Advanced Design Lozenges
Chapter 7.C. - Advanced Design Lozenges

Development of an advanced design zinc acetate lozenge was suggested because it may be preferable to have a smaller lozenge than the standard 7/8 inch standard design or a sweeter lozenge without saccharin or a less astringent, less potent lozenge. Table 13 shows that 3/4-inch 3.5-gram lozenges produce a higher

Medicinal additives may be directly incorporated within compositions if chemically nonreactive with zinc acetate in solution between salivary and physiologic pH 7.4 and if stable in solid state reactions in thermal stresses and multi-year lozenge storage tests. Micro-encapsulation within insoluble and noncrushable membranes will be required for certain medicinal additives. A time-release capability will be necessary for ingredients interfering with release of Zn2+ ions or adversely affecting taste. Time release may be activated by low stomach pH. Inclusion of medicinal additives within beta-cyclodextrins within insoluble microcapsules might be justified. ion concentration than 5.0 gram lozenges but results in lower ZIA values. The higher mMol concentration of the 3.5-gram lozenges is closer to the original 1984 Eby and co-workers' 7.4 Zn2+ ion mMol concentration, but the heavier 5.0-gram lozenges are considerably closer in ZIA value to the original 1984 Eby and co-worker lozenges and are less astringent due to lower Zn2+ ion concentration.

Mendell's Sweetrex(r) (70 percent Emdex(r) and 30 percent crystalline fructose) is used as the tablet base for all advanced design zinc acetate lozenges. Use of Sweetrex(r) results in a higher lozenge ZIA value, less variation in s.e.m., and sweeter lozenges than Emdex(r)-based lozenges. Sweetrex(r)-based lozenges do not need added saccharin or flavor oils to have an acceptable taste, unless the weight ratio of zinc to Sweetrex is above 1:200.

Table 13. Advanced design 15 mg zinc (zinc acetate) lozenge characteristics (3.5 and 5.0 gram) 

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Research      Flavor	ZIA 	Zn2+ ion  Dissolution Dose Saliva
Lozenge	      rating		mMolvT	  Time (min)
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3/4 inch diameter - 3.5 gram lozenges

Tester 1 	10	129	  7.7	  37.0	      9	    31.0
Tester 1	10	102	  7.8	  29.0	      9	    30.7
Tester 2	10	 51	  6.3	  18.0	      9	    37.7
Tester 3	10	 68	  5.2	  29.0	      9	    45.7
Tester 4	10	 59	  6.8	  19.0	      9	    34.9
Average + sem	10	 82+14.   6.8	  26.4	      9	    36.0

7/8 inch diameter - 5 gram lozenges

Tester 1 	10	109	  6.0	  40.0	      9	    39.9
Tester 1	10	116	  6.2	  42.0	      9	    39.2
Tester 2	10	 73	  4.5	  36.0	      9	    52.9
Tester 3	10	 95	  5.0	  42.0	      9	    47.9
Tester 4	10	 75	  5.6	  30.0	      9	    43.2
Average + sem	10	 94+8.7	  5.5	  38.0	      9	    44.6
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Fructose is an isomer of dextrose and is believed upon evidence of equivalent efficacy to have the same stability constant for zinc as dextrose.

Both 3/4- and 7/8-inch lozenges contained 50.3 mg zinc acetate dihydrate (15 mg zinc), 50 mg magnesium stearate, with no added sweeteners or flavors. A 9-ton compressive force was applied. Lozenge taste is pleasantly sweet, and the lozenges are flavor-stable for years. Advanced design lozenges are not particularly hygroscopic, and lozenges left on counter-tops for months in air-conditioned rooms remain dry.

The disadvantages of Sweetrex(r) include (a) it is hygroscopic until tableted, (b) it is more expensive than Emdex(r) (unless Emdex(r) and fructose are mixed on site), and (c) it runs slower than Emdex(r) in most tablet presses.

Effect of Compressive Force on Lozenge Dissolution Rate

Advanced design 15-mg zinc 5-gram lozenges (Sweetrex(r) tablet base with 50 mg magnesium stearate and no other ingredients) were tested for effects of compressive forces upon aqueous dissolution time. Results of flowing water bath tests at 37 degrees Celsius were compared with oral dissolution rates for identical lozenges. The results are shown in Figure 21. Above two tons of applied force, lozenge dissolution time in the water bath tester hardly increased. Lozenges compressed with less than 4 tons of applied force did not have smooth dissolution characteristics. Those lozenges had a pitted surface appearance, and considerable variation in dissolution rate. Lozenges compressed from 6 to 10 tons have smooth lozenge dissolution surfaces, and dissolve in a uniform manner.

Effect of compressive force upon dissolution times Figure 21. Effect of compressive force upon dissolution times.

In oral dissolution tests of lozenges, effects of salivary enzymes and resistance to crumbling by partially dissolved lozenges are major determining factors in lozenge dissolution rates. Using 1 ton of compression, lozenge surface was rough, and intact grains of tablet base floated into the saliva, resulting in a gritty oral sensation. Lozenges tended to crumble from the beginning. Using 2 tons of compression, lozenges retained their rough surface texture but were not gritty and started to crumble 4 to 5 minutes before totally dissolving. As compressive forces were increased from 1 to 6 tons, the dissolution times rapidly increased. With 6 tons of compression, lozenges had a smooth surface and uniformly dissolved to thin wafers. The nearly dissolved thin wafers tended to break about 1 minute before lozenges were totally dissolved. At 10 tons of compression, lozenges dissolved even more uniformly, had a smoother surface texture, and did not crumble or crack at all.

Figure 21 shows the importance of conducting oral dissolution tests to confirm and extend dissolution time data gathered from water bath testing. If reliance upon water bath tests were solely used, serious errors in the determination of oral dissolution rate and ZIA values would occur. These results appear representative of all advanced design lozenges, regardless of zinc content.

Effect of Compressive Force on ZIA

Compressive forces are also an important determinant of lozenge ZIA values. Figure 22 shows the effect of compressive force upon ZIA values of advanced design 15-mg zinc 5-gram lozenges. A three-fold difference in ZIA value results between one and six tons of compressive forces, at ZIA 29 and 92, respectively.

Effect of compressive force on ZIA valuesFigure 22. Effect of Compressive Force on ZIA values.

No difference in ZIA value results with compressive forces between 6 and 10 tons. Lack of difference in ZIA values throughout the 6- to 10-ton range suggests compressive force variations within the 6- to 10-ton range in commercial operations will have essentially no effect upon lozenge utility or quality. These results appear representative of all advanced design lozenges, regardless of zinc content.

Determination of Recommended Dosage Strength

Determining the amount of zinc acetate in advanced design lozenges necessary to obtain the same ZIA and mMol Zn2+ ion concentration as was present in the original 1984 zinc gluconate lozenges is desirable. Experimental lozenges contained varying amounts of zinc acetate and Sweetrex(r) lubricated with 50 mg magnesium stearate. The total tablet weight was held at 5.00 grams. The compressive force was 9.0 tons.

Effect of zinc content on ZIA and zinc ion mMolT Figure 23. Effect of zinc content on ZIA and Zn2+ ion mMolT concentration.

From Table 10 of Chapter 5, the original 1984 lozenges are observed to have produced a ZIA value of 100 and a salivary Zn2+ ion concentration of 7.4 mMol, while the less successful MRC lozenges produced a ZIA value of 43.9 and a 5.0 mMol Zn2+ ion concentration.

From Figure 23 and Table 14, it is clearly shown that 18-mg zinc (zinc acetate) lozenges produce a ZIA value of 108.6 and a salivary Zn2+ ion mMolT concentration of 6.0. Lozenges containing 20 mg zinc produce a ZIA value of 138.4 and a Zn2+ ion concentration of 7.5. Consequently, both ZIA 100 and a 7.4 mMolT Zn2+ ion concentration do not occur together using the 5-gram Sweetrex(r) base.

Relationship of lozenge zinc content to saliva production Figure 24. Relationship of lozenge zinc content to saliva production.

ZIA values and mMolT concentration of Zn2+ ions increase at a faster rate than expected from increases of zinc acetate in lozenges (see Figure 23). Non-linearity suggests factors other than lozenge zinc content play a larger role in efficacy of zinc lozenges than previously realized, and consideration of non-linearity is required in future studies. Preliminary evaluation of 25 mg zinc lozenges shows them them to have a ZIA value of 280 and a salivary Zn2+ ion concentration of 14 mMolT.

Table 14. Average zinc content, ZIA, Zn2+ ion concentration, saliva production, and lozenge duration from zinc acetate lozenges.

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Zinc	     ZIA + 	   mMolT	    Saliva           Dissolution
(mg)	     s.e.m	   Zn2+ ion          (g)	     Time (min)
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 0	   0.0 +  0	    0.0	            46.68 	 	34.0
 5	  27.6    5	    1.7	            46.66	 	35.8
10	  54.3 + 12	    3.2	            50.12		38.0
15	  92.0 + 10	    5.4	            44.60		38.0
18	 108.6 + 22	    6.0	            47.80		40.2
20	 138.4 + 29	    7.5	            42.90		41.2
23	 185.2 + 27	    9.9	            37.28		41.4
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Table 14 and Figure 24 show saliva production falling by 20 to 25 percent as zinc content is increased, demonstrating the effect of Zn2+ ion as an oral salivary astringent and drying agent.

Evaluation of dissolution time data shown in Table 14 and Figure 25 indicates increases in zinc content increase lozenge dissolution times. Increases in dissolution times result from lower saliva generation and may also show the effect of minor decreases in sweetness from larger amounts of zinc acetate. If sweetness is artificially increased with saccharin or sweet flavorings, dissolution times are reduced.

Effect of lozenge zinc content on dissolution rate of lozenges Figure 25. Effect of lozenge zinc content on dissolution rate of lozenges.

Taken together, the effects of saliva reduction and increases in dissolution times explain non-linear increases in ZIA and Zn2+ ion concentration from linear increases of zinc acetate in lozenges.

The concept of ZIA values as the determinant of efficacy appears reasonable, but the ZIA concept remains to be proved. Therefore, the recommended formulation is in the range from 15 to 23 mg zinc (50.37 to 77.2 mg zinc acetate dihydrate USP) in a 5-gram Sweetrex(r)-based lozenge, lubricated with 50 mg magnesium stearate, compressed at between 6 and 10 tons with precompression. Theoretically, lozenges will have a ZIA of 92 and a 5.4 mMolT Zn2+ ion concentration, and ZIA of 185 and 9.9 mMolT Zn2+ ion concentration, respectively.

Effect of Force Applied on Lozenge Thickness

Compressive force has an obvious effect upon lozenge thickness. ZIA has been shown to be related to the compressive forces applied. Therefore compressive forces and ZIA are related when measurements are taken using the same equipment. The effect of compressive force in tons of applied force compared to lozenge thickness is shown in Figure 26 using the author's static press. Lozenges were standard convex, 7/8-inch diameter, 5-gram, advanced design zinc acetate lozenges. Uncompressed column height was 0.685 inches.

Effect of compressive force upon lozenge thickness Figure 26. Effect of compressive force upon lozenge thickness.

The thickness data in Figure 26 are not directly applicable to the determination of forces used, or to the determination of ZIA on equipment other than the author's equipment. However, the first differential of lozenge thickness is applicable to determining the effect of added pressure with any equipment. To maximize ZIA, applied forces must be over 6 tons (from Figure 22). Decreasing differences in thickness from 1-ton incremental forces applied, as shown in Figure 26, suggest comparison to lozenges made using 10 tons of applied force is better with lozenges made at pressures higher than 6 tons. Perhaps lozenges made using 8 tons of applied force produce -- for practical purposes -- identical ZIA values to lozenges made at 10 tons of applied force.

ZIA values and mMolT concentration of Zn2+ ions increase at a faster rate than expected from increases of zinc acetate in lozenges (see Figure 23). Non-linearity suggests factors other than lozenge zinc content play a larger role in efficacy. From the appearance of the low slope of the curve at 8 tons of applied force, one may reasonable conclude 10 tons is excessive pressure.

7.D. - Sources of Lozenge Components

All components of zinc acetate lozenges are standard pharmaceutical items with well-established records in the pharmaceutical industry. However, no record of use of zinc acetate in pharmaceuticals other than in dental preparations has been found. Additional information about zinc acetate USP is found in Chapter 8, Zinc Biochemistry. Sources for zinc acetate lozenge components for standard and advanced design lozenges are shown in Table 15.

Cost of ingredients for standard design 23 mg zinc, 5-gram ZIA 148 lozenges is one cent per lozenge. Tablet base (Emdex(r)) contributes 71 percent or more of the total cost of the standard lozenge. Of the total ingredient costs, zinc acetate contributes about 6 percent, and peppermint flavor contributes up to 21 percent.

Cost of ingredients for advanced design 20-mg zinc 5-gram ZIA 138 lozenges is about 0.7 cents per lozenge, when Emdex(r) is mixed with Krystar(r) 300 crystalline fructose from A. E. Staley on site.

Table 15. Source and cost of zinc acetate lozenge ingredients.

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Ingredient			Source				  $/kg
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Zinc acetate dihydrate USP	Heico Chemical, Delaware Gap, PA  8.36

Emdex(r)			Edward Mendell, Carmel, NY	  1.53*

Sweetrex(r)  			Edward Mendell, Carmel, NY	  2.48#

Fructose - Krystar(r) 300 	A. E. Staley, Decatur, IL 	  0.77*

Peppermint oil (Bell 113.042)   Bell Flavors, Northbrook, IL	108.46

Silica gel (Syloid(r) 244FP)    Davidson Chem., Baltimore, MD  	  5.13

Sodium saccharin Syncal(r)SDS   PMC Specialties, Cincinnati, OH	  2.20

Magnesium stearate (NF-food)    Mallinckrodt, St. Louis, MO       3.63

	* in truckloads
	# currently in 100 kilogram drums only

No considered price estimate for finished, packaged, ready-to-ship lozenges is presented as too many variables contribute. Rough estimates of total factory costs are in the $0.25 to $1.50 range for a package of 24 lozenges. The price of lozenge ingredients is very low, resulting in a feasible common cold treatment having wide appeal to price-conscious consumers.

7.E. - Other Comments

The purpose of this chapter has been to present zinc acetate lozenges as the successor to zinc gluconate lozenges in the treatment and cure for common colds. Additionally, different types of analyses required to obtain reliable results using off-the-shelf pharmaceutical ingredients have been demonstrated. The present research does not mean other zinc compounds, formulations, or lozenge tablet bases have been or should be excluded from consideration.

Other Formulations

Although not all possible formulations were tested, many other zinc compounds and tablet bases were evaluated before development of the preliminary lozenges presented in the first part of this chapter. Favored alternatives to the 30 percent fructose and 70 percent Emdex(r) base formulation is increased fructose in the base. Ratios as high as 50:50 have been used, with improvement in lozenges flavor.

Many of the other formulations were rejected for further study or presentation as they produced objectionable tastes and aftertastes and/or soft, quickly dissolving, or capped tablets. Some showed a tendency towards minor internal capping at the high static pressures applied (6 to 10 tons). Although they usually showed no outward signs of capping and appeared highly usable, capping became evident in these rejects only during break-strength and dissolution testing. Lozenges having a directly compressible lactose base were quite elegant but were insufficiently sweet without addition of much saccharin.

Addition of non-soluble waxes has been suggested to help maintain a slow and perhaps more uniform lozenge dissolution rate than can be obtained by reliance upon compression alone. However, such testing has not been conducted, because a primary focus of the research is to keep the total number of ingredients in the lozenges to a minimum, and because maintaining natural sweetness with minimum bulk and oral residue is a priority. This is not to say addition of wax is ill-advised, but rather that wax has not been added at this time. Wax and crystalline fructose tablet bases may have highly desirable features including the potential for reduced size while retaining a high ZIA value.

Advanced design zinc acetate lozenges are the simplest zinc compositions studied and are also the most pleasant tasting without addition of extra sweeteners or flavors. If peppermint oil is added, the amount should be kept low, perhaps at 5 mg per lozenge. Saccharin and other additives should never be added to advanced design lozenges.

Hard-boiled sweets containing pharmaceutically active amounts of zinc acetate usually have an unpleasant metallic taste, can be unpleasantly astringent, and often "set teeth on edge", while otherwise identical compacts (made at room temperature) usually have excellent taste parameters previously described.

Eliminating Astringency from Zinc Lozenges

Perhaps the best indicator of the presence of Zn2+ ions, without complex technical analysis, are the presence of astringency and precipitated salivary proteins in expectorated saliva containing residue from a zinc lozenge. However, astringency at salivary pH 5 to 6 does not guarantee equivalent availability of Zn2+ ions at tissue pH 7.4, as was demonstrated with the zinc gluconate-glycine lozenges (see Chapter 4.C.3.).

ZIA values and mMolT concentration of Zn2+ ions increase at a faster rate than expected from increases of zinc acetate in lozenges (see Figure 23). Non-linearity suggests factors other than lozenge zinc content play a larger role in efficacyLarge amounts of Zn2+ ions (over 50 mg zinc from zinc acetate) in 5-gram lozenges are very astringent and have extremely high ZIA values. Such dosage strength is usually unnecessary, and can result in uncomfortable astringency, oral irritation, and palpable protein precipitates in saliva. Zinc acetate 5-gram sugar lozenges (5 to 25 mg zinc) produce none-to-moderate astringency; however, this astringency is not considered unpleasant or irritating by most patients. Indeed, to most patients astringency is welcome, prompting such comments as, "They really clean my mouth."

ZIA values and mMolT concentration of Zn2+ ions increase at a faster rate than expected from increases of zinc acetate in lozenges (see Figure 23). Non-linearity suggests factors other than lozenge zinc content play a larger role in efficacyAddition of sweet flavor oils, such as peppermint, can minimize the effects of astringency by increasing saliva production, albeit with possible resultant reduction in lozenge ZIA values.

ZIA values and mMolT concentration of Zn2+ ions increase at a faster rate than expected from increases of zinc acetate in lozenges (see Figure 23). Non-linearity suggests factors other than lozenge zinc content play a larger role in efficacyZinc lozenges with negatively charged zinc species from excess acid can result in acid-related pseudo-astringency, although not as much astringency as results from the presence of therapeutic Zn2+ ion dosages. Pseudo-astringency must not be confused with astringency from positively charged zinc, as acidified negatively charged zinc compositions appear to increase duration of common colds.

ZIA values and mMolT concentration of Zn2+ ions increase at a faster rate than expected from increases of zinc acetate in lozenges (see Figure 23). Non-linearity suggests factors other than lozenge zinc content play a larger role in efficacyIf completely eliminating astringency from zinc lozenges is more important than curing the common cold, then zinc lozenges will not become a useful treatment for common colds. Astringency is not viewed as a legitimate reason to reject zinc acetate lozenges as a cure for the common cold. Rather, future clinical studies should focus on finding the minimum effective ZIA and mMolT Zn2+ ion concentration to produce a 7-day average reduction in the duration of colds without objectionable astringency.

ZIA values and mMolT concentration of Zn2+ ions increase at a faster rate than expected from increases of zinc acetate in lozenges (see Figure 23). Non-linearity suggests factors other than lozenge zinc content play a larger role in efficacyBecause of the linearity in the relation between ZIA and efficacy demonstrated in Chapter 5, the present author suggests 23-mg zinc (77.2 mg zinc acetate dihydrate USP) lozenges with a 185 ZIA and 9.9 mMolT Zn2+ ion concentration will shorten common colds by an average of seven days or more. This dosage seems too astringent and too strong in well people doing flavor tests, but is not perceived as too astringent or too strong in people suffering from common colds.

Alternatively, ZIA 100 zinc acetate lozenges containing 16 mg zinc are essentially always perceived as having a pleasant taste, and may also be expected to shorten colds by 7 days, although initial response may not be quite as strong.

NOTE: Since this handbook was published in 1994, major improvements in the formula for zinc acetate lozenges having a ZIA value of 100 have been discovered and some are in commercial use.

Chapter 7. - References


Chapter 8 - Zinc Biochemistry