WO2015126265A1

WO2015126265A1 - Oral liquid vitamin supplements containing zinc and stabilized vitamin c with reduced astringency

Info

Publication number: WO2015126265A1
Application number: PCT/PH2014/000007
Authority: WO
Inventors: Joyce Bedelia B. SANTOS; Kennie U. Dee
Original assignee: Santos Joyce Bedelia B; Dee Kennie U
Priority date: 2014-02-18
Filing date: 2014-02-18
Publication date: 2015-08-27
Also published as: PH12016501647B1; PH12016501647A1

Abstract

An aqueous oral liquid composition containing vitamin C, zinc, a stabilizing amount of carbomer to reduce the zinc-catalyzed degradation of vitamin C, and a combination of chloride ion and high intensity sweetener to reduce the astringency of the formulation.

Description

ORAL LIQUID VITAMIN SUPPLEMENTS CONTAINING ZINC AND STABILIZED VITAMIN C WITH REDUCED ASTRINGENCY

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to aqueous oral liquid vitamin supplements containing vitamin C, zinc, a stabilizing amount of carbomer to improve the stability of vitamin C, and a combination of chloride ion and high intensity sweetener to reduce the astringency of the formulation.

2. Background of the Invention

Zinc is one of the most important mineral nutrients. One third of the global population is believed to be zinc deficient. Zinc deficiency is associated with impaired immune function. Good clinical evidence exists that zinc supplementation in children under five years of age reduces the incidence of diarrhea and pneumonia, which are the top two killer diseases of children in this age group in developing countries. Vitamin C is one of the most important vitamins taken for immunity. It is desirable to combine Vitamin C and zinc in a single formulation. Vitamin C is widely available as an oral vitamin supplement, either as a single ingredient, or in combination with other vitamins and minerals. When combined with zinc, the vitamin C supplement is normally available in dry solid dosage formats, such as peroral tablet and chewable tablets, to prevent degradation of vitamin C.

Many children however have difficulty swallowing solid dosage formats, and in this case, the vitamin supplement can be given as a chewable tablet or in liquid form as syrup. Liquid syrup is a highly desirable format for young children.

It is known, however, that zinc catalyzes the degradation of vitamin C in aqueous solutions. Vitamin C and zinc can be given as separate liquid preparations, but this is highly inconvenient. Alternatively, vitamin C and zinc can be combined in a single liquid preparation but with a very short shelf life. Therefore, there is a need for an oral liquid preparation with improved vitamin C stability that combines vitamin C with zinc.

WO2006/130027A 1 teaches an aqueous oral vitamin supplement that combines vitamin C with zinc, wherein the stability of vitamin C is improved by the addition of a carbomer, and wherein the composition has a pH of less than about 5. The addition of carbomer, however, increases the astringency of zinc, resulting in a product of bad taste. Astringency is a sensory attribute that is described as drying-out, roughening, and puckery sensation felt in the mouth. We have surprisingly found that a combination of a chloride ion and a high intensity sweetener can significantly reduce this astringency without affecting the stabilizing effect of the carbomer.

BRIEF SUMMARY OF THE INVENTION

The instant invention provides an aqueous oral vitamin supplement that combines vitamin C, zinc,. and a stabilizing amount of carbomer, wherein the composition further contains a combination of chloride ion and high intensity sweetener to reduce the astringency of the formulation.

DETAILED DESCRIPTION OF THE INVENTION

The vitamin C is preferably ascorbic acid which is the cheapest form, but other pharmacologically acceptable salts of ascorbic acid, such as sodium ascorbate and potassium ascorbate, can also be used. The ascorbic acid, or its salt, is preferably present at a concentration from about 0.5% w/v to about 12% w/v, most preferably from about 1% w/v to about 5% w/v.

Zinc compounds useful in this invention can be in any of the forms commonly used for oral supplementation. The preferred zinc compounds are the soluble zinc salts: zinc sulfate, zinc gluconate, and zinc acetate. These three soluble zinc salts have been used extensively in clinical trials of zinc in humans. The zinc concentration (as metallic zinc) in the final product is preferably from about 0.01% w/v to about 1% w/v, most preferably from about 0.05% w/v to about 0.5% w/v.

Carbomers useful in this instant invention are those disclosed in WO2006/130027A1. Carbomers are polymers of acrylic acid crosslinked with allyl sucrose or allylpentaerythritol. The molecular weight of carbomer is between 740,000 and 5 million. Pharmaceutical grades of carbomers are available from B.F. Goodrich under the trade name Carbopol 934P, Carbopol 97 IP, and Carbopol 974P. Carbomers are acidic polymers that have to be neutralized to pH 5-10 to thicken. The concentration of the carbomer in the aqueous preparations of the instant invention is preferably from about 0.05% w/v to about 3% w/v, most preferably from about 0.1% w/v to about 1% w/v.

The pH of the aqueous preparations of this instant invention, similar to WO2006/130027A1, is less than about 5, most preferably less than about pH 4. A pH above 5 results in the neutralization of the carbomer which significantly increases the viscosity causing the product to assume a semi-solid to gel consistency which is difficult to pour. In addition, when the pH is above 5.5, zinc precipitates out of solution due to the formation of zinc hydroxide.

The chloride ions useful in this instant invention can be from any soluble chloride salts. The preferred chloride salts are monovalent chloride salts such as sodium chloride and potassium chloride.

The high intensity sweetener can be any high intensity sweetener which is at least fifty times sweeter than sugar, preferably at least one hundred times sweeter than sugar. The preferred high intensity sweetener is selected from sucralose, saccharin, aspartame, acesulfame, stevioside, or mixtures thereof.

The final product is preferably a readily flowable liquid with a viscosity less than about 2,500 cps at a shear rate of 6/sec, preferably less than about 2,000 cps, and most preferably less than about 1,000 cps. A readily flowable liquid is easier to pour, in contrast to semi-solid or gelled liquid preparations.

The liquid composition of the present invention may contain additional ingredients normally used in liquid pharmaceutical formulations, herein referred to as additives. Additives include well-known components, but are not limited to sweetening agents, flavors, colorants, antioxidants, chelating agents, surfactants, pH modifiers, acidifiers, preservatives, and mixtures thereof.

A cosolvent may optionally be used to dissolve or rapidly disperse additives. Ethanol and polyhydric alcohols such as glycerin, propylene glycol, low molecular weight polyethylene glycols, and mixtures thereof are generally employed as cosolvents.

The composition of the present invention may optionally contain viscosity-building agents from 0 to about 7 weight percent of total composition, preferably from about 0.05 to about 5 weight percent, and most preferably from about 0.1 to about 3 weight percent. The viscosity-building agents may be selected from but not limited to xanthan gum, carrageenan, tragacanth, guar gum, pectin, carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose, microcrystalline cellulose and carboxymethylcellulose sodium blends, and mixtures thereof. The viscosity-building agent provides both body and mouthfeel to the preparation. The viscosity-building agent must be selected carefully to ensure compatibility with vitamin C and other components of the formulations.

The invention will now be described with respect to the following specific examples.

Experiment 1

Table 1

* the higher the number, the darker the solution; + the higher the number, the more astringent

The syrups containing 10 mg of zinc per 5 ml were prepared in the following manner:

5 Sucrose syrup was prepared. The hot syrup was cooled down to 30°C. The sucrose syrup, glycerin and sorbitol were blended together to form Phase A.

A concentrated aqueous solution of ascorbic acid was prepared (Phase B). An aqueous solution containing sodium citrate and citric acid was prepared to form Phase C. An aqueous solution of zinc sulfate or zinc sulfate/carbomer was also prepared to form 10 Phase D. Phases B, C, D, and the flavor were added to Phase A to form Phase E. When sodium chloride and/or sucralose are present, they are added to Phase E and dissolved with stirring. Purified water was then added to adjust to final volume.

The viscosity of the samples were measured using a Haake VT550 viscometer at a shear rate of 6/sec. The viscosity of the samples did not differ significantly from each other.

According to WO2006/130027A1 , discoloration at 60°C for 14 days is a surrogate measure of chemical stability. The darker the color, the more degraded the Vitamin C. Comparison of Example 1A and Example IB clearly shows the stabilizing effect of the carbomer on the stability of Vitamin C as taught in WO2006/130027A1. Comparison of Example IC, Example I D, and Example I E with Example I B shows that sodium chloride, sucralose, and their combination do not affect the stabilizing effect of carbomer on Vitamin C.

Comparison of the astringency of Example 1A and Example IB clearly shows that addition of carbomer to zinc significantly increases the astringency of zinc. Sodium chloride (Example IC) or sucralose (Example ID) improves astringency when zinc sulfate is used, but the combination of the two ingredients (Example IE) is more effective.

Example 1 shows that a combination of chloride ion and high intensity sweetener according to our instant invention significantly reduced the astringency of the stable aqueous Vitamin C/Zinc formulations of WO2006/130027A 1, without affecting the stabilizing effect of the carbomer.

Experiment 2

Experiment 1 was repeated using potassium chloride as source of chloride ion and sucralose as high-intensity sweetener.

Table 2

The syrups were prepared in the following manner:

Sucrose syrup was prepared. The hot syrup was cooled down to 30°C. The sucrose syrup, glycerin and sorbitol were blended together to form Phase A.

A concentrated aqueous solution of ascorbic acid was prepared (Phase B). An aqueous solution containing sodium citrate and citric acid was prepared to form Phase C. An aqueous solution of zinc sulfate/carbomer was also prepared to form Phase D. Phases B, C, D, and the flavor were added to Phase A to form Phase E. When potassium chloride and/or sucralose are present, they are added to Phase E and dissolved with stirring. Purified water was then added to adjust to final volume. The viscosity of the samples were measured using a Haake VT550 viscometer at a shear rate of 6/sec. The viscosity of the samples did not differ significantly from each other.

Comparison of Example 2B, Example 2C, and Example 2D with Example 2A shows that potassium chloride, sucralose, and their combination do not affect the stabilizing effect of carbomer on Vitamin C. Potassium chloride (Example 2B) or sucralose (Example 2C) improves astringency when zinc sulfate is used, but the combination of the two ingredients (Example 2D) is more effective.

Experiment 3

Experiment 1 was repeated using sodium chloride as source of chloride ion and saccharin as high-intensity sweetener.

Table 3

Water q.s. q.s. q.s. q.s. pH 2.7-3.1 2.7-3.1 2.7-3.1 2.7-3.1

Discoloration (1 -10

scale)* after 14 days 3 3 3 3 @ 60 °C

Astringency (1 - 10)⁺ 8 6 6 4 the higher the number, the darker the solution; + the higher the number, the more astringent

The syrups were prepared in the following manner:

Sucrose syrup was prepared. The hot syrup was cooled down to 30°C. The sucrose syrup, glycerin and sorbitol were blended together to form Phase A. A concentrated aqueous solution of ascorbic acid was prepared (Phase B). An aqueous solution containing sodium citrate and citric acid was prepared to form Phase C. An aqueous solution of zinc sulfate/carbomer was also prepared to form Phase D. Phases B, C, D, and the flavor were added to Phase A to form Phase E. When sodium chloride and/or saccharin are present, they are added to Phase E and dissolved with stirring. Purified water was then added to adjust to final volume.

Comparison of Example 3B, Example 3C, and Example 3D with Example 3A shows that sodium chloride, saccharin, and their combination do not affect the stabilizing effect of carbomer on Vitamin C. Sodium chloride (Example 3B) or saccharin (Example 3C) improves astringency when zinc sulfate is used, but the combination of the two ingredients (Example 3D) is more effective. Experiment 4

Experiment 1 was repeated but using 10 mg of zinc per 5 ml from zinc gluconate instead of zinc sulfate.

Table 4

The syrups were prepared in the following manner:

A concentrated aqueous solution of ascorbic acid was prepared (Phase B). An aqueous solution containing sodium citrate and citric acid was prepared to form Phase C. An aqueous solution of zinc gluconate or zinc gluconate/carbomer was also prepared to form Phase D. Phases B, C, D, and the flavor were added to Phase A to form Phase E. When sodium chloride and/or sucralose are present, they are added to Phase E and dissolved with stirring. Purified water was then added to adjust to final volume.

Comparison of Example 4A and Example 4B clearly shows the stabilizing effect of the carbomer on the stability of Vitamin C as taught in WO2006/130027A1.

Comparison of Example 4C and Example 4D with Example 4B shows that sodium chloride and sucralose do not affect the stabilizing effect of carbomer on Vitamin C. Sodium chloride (Example 4C) has no effect on astringency when zinc gluconate is used, but the combination of sodium chloride and sucralose (Example 4D) is effective in reducing astringency.

U

Claims

We claim:

1. A stable aqueous oral liquid composition comprising:

i) . vitamin C;

ii) . zinc;

iii). a carbomer;

iv) . a source of chloride ion; and

v) . a high intensity sweetener; wherein the pH of the composition is less than about 5.

2. The composition according to Claim 1 , wherein the vitamin C is present from about 0.5% w/v to about 12% w/v.

3. The composition according to Claim 2, wherein the vitamin C is present from about 1% w/v to about 5% w/v.

4. The composition according to claim 1, wherein the zinc is present from about 0.01% w/v to about 1% w/v.

5. The composition according to claim 4, wherein the zinc is present from about 0.05% w/v to about 0.5% w/v.

6. The composition according to claim 1 wherein the zinc is derived from zinc sulfate, zinc gluconate, zinc acetate, and mixtures thereof.

7. The composition according to Claim 1, wherein the carbomer is present from about 0.05% w/v to about 3% w/v.

8. The composition according to Claim 7, wherein the carbomer is present from about 0.1% w/v to about 1% w/v.

9. The composition according to Claim 1, wherein the pH is less than about 4.

10. The composition according to Claim 1, wherein the chloride ion is derived from a monovalent chloride salt.

1 1. The composition according to claim 10, wherein the monovalent chloride salt is sodium chloride, potassium chloride, or mixtures thereof.

12. The composition according to Claim 1, wherein the high intensity sweetener is at least fifty times sweeter than sugar.

13. The composition according to Claim 12, wherein the high intensity sweetener is at least one hundred times sweeter than sugar.

14. The composition according to Claim 1, wherein the high intensity sweetener is sucralose, saccharin, aspartame, acesulfame, stevioside, or mixtures thereof.

15. A stable aqueous oral liquid composition comprising:

i) . 1 -5% w/v vitamin C;

ii) . 0.05-0.5% w/v zinc;

iii) . 0.1-1% w/v carbomer;

iv). 0.01 -0.3% w/v chloride; and

v). 0.01 -0.5% w/v high intensity sweetener; wherein the pH of the composition is less than about 5.

16. The composition according to Claim 15 wherein the zinc is derived from zinc sulfate, zinc gluconate, zinc acetate, and mixtures thereof.

17. The composition according to Claim 1 , wherein the pH is less than about 4.