WO2006130027A1 - Supplements vitamines liquides aqueux pour administration orale contenant de la vitamine c stabilisee et des ions metalliques - Google Patents

Supplements vitamines liquides aqueux pour administration orale contenant de la vitamine c stabilisee et des ions metalliques Download PDF

Info

Publication number
WO2006130027A1
WO2006130027A1 PCT/PH2006/000009 PH2006000009W WO2006130027A1 WO 2006130027 A1 WO2006130027 A1 WO 2006130027A1 PH 2006000009 W PH2006000009 W PH 2006000009W WO 2006130027 A1 WO2006130027 A1 WO 2006130027A1
Authority
WO
WIPO (PCT)
Prior art keywords
vitamin
zinc
composition according
carbomer
iron
Prior art date
Application number
PCT/PH2006/000009
Other languages
English (en)
Inventor
Ma. Joyce Bedelia B. Santos
Kennie U. Dee
Original Assignee
Santos Ma Joyce Bedelia B
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Santos Ma Joyce Bedelia B filed Critical Santos Ma Joyce Bedelia B
Publication of WO2006130027A1 publication Critical patent/WO2006130027A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/30—Zinc; Compounds thereof

Definitions

  • 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.
  • 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.
  • 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.
  • vitamin C and mineral(s) can be given as separate liquid preparations, but this is highly inconvenient.
  • 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
  • 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 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.
  • 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.
  • 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.
  • 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.
  • carbomer improves the stability of vitamin C in the presence of metal ions only when the pH is low.
  • zinc and iron interact with the carboxylate moiety of the carbomer, preventing these metal ions from interacting with vitamin C.
  • 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 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.
  • Phase B 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.
  • Example 1-B 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.
  • Example 1-B 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.
  • Example 1-B 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.
  • the syrups were prepared in the following manner:
  • Sucrose syrup containing sodium benzoate was prepared. The hot syrup was cooled down to 30 0 C. The sucrose syrup and sorbitol were blended together to form Phase A. An aqueous dispersion of pectin was prepared and added to Phase A.
  • Phase B 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.
  • Example 2-B 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.
  • 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.
  • 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.
  • 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.
  • 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 30 0 C. The sucrose syrup, glycerin, and sorbitol were blended together to form Phase A.
  • Phase B An aqueous solution containing ascorbic acid and edetate disodium was prepared to form Phase B.
  • Examples 3-B and 3-C were also prepared and added to Phase A. The mixture was stirred for one hour. Purified water was then added to adjust to final volume.
  • Example 3-C concentrated sodium hydroxide solution was added to adjust the pH to
  • Example 3-C 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 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.
  • Phase B A concentrated aqueous solution of ascorbic acid was prepared (Phase B).
  • Phase B, Phase C, and the flavor were added to Phase A.
  • Example 4- 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.
  • 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.
  • 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.
  • Phase B A concentrated aqueous solution of ascorbic acid was prepared (Phase B).
  • Example 5-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.
  • 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.
  • Example 1-C 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,

Abstract

La présente invention concerne une composition liquide aqueuse pour administration orale contenant de la vitamine C, du zinc et/ou des composés ferreux, ainsi qu’une quantité stabilisante de carbomère visant à réduire la dégradation de la vitamine C catalysée par des métaux.
PCT/PH2006/000009 2005-05-31 2006-05-30 Supplements vitamines liquides aqueux pour administration orale contenant de la vitamine c stabilisee et des ions metalliques WO2006130027A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PH1-2005-000271 2005-05-31
PH12005000271 2005-05-31

Publications (1)

Publication Number Publication Date
WO2006130027A1 true WO2006130027A1 (fr) 2006-12-07

Family

ID=37481880

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/PH2006/000009 WO2006130027A1 (fr) 2005-05-31 2006-05-30 Supplements vitamines liquides aqueux pour administration orale contenant de la vitamine c stabilisee et des ions metalliques

Country Status (1)

Country Link
WO (1) WO2006130027A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102716150A (zh) * 2012-06-26 2012-10-10 马应龙药业集团股份有限公司 一种硫酸锌糖浆口服液体制剂
US20150079268A1 (en) * 2012-10-18 2015-03-19 Patrick Monsivais Formulation for iron supplements
GB2522539A (en) * 2013-12-11 2015-07-29 Snowdonia Res Sarl Mineral water composition containing bioavailable iron
WO2015126265A1 (fr) * 2014-02-18 2015-08-27 Santos Joyce Bedelia B Suppléments liquides oraux à base de vitamine contenant du zinc et de la vitamine c stabilisée avec une astringence réduite
EP3153162A1 (fr) * 2015-10-05 2017-04-12 Navinta, llc. Préparation de formes dosifiées pharmaceutiques contenant des sels (iii) de fer
WO2017123103A1 (fr) * 2016-01-15 2017-07-20 Dee, Kennie U. Composition stable et de goût agréable de comprimés à sucer de vitamine c et de zinc
CN112451543A (zh) * 2020-12-28 2021-03-09 浙江大学医学院附属儿童医院 一种硫酸锌和硫酸亚铁口服液及其制备方法
US20220160641A1 (en) * 2015-10-09 2022-05-26 Combocap, Inc. Capsule with internal diaphragm for improved bioavailability

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5312629A (en) * 1991-07-24 1994-05-17 Beres Export-Import Rt. Method for treating mucoviscidosis and chronic pain syndromes deriving from degenerative locomotor diseases
GB2353936A (en) * 1999-07-06 2001-03-14 Novartis Nutrition Ag Alkyl parabens in enteral feeding solutions
US6365218B1 (en) * 2000-02-04 2002-04-02 Abbott Laboratories Pediatric formula and methods for providing nutrition and improving tolerance
US6852332B2 (en) * 2000-03-24 2005-02-08 Adisseo France S.A.S. Liquid vitamin composition

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5312629A (en) * 1991-07-24 1994-05-17 Beres Export-Import Rt. Method for treating mucoviscidosis and chronic pain syndromes deriving from degenerative locomotor diseases
GB2353936A (en) * 1999-07-06 2001-03-14 Novartis Nutrition Ag Alkyl parabens in enteral feeding solutions
US6365218B1 (en) * 2000-02-04 2002-04-02 Abbott Laboratories Pediatric formula and methods for providing nutrition and improving tolerance
US6852332B2 (en) * 2000-03-24 2005-02-08 Adisseo France S.A.S. Liquid vitamin composition

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SCHMID A. ET AL.: "Effect of physical exercise and vitamin C on absorption of ferric sodium citrate", MEDICINE AND SCIENCE IN SPORT AND EXERCISE, vol. 28, no. 12, 1996, pages 1470 - 1473, XP008073368 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102716150A (zh) * 2012-06-26 2012-10-10 马应龙药业集团股份有限公司 一种硫酸锌糖浆口服液体制剂
CN102716150B (zh) * 2012-06-26 2013-06-19 马应龙药业集团股份有限公司 一种硫酸锌糖浆口服液体制剂
US20150079268A1 (en) * 2012-10-18 2015-03-19 Patrick Monsivais Formulation for iron supplements
US11395502B2 (en) * 2012-10-18 2022-07-26 Patrick Monsivais Formulation for iron supplements
GB2522539A (en) * 2013-12-11 2015-07-29 Snowdonia Res Sarl Mineral water composition containing bioavailable iron
WO2015126265A1 (fr) * 2014-02-18 2015-08-27 Santos Joyce Bedelia B Suppléments liquides oraux à base de vitamine contenant du zinc et de la vitamine c stabilisée avec une astringence réduite
EP3153162A1 (fr) * 2015-10-05 2017-04-12 Navinta, llc. Préparation de formes dosifiées pharmaceutiques contenant des sels (iii) de fer
US10456418B2 (en) 2015-10-05 2019-10-29 Navinta, Llc Preparation of pharmaceutical dosage forms containing iron (III) salts
US20220160641A1 (en) * 2015-10-09 2022-05-26 Combocap, Inc. Capsule with internal diaphragm for improved bioavailability
WO2017123103A1 (fr) * 2016-01-15 2017-07-20 Dee, Kennie U. Composition stable et de goût agréable de comprimés à sucer de vitamine c et de zinc
CN112451543A (zh) * 2020-12-28 2021-03-09 浙江大学医学院附属儿童医院 一种硫酸锌和硫酸亚铁口服液及其制备方法

Similar Documents

Publication Publication Date Title
US20210353603A1 (en) Bowel cleansing composition
WO2006130027A1 (fr) Supplements vitamines liquides aqueux pour administration orale contenant de la vitamine c stabilisee et des ions metalliques
ES2539414T3 (es) Formulación líquida para deferiprona con sabor apetecible
US11147810B2 (en) Pharmaceutical composition of oral suspension of anti-neoplastic alkylating agents
AU2017203079B2 (en) Citrate-rich calcium-magnesium supplement and uses thereof
EP2838510A1 (fr) Solution d'atomoxétine
JPH09502709A (ja) エストロン誘導体及びカルシウム塩含有の経口、水溶性製薬組成物
KR100825572B1 (ko) 칼슘, 마그네슘 및 비타민을 포함하는 액제 조성물 및 그의제조방법
JP4959864B2 (ja) グルタミン酸塩含有液剤
JP4403595B2 (ja) 鉄化合物含有内服液剤組成物
KR102342514B1 (ko) 글리세로인산마그네슘을 포함하는 경구투여용 수성 용액 형태의 약학 조성물
EP2903596A1 (fr) Solutions à usage oral comprenant de l'acide folique
EP3678498B1 (fr) Composition pour supplémentation de calcium
JP2665764B2 (ja) カルシウム水溶液剤
WO2015126265A1 (fr) Suppléments liquides oraux à base de vitamine contenant du zinc et de la vitamine c stabilisée avec une astringence réduite
US20230082870A1 (en) Composition for calcium supplementation
JP2000044469A (ja) 内服液剤
JP3027696B2 (ja) 安定な水性医薬組成物
US20220288113A1 (en) Enhanced nitrate, elemental metal, and amino acid compositions and methods of use
WO2022192743A1 (fr) Compositions améliorées de nitrate, de métal élémentaire et d'acides aminés et leurs procédés d'utilisation
CA3074893A1 (fr) Composition de supplementation en calcium
GB2544782A (en) Solution
SG190579A1 (en) Liquid formulation for deferiprone with palatable taste

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

NENP Non-entry into the national phase

Ref country code: RU

122 Ep: pct application non-entry in european phase

Ref document number: 06747713

Country of ref document: EP

Kind code of ref document: A1