WO2006130027A1

WO2006130027A1 - Aqueous oral liquid vitamin supplements containing stabilized vitamin c and metal ions

Info

Publication number: WO2006130027A1
Application number: PCT/PH2006/000009
Authority: WO
Inventors: Ma. Joyce Bedelia B. Santos; Kennie U. Dee
Original assignee: Santos Ma Joyce Bedelia B
Priority date: 2005-05-31
Filing date: 2006-05-30
Publication date: 2006-12-07

Abstract

An aqueous oral liquid composition containing vitamin C, zinc and/or iron compounds, and a stabilizing amount of carbomer to reduce the metal-catalyzed degradation of vitamin C.

Description

AQUEOUS ORAL LIQUID VITAMIN SUPPLEMENTS CONTAINING STABILIZED VITAMIN C AND METAL IONS

BACKGROUND OF THE INVENTION

1. Field of the Invention The present invention relates to aqueous oral liquid vitamin supplements containing vitamin C, zinc and/or iron compounds, and carbomer to improve the stability of vitamin C.

2. Background of the Invention

Vitamin C is one of the most important vitamins. It is widely available as an oral vitamin supplement, either as a single ingredient, or in combination with other vitamins and minerals. When combined with minerals, especially zinc and/or iron, the vitamin C supplement is normally available in dry solid dosage formats, such as tablet and capsule, to prevent degradation of vitamin C.

Many children and some adults 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. Chewable tablet combining vitamin C and the minerals however has a taste problem: zinc is astringent, and iron leaves a metallic taste.

A liquid format avoids the taste problem of chewable tablets because the minerals can be sufficiently diluted, high levels of sweeteners can be added, the contact time of the liquid with the mouth is short relative to a chewable tablet, and the ingestion of syrup is normally followed by water intake.

It is known, however, that zinc and iron catalyze the degradation of vitamin C in aqueous solutions. The vitamin C and mineral(s) can be given as separate liquid preparations, but this is highly inconvenient. Alternatively, vitamin C and the minerals can be combined in a single liquid preparation but with a short shelf life which is commercially difficult. There is therefore a need for an oral liquid preparation with improved vitamin C stability that combines vitamin C with zinc and/or iron.

US 6,183,729 discloses topical compositions of vitamin C concentrate that is stable to degradation which has a pH greater than 5, and a viscosifying agent that includes carbomer. This patent shows that significant vitamin C degradation occurs at low pH in presence of certain viscosifiers including carbomer. This patent does not teach oral aqueous compositions of vitamin C with zinc and/or iron, wherein the vitamin C has improved stability.

US 5,140,043 discloses stable topical compositions of vitamin C in a carrier wherein the ratio of water to carrier is at least 1:1, and the pH of the composition is less than

3.5. The carrier is an alkylene glycol, or a combination of alkylene glycol and hydroxyalkylcellulose. This patent does not teach oral aqueous compositions of vitamin C with zinc and/or iron, wherein the vitamin C has improved stability.

US 2001/0003754 discloses stable liquid mineral ascorbate in a liquid organic polyol solvent, wherein the pH of the composition is between 5 and 7. Mineral ascorbate in this patent means a pharmacologically acceptable salt of ascorbic acid. This patent does not teach that carbomers can be used to enhance the stability of vitamin C in the presence of zinc and/or iron.

US 6,217,914 discloses a method for treatment of aging or damaged skin by applying a topical composition comprising ascorbic acid, zinc salt, and a tyrosine compound, wherein the composition has a pH between 3.6 and 4.2. This patent does not teach that carbomers can be used to enhance the stability of vitamin C in the presence of zinc and/or iron.

BRIEF SUMMARY OF THE INVENTION

SUBSTITUTE C !3T(HULE 26) The instant invention provides an aqueous oral vitamin supplement that combines vitamin C with zinc and/or iron, wherein the vitamin C has improved stability. The composition comprises vitamin C or its pharmacologically equivalent salts, zinc and/or iron compounds, and a stabilizing amount of carbomer, wherein the composition has a pH of less than about 5.

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, potassium ascorbate, calcium ascorbate, and magnesium 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, such as zinc sulfate, zinc chloride, zinc gluconate, zinc oxide, zinc stearate, zinc picolinate, zinc acetate, zinc lactate, and mixtures thereof. The zinc compound(s) must be used at levels where it is totally dissolved. 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. The preferred zinc compound is zinc sulfate because it is cheap and medically well-studied.

Iron compounds can be selected from both ferrous and ferric compounds, such as ferrous sulfate, ferrous citrate, ferrous fumarate, ferrous gluconate, ferrous lactate, ferrous succinate, ferric pyrophosphate, ferric orthophosphate, ferric ammonium citrate, ferric saccharate, and mixtures thereof. The iron compound(s) must be used at levels where it is totally dissolved. The iron concentration (as metallic iron) 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. The preferred iron compounds are ferrous sulfate and ferric pyrophosphate.

SUBSTITUTESMEEi (RULE 26) Carbomers are widely used thickeners. They 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 971P, 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 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 swallow. More importantly, carbomer improves the stability of vitamin C in the presence of metal ions only when the pH is low. Not wishing to be bound by theory, it is believed that zinc and iron interact with the carboxylate moiety of the carbomer, preventing these metal ions from interacting with vitamin C. At pH above 5, neutralization of the caboxylate moiety disrupts its interaction with zinc and iron, freeing up these metal ions to catalyze the degradation of vitamin C.

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 swallow, 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

The stability enhancing effect of carbomer on vitamin C syrup with zinc was studied.

Table 1

SUBSTITUTE SHEET (uϋLE 26)

* the higher the number, the darker the solution

The syrups were prepared in the following manner:

Sucrose syrup containing sodium benzoate was prepared. The hot syrup was cooled down to 30°C. The sucrose syrup, invert sugar 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. Xanthan gum was dispersed in glycerin to form Phase D. An aqueous dispersion of sorbitan monolaurate and FD&C Yellow #6 was prepared to form Phase E. Phases B, C, D, E and the flavor were added to Phase A.

For examples 1-B and 1-C, an aqueous solution of zinc sulfate (Example 1-B) or zinc sulfate and carbomer (Example 1-C) was also prepared and added to Phase A. The mixture was stirred for one hour. 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.

SUBSTITUTE Sl ,¹ZLT₁U¹JLE 26) Comparison of the chemical assay of Example 1-A and Example 1-B after 14 days of accelerated stability at 60⁰C shows that zinc enhanced the degradation of vitamin C. This comparison also shows that discoloration can be used as a surrogate measure of stability since vitamin C is known to discolor when degraded.

Comparison of Example 1-B and Example 1-C shows that the addition of carbomer improved the stability of vitamin C in the presence of zinc.

Ten respondents were asked to taste 5 ml each of Example 1-B and Example 1-C in random order. The respondents were asked to drink water and take unsalted crackers between samples to remove traces of the first sample tasted. Each respondent was asked to pick a preference. Example 1-B was preferred by 6 of 10 respondents, which is not statistically significant. This result indicates that carbomer can be added to an aqueous oral liquid composition of vitamin C and zinc without negatively affecting the taste.

Experiment 2

Experiment 1 was repeated using a different base formulation.

Table 2

SUBSTITUTE SiS-(TiULE 28)

The syrups were prepared in the following manner:

Sucrose syrup containing sodium benzoate was prepared. The hot syrup was cooled down to 30⁰C. The sucrose syrup and sorbitol were blended together to form Phase A. An aqueous dispersion of pectin was prepared and added to Phase A.

An aqueous solution containing ascorbic acid and edetate disodium was prepared to form Phase B. An aqueous solution containing sodium citrate and citric acid was prepared to form Phase C. An aqueous dispersion of sorbitan monolaurate and FD&C Yellow #6 was prepared to form Phase D. Phases B, C, D and the flavor were added to Phase A.

For examples 2-B and 2-C, an aqueous solution of zinc sulfate (Example 2-B) or zinc sulfate and carbomer (Example 2-C) was also prepared and added to Phase A. The mixture was stirred for one hour. Purified water was then added to adjust to final volume.

Comparison of Example 2-A and Example 2-B shows that zinc enhanced the degradation of vitamin C. Comparison of Example 2-B and Example 2-C shows that the addition of carbomer improved the stability of vitamin C in the presence of zinc.

SUBSTITUTE EnEZT (RULE 26) Ten respondents were asked to taste 5 ml each of Example 2-B and Example 2-C in random order. The respondents were asked to drink water and take unsalted crackers between samples to remove traces of the first sample tasted. Each respondent was asked to pick a preference. Example 2-B was preferred by 5 of 10 respondents, indicating that carbomer can be added to an aqueous oral liquid composition of vitamin C and zinc without negatively affecting the taste.

Experiment 3

The effect of pH on the stabilizing property of carbomer was studied.

The syrups were prepared in the following manner;

SUBSTITUTE SHEET (nULE 26) Sucrose syrup containing sodium benzoate was prepared. The hot syrup was cooled down to 30⁰C. The sucrose syrup, glycerin, and sorbitol were blended together to form Phase A.

An aqueous solution containing ascorbic acid and edetate disodium was prepared to form Phase B. An aqueous solution containing sodium citrate and citric acid in the case of Examples 3-A and 3-B was prepared to form Phase C. Phases B and C were added to Phase A.

An aqueous solution of zinc sulfate (Example 3-A) or zinc sulfate and carbomer

(Examples 3-B and 3-C) was also prepared and added to Phase A. The mixture was stirred for one hour. Purified water was then added to adjust to final volume. For

Example 3-C, concentrated sodium hydroxide solution was added to adjust the pH to

7.

The viscosity of the samples were measured using a Haake VT550 viscometer at a shear rate of 6/sec. Note the significant increase in the viscosity of Example 3-C, which has the consistency of a semi-solid, because of the neutralization of the carbomer.

The accelerated stability results indicate that when the carbomer is neutralized, it is unable to significantly improve the stability of vitamin C in the presence of zinc. Not wishing to be bound by theory, it is believed that the sodium ions displaced zinc from its interaction with the carboxylate moiety of the carbomer, freeing up zinc to catalyze the degradation of vitamin C.

Experiment 4

The stability enhancing effect of carbomer on vitamin C syrup with iron was studied.

Table 4

Ingredient Example 4- A Example 4-B

IO

SUBSTITUTE SHEET PULE 26)

The syrups were prepared in the following manner:

Sucrose syrup containing sodium benzoate was prepared. The hot syrup was cooled down to 30°C. The sucrose syrup, invert sugar, 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. Phase B, Phase C, and the flavor were added to Phase A.

An aqueous solution of ferrous sulfate heptahydrate (Example 4- A) or ferrous sulfate heptahydrate and carbomer (Example 4-B) was also prepared and added to Phase A. The mixture was stirred for one hour. Purified water was then added to adjust to final volume.

11

SUBSTITUTE Si ΣL F (r, ULE 26) 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.

The accelerated stability results indicate that the addition of carbomer improved the stability of vitamin C in the presence of iron.

Ten respondents were asked to taste 5 ml each of Example 4-A and Example 4-B in random order. The respondents were asked to drink water and take unsalted crackers between samples to remove traces of the first sample tasted. Each respondent was asked to pick a preference. Example 4-A was preferred by 6 of 10 respondents, which is not statistically significant. This result indicates that carbomer can be added to an aqueous oral liquid composition of vitamin C and iron without negatively affecting the taste.

Experiment 5

Experiment 4 was repeated using a different iron source.

Table 5

12

SUBSTITUTE 8HEEi r^ M c

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. Phase B, Phase C, and the flavor were added to Phase A

An aqueous solution of ferric pyrophosphate (Example 5-A) or ferric pyrophosphate and carbomer (Example 5-B) was also prepared and added to Phase A. The mixture was stirred for one hour. Purified water was then added to adjust to final volume.

Experiment 6

To determine if zinc or ascorbic acid forms a complex with the carbomer, an experiment was conducted with Example 1-C. 1.5 ml samples of Example 1-C were placed in Eppendorf tubes and centrifuged in aMicrofuge^® 18 microcentrifuge (Beckman Coulter,

13

SUBSTITUTE SHEET^' fRULE 26) US) at 12,000 rpm for 60 minutes. The supernatants were carefully removed, pooled, transferred to Microsep^® (Pall Corporation, US) tubes with 1OK cutoff filter, and centrifuged at 500g for 2 hours to remove the residual carbomer. The filtrate was then chemically analyzed for vitamin C and zinc. Assay results show that all of the vitamin C and zinc were fully recovered in the filtrate, indicating that neither ascorbic acid nor zinc formed a complex with the carbomer. If complex formation occurred, the zinc or ascorbic acid would have been removed together with the carbomer during filtration, reducing their concentrations in the filtrate.

The absence of complex formation, and the fact that the carboxylate moiety of the carbomer is negatively charged under acidic condition, and zinc is a cation, leads us to believe, without wishing to be bound by theory, that the carbomer interacts with zinc through fairly weak electrostatic attraction. This electrostatic interaction, albeit weak, appears adequate enough to prevent zinc from catalyzing the degradation of ascorbic acid. However, when the carbomer is neutralized, this electrostatic attraction is disrupted, freeing up zinc to catalyze the degradation of vitamin C.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Claims

We claim:

1. An aqueous oral liquid composition comprising: i). vitamin C; ii). a mineral selected from zinc, iron, and mixtures thereof; and iii). a carbomer;

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/vto 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 and/or iron is each present from about 0.01% w/v to about 1% w/v.

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

6. The composition according to Claim 1, wherein the iron is a ferrous compound, or a mixture of ferrous compounds.

7. The composition according to Claim 1, wherein the iron is a ferric compound, or a mixture of ferric compounds.

8. The composition according to Claim 1, wherein the iron is a mixture of ferrous and ferric compounds.

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

10. The composition according to Claim 9, wherein the carbomer is present from about 0.1% w/v to about 1% w/v.

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

12. The composition according to Claim 1, wherein the viscosity at a shear rate of 6/sec is less than about 2,500 cps.

13. The composition according to Claim 12, wherein the viscosity at a shear rate of 6/sec is less than about 2,000 cps.

14. The composition according to Claim 13, wherein the viscosity at a shear rate of 6/sec is less than about 1,000 cps.

15. An aqueous oral liquid composition comprising: i). 1-5% w/v vitamin C; ii). 0.05-0.5% w/v each of zinc and/or iron; and iii). 0.1-1% w/v carbomer;

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.

17. The composition according to Claim 15, wherein the iron is derived from ferrous sulfate, ferric pyrophosphate, and mixtures thereof.

18. The composition according to Claim 15, wherein the viscosity at a shear rate of 6/sec is less than about 1,000 cps.

19. The composition according to Claim 15, wherein the pH is less than about 4.

17

SUBSTITUTE GHEET (RULE 26)