Fructose is the sweetest of the natural sugars and is 1.73 times sweeter than sucrose. Fructose is a component of sucrose, a disaccharide, and is an isomer of dextrose, the other component of sucrose. Dextrose is 0.74 times as sweet as sucrose. The stability constant of dextrose for zinc is log K1 = 0.01.(1) Similar exceedingly low values are found for other carbohydrates and zinc, and similar low stability is also expected for sucrose and fructose. Most nutrients seem to decrease absorption of zinc, but sucrose may increase absorption according to animal studies.(4)

Surprisingly and unexpectedly, fructose does not visibly react, change color, or form bitter compounds with zinc acetate at higher ambient temperatures, as this monosaccharide is a polyhydroxy ketone and is usually considered highly reactive. Fructose is hygroscopic, and relative humidity should be less than 55 percent during production to avoid moisture accumulation.

Use of pharmaceutical tablet bases and other pharmaceutical tableting materials suitable to make zinc acetate lozenges are well described in Pharmaceutical Dosages Forms, Volumes 1, 2 and 3.(5) Tablet formulation(6) is well covered as are chewable tablets.(7) Each has application to formulating zinc lozenges. The chapter on directly compressed tablets also has special significance, as properties of tableting ingredients are discussed in detail.(8)

Mendell's Sugartab(r) is a white, free-flowing storage-stable, inert tablet base of agglomerated sugar containing 90 to 93 percent agglomerated sucrose with the balance being invert sugar. Sugartab(r) has a sweetness value of 1, identical to sucrose. When blended with the active ingredient plus a suitable lubricant and compressed, Sugartab(r) produces moderately hard, nonfriable tablets. Sugartab(r) has good flow characteristics, good compressibility, flavor-masking, low hygroscopicity, chemical stability, noncloying sweetness, a wide range of compatibilities, smooth disintegration, and pleasant aftertaste. Sugartab(r) is a white granular powder having an average particle size of 296 microns.(9) Even though Sugartab(r) is sweeter than Emdex(r) and equivalent in sweetness to Sweetrex(r), zinc acetate lozenges made with Sugartab(r) have a sharp flavor and aftertaste.

Mendell's Sweetrex(r) is a directly compressible chewable tablet base with a sweetness value of 1, equivalent in sweetness to Sugartab(r) and sucrose. Sweetrex(r) does not contain sucrose. Sweetrex(r) is a blend of 70 percent Emdex(r) and 30 percent Krystar(r) 300 crystalline fructose (A. E. Staley, Decatur, IL). Sweetrex(r) has a demonstrated binding capacity of up to 50 percent active ingredients with no significant loss of compressibility. Sweetrex is claimed by the manufacturer to be ideally suited for the direct compression of chewable tablets since it possesses qualities of cool mouth-feel and is naturally sweet without the incorporation of artificial sweetening agents. Sweetrex(r) is a white granular powder, having an average particle size of 210 microns.(9) Because Sweetrex(r) contains fructose, it is hygroscopic and must be stored at less than 55 percent humidity.

Peppermint oil (flavor #113.042, Bell Flavors, Northbrook, Illinois) is recommended as it is sweet, highly acceptable to essentially all patients, and has a menthol effect in the nose without menthol bitterness. Peppermint oil is considered a food product and not a drug. Bell peppermint oil also has proven multi-year stability in directly compressed zinc acetate lozenges.

Peppermint oil can be directly absorbed into Emdex(r) with high pressure micro fine mists of peppermint oil, and thorough mixing. Peppermint oil can also be dried with silica gel (Siloid(r) 244FP - Davison Chemical, Baltimore, Maryland). Peppermint oil will become dry at a 1:1 ratio with silica gel, but flavor losses occur. Perhaps losses result from retention of peppermint oil by silica gel. For example, lozenges containing 5 mg of peppermint oil sprayed directly into Emdex(r) have a flavor equivalent to lozenges containing 17 mg of peppermint oil platted onto 17 mg of silica gel.

According to the Code of Federal Regulations, use of amorphous silica gel cannot exceed 2 percent of the finished weight and currently can only be used to encapsulate lemon, distilled lime, orange, peppermint, and spearmint oils.(10,11) Other drying agents are not used because of their bulk and potential for chelating Zn²⁺ ion either in solid state reactions or solutions.

Most flavorings can be used in zinc acetate lozenges given a suitable carrier. Eucalyptol, wintergreen, clove, cinnamon, spearmint, cherry, lemon, orange, lime, menthol and various combinations are all possible flavorings. However, some flavor oils are not stable in long-term storage in zinc acetate lozenges and may require costly protection from contact with zinc acetate, evaporation, degradation, and oxidization generally.

In zinc acetate lozenges, flavors might be stabilized by spray drying with National Starch's N-Lok(r) or other similar modified starches, or flavors might be included within cyclodextrins and/or coated with PEG 8000. Spray-dried flavors must not include acacia (gum arabic) and other zinc-chelating vegetable gums. All spray dry agents, including N-Lok(r), must be tested for Zn²⁺ ion-chelating ability and stability before use or clinical testing, as none have been tested.

Plated onto silica gel or sprayed into Emdex(r), menthol and eucalyptol appear stable for at least three years in directly compressed zinc acetate lozenges in sealed bottles.

Zinc acetate compositions for treating common colds must exclude Zn²⁺ ion-depleting ingredients and other incompatibles. Acacia (gum arabic), alkalis and their carbonates, oxalates, phosphates, sulfides, caustic lime and vegetable decoctions are considered incompatible with zinc acetate.(12)

Other vegetable gums, anethole, mannitol, sorbitol, super sweeteners, ascorbic acid (vitamin C) citric acid, tartaric acid, other food acids, and lake colors may cause compositions to become flavor unstable, cause a loss of efficacy against common colds, or both and must not be added to zinc acetate lozenges.

Overemphasizing the necessity to avoid inadvertent chelation of Zn²⁺ ions by addition of chelating ingredients is not possible.

Extensive multi-year flavor-testing research led to the development of numerous basic formulations and variants. Several preliminary formulations are discussed next as being representative of the general theme of incorporating zinc acetate in sucrose, fructose, and dextrose lozenges. Even though these lozenge formulations appear similar, their performances are significantly different. Differences in ZIA values are dependent upon tablet bases, zinc content, sweetness, compressive forces used in lozenge manufacture and physiologic characteristics of the user. Consequently, it is imperative that changes not be made to zinc acetate lozenge design once comprehensive tests with a given formulation -- including compressive forces -- are completed: clinical results are dependent upon too many factors to change any variable, even by a small amount.

To make 5-gram Sweetrex(r)-based lozenges containing 23 mg zinc, mix 77.2 mg zinc acetate dihydrate USP, 0.5 to 5.0 mg peppermint oil (sprayed onto Sweetrex(r)), 50 mg magnesium stearate, and sufficient Sweetrex(r) to make a 5-gram lozenge and compress tablets.

To make 5-gram Sugartab(r) and fructose-based lozenges containing 23 mg zinc, mix 77.2 mg zinc acetate dihydrate USP, 0.5 to 5.0 mg peppermint oil (sprayed onto Sugartab(r)), 50 mg magnesium stearate, about 2450 mg Sugartab(r), and sufficient crystalline fructose to make a 5-gram lozenge and compress tablets.

To make a 5-gram Emdex(r)-based directly compressible tablet containing 23 mg zinc, mix 77.2 mg zinc acetate dihydrate USP, 0.5 to 5.0 mg peppermint oil (sprayed onto Emdex(r)), 1 to 10 mg sodium saccharin, 50 mg magnesium stearate, and sufficient Emdex(r) to make a 5-gram lozenge and compress tablets.

All research tablet press data, such as compressive forces applied and resultant information found in Handbook for Curing the Common Cold were developed using an instrumented, static hand press capable of 10 tons applied force. Rotary presses have been used to manufacture sample, and commercial lozenges using the formulations given.

For commercial purposes, instrumented tableting equipment such as the Korsch Pharmapress 230, 250, and 350 presses (Korsch Tableting, Somerville, New Jersey) can show the exact pressures and precompression needed to maintain a stable and uniform ZIA. Other presses, including the Manesty D3B and the Stokes RD-4, having adequate capacity can be used.

In previous chapters, salivary Zn²⁺ ion concentration and ZIA were calculated excluding the weight of the non-soluble or soluble tablet. As the tablet weights of the two most efficacious studies were low (0.66 and 1 gram), significance of the omission was negligible. Even with omission, aqueous ion concentration remained inaccurately represented because water in saliva contains other salivary constituents.

As the lozenge weight is increased in this chapter to between 3.5 and 5 grams, consideration of the lozenge becomes more important. Better estimates of the concentration and dispersion of Zn²⁺ ion in the mixture of saliva and the dissolved lozenge constituents are suggested to be obtained by including the lozenge in calculations of Zn²⁺ ion total molality (mMolT) and ZIA.

Flavor tests show different tablet bases strongly affect Zn²⁺ ion concentration, ZIA values, and flavor of lozenges. With no changes other than tablet base, major variations in ZIA values and lesser variations in Zn²⁺ ion concentration are readily observed. The formulation with the highest ZIA value was also the formulation perceived by the taste testers to have the best taste and aftertaste, although it had an intermediate Zn²⁺ ion concentration. Too much lozenge sweetness as well as insufficient sweetness can have detrimental effects on ZIA values by stimulating saliva production.

For purposes of the following preliminary flavor research, all tested lozenges contained 77.2 mg zinc acetate (23 mg zinc), 17 mg peppermint oil plated onto an equal amount of silica gel, and 50 mg magnesium stearate. All ZIA calculations used an available Zn²⁺ ion fraction of 100 percent for zinc acetate, 9 doses per day and 23 mg zinc per lozenge.

Break strength of the Sugartab(r) and fructose, Sweetrex(r), and Emdex(r) lozenges was 6, 12 and 22 kilograms, respectively, at 9 to 10 tons applied force.

Sodium saccharin may be added to Emdex(r)-based lozenges to increase sweetness, but addition requires recalculation of ZIA values.

Flavor testing is a highly subjective process not amenable to technical evaluation except by use of an expert taste-panel. The same taste-testers tasting previous lozenges described in Chapter 4 also tasted samples of the zinc acetate lozenges described in this chapter. Comparison between compositions on an individual basis is possible. Tester #1, who repeated tests, showed reasonable agreement between values with each composition. Tester #2 had considerably more saliva generation with each composition than the other testers and consistently produced the lowest ZIA value. Every effort was made to be as consistent as possible in taste evaluation.

On a scale of 0 to 10 (with 0 being dreadfully bitter, 5 being acceptable but not necessarily pleasant, and 10 being as pleasant as candy or no taste sensation other than astringency) the lozenges are flavor rated as shown in Table 11. The Sweetrex(r) (dextrose and fructose) lozenges were perceived as having the best taste. Without added saccharin, the Emdex(r) lozenges were perceived as being bland in taste and not as pleasant-tasting as the other two preliminary samples. As lozenge sweetness was borderline using Emdex(r) and no saccharin, more peppermint flavor was needed. Sugartab(r)/fructose lozenges were perceived as being the sweetest and the sharpest tasting of the preliminary lozenges.

Sucrose within Sugartab(r) may cause the sharp flavor perceived as a mild burning sensation in the throat or as a slight throat irritation. Because of the oral burning sensation perceived by the taste testers, neither Sugartab(r) nor sucrose were evaluated past preliminary tests. Sharpness in flavor and oral irritation did not seem to appear in zinc acetate lozenges without sucrose or Sugartab(r). None of the preliminary lozenge samples tasted bitter.

Sugartab(r)/fructose lozenges tended to produce less saliva and dissolve considerably faster than lozenges having a base of Sweetrex(r) or Emdex(r). The Emdex(r)-based lozenges required the most time to dissolve and consistently produced the most saliva. Lozenges made with Sweetrex(r) had intermediate dissolution times and saliva generation characteristics, and the highest ZIA values. Dissolution times for Sweetrex(r) and Emdex(r) lozenges were reasonably comparable.

Zinc acetate lozenges having a Sweetrex(r) base had the highest ZIA value at 171+25, and were also perceived as tasting best. Zn²⁺ ion concentration for the Sweetrex(r)-based lozenge was 107 times the amount needed for in vitro antirhinoviral activity. The Sugartab(r)-fructose based zinc acetate lozenges had the highest Zn²⁺ ion concentration (135 times antirhinoviral) but the lowest ZIA value at 111+14.6 primarily because lozenges quickly dissolved. The Emdex(r) based lozenges had the most uniform ZIA values (148+12.5) but lowest Zn²⁺ ion molar concentration (83 times antirhinoviral).

Average ZIA value variation of 60 points between the tablet bases is important and demonstrates the necessity for careful ZIA testing in human beings.

Variables affecting ZIA factors of zinc acetate lozenges (Zn²⁺ ion concentration and time applied) and product acceptability include the dosage strength, lozenge diameter, lozenge shape, lozenge weight, compression pressure, mass-to-surface area ratio, and porosity. Lower dosage results in taste improvement and little if any decrease in saliva production, while larger dosages result in increased efficacy and reduced saliva generation. Equivalent dosages in larger and smaller lozenges of the same tablet base will not have equivalent ZIA values. Identical formulas in larger and smaller lozenges will not have proportionately identical ZIA values. Smaller diameter lozenges allow higher applied pressure per square inch, increased hardness, and dissolution times, perhaps resulting in improved patient acceptance. Larger diameter reduces applied pressure, reduces hardness, and reduces dissolution times. Lozenges over 7/8 inch diameter have decreased patient acceptance. Spherical shape (lowest surface area) minimizes dissolution rate; thin wafers (higher surface area) increase dissolution rates. Higher weight allows longer dissolution time and lower Zn²⁺ ion concentration. Less weight economizes on raw material and finished product costs. High pressure minimizes dissolution rate, while low pressure increases dissolution rate. Less porous lozenges decrease surface area and decrease dissolution time, while more porous lozenges increase surface area and lower dissolution time.

The many variables affecting ZIA demonstrate that unique compositions must be tested in human beings to determine their average ZIA values. Generally, 5/8 to 3/4 inch diameter, standard concave tooling produces the most favorable results, and the greatest patient acceptance.