McNeil 11.5-mg Zinc Gluconate Lozenge Study

Chapter 4.A.3. McNeil 11.5-mg Zinc Gluconate Lozenge Study

In a study conducted by McNeil Consumer Products Company, low-dosage zinc gluconate lozenges reduced the duration of natural colds with effects occurring during the last 2 days of the 7-day double-blind trial.(12) Lozenges contained 11.5 mg zinc as zinc gluconate or sucrose octa-acetate, a bitter substance, in the placebo. The compressed lozenges weighed 1.56 grams and had a 15-minute dissolution time. Zinc gluconate lozenges produced 17.5 grams zinc-laden saliva and were slightly astringent. Zinc gluconate lozenges produced a salivary pH of 6.4. Salivary Zn²⁺ ion concentration was 3.3 mMol or less at pH 7.4.

Confounding the analysis of ZIA, was the inclusion of many ingredients including sucrose, fructose, sorbitol, mannitol, mineral and acid stearates, Methocel(R), pineapple powder and three spray-dried flavors in both the zinc and placebo lozenges. Bitterness increases of one to three orders of magnitude over plain zinc gluconate that occurred in many zinc gluconate lozenges after aging is now known to be caused by solid-state reactions between zinc gluconate and all non-fructose carbohydrates. Extreme bitterness prevented nearly all patients from using the planned 20 lozenges per day; hence, the study could only report the effects of 10 or more lozenges per day, which was one-half the original planned dosage. Lozenges had a ZIA value of 25 and a 1.6 day average reduction in duration of zinc-treated colds. Reduction was determined from the half-lives (H) of the two groups by projecting the slopes of symptom duration curves and by dividing by ln 2 to arrive at average duration.

According to the authors and the study coordinators, no one at McNeil Consumer Products knew the contents of the lozenges, other than the zinc lozenges contained 11.5-mg zinc from zinc gluconate. McNeil representative Eileen C. Helzner identified the manufacturer of the lozenges as General Nutrition Products, Inc., in Greenville, South Carolina. Lozenges were an over-the-counter health food store product that had been discontinued because of lozenge bitterness upon aging. No pre-formulation testing for Zn²⁺ ion was conducted.

The McNeil study was conducted at three colleges and one family practice clinic January to May of 1986. All eligible patients had a clinical diagnosis of acute upper respiratory infection. Patients were given bottles of zinc or placebo lozenges to use to treat their colds at home. Zinc gluconate lozenges were half-strength at 11.5 mg zinc per lozenge. Patients were originally instructed to take an initial dose of 4 lozenges followed by 2 lozenges every two hours while awake in an effort to exactly replicate the original Eby protocol. Compliance was assessed through daily estimates by patients and by pill counts by investigators.

These patients rated their symptoms on a scale of 0 to 3 with zero meaning no symptoms and 3 meaning severe symptoms. Patients were excluded from analysis if they took an insufficient dose (fewer than 10 lozenges per day) or if they did not take the lozenges for an adequate duration. Of 174 eligible patients with a clinical diagnosis of acute upper respiratory infection, 88 were assigned to receive placebo and 86 were assigned to receive zinc gluconate. Thirty-five (39.7 percent) of the placebo group and 29 (33.7 percent) of the zinc-treated group were excluded from analysis for reasons of insufficient dose (fewer than 10 lozenges) or duration of therapy.

Results of Study

Early response to zinc gluconate did not differ from placebo, as reflected in proportion of patients who continued to have symptoms (Figure 7). Response to zinc became directionally superior to placebo on days 6 and 7. About 41.4 percent of zinc-treated patients and 54 percent of placebo-treated patients remained ill on the seventh day of the study. Difference (12.6 percent) seen on day seven of the study was almost statistically significant (P = 0.09; 95% confidence level).

Severity of illness was shown by the sum of individual symptom severity scores on any day as a proportion of baseline score. Patients using zinc gluconate lozenges had lower severity scores than those in the corresponding placebo group on day 4 (12 percent lower) through day 7 (40 percent lower) of treatment. The difference was statistically significant (P = 0.02).

Figure 7. Duration of common colds using bitter ZIA 25 zinc gluconate and placebo lozenges. (courtesy of Smith and Antimicrobial Agents & Chemotherapy).

Examination of the McNeil data from Figure 7 shows from day 5 through 7, zinc-treated patients recovered at a faster rate than placebo-treated colds. Data and slope of curves show the half-life of zinc-treated colds to have been 6.5 days and the half-life of placebo-treated colds to have been 7.7 days by projection of the curves. Average duration of zinc-treated colds was calculated to be 9.4 days, and average duration of placebo-treated colds was calculated to be 11.1 days. Estimated reduction of half-life by zinc treatment was 1.2 days and estimated reduction in average duration for zinc treatment, 1.6 days.

Adverse effects of medication included "dreadfully bitter" taste, nausea, altered taste, and dry mouth. Placebo was identical to the active lozenge except it contained sucrose octa-acetate, a bitter substance found to approximate the bitter taste of General Nutrition zinc gluconate lozenges used in the study. C. B. Goswick, a physician at Texas A & M University, and the study coordinator both reported that the study was a "bomb," or a "bust," as both zinc and placebo lozenges were so bitter that most patients refused to take the full dose, causing a high drop-out rate with little compliance in study dosage requirements. To save the study, physicians recommended patients use one lozenge, rather than two, every 2 wakeful hours.

Cause of Lozenge Bitterness

Lozenges became bitter as a result of reactions between zinc gluconate and dextrose, a reaction that occurs between zinc gluconate and all carbohydrate sweeteners except fructose. Additionally, stability constants of mannitol and sorbitol are four times higher than dextrose,(13) suggesting these sugar-alcohols not be used in lozenges intended to release Zn²⁺ ions. Absence of significant astringency and the presence of 12 identified chemicals plus four or more unidentified spray-dry chemicals resulted in a large number of possible reactions between zinc gluconate and other ingredients, all of which contributed to objectionable taste. These reactions rendered uncertain the availability of Zn²⁺ ions using this formulation. Little salivary protein precipitate was noted in expectorated saliva, suggesting near absence of Zn²⁺ ions.

Lozenge Formulation

The zinc gluconate lozenge formula tested by Smith and co-workers for McNeil Consumer Products Company was provided to the author by Bill Bannen of the Product Development Laboratory at General Nutrition Products, in Greenville, South Carolina, (Table 5). Lozenges were General Nutrition product code 1033, a 1985 over-the-counter heath food formulation, quickly manufactured and placed on the health food market without preformulation testing for Zn²⁺ ion bioavailability in response to the original article by Eby and co-workers.(14)

The zinc gluconate and placebo lozenges contained 11.5 mg zinc gluconate or placebo. Lozenges weighed 1.560 grams, were 5/8 inch in diameter, and were 0.235 inch thick. The lozenges had a hardness of 12 KG and were flat faced with beveled edges. Dissolution rate was highly dependent upon tablet hardness.

At the time of exact re-manufacture by this author in 1992, lozenges had a pleasant fruity taste, with moderate astringency and little taste of zinc gluconate. After aging for several months, the lozenges became increasingly bitter, to the point of extreme bitterness. Coupled with mucus-like texture of saliva from Methocel, the taste became really nasty and was much too bitter to use on an every 2-hour basis.

Zinc Ion Availability

Experimentation with exact copies of the McNeil lozenges, including tablet hardness and thickness, showed the zinc gluconate lozenges each produced 17.5 mg viscous zinc-laden saliva and required 15 minutes to dissolve, resulting in a ZIA value of 25.0 when used 10 times per day.

Table 5. 11.5-mg zinc lozenge formulation-McNeil Consumer Products Company

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Ingredient				               Quantity (mg)
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zinc gluconate			  			 89.636
compressible sucrose					627.368
hydroxypropyl methyl cellulose (Methocel K4M)	         78.00
     --- granulate above with water----
orange oil (2.5 fold) spray dried			  2.00
lime flavor spray dried					  3.70
natural cranberry flavor spray dried			 22.50	
pineapple powder spray dried				 22.50
fructose						118.554
sorbitol - granular spray dried				200.00
mannitol - granular					373.242
magnesium stearate			    		  7.50
stearic acid powder					 15.00

Manufacturers of some McNeil lozenge components:

Orange oil 2.5 fold  product 1606M - Borden
Lime natural flavor  product 3823 (aura) - W. J. Flavors
Natural Cranberry    product Trusil wonf # 5-9555 - Bush, Boake & Allen
Pineapple powder     product flavor # 4737 - Borden
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Had lozenges not been so objectionably bitter and had compliance been better, the McNeil zinc gluconate lozenges could have produced a ZIA of 50.0 using 20 doses per day, the recommended dosage. Low ZIA values resulted primarily from low zinc content and low usage rate. However, the bitter flavor stimulated saliva production, helping to lower lozenge ZIA value. Zn²⁺ ion salivary concentration was 3.3 mMol or less.

Chapter 4.A.4. - Danish 4.5 mg Zinc Gluconate Lozenge Study