is commercially available from a num the taste masking effect of high molecular weight polyeth
ber of Suppliers. The water-soluble PVPs or povidone sold ylene glycol and PVP and/or copolyvidone are not limited to
under the Trademark KOLLIDON K25, K30, K90 having Suspensions but also to fully dissolved drugs (syrups) Such
molecular weights of 28,000-34,000, 44,000-54,000, and as for example Guaifenesin or lower levels of acetami
1,000,000-1,500,000, respectively, are preferred for use, nophen. The mechanism by which debittering is achieved is
with the K25 and K30 being most preferred. Water-insoluble unknown. However, without wishing to be bound by theory,
PVPs referred to as crospovidone or crospolyvidone are it is believed that a complex is formed between the drug and
crosslinked insoluble polyvinyl pyrrollidone. CrospoVidone PVP and/or copolyvidone, with the high molecular weight
is available from BASF under the Trademark KOLLIDON polyethylene glycol potentiating debittering by competing
CL, KOLLIDON CL-M, CROSPOVIDONE M. Copolyvi with unbound drug for taste receptors of bitterneSS.
US 2003/0118654 A1 Jun. 26, 2003
0024. The taste masked liquid composition of the present 0032. The invention will now be described with respect
invention may contain additional ingredients used in the to the following Specific examples.
drug industry, herein referred to as additives. Additives 0033 Experiment 1
include well-known components, but are not limited to
Sweetening agents, flavors, colorants, antioxidants, chelating 0034. The effective amount of crospovidone needed to
agents, Viscosity-building agents, Surfactants, pH modifiers, reduce the bitterneSS of a liquid Suspension containing
bulking agents, acidifiers, coSolvents, and mixtures thereof. acetaminophen was determined by evaluating compositions
0.025 Representative Sweetening agents include but not containing 0, 2.5%, 5% and 10% crospovidone.
limited to:
TABLE 1.
0026 (1) Water-soluble Sweetening agents such as
monosaccharides, disaccharides, Sugar alcohols, and Acetaminophen Suspension
polysaccharides, e.g., glucose, fructose, invert Sugar, Sorbi
tol, Sucrose, maltose, Xylose, ribose, mannose, corn Syrup Example Example Example Example
1-A 1-B 1-C 1-D
Solids, Xylitol, mannitol, maltodextrins, and mixtures (grams per (grams per (grams per (grams per
thereof. In general, water-Soluble Sweetening agents Selected Ingredient 100 ml) 100 ml) 100 ml) 100 ml)
from Sugar, invert Sugar, Sorbitol, mannitol, and mixtures Acetaminophen 5 5 5 5
thereof are useful at amounts of about 20 to about 95 weight Xanthan gum O.3 O.3 O.3 O.3
percent, with amounts of about 30 to about 90 weight Sucrose 55 55 55 55
percent being preferred, and about 40 to about 85 weight 70% Sorbitol Solution 1O 1O 1O 1O
percent being more preferred. Invert Sugar
Glycerin
2O
5
2O
5
2O
5
2O
5
0027 (2) Water-soluble artificial Sweeteners and dipep Crospovidone (Kollidon O 2.5 5 1O
tide-based SweetenerS Such as Saccharin Salts, aceSulfame-K, CL-M)
Sodium Benzoate O.2 O.2 O.2 O.2
Sucralose, aspartame, and mixtures thereof. In general, these Sorbitan Monolaurate O.05 O.OS O.05 O.OS
Sweeteners are used in combination with water-Soluble Disodium Edetate O.2 O.2 O.2 O.2
Sweetening agents to enhance Sweetness. Sucralose O.2 O.2 O.2 O.2
Saccharin sodium O.13 O.13 O.13 O.13
0028 Flavors that may optionally be added to the taste Coloring OOO6 O.OO6 OOO6 O.OO6
masked liquid excipient base of the present invention are Flavoring O.3 O.3 O.3 O.3
those known in the pharmaceutical art. For example, Syn Citric Acid
Sodium Citrate Dihydrate
O1
0.295
O.1
0.295
O1
0.295
O.1
0.295
thetic flavor oils, and/or naturally derived oils from plants, Purified Water q.S. to 100 q.S. to 100 q.s. to 100 q.s. to 100
flowers, leaves, and So forth, and combinations thereof are mL mL mL mL
useful. In general, amounts of about 0.05 to about 5 weight pH 5-6 5-6 5-6 5-6
percent of the total composition are useful with amounts of
about 0.1 to about 1.5 weight percent being preferred and
about 0.2 to about 1 weight percent being most preferred. 0035. The acetaminophen suspensions were prepared in
0029. The taste masked liquid composition of the present the following manner:
invention may optionally contain Viscosity-building agents 0036 Sucrose syrup containing sodium benzoate was
from 0 to about 7 weight percent of total composition, prepared. The hot syrup was cooled down to 30OC. The
preferably from about 0.05 to about 5 weight percent, and Sucrose Syrup, Sorbitol and invert Sugar were blended
most preferably from about 0.1 to about 3 weight percent. together to form Phase A. Sorbitan monolaurate was added
The Viscosity-building agents may be selected from but not to the mixture to form Phase B. Phase B was stirred for 15
limited to Xanthan gum, carrageenan, tragacanth, guar gum, minutes.
pectin, carboxymethylcellulose, hydroxypropyl methylcel
lulose, hydroxypropylcellulose, methylcellulose, microcryS 0037. The required amount of crospovidone (for
talline cellulose and carboxymethylcellulose Sodium blends, Examples 1-B, 1-C and 1-D) was dispersed into Phase B.
and mixtures thereof. The Viscosity-building agent provides The admixture was stirred for 30 minutes after which
both body and mouthfeel to the preparation. The viscosity acetaminophen was added. The resulting admixture was
building agent must be Selected carefully to ensure compat stirred for one hour to form Phase C.
ibility with the drug and the other components of the 0038 Xanthan gum was dispersed in glycerin. The result
formulations.
ing dispersion was added to Phase C. The admixture was
0.030. A cosolvent may optionally be used to dissolve or stirred for 15 minutes to form Phase D.
rapidly disperse additives, or as a Solubilizer for the drugs.
Ethanol and polyhydric alcohols Such as glycerin, propylene 0039. An aqueous solution of citric acid and sodium
glycol, low molecular weight polyethylene glycols, and citrate dihydrate was prepared to form Phase E. An aqueous
mixtures thereof are generally employed as coSolvents. Solution of disodium edetate, Saccharin Sodium and Sucral
0031. In the case of dry powders for reconstitution, the ose was prepared to form Phase F.
powders or granules may optionally contain anti-caking 0040 Phases E and F were added to Phase D. The
agents to improve the flow properties of dry powders during admixture was stirred for one hour and then homogenized in
processing and prevent the powders from caking during a colloid mill. Color and flavor were added to the homog
Storage. The anti-caking agents may be Selected from but not enized bulk, which was stirred for two more hours before
limited to colloidal Silicon dioxide, tribasic calcium phos adjusting to the desired Volume with Sugar Syrup. The
phate, powdered cellulose, magnesium trisilicate, Starch, suspensions were allowed to stand for 24 hours before
and mixtures thereof. tasting.
US 2003/0118654 A1 Jun. 26, 2003
0067. The formulation containing crospovidone and Solution of disodium edetate, Saccharin Sodium and Sucral
polyethylene glycol (Example 3-C) was preferred over the ose was prepared to form Phase F.
formulation containing only crospovidone (Example 3-A) 0075 Phases C, E and F were added to Phase D. The
by 10 of 11 respondents. The same formulation containing admixture was stirred for one hour and then homogenized in
crospoVidone and polyethylene glycol (Example 3-C) was a colloid mill. Color and flavor were added to this homog
also preferred over the formulation containing only poly enized bulk which was stirred for two more hours before
ethylene glycol (Example 3-B) by 9 of 11 respondents. adjusting to the desired Volume with Sugar Syrup. The
These results indicate that Significant taste masking effect suspensions were allowed to stand for 24 hours before
was achieved when polyvinyl pyrrolidone is used in com tasting.
bination with a high molecular weight polyethylene glycol,
and that a significantly lower level of PEG is required for 0076 Seven respondents were asked to taste 2.5 ml each
tastemasking in the presence of polyvinyl pyrrolidone than of Example 4-A and Example 4-B in random order. The
when using PEG alone. respondents were asked to drink water after each medica
0068 Experiment 4 tion, and take unsalted crackers between Samples to remove
traces of the first Sample tasted.
0069. This example describes the production of a liquid 0077 All respondents perceived either a Sweet aftertaste
taste masked Suspension containing the analgesic acetami or no aftertaste for the formulation containing croSpoVidone
nophen. and PEG (Example 4-A), while 5 of 7 respondents detected
TABLE 10
bitter aftertaste in the formulation containing croSpoVidone
only (Example 4-B).
Acetaminophen Suspension 0078. The result shows the significant reduction/elimina
Example 4-A Example 4-B tion of bitterness when high MW polyethylene glycol is used
Ingredient (grams per 100 ml) (grams per 100 ml) with PVP.
Acetaminophen 5 5 0079 Example 4-A was further compared to Calpol Six
Xanthan gum
Sucrose
O.3
55
O.3
55
Plus (UK, GlaxoWellcome), a commercial acetaminophen
Sorbitol Solution 1O 1O Suspension containing the same drug concentration which is
Invert Sugar 2O 2O relatively good-tasting among the other brands in the mar
Glycerin 5 5 ket. Seven of Seven respondents preferred Example 4-A to
Crospovidone (Kollidon CL)
Polyethylene Glycol 4000
2.5
0.25
2.5
O
Calpol Six Plus. All the respondents perceived bitterness in
Sodium Benzoate O.2 O.2
Calpol Six Plus.
Sorbitan Monolaurate O.OS O.OS 0080 Experiment 5
Disodium Edetate O.2 O.2
Sucralose O.2 O.2 0081. The effect of the molecular weight of polyethylene
Saccharin sodium O.13 O.13
Coloring O.OO6 O.OO6 glycol on the taste of a liquid Suspension containing
Flavoring O.3 O.3 acetaminophen was determined.
Citric Acid O.1 O.1
Sodium Citrate Dihydrate 0.295 0.295 TABLE 11
Purified Water C.S. C.S.
pH 5-6 5-6 Acetaminophen Suspension
Example 5-A Example 5-B Example 5-C
0070 The acetaminophen suspensions were prepared in (grams per (grams per (grams per
the following manner: Ingredient 100 ml) 100 ml) 100 ml)
Acetaminophen 5 5 5
0071. Sucrose syrup containing sodium benzoate was Xanthan gum O.3 O.3 O.3
prepared. The hot syrup was cooled down to 30OC. The Sucrose 55 55 55
Sucrose Syrup, Sorbitol and invert Sugar were blended Sorbitol Solution 1O 1O 1O
Invert Sugar 2O 2O 2O
together to form Phase A, which was then divided into two Glycerin 5 5 5
portions. Crospovidone (Kollidon CL- 5 5 5
M)
0072 A solution of polyethylene glycol (for Example Polyethylene Glycol 0.5 O O
4-A) in water was prepared. The resulting Solution was (MW = 4000)
Polyethylene Glycol O 0.5 1.
added to one portion of Phase A. The admixture was stirred (MW = 1450)
for 15 minutes after which Sorbitan monolaurate was added Sodium Benzoate O.2 O.2 O.2
directly to the admixture to form Phase B. Crospovidone Sorbitan Monolaurate O.OS O.OS O.05
was dispersed into Phase B. The admixture was stirred for 30 Disodium Edetate
Sucralose
O.2
O.2
O.2
O.2
O.2
O.2
minutes after which acetaminophen was added. The result Saccharin sodium O.13 O.13 O.13
ing admixture was stirred for one hour to form Phase C. Coloring OOO6 O.OO6 OOO6
Flavoring O.3 O.3 O.3
0.073 Xanthan gum was dispersed in glycerin. The result Citric Acid O1 O.1 O1
ing dispersion was added to the Second portion of Phase A. Sodium Citrate Dihydrate 0.295 0.295 0.295
The admixture was stirred for 15 minutes to form phase D. Purified Water
pH
C.S.
5-6
C.S.
5-6
C.S.
5-6
0.074 An aqueous solution of citric acid and sodium
citrate dihydrate was prepared to form Phase E. An aqueous
US 2003/0118654 A1 Jun. 26, 2003
0099. The Guaifenesin solution was prepared in the fol 0108. The Amoxicillin dry powder was prepared by siev
lowing manner: ing all the excipients prior to use. The Screened excipients
0100 Sucrose syrup containing sodium benzoate was were premixed for 10 minutes. Amoxicillin Trihydrate was
prepared. The hot syrup was cooled down to 30OC. The added to the excipient premix. The resulting powders were
Sucrose Syrup, glycerin and Sorbitol were blended together mixed for another 10 minutes.
to form Phase A.
0101 An aqueous solution of polyethylene glycol (for 0109 The equivalent weight of granules for 100 mL of
Example 7-A) was prepared. An aqueous Solution of reconstituted product was weighed and placed into a bottle.
Guaifenesin was prepared. The Solutions were combined Water was then added to the powders to a volume of 100 mL.
and stirred for 15 minutes to form Phase B. The powder-water mixture was shaken until a visually
homogeneous Suspension was obtained.
0102 Povidone was dissolved in water. The resulting
Solution was added to phase A. The admixture was Stirred for 0110. Example 8-A was compared to Example 8-B. Ten
15 minutes to form Phase C. Phase B was added to Phase C respondents were requested to taste 1 mL of each Sample in
to form Phase D. random order. Each respondent was requested to drink water
0103) An aqueous solution of citric acid was prepared to after each medication, and take unsalted crackers between
form phase E. An aqueous Solution of Sucralose was pre Samples to remove traces of the first Sample tasted. Each
pared to form Phase F. Phases E and F were added to Phase respondent was asked to pick a preference based on reduced
D. The admixture was stirred for one hour and the flavor bitterness.
added. The resulting admixture was stirred for two more 0111 Eight out often respondents preferred Example 8-A
hours to achieve homogeneity, and then purified water was to Example 8-B, illustrating the Significant reduction/elimi
added to adjust to the final volume. The syrups were allowed nation of bitterneSS in extemporaneously prepared liquid
to Stand for 24 hours before tasting. Suspensions when high MW polyethylene glycol is used
0104 Eleven respondents were asked to taste 1 ml each with PVP.
of Example 7-A and Example 7-B in random order. The
respondents were asked to drink water after tasting each 0112 Experiment 9
Sample, and rest between Samples taking unsalted crackers 0113. This example describes the preparation of Clox
to remove traces of the first Sample tasted. Each respondent
was asked to pick a preference based on reduced bitterness. acillin Sodium granules for reconstitution with water.
0105 Eight out of eleven respondents preferred Example TABLE 1.5
7-A (2.5% PVP+1.25% PEG 4000) to Example 7-B (2.5%
PVP). The result illustrates the significant reduction/elimi Cloxacillin Sodium Granules
nation of bitterness in syrups when high MW polyethylene Example 9-A Example 9-B
glycol is used with PVP. Ingredient Grams per 100 mL Grams per 100 mL
0106 Experiment 8 Cloxacillin 2.5 2.5
0107 This example describes the preparation of Amox Sucrose 45 45
Sorbitan Monolaurate O.O6 O.O6
icillin Trihydrate granules for reconstitution with water. Copolyvidone 2.5 2.5
Polyethylene Glycol 4000 1. O
TABLE 1.4 Methylparaben O.10 O.10
Propylparaben O.O2 O.O2
Amoxicillin Trihydrate Granules Sodium Citrate Anhydrous O.10 O.10
Precipitated Silica 1.2 1.2
Example 8-A Example 8-B Color O.OO)4 OOO)4
Ingredient Grams per 100 mL Grams per 100 mL Flavoring O.80 O.8O
Purified Water q.S. to 100 mL. q.S. to 100 mL.
Amoxicillin Trihydrate 13 13
Sucrose 45 45
Sorbitan Monolaurate O.O6 O.O6
Povidone (Kollidon K30) 2.5 2.5 0114. The Cloxacillin dry powder was prepared by siev
ing all the excipients prior to use.
US 2003/0118654 A1 Jun. 26, 2003
0115 The screened excipients were premixed for 10 resulting admixture was stirred for two more hours to
minutes. Cloxacillin Sodium was added to the excipient achieve homogeneity, and then purified water was added to
premix. The resulting powders were mixed for another 10 adjust to the final Volume.
minutes.
0116. The equivalent weight of granules for 100 mL of 0.125 The formulation has an acceptable taste with no
bitterness.
reconstituted product was weighed and placed into a bottle.
Water was added to the powders to a volume of 100 mL. 0126 Experiment 11
0117 The powder-water mixture was shaken until a 0127. This example describes the production of a liquid
Visually homogeneous Suspension was obtained. Example taste masked Syrup containing the antihistamine Diphenhy
9-A was compared to Example 9-B. Eight respondents were
requested to taste 1 mL of each Sample in random order. dramine Hydrochloride.
Each respondent was requested to drink water after each
medication, and take unsalted crackers between Samples to TABLE 1.7
remove traces of the first Sample. Each respondent was Diphenhydramine Hydrochloride Syrup
asked to pick a preference based on reduced bitterneSS.
Ingredient grams per 100 ml
0118 Seven out of ten respondents preferred Example
9-A to Example 9-B. The result illustrates the significant Diphenhydramine O.3
reduction/elimination of bitterneSS in extemporaneously pre Hydrochloride
pared liquid Suspensions when high molecular weight poly Sorbitol 40
ethylene glycol is used with CopolyVidone. Glycerin 3O
Povidone (Kollidon K25) 5.0
0119) Experiment 10 Polyethylene Glycol 8000 2.25
Sodium Benzoate O.2
0120) This example describes the production of a liquid Sucralose O.2
tastemasked Syrup containing the antituSSive Dextrometho Saccharin sodium O.13
rphan Hydrobromide. Flavoring O.3
Citric Acid O.64
TABLE 16 Sodium Citrate Dihydrate 2.66
Purified Water q.S. to 100 mL.
Dextromethorphan Hydrobromide Syrup pH 4.5-5.5
19. The liquid pharmaceutical composition according to tromethrophan hydrobromide, codeine phosphate, codeine
claim 16, wherein Said decongestant is Selected from phe Sulfate, guaifenesin, and combinations thereof.
nylpropanolamine, pseudoephedrine, phenylephrine, and 34. The liquid pharmaceutical composition according to
combinations thereof.
claim 29, wherein Said mucolytic is Selected from the group
20. The liquid pharmaceutical composition according to consisting of ambroXol, carbocisteine, and bromheXine, and
claim 16, wherein Said anti-infective is Selected from amox combinations thereof.
icillin, amplicillin, cloxacillin, flucloxacillin, penicillin, 35. A liquid pharmaceutical composition comprising:
cephalexin, and combinations thereof.
21. The liquid pharmaceutical composition according to 5 g acetaminophen, 0.3 g Xanthan gum, 55 g Sucrose, 10
claim 16, wherein Said mucolytic is Selected from the group g 70%. Sorbitol Solution, 20 g invert Sugar, 5 g glycerin,
consisting of ambroXol, carbocisteine, and bromheXine, and 2.5 to 5 g croSpoVidone, 0 to 2.5g polyethylene glycol
combinations thereof.
22. The liquid pharmaceutical composition according to with an average molecular weight between 1000 to
claim 16, wherein Said antituSSive or said expectorant is 4000, 0.2 g sodium benzoate, 0.05 g Sorbitan mono
Selected from the group consisting of caramiphen, dex laurate, 0.2 g edetate disodium, 0.2 g Sucralose, 0.13 g
tromethrophan hydrobromide, codeine phosphate, codeine Saccharin Sodium, 0 to 0.006 g FD&C or D&C color,
Sulfate, guaifenesin, and combinations thereof. 0.2 to 0.4 g flavor, water to a volume of 100 mL, citric
23. The liquid pharmaceutical composition according to acid-sodium citrate dihydrate to a pH of 5 to 6.
claim 22, wherein Said guaifenesin is present in an amount 36. A liquid pharmaceutical composition comprising:
of about 1 to about 5 weight percent. 10g acetaminophen, 0.3 g Xanthan gum, 54g Sucrose, 10
24. The liquid pharmaceutical composition according to g 70%. Sorbitol Solution, 20 g invert Sugar, 5 g glycerin,
claim 23, further comprising at least one additional drug 5 to 10 g croSpoVidone, 0 to about 1 g polyethylene
Selected from the group consisting of a bronchodilator, a glycol with an average molecular weight between 1000
mucolytic, an antituSSive, and combinations thereof. to 4000, 0.2 g sodium benzoate, 0.05 g Sorbitan mono
25. The liquid pharmaceutical composition according to laurate, 0.2 g edetate disodium, 0.4g Sucralose, 0.26 g
claim 24, wherein said bronchodilator is selected from the Saccharin Sodium, 0 to 0.006 g FD&C or D&C color,
group consisting of Salbutamol, terbutaline, theophylline, 0.2 to 0.4 g flavor, water to a volume of 100 mL, citric
and combinations thereof.
26. The liquid pharmaceutical composition according to acid-sodium citrate dihydrate to a pH of 5 to 6.
37. A liquid pharmaceutical composition comprising:
claim 24, wherein Said antitussive is selected from the group
consisting of caramiphen, dextromethrophan hydrobromide, 2 to 4 g. guaifenesin, 51 g sucrose, 30 g 70% sorbitol
codeine phosphate, codeine Sulfate, and combinations Solution, 7.5 g glycerin, 2.5 g to 5g poVidone, 0 to 1.5
thereof. g polyethylene glycol with an average molecular
27. The liquid pharmaceutical composition according to weight between 1000 to 4000, 0.2 g sodium benzoate,
claim 24, wherein Said mucolytic is Selected from the group 0.1 g sucralose, from about 0.2 to about 0.4 g flavor,
consisting of ambroXol, carbocisteine, and bromheXine, and water to a volume of 100 mL, citric acid to a pH of 3
combinations thereof. to 4.
28. The liquid pharmaceutical composition according to 38. A liquid pharmaceutical composition comprising:
claim 17, wherein Said acetaminophen is present in an
amount of about 1 to about 10 weight percent. 0.3 g dextromethorphan hydrobromide, 60 g sucrose, 20
29. The liquid pharmaceutical composition according to g invert Sugar, 2.5 g to 5g povidone, from about 0 to
claim 28, further comprising at least one additional drug 1 g polyethylene glycol with an average molecular
Selected from the group consisting of an analgesic, an weight between 1000 to 6000, 0.2 g sodium benzoate,
anti-inflammatory drug, an antihistamine, a decongestant, an 0.2 g Sucralose. 0.13 g Saccharin Sodium, 0.2 to about
antituSSive, an expectorant, a mucolytic, and combinations 0.4 g flavor, water to a volume of 100 mL, citric
thereof. acid-sodium citrate dihydrate to a pH of 4.5 to 5.5.
30. The liquid pharmaceutical composition according to 39. A liquid pharmaceutical composition comprising:
claim 29 wherein Said analgesic or said anti-inflammatory 0.3 g diphenhydramine hydrochloride, 40 g 70% sorbitol
agent is Selected from the group consisting ibuprofen, Solution, 30 g glycerin, 2.5 g to 5g povidone, 0 to 2.25
naproxen, mefenamic acid, ketoprofen, celecoxib, rofe g polyethylene glycol with an average molecular
coxib, tramadol, and combinations thereof. weight between 1000 to 8000, 0.2 g sodium benzoate,
31. The liquid pharmaceutical composition according to 0.2 g Sucralose. 0.13 g Saccharin Sodium, 0.2 to 0.4g
claim 29, wherein Said antihistamine is Selected from the flavor, water to a volume of 100 mL, citric acid-Sodium
group consisting of loratadine, descarboethoxyloratadine, citrate dihydrate to a pH of 4.5 to 5.5.
diphenhydramine, brompheniramine, chlorpheniramine, ter 40. A liquid pharmaceutical composition comprising:
fenadine, cetirizine, and combinations thereof.
32. The liquid pharmaceutical composition according to 0.08 g brompheniramine maleate, 40 g 70% sorbitol
claim 29, wherein the decongestant is Selected from the Solution, 30 g glycerin, 2.5 g to 5g povidone, 0 to 2.25
group consisting of phenylpropanolamine, pseudoephe g polyethylene glycol with an average molecular
drine, phenylephrine, and combinations thereof. weight between 1000 to 8000, 0.2 g sodium benzoate,
33. The liquid pharmaceutical composition according to 0.2 g Sucralose. 0.13 g Saccharin Sodium, 0.2 to 0.4g
claim 29, wherein Said antituSSive or said expectorant is flavor, water to a volume of 100 mL, citric acid-Sodium
Selected from the group consisting of caramiphen, dex citrate dihydrate to a pH of 3 to 4.
US 2003/0118654 A1 Jun. 26, 2003
12
41. A ready-to-use powder or granules for reconstitution 43. A method for preparing a taste-masked liquid phar
wherein after reconstitution to 100 mL with water, the liquid maceutical composition, comprising combining:
pharmaceutical composition comprises: at least one unpleasant-tasting drug,
3.25 to 13 g amoxicillin trihydrate, 45 g sucrose, 0.06 g polyethylene glycol with a molecular weight of at least
Sorbitan monolaurate, 0.5 to 2.5 g povidone and/or 900;
copolyVidone, 0.1 to about 0.5g polyethylene glycol polyvinyl pyrrollidone and/or a copolyVidone; and
with an average molecular weight between 1000 to an aqueous liquid excipient base.
8000, 0.10 g methylparaben, 0.02 propylparaben, 0 to 44. The method according to claim 43, wherein said
0.004 g FD&C or D&C color, 0.20 to 1 g flavor, 1.2g polyethylene glycol has an average molecular weight of
precipitated Silica, and Sodium citrate to pH 4-6. from about 2000 to about 8000.
42. A ready-to-use powder or granules for reconstitution 45. The method according to claim 43, wherein said
wherein after recontitution to 100 mL with water, the liquid polyethylene glycol has an average molecular weight of
from about 4000 to about 6000.
pharmaceutical composition comprises:
46. The method according to claim 43, wherein said liquid
2 to 10g cloxacillin Sodium, 45g Sucrose, 0.06 g Sorbitan pharmaceutical composition further comprises one or more
monolaurate, 0.5 to 2.5 g poVidone and/or copolyvi additives Selected from the group consisting of Sweetening
done, 0.1 to about 0.5g polyethylene glycol with an agents, flavors, colorants, antioxidants, chelating agents,
average molecular weight between 1000 to 8000, 0.10 Viscosity-building agents, Surfactants, pH modifiers, bulking
g methylparaben, 0.02 propylparaben, 0 to 0.004 g agents, acidifiers, coSolvents, anticalking agents, and mix
tures thereof.
FD&C or D&C color, 0.20 to 1 g flavor, 1.2 g precipi
tated Silica, and Sodium citrate to pH 4-6.