Antitussive drugs delivered by ion exchange resins

The present invention relates generally to a mixture of coated and non-coated sulfonic acid cation exchange resins (Amberlite IR69) cross-linked with about 8% divinyl benzene onto which dextromethorphan has been loaded. About 30% of the drug/resin complexes are coated with a mixture of ethyl cellulose or ethyl cellulose latexes with plasticizers and water dispersible polymers such as SURELEASE. The coating level is about 50% w/w drug. Coated and uncoated drug/resin complexes are loaded with drug to about 45% by weight drug/resin complex. The ratio of coated and uncoated drug/resin complexes is about 55/45. The particle sizes of the coated and uncoated drug/resin complexes is about 20 to about 300 and about 20 to about 250 microns, respectively.

FIELD OF THE INVENTION 
The present invention relates generally to a controlled-release syrup 
suspension for oral administration, preferably containing a 
dextromethorphan polystyrene sulfonate resin. The composition provides up 
to 12 hours of symptomatic relief from dry coughing. 
BACKGROUND OF THE INVENTION 
Dextromethorphan is an antitussive used in many over-the-counter cold 
medications. It has an opioid-like structure but, being a d-isomer, it 
does not possess the analgesic or addicveti retes of opioids. It acts 
centrally to relieve cough, similarly as opioids. It is active against dry 
cough and does not exhibit significant expectorant properties for 
productive cough. 
As is well known, the maximum time of effectiveness in dextromethorphan 
compositions is only a few hours because of biological modification and/or 
elimination of the medication in the body (i.e., the usual doses for 
immediate-release formulations range from 15-30 mg every 4-6 hours). 
Consequently, repeated dosages must be taken at frequent intervals to 
obtain long term therapeutic levels of drug. Furthermore, this drug 
usually dissolves readily in the digestive juices and the total dosage is 
immediately fed into the blood stream. After high initial peak 
concentrations, the level of drug in the blood stream constantly decreases 
because of the biological elimination, so there is little or no 
therapeutic effect at the end of the period between dosages. As a result, 
the therapeutic effect fluctuates between dosages corresponding to the 
peaks and valleys in the level of drug in the blood as commonly measured 
by trough to peak ratios. 
It is possible to incorporate materials into dextromethorphan compositions 
in such a manner that the dextromethorphan is liberated from the 
compositions at a predetermined rate. In this way, it is possible, for 
example, to achieve a prolongation of the period of action and thus to 
avoid too quick and/or too concentrated a release of the dextromethorphan 
and too high peaks of the blood or tissue levels, which can lead to 
undesirable side effects. DELSYM DM, marketed by Ciba Pharmaceuticals, is 
an example of a sustained-release dextromethorphan composition. The 
sustained-release characteristics of the composition are achieved by use 
of small particles of an ion-exchange resin bound to the dextromethorphan 
which delay release of the drug in the gastrointestinal tract. 
While sustained-release of dextromethorphan is achieved by compositions 
such as DELSYM DM, certain advances to this area of technology are 
required. The bioavailability of dextromethorphan from these type of 
compositions is relatively low due to the strong bond between residual 
amounts of dextromethorphan and the ion exchange resin. The total 
percentage of dextromethorphan released from dextromethorphan/ion exchange 
resin complexes is incomplete, and under certain in vitro conditions it 
has been observed that even after a twelve hour period of time, about 20% 
of dextromethorphan remains bound to the ion exchange resin. 
It is an object of the present invention to provide a sustained-release 
antitussive liquid formulation. 
A further object of the present invention is to provide a sustained-release 
antitussive liquid formulation which is not dependent on the presence of 
large amounts of drug/resin complexes. 
Another object of the present invention is to provide a sustained-release 
antitussive liquid formulation which is capable of demonstrating a release 
profile which will result in up to a twelve hour cough relief 
SUMMARY OF THE INVENTION 
Surprisingly and unexpectedly, these and other objectives, which are 
apparent from the following, have now been realized with a 
sustained-release antitussive composition comprising in a preferred 
embodiment, a mixture of coated and non-coated sulfonic acid cation 
exchange resins (Amberlite IRP-69) cross-linked with preferably about 8% 
divinyl benzene onto which dextromethorphan has been loaded. About 30% of 
the drug/resin complexes are coated with a mixture of ethyl cellulose or 
ethyl cellulose latexes with plasticizers and water dispersible polymers 
such as SURELEASE. The coating level is about 50% w/w of the drug/resin 
complex. Coated and uncoated drug/resin complexes are loaded with drug to 
about 30 to about 50% w/w drug. The ratio of coated and uncoated 
drug/resin complexes is about 55/45. The particle sizes of the coated and 
uncoated drug/resin complexes are about 20 to about 300 and about 20 to 
about 250 um, respectively. 
The invention further relates to methods of using the sustained-release 
compositions in the treatment, management or mitigation of cough, cold, 
cold-like and/or flu symptoms and the discomfort, pain, fever and general 
malaise associated therewith.

DETAILED DESCRIPTION OF THE INVENTION 
The ion exchange resins suitable for use in these preparations are 
water-insoluble and consist of a pharmacologically inert organic or 
inorganic matrix containing covalently bound functional groups that are 
ionic or capable of being ionized under the appropriate conditions of pH. 
The organic matrix may be synthetic (e.g., polymers or copolymers of 
acrylic acid, methacrylic acid, sulfonated styrene, sulfonated 
divinylbenzene), or partially synthetic (e.g., modified cellulose and 
dextrans). The inorganic matrix can also be, e.g., silica gel modified by 
the addition of ionic groups. The covalently bound ionic groups may be 
strongly acidic (e.g., sulfonic acid), weakly acidic (e.g., carboxylic 
acid), strongly basic (e.g., quaternary ammonium), weakly basic (e.g., 
primary amine), or a combination of acidic and basic groups. In general, 
those types of ion exchangers suitable for use in ion exchange 
chromatography and for such applications as deionization of water are 
suitable for use in these controlled release drug preparations. Such ion 
exchangers are described by H. F. Walton in "Principles of Ion Exchange" 
(pp. 312-343), incorporated by reference herein. The ion exchange resins 
useful in the present invention have exchange capacities below about 6 
milliequivalents per gram (meq./g) and preferably below about 5.5 meq./g. 
The resin is cross-linked with a crosslinking agent selected from 
difunctional compounds capable of cross-linking polystyrenes; these are 
commonly known in the art. Preferably, the cross-linking agent is a 
divinyl or polyvinyl compound. Most preferably the cross-linking agent is 
divinylbenzene. The resin is cross-linked to an extent of about 3 to about 
20%, preferably about 4 to about 16%, more preferably about 6 to about 
10%, and most preferably about 8% by weight based on the total resin. The 
resin is cross-linked with the cross-linking agent by means well known in 
the art. 
The size of the ion-exchange resins should preferably fall within the range 
of about 20 to about 200 um Particle sizes substantially below the lower 
limit are difficult to handle in all steps of the processing. Particle 
sizes substantially above the upper limit, e.g. commercially-available 
ion-exchange resins having a spherical shape and diameters up to about 
1000 um, are gritty in liquid dosage forms and have a greater tendency to 
fracture when subjected to drying-hydrating cycles. Moreover, it is 
believed that the increased distance that a displacing ion must travel in 
its diffusion into these large particles, and the increased distance the 
displaced drug must travel in its diffusion out of these large particles, 
cause a measurable but not readily controlled prolongation of release even 
when the drug/resin complexes are uncoated. 
Representative resins useful in this invention include Amberlite IRP-69 
(obtained from Rohm and Haas) and Dow XYS-40010.00 (obtained from The Dow 
Chemical Company). Both are sulfonated polymers composed of polystyrene 
cross-linked with 8% of divinylbenzene, with an ion exchange capacity of 
about 4.5 to 5.5 meq./g of dry resin (H+-form). Their essential difference 
is in physical form. Amberlite IRP-69 consists of irregularly-shaped 
particles with a size range of 47 to 149 um, produced by milling the 
parent, large-sized spheres of Amberlite IRP-120. The Dow XYS-40010.00 
product consists of spherical particles with a size range of 45 to 150 um. 
Another useful exchange resin, Dow XYS-40013.00, is a polymer composed of 
polystyrene cross-linked with 8% of divinylbenzene and functionalized with 
a quaternary ammonium group; its exchange capacity is normally within the 
range of approximately 3 to 4 meq./g of dry resin. 
The most preferable resin for complexing with antitussives, such as 
dextromethorphan, is commercially available under the trade name Amberlite 
IRP-69 (Rohm and Haas). 
Adsorption of the drug onto the ion exchange resin particles to form the 
drug/resin complex is a well known technique as shown in U.S. Pat. Nos. 
2,990,332 and 4,221,778. In general the drug is mixed with an aqueous 
suspension of the resin, and the complex is then washed and dried. 
Adsorption of drug onto the resin may be detected by measuring a change in 
the pH of the reaction medium, or by measuring a change in concentration 
of sodium or drug. 
Binding of drug to resin can be accomplished according to four general 
reactions. In the case of a basic drug, these are: (a) resin (Na-form) 
plus drug (salt form); (b) resin (Na-form) plus drug (as free base); (c) 
resin (H-form) plus drug (salt form); and (d) resin (H-form) plus drug (as 
free base). All of these reactions except (d) have cationic by-products, 
by competing with the cationic drug for binding sites on the resin, reduce 
the amount of drug bound at equilibrium. For basic drugs, stoichiometric 
binding of drug to resin is accomplished only through reaction (d). 
Four analogous binding reactions can be carried out for binding an acidic 
drug to an anion exchange resin. These are: (a) resin (Cl--form) plus drug 
(salt form); (b) resin (Cl--form) plus drug (as free acid); (c) resin 
(OH--form) plus drug (salt form); and (d) resin (OH--form) plus drug (as 
free acid). All of these reactions except (d) have ionic by-products and 
the anions generated when the reactions occur compete with the anionic 
drug for binding sites on the resin with the result that reduced levels of 
drug are bound at equilibrium. For acidic drugs, stoichiometric binding of 
drug to resin is accomplished only through reaction (d). The binding may 
be performed, for example, as a batch or column process, as is known in 
the art. 
The drug/resin complex formed is collected and washed with ethanol and/or 
water to insure removal of any unbound drug. The complexes are usually 
air-dried in trays at room or elevated temperature. 
The drug/resin complex has a ratio of dextromethorphan to resin of about 
1:3 to about 3:1, preferably about 1:2 to about 2:1, most preferably about 
1:1. The only limit to using ratios in excess of 1:6 is an economic and 
aesthetic one. 
The amount of the drug bonded to the ion exchange resin is in the range 
from about 25 to about 75% by weight of the drug/resin complex. More 
preferably, the amount of the drug bonded to the ion exchange resin is in 
the range from about 33 to about 77% by weight of the drug/resin complex. 
Most preferably, the amount of the drug bonded to the ion exchange resin 
is in the range from about 40 to about 60% by weight of the drug/resin 
complex. 
The amount of resinate in the formulation is sufficient to deliver, when 
administered at one dose every 12 hours, an antitussive effective amount 
of a drug like dextromethorphan over a period of approximately 12 hours to 
a patient in need of such administration. A typical adult dose of 10 mL 
will contain approximately 120 mg of drug/resin complex, i.e. to deliver 
equivalent to 60 mg of dextromethorphan hydrobromide when the average 
drug:resin ratio is about 1:1. 
The antitussive drugs that are suitable for use in these preparations are 
acidic, amphoteric or most often basic antitussives. Examples of basic 
drugs useful in the present invention include, but are not limited to 
dextromethorphan, diphenhydramine, caramiphen, carbapentane, 
ethylmorphine, noscapine and codeine. 
In the preferred embodiment, the invention relates to pharmaceutical 
compositions of matter comprising drug/resin complexes having only one 
active ingredient. In another embodiment, the invention also relates to 
pharmaceutical compositions of matter comprising the drug/resins in 
combination with suitable pharmaceutically acceptable non-toxic carriers 
or excipients, and optionally at least one of an antihistamine, 
sympathomimetic drug (nasal decongestant, bronchodilator), analgesic, 
antiinflammatory, cough suppressant and/or expectorant. Compounds which 
are antihistamines, sympathomimetic drugs (nasal decongestant, 
bronchodilator), analgesic, antiinflammatory, cough suppressants and/or 
expectorants are well known to those of skill in the art and need not be 
discussed in detail herein. 
Only a certain percentage of the compositions disclosed herein will contain 
non-coated drug/resin complexes. The remaining drug/resin complexes are 
further characterized by the presence of a coating. In the preferred 
embodiment of the present invention, about 20 to about 80% of the 
drug/resin complexes in the sustained-release compositions are coated, 
most preferably about 40 to about 60% of the drug/resin complexes. The 
coating is a water-permeable, diffusion barrier coating material. The 
presence of a coating allows one to selectively modify the dissolution 
profile as desired of a pharmaceutical composition comprising the 
drug/resin complexes of the present invention. 
The coating materials can in general be any of a large number of 
conventional natural or synthetic film-forming materials used singly, in 
admixture with each other, and in admixture with plasticizers, pigments, 
etc. with diffusion barrier properties and with no inherent 
pharmacological or toxic properties. In general, the major components of 
the coating should be insoluble in water, and permeable to water and drug. 
However, it might be desirable to incorporate a water-soluble substance, 
such as methyl cellulose, to alter the permeability of the coating, or to 
incorporate an acid-insoluble, base-soluble substance to act as an enteric 
coating. The coating materials may be applied as a suspension in an 
aqueous fluid or as a solution in organic solvents. Suitable examples of 
such coating materials are described by R. C. Rowe in Materials used in 
Pharmaceutical Formulation. (A. T. Florence, editor), Blackwell Scientific 
Publications, Oxford, 1-36(1984), incorporated by reference herein. 
Preferably the water-permeable diffusion barrier is selected from the 
group consisting of ethyl cellulose, methyl cellulose and mixtures thereof 
Most preferably, the coating material is SURELEASE, manufactured by 
Colorcon which is water based ethyl cellulose latex, plasticized with 
dibutyl sebacate or with vegetable oils. Other non-limiting coating 
materials included within the scope of the present invention are AQUACOAT, 
manufactured by FMC Corporation of Philadelphia, which is ethylcellulose 
pseudolatex; solvent based ethylcellulose; shellac; zein; rosin esters; 
cellulose acetate; EUDRAGITS, manufactured by Rohm and Haas of 
Philadelphia, which are acrylic resins; silicone elastomers; poly(vinyl 
chloride) methyl cellulose; and hydroxypropylmethyl cellulose. 
Conventional coating solvents and coating procedures (such as fluid bed 
coating and spray coating) can be employed to coat the particles. 
Techniques of fluid bed coating are taught, for example, in U.S. Pat. Nos. 
3,089,824; 3,117,027; and 3,253,944. The coating is normally applied to 
the drug/resin complex, but alternatively can be applied to the resin 
before complexing with the drug. Non-limiting examples of coating solvents 
include ethanol, a methylene chloride/acetone mixture, coating emulsions, 
methyl acetone, tetrahydrofuran, carbonetetrachloride, methyl ethyl 
ketone, ethylene dichloride, trichloroethylene, hexane, methyl alcohol, 
isopropyl alcohol, methyl isobutyl ketone, toluene, 2-nitropropane, 
xylene, isobutyl alcohol, n-butyl acetate. 
It is preferred that the coated drug/resin complexes are coated in the 
range from about 40 to about 70% w/w drug/resin complex. More preferably, 
the drug/resin complex is coated in the range from about 45 to about 55% 
w/w drug/resin complex. Most preferably, the drug/resin complex is coated 
about 50% w/w drug/resin complex. Variation in the amount of coating 
and/or the use of coated/uncoated complex mixtures can be employed to 
selectively modify the dissolution profile as desired. 
The average particle sizes of the non-hydrated coated and uncoated 
drug/resin complexes is about 60 to about 200 and about 60 to about 250 
um, respectively. More preferably, average particle sizes of the coated 
drug/resin complexes is between about 70 and about 190 um, and most 
preferably about 70 to about 180 um. More preferably, average particle 
sizes of the uncoated drug/resin complexes is between about 55 and about 
160 um, and most preferably about 60 to about 150 um. It is desirable that 
about 85%, preferably about 95%, and most preferably about 98% of the 
resin particles have sizes within the ranges set forth above. Adjustments 
within these ranges can be made to accommodate desired aesthetic qualities 
of the final formulation product. It is more preferable that the resin 
dextromethorphan complex have particle sizes within these ranges as well. 
Preparation of the compositions as disclosed above leads to the reduction 
in the amount of dextromethorphan/ion exchange resin complexes required in 
a composition while still achieving a pharmaceutically effective activity 
level over a twelve hour period of time. While not intending to be limited 
by theory, it is believed that the inventors have discovered a way to use 
coatings in conjunction with increased drug loading to achieve plasma drug 
concentration levels that will provide relief for up to twelve hours. The 
amount of drug/resin in DELSYM DM dextromethorphan/resin compositions is 
estimated to be about 100 mg/5 ml, whereas the amount of drug/resin in the 
compositions of the present invention can be about 60 mg/ml. 
Furthermore, unlike the drug/ion exchange resin preparations of the prior 
art, the sustained-release antitussivelion exchange resin compositions of 
the present invention have been surprisingly and unexpectedly found to 
release up to about 90%, and even up to about 95% of an antitussive like 
dextromethorphan from the compositions over a twelve hour period. The 
bioavailability of dextromethorphan from the compositions of the present 
invention is high despite the strong bond between residual amounts of 
dextromethorphan and the ion exchange resin. If equivalent amounts of 
dextromethorphan/resin compositions of the present invention and DELSYM DM 
dextromethorphan/resin compositions are compared, the activity levels of 
the compositions of the present invention can be up to 15% more active 
than the DELSYM DM compositions. The foregoing assertions are evidenced by 
FIG. 1 which illustrates the in vitro dissolution profiles of the 
compositions of the present invention and DELSYM DM. 
An additional advantages achieved by the compositions of the present 
invention, not available from other sustained-release dextromethorphan 
compositions relates to taste. Dextromethorphan is a drug which is 
unpleasant to take orally. Compositions, such as liquid suspension, 
comprising the drug/resin complexes of the present invention surprisingly 
and unexpectedly are pleasant tasting with good mouth-feel, even in the 
absence of sugars. 
The drug/resin composition thus prepared may be stored for future use or 
formulated with conventional pharmaceutically acceptable carriers to 
prepare liquid compositions. The compositions according to this invention 
may, for example, take the form of liquid preparations such as 
suspensions, or solid preparations such as capsules, tablets, caplets, 
liquigells, powders. 
The compositions may be formulated using conventional carriers or 
excipients and well established techniques. Without being limited thereto, 
such conventional carriers or excipients include diluents, binders and 
adhesives (i.e., cellulose derivatives and acrylic derivatives), 
lubricants (i.e., magnesium or calcium stearate, or vegetable oils, 
polyethylene glycols, talc, sodium lauryl sulphate, polyoxy ethylene 
monostearate), solubilizers, humectants, disintegrants, colorants, 
flavorings, preservatives, sweeteners and miscellaneous materials such as 
buffers and adsorbents in order to prepare a particular medicated 
composition. 
Suitable thickeners include: tragacanth; xanthan gum; bentonite; acacia and 
lower alkyl ethers of cellulose (including the hydroxy and carboxy 
derivatives of the cellulose ethers). Preferably, tragacanth is used and 
incorporated in an amount of from about 0.1 to about 1.0% w/v of the 
composition, and more preferably about 0.5% w/v of the composition. 
Xanthan gum is used in the amount of from about 0.025 to about 0.5% w/v 
and preferably about 0.25% w/v. 
The sustained-release antitussive/ion exchange resin compositions also 
include a humectant composition to also give the liquid greater viscosity 
and stability. Suitable humectants useful in the formulations of the 
present invention include glycerin, polyethylene glycol, propylene glycol 
and mixtures thereof. Preferably, polyethylene glycol is used and 
incorporated in an amount of from about 5 to about 20% w/v of the 
composition and preferably in an amount of from about 5 to about 15% w/v 
of the composition and most preferably in an amount of about 8% w/v of the 
composition. 
The oral liquid compositions of the present invention will also comprise at 
least one and preferably two surfactants in amounts of up to about 5.0% 
w/v and preferably from about 0.02 to about 3.0% w/v of the total 
formulation. The surfactants useful in the preparation of the compositions 
of the present invention are generally organic materials which aid in the 
stabilization and dispersion of the ingredients in aqueous systems for a 
suitable homogenous composition. Preferably, the surfactants of choice are 
non-ionic surfactants such as poly(oxyethylene)(20)sorbitan monooleate and 
sorbitan monooleate. These are commercially known as Tweens and Spans and 
are produced in a wide variety of structures and molecular weights. 
Whereas any one of a number of surfactants may be used, preferably a 
compound from the group comprising polysorbate copolymers 
(sorbitan-mono-9-octadecenoate-poly(oxy-1,2-ethanediyl)) is employed. This 
compound is also added and functions to keep any flavors and sweeteners 
homogeneously dissolved and dispersed in solution. It is also believed 
without being bound to any theory, that the polymers may provide a taste 
masking function as well by binding with the active. 
Suitable polysorbates include polysorbate 20, polysorbate 40, polysorbate 
80 and mixtures thereof Most preferably, polysorbate 80 is employed. The 
surfactant component will comprise from about 0.01 to about 2.0% w/v of 
the total composition and preferably will comprise about 0.1% w/v of the 
total weight of the composition. 
A second emulsifier/surfactant useful in combination with polysorbates in 
the practice of the present invention may be employed and is preferably a 
poloxamer such as Poloxamer 407. Polyxamer 407 has an HLB 
(hydrophilic/lipophilic balance) of about 22 and is sold under the 
tradename Pluoronic-127 (BASF-Wyandotte; Parsippany, N.J.). The two 
surfactants can be employed in substantially equivalent amounts. For 
example, the Poloxamer 407 and polysorbate 80 may each be employed 
together at levels of approximately from about 0.02 to about 4.0% w/v of 
the total weight of the formulation. 
Aqueous suspensions may be obtained by dispersing the drug/resin 
compositions in a suitable aqueous vehicle, optionally with the addition 
of suitable viscosity enhancing agent(s) (e.g., cellulose derivatives, 
xanthan gum, etc.). Non-aqueous suspensions may be obtained by dispersing 
the drug/resin compositions in a suitable non-aqueous based vehicle, 
optionally with the addition of suitable viscosity enhancing agent(s) 
(e.g., hydrogenated edible fats, aluminum stearate, etc.). Suitable 
non-aqueous vehicles include, for example, almond oil, arachis oil, 
soybean oil or fractionated vegetable oils such as fractionated coconut 
oil. 
Preservatives useful in the present invention include, but are not limited 
to sodium benzoate, potassium sorbate, salts of edetate (also known as 
salts of ethylenediaminetetraacetic acid, or EDTA, such as disodium EDTA) 
and parabens (e.g., methyl, ethyl, propyl or butyl-hydroxybenzoates, etc.) 
or sorbic acid. The preservatives listed above are exemplary, but each 
preservative must be evaluated on an empirical basis, in each formulation, 
to assure the compatibility and efficacy of the preservative. Methods for 
evaluating the efficacy of preservatives in pharmaceutical formulations 
are known to those skilled in the art. Preferred preservatives are the 
paraben preservatives are methyl, ethyl, propyl, and butyl paraben. methyl 
and propyl paraben are most preferable. Preferably, both methyl and propyl 
paraben are present in the formulation in a ratio of methyl paraben to 
propyl paraben of from about 2.5:1 to about 7.5:1, preferably 3:1. 
In the instance where auxiliary sweeteners are utilized, the present 
invention contemplates the inclusion of those sweeteners well known in the 
art, including both natural and artificial sweeteners. Thus, additional 
sweeteners may be chosen from the following non-limiting list: 
A. Water-soluble sweetening agents such as monosaccharides, disaccharides 
and polysaccharides such as xylose, ribose, glucose, mannose, galactose, 
fructose, dextrose, sucrose, sugar, maltose, partially hydolyzed starch, 
or corn syrup solids and sugar alcohols such as sorbitol, xylitol, 
mannitol and mixtures thereof 
B. Sucralose. 
C. Dipeptide based sweeteners such as L-aspartyl-phenylalanine methyl ester 
and materials described in U.S. Pat. No. 3,492,131 and the like. 
In general, the amount of sweetener will vary with the desired amount of 
sweeteners selected for a particular liquid formulation. This amount will 
normally be 0.001 to about 90% by weight when using an easily extractable 
sweetener. The water-soluble sweeteners described in category A above, are 
preferably used in amounts of about 5 to about 70% by weight, and most 
preferably from about 10 to about 50% by weight of the final liquid 
composition. In contrast, the artificial sweeteners described in 
categories B and C are used in amounts of about 0.005 to about 5.0% and 
most preferably about 0.01 to about 2.5% by weight of the final liquid 
composition. These amounts are ordinarily necessary to achieve a desired 
level of sweetness independent from the flavor level achieved from flavor 
oils. 
Suitable flavorings include both natural and artificial flavors, and mints 
such as peppermint, menthol, artificial vanilla, cinnamon, various fruit 
flavors, both individual and mixed, essential oils (i.e. thymol, 
eculyptol, menthol and methyl salicylate) and the like are contemplated. 
The amount of flavoring employed is normally a matter of preference 
subject to such factors as flavor type, individual flavor, and strength 
desired. Thus, the amount may be varied in order to obtain the result 
desired in the final product. Such variations are within the capabilities 
of those skilled in the art without the need for undue experimentation. 
The flavorings are generally utilized in amounts that will vary depending 
upon the individual flavor, and may, for example, range in amounts of 
about 0.01 to about 3% by weight of the final composition weight. 
The colorants useful in the present invention, include the pigments such as 
titanium dioxide, that may be incorporated in amounts of up to about 1% by 
weight, and preferably up to about 0.6% by weight. Also, the colorants may 
include other dies suitable for food, drug and cosmetic applications, and 
known as D&C 10 and F.D. & C. dyes and the like. The materials acceptable 
for the foregoing spectrum of use are preferably water-soluble. 
Illustrative examples include indigoid die, known as F.D. & C. Blue No. 2, 
which is the disodium salt of 5,5'indigotindisulfonic acid. Similarly, the 
dye known as F.D. & C. Green No. 1, comprises a triphenylmethane dye and 
is the monosodium salt of 
4-[4-Nethyl-p-sulfobenzylamino)diphenylmethylene]-[1-(N-ethyl-N-p-sulfoniu 
mbenzyl)-2,5-cyclohexadienimine]. A full recitation of all F.D. & C. and D. 
& C. and their corresponding chemical structures may be found in the 
Kirk-Othmer Encyclopedia of Chemical Technology, in Volume 5, at Pages 
857-884, which text is accordingly incorporated herein by reference. 
Suitable oils and fats that are useable would include partially 
hydrogenated vegetable or animal fats, such as coconut oil, palm kernel 
oil, beef tallow, lard, and the like. These ingredients are generally 
utilized in amounts with respect to the comestible product of up to about 
7.0% by weight, and preferably up to about 3.5% by weight of the final 
product. 
Wetting agents also may be employed in the inventive compositions to 
facilitate the dispersion of any hydrophobic ingredients. The 
concentration of wetting agents in the composition should be selected to 
achieve optimum dispersion of the ingredient within the composition with 
the lowest feasible concentration of wetting agent. It should be 
appreciated that an excess concentration of wetting agent may cause the 
composition, as a syrup suspension, to flocculate. Those skilled in the 
art are well versed in suitable empirical methods to determine the 
appropriate wetting agents and concentrations to achieve optimum 
dispersion and avoid flocculation. Suitable wetting agents are listed in 
the U.S. Pharmacoepia XXI. 
The invention further relates to methods of using the compositions in the 
treatment, management or mitigation of cough, cold, cold-like and/or flu 
symptoms and the discomfort, pain, fever and general malaise associated 
therewith. 
The following examples are provided to more specifically teach and better 
define the sustained-release compositions of the present invention. They 
are for illustrative purposes only and it is realized that minor changes 
and variations can be made that are not disclosed therein. Such 
alternatives are still to be considered as falling within the spirit and 
scope of the present invention as recited by the claims that follow. 
EXAMPLES 
Example 1 Formulation 
______________________________________ 
Ingredient (and Percentage Formula (%) 
Test Standard) Strength: 30 mg/5 mL 
______________________________________ 
Formula N.degree. 
1 
Dextromethorphan DRC-UNCOATED.sup.1 Mfr 
0.276 
Dextromethorphan DRC50-COATED.sup.2 Mfr 
0.970 
Tragacanth NF 0.40 
Xanthan Gum NF 0.10 
Sucralose 0.02 
D&C Red N.degree. 33 Mfr. 
0.001 
Xylitol NF 15.00 
Polyethylene Glycol 600 NF 
8.00 
Methylparaben NF 0.08 
Propylparaben NF 0.05 
/-Menthol USP 0.04 
Polysorbate 80 NF 0.05 
Sorbitan Monooleate NF 
0.05 
Artificial Raspberry Flavour Mfr 
0.30 
Purified Water USP qs 
TOTAL 100.00% 
.sup.1 Dextromethorphan DRC-UNCOATED 
0.276% 
Consists of: 
Dextromethorphan 0.132% 
(From Dextromethorphan 
Hydrobromide USP) 
Polystyrene Sulfonate 
0.144% 
(From Sodium Polystyrene Sulfonate USP) 
Equivalent to Dextromethorphan 
9 mg/5 mL 
Hydrobromide USP 
.sup.2 Dextromethorphan DRC50-COATED 
0.970% 
Consists of: 
Dextromethorphan 0.308% 
(From Dextromethorphan 
Hydrobromide USP) 
Polystyrene Sulfonate 
0.336% 
(From Sodium Polystyrene 
Sulfonate USP) 
SURELEASE (dry basis) 
0.326% 
Colloidal silicon dioxide USP 
.about.0.001% 
Equivalent to Dextromethorphan 
21 mg/5 mL 
Hydrobromide USP 
.sup.1+2 Label Claim (Equivalent 
30 mg/5 mL 
to Dextromethorphan 
Hydrobromide USP 
______________________________________ 
Sustained Release Cough Syrup Preparation Procedure 
Example 1 is prepared in accordance with the formulation set forth above, 
and the methods set forth in the specification. A dispersion of gums and 
stabilizers is prepared in a portion of water. The mixture is pasteurized 
by raising the temperature of the dispersion to between 60 and 90.degree. 
C. for 0.5 to 2 hrs. To this dispersion preservatives and a portion of 
humectant and sweetener are added followed by the addition of the 
predispersed drug resin complexes in humectant and surfactants. After the 
addition of the remainder of the sweeteners and humectants, dyes and 
flavourings are added and the suspension is q.s ed with water. 
Example 2 Formulation 
Example 2 is prepared in a similar manner as Example 1. 
______________________________________ 
Ingredient (and Percentage Formula (%) 
Test Standard) Strength: 30 mg/5 mL 
______________________________________ 
Formula N.degree. 
2 
Dextromethorphan DRC-UNCOATED.sup.1 Mfr 
0.735 
Dextromethorphan DRC50-COATED.sup.2 Mfr 
0.277 
Tragacanth NF 0.40 
Xanthan Gum NF 0.10 
Sucralose 0.02 
D&C Red N.degree. 33 Mfr. 
0.001 
Xylitol NF 15.00 
Polyethylene Glycol 600 NF 
8.00 
Methylparaben NF 0.08 
Propylparaben NF 0.05 
/-Menthol USP 0.04 
Polysorbate 80 NF 0.05 
Sorbitan Monooleate NF 
0.05 
Artificial Raspberry Flavour Mfr 
0.30 
Purified Water USP qs 
TOTAL 100.00% 
`Dextromethorphan DRC-UNCOATED 
0.735% 
Consists of: 
Dextromethorphan 0.352% 
(From Dextromethorphan Hydrobromide USP) 
Polystyrene Sulfonate 0.383% 
(From Sodium Polystyrene Sulfonate USP) 
Equivalent to Dextromethorphan Hydrobromide 
24 mg/5 mL 
USP 
.sup.2 Dextromethorphan DRC50-COATED 
0.277% 
Consists of: 
Dextromethorphan 
(From Dextromethorphan Hydrobromide USP) 
0.088% 
Polystyrene Sulfonate 
(From Sodium Polystyrene Sulfonate USP) 
0.096% 
SURELEASE (fry basis) 0.092% 
Colloidal silicon dioxide USP 
0.001% 
Equivalent to Dextromethorphan Hydrobromide 
6 mg/5 mL 
USP 
.sup.1+2 Label Claim (Equivalent to Dextromethorphan 
30 mg/5 mL 
Hydrobromide USP 
______________________________________ 
Example 3 Formulation 
Example 3 is prepared in a similar manner as Example 1. 
______________________________________ 
Ingredient (and Percentage Formula (%) 
Test Standard) Strength: 30 mg/5 mL 
______________________________________ 
Formula N.degree. 
3 
Dextromethorphan DRC-UNCOATED.sup.1 Mfr 
0.436 
Dextromethorphan DRC50-COATED.sup.2 Mfr 
0.797 
Tragacanth NF 0.40 
Xanthan Gum NF 0.10 
Sucralose 0.02 
D&C Red N.degree. 33 Mfr. 
0.001 
Xylitol NF 15.00 
Polyethylene Glycol 600 NF 
8.00 
Methylparaben NF 0.08 
Propylparaben NF 0.05 
/-Menthol USP 0.04 
Polysorbate 80 NF 0.05 
Sorbitan Monooleate NF 
0.05 
Artificial Raspberry Flavour Mfr 
0.30 
Purified Water USP qs 
TOTAL 100.00% 
.sup.1 Dextromethorphan DRC-UNCOATED 
0.436% 
Consists of: 
Dextromethorphan 0.198% 
Polystyrene Sulfonate 0.237% 
Equivalent to Dextromethorphan Hydrobromide USP 
13.5 mg/5 mL 
.sup.2 Dextromethorphan DRC50-COATED 
0.797% 
Consists of: 
Dextromethorphan 0.242% 
Polystyrene Sulfonate 0.290% 
SURELEASE (dry basis) 0.264% 
Colloidal silicon dioxide USP 
.about.0.001% 
Equivalent to Dextromethorphan Hydrobromide USP 
16.5 mg/5 mL 
.sup.1+2 Label Claim (Equivalent to Dextromethorphan 
30 mg/5 mL 
Hydrobromide USP 
______________________________________ 
Example 4 
In-vitro dissolution studies were carried out comparing the composition 
prepared according to Example 1 and 2 and DELSYM. The in-vitro dissolution 
test was carried out using USP apparatus II, 6 vessels with a stirring 
speed of 100 rpm. The dissolution medium was 750 g of 0.1 N HCl for the 
first hour and 250 g of sodium phosphate buffer was added after 1 hour to 
each vessel to give a sodium ion concentration of about 0.4 N and a pH of 
about 6.6. The dissolution media were maintained at 37.degree. C. Samples 
were taken from each dissolution vessel at 0.5, 1, 2,3 4, 5, 7 and 12 
hours with an automatic sampling device and analyzed by HPLC method. 
The dissolution profiles of Example 1 and 2 and DELSYM are indicated by the 
results shown in Table 1 and graphically represented by FIG. 1. 
TABLE 1 
______________________________________ 
Percent of Dextromethorphan HBr H2O Release in Hours 
Product 
0 0.5 1 2 3 4 5 7 12 
______________________________________ 
Example 1 
0 0.34 0.42 0.65 0.73 0.80 0.84 0.90 0.93 
Example 2 
0 0.52 0.62 0.84 0.84 0.87 0.88 0.90 0.91 
DELSYM 0 0.42 0.48 0.71 0.73 0.75 0.77 0.79 0.82 
______________________________________