WO2014090889A1

WO2014090889A1 - Oral solutions comprising folic acid

Info

Publication number: WO2014090889A1
Application number: PCT/EP2013/076255
Authority: WO
Inventors: Angelos Karatzas
Original assignee: LAMDA LABORATORIES SA
Current assignee: LAMDA LABORATORIES SA
Priority date: 2012-12-12
Filing date: 2013-12-11
Publication date: 2014-06-19
Anticipated expiration: 2015-06-12
Also published as: GR1008101B; EP2903596A1

Abstract

Oral solutions comprising folic acid as active ingredient and a liquid carrier comprising propylene glycol, glycerin and water. The pH of the solution is adjusted to the range of 7.5 to 9.5. The solutions of the present invention exhibit excellent stability even without the presence of further antimicrobial and/or antioxidant agents, in addition to propylene glycol and glycerin.

Description

ORAL SOLUTIONS COMPRISING FOLIC ACID

TECHNICAL FIELD

The present invention refers to oral solutions comprising folic acid.

BACKGROUND OF THE INVENTION

Folic acid (Formula I), which is also known as vitamin B9, is necessary for synthesis, repair and function of DNA and RNA, the basic building blocks of life.

Formula I

Lack of folic acid results in the non-simultaneous maturing and function of the nucleus with respect to the synthesis of DNA and cytoplasmic proteins. Megaloblastic cell lesions follow, which are not limited to the erythrocytes but they also occur in other cells such as those of the gastrointestinal mucosa, the vagina and the cervix of the uterus among others.

At present a large number of liquid preparations of folic acid in the form of oral solutions is available on the market, at concentrations ranging from 0.08 mg/ml to 1 mg/ml, as well as in the form of oral drops at concentrations of up to 16 mg/ml.

Folic acid undergoes extensive decomposition when admixed with common excipients and presents low stability under conditions of elevated temperature and humidity. According to US4931442 and GB725683, the aqueous solutions of folic acid exhibit reduced stability, especially in the presence of atmospheric oxygen.

A recent study published in the journal "International Journal of Pharmaceutical and chemical sciences, Vol. 1 (1 ) Jan - Mar 2012", refers to extended stability problems exhibited by aqueous solutions of vitamins generally and in particular by solutions containing folic acid. According to the study, stable folic acid solutions may be prepared by mixing the active ingredient with a liquid organic carrier which comprises liquid sorbitol, glycerin and propylene glycol and by simultaneous adjustment of the pH of the solution to the range of 5 to 5.5. It is important that according to the study, the presence of water as an excipient in the proposed compositions is excluded due to its strong destabilising action.

As main impurities of folic acid are considered impurities A, D and E, as described in the relevant European Pharmacopoeia monograph of folic acid.

Impurity A

Impurity D

Impurity E

However, a review of the literature leads to the conclusion that no much attention has been placed, in the prior art, on decreasing the presence of impurities during manufacturing and storage of folic acid oral solutions.

The present invention addresses the problem of the prior art by advantageously providing folic acid oral solutions, which exhibit as low as possible levels of known and unknown impurities during their manufacturing and storage.

SUMMARY OF THE INVENTION

The present invention provides oral solutions of folic acid that exhibit excellent stability and extended lifetime.

According to the invention the oral solutions comprise folic acid as active ingredient and a liquid carrier comprising 300 mg/ml to 600 mg/ml propylene glycol, 100 mg/ml to 300 mg/ml glycerin and water, wherein the pH of the solution is from 7.5 to 9.5.

Preferably, the concentration of folic acid in the solutions of the present invention is up to 30 mg/ml. More preferably, the concentration of folic acid is from 5 mg/ml to 25 mg/ml.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides stable oral solutions comprising folic acid in combination with a liquid carrier. The folic acid oral solutions according to the invention may have application both as food supplements and as pharmaceutical products. Preferably the folic acid oral solutions are pharmaceutical products and in this case the liquid carrier is a pharmaceutically acceptable carrier.

As used throughout this description and claims, the term "impurity" refers to reaction products or decomposition products of folic acid which may be present in the active ingredient or formed during the preparation and storage of the oral solution. Similarly, the term "total impurities" refers to the sum of all folic acid impurities being present in the oral solution.

Commercial oral solutions that comprise folic acid were included in a set of preliminary studies. Specifically, two commercial medicinal preparations, with theoretical concentrations of 0.5 mg/ml and 3.2 mg/ml of folic acid, were analyzed.

The commercially available pharmaceutical aqueous Lexpec® 2.5mg/5ml Oral Solution which is marketed in the United Kingdom by Rosemont Laboratories Inc., contains 0.5 mg/ml folic acid. As stated in the Patient Information Leaflet (PIL), this product also comprises as excipients mannitol, glycerin, disodium edetate, methyl-p- hydroxybenzoic acid, propyl-p-hydroxybenzoic acid, ethyl-p-hydroxybenzoic acid, dihydrogen phosphate sodium, disodium phosphate, strawberry flavour (containing propylene glycol) and water.

The quantitative composition of the product was approached by a set of laboratory studies, including inter alia a study of the rheological behavior of the solution for assessing the concentration of mannitol and glycerol, a pH measurement for assessing the concentration of phosphates and organoleptic tests for the assessment of the concentration of the flavouring agent. This approach resulted in the following concentration values for the excipients of the product Lexpec ® 2.5mg/5ml Oral Solution: approximately 100 mg/ml for mannitol, about 200 mg/ml for glycerin, about 2.5 mg/ml for sodium dihydrogen phosphate, about 2.5 mg/ml for disodium phosphate and about 5 mg/ml for the strawberry flavour (which contains propylene glycol). The pH value of the commercial solution was measured and found to be 6.3. The commercially available aqueous solution "Folic acid liquid nutritional supplement" which is marketed in the United States by Pure Encapsulations contains 3.2 mg/ml folic acid. This product, as stated in the PIL also comprises as excipients 300 mg/ml glycerin and about 700 mg/ml purified water.

These compositions were studied in relation to their stability at accelerated conditions of temperature (40°C) and relative humidity (75%) for six months. The quantification of the major impurities and total impurities in the solutions before and after the storage period was carried out by HPLC. All compositions were analyzed in triplicate and the results are reported in Table 1.

Table 1 : Commercial oral aqueous solutions - stability results

All tested solutions, were proved to exhibit high levels of known and unknown impurities six months after storage at temperature of 40°C and relative humidity of 75 %, indicating that folic acid is extensively decomposed. Under the above described circumstances the present inventors conducted an extensive research program with view towards solving the stability problems with regard to the uncontrolled appearance of folic acid degradation products. The present inventors developed oral solutions, which remain physicochemically stable when stored for at least six months at accelerated temperature conditions (40°C) and relative humidity (75%) and for at least twenty-four months at room temperature (15-30°C).

It has surprisingly been found that a combination of propylene glycol and glycerin, in certain concentration ranges along with pH adjustment to the range of 7.5 to 9.5 leads to folic acid compositions which exhibit greater stability compared with the compositions of the prior art.

According to the invention the oral solutions comprise folic acid as active ingredient and a liquid carrier comprising from 300 mg/ml to 600 mg/ml propylene glycol, 100 mg/ml to 300 mg/ml glycerin and water, wherein the pH of the solution is from 7.5 to 9.5.

Preferably, the concentration of folic acid in the solutions of the present invention is up to 30 mg/ml.

Most preferably, the concentration of folic acid is from 5 mg/ml to 25 mg/ml.

Propylene glycol and glycerin are known to exhibit antimicrobial activity. Propylene glycol has been defined as a true preservative with fungistatic and fungicidal effect, while glycerin displays general antimicrobial action especially in combination with other antimicrobial agents.

The compositions of the present invention exhibit excellent stability even when they do not comprise additional antioxidants and/or antimicrobial agents. Thus, preferably, the folic acid oral solutions of the present invention do not comprise, in addition to propylene glycol and glycerin, further antimicrobial agents and/or antioxidants. The presence of such further antimicrobial agents and/or antioxidants may raise additional safety and toxicity issues. The absence of antimicrobial agents and antioxidants is very important, especially in the case of preparations intended for children. The oral solutions of folic acid according to the invention may also optionally comprise additional excipients commonly used in the preparation of oral liquid compositions, such as viscosity adjusting agents, natural sweetening agents, non- sugar based artificial sweetening agents and flavouring agents. Viscosity adjusting agents may be, for example, starch, sodium carboxy methylcellulose, methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, maltitol or mixtures thereof.

Natural sweetening agents that can be used in the present invention comprise mannitol, maltitol, sorbitol and mixtures thereof.

The non-sugar based artificial sweetening agents which may be used in the present invention comprise saccharin sodium, sucralose, saccharin, aspartame and acesulfame potassium and mixtures thereof.

Appropriate flavouring agents may comprise any of the many non-toxic natural or artificial flavouring agents known in the daily practice. In particular, the flavouring agents used may comprise one or more of a variety of natural or artificial fruit flavours. Alternatively, or in addition, the flavouring agents may comprise one or more of natural or artificial vanilla, chocolate, and caramel flavourings, amongst others.

The solutions of the present invention exhibit excellent stability and extended lifetime. According to a preferred example, the solutions of the present invention remain physicochemically stable when stored for at least six months at a temperature of 40°C and relative humidity of 75%, with impurity A being less than 1 .0%, impurity D being less than 0.4%, impurity E being less than 0.3% and total impurities being less than 2.0% of the initial amount of folic acid. Additionally, the solutions of the present invention remain physicochemically stable when stored for at least twenty four months at room temperature (15-30°C).

The present invention also provides stable folic acid solutions at concentrations much higher than those of the corresponding prior art solutions.

The compositions of the present invention may be prepared using methods well known in the art. For example, they can be prepared using the following process: 1 . An amount of water is added to a main mixing vessel.

2. Sufficient amount of sodium hydroxide solution for preventing precipitation of folic acid is added to the main mixing vessel.

3. Folic acid is added to the above solution under continuous stirring until completely dissolved.

4. The pH of the solution is adjusted to the range of 7.5 to 9.5.

5. Propylene glycol and glycerin are added to the above solution under continuous stirring.

6. The volume is adjusted to the desired batch volume by adding water. The pH of the solution is adjusted, if needed, to the range of 7.5 to 9.5 by adding sodium hydroxide solution.

EXAMPLES

The following examples show the influence of the proposed co-solvents system on the stability of folic acid. Solutions were prepared by a process where an amount of water is added to a main mixing vessel. Adequate quantity of sodium hydroxide solution for preventing precipitation of folic acid is added to the same of mixing vessel. Then, folic acid is added to the above solution under continuous stirring until it is completely dissolved and the pH of the solution is adjusted to the range of 7.5 to 9.5. Propylene glycol and glycerin are added to the above solution under continuous stirring. The volume of the solution is adjusted to the desired batch volume by adding water. The pH of the solution is adjusted, if needed, to the range of 7.5 to In the following examples the pH of the solution is adjusted to the range of 7.5 to 9.5, since the solubility study of folic acid shows the best solubility behaviour at this pH range.

EXAMPLE 1

The following compositions were studied in relation to their stability at storage conditions of 40°C temperature and 75% relative humidity for six months. The quantitative determination of impurities in the prepared compositions, before and after the storage period, was carried out by HPLC.

Table 2: Compositions with increasing concentration of propylene glycol

N.D.: Not Detected Table 3: Compositions with increasing concentration of glycerin

Composition Composition Composition Composition 5 6 7 8

Ingredients mg/ml

Active ingredient

Folic acid 10 10 10 10

Excipients

Propylene glycol 400 400 400 400

Glycerin 50 100 300 350

Water q.s. 1 ml q.s. 1 ml q.s. 1 ml q.s. 1 ml pH of solution 8.0 8.0 7.8 8.0

(initial) 0.12 0.13 0.15 0.17

Impurity A %

(6 months) 3.1 1 0.69 0.48 1.02

(initial) 0.23 0.26 0.25 0.24

Impurity D %

(6 months) 0.43 0.24 0.26 0.30

(initial) N.D. N.D. N.D. N.D.

Impurity E %

(6 months) 0.61 0.28 0.24 0.36

Total (initial) 0.48 0.52 0.49 0.45 impurities % (6 months) 5.1 1 1.39 1.21 2.19

N.D.: Not Detected

Table 4: Compositions with increasing concentration of folic acid

N.D.: Not Detected

It was found that the gradual increase of the concentration of propylene glycol over 300 mg/ml significantly contributes to the stability of the composition. Conversely, the increase of the concentration above 600 mg/ml is not accompanied by further improvement.

Furthermore it was revealed that the gradual increase of the concentration of glycerin over 100 mg/ml significantly contributes to the stability of the composition. Conversely, the increase of the concentration above 300 mg/ml is not accompanied by further improvement. Finally it was found that the proposed liquid carrier provides stable compositions for folic acid concentrations much higher than the concentrations of the solutions of the prior art (such as those of Table 1 ).

EXAMPLE 2

Table 5 shows preferred oral solution compositions according to the present invention.

Storage conditions of 40°C temperature and 75% relative humidity were applied to both compositions for a period of six months.

Table 5: Preferred compositions according to the invention

EXAMPLE 3

Table 6 shows preferred oral solution compositions according to the present invention. Room storage conditions were applied to both compositions for a period of twenty four months.

Table 6: Preferred compositions according to the invention

Composition 15 Composition 16

Active ingredient mg/ml

Folic acid 10 20

Excipients

Propylene glycol 500 500

Glycerin 200 150

Water q.s. 1 ml q.s. 1 ml pH of solution 8.0 8.0

Impurity A % 0.44 0.56

Impurity D % 0.24 0.27

Impurity E % 0.24 0.28

Total impurities % 1.19 1.26

Claims

1 . Oral solution comprising folic acid as active ingredient and a liquid carrier comprising

300 mg/ml to 600 mg/ml propylene glycol,

100 mg/ml to 300 mg/ml glycerol,

and water,

and wherein the pH of the solution is from 7.5 to 9.5.

2. Oral solution according to claim 1 , wherein the concentration of folic acid is up to 30 mg/ml.

3. Oral solution according to claim 2, wherein the concentration of folic acid is from 5 mg/ml to 25 mg/ml.

4. Oral solution according to any one of claims 1 to 3, wherein the solution does not comprise further antimicrobial agents and/or antioxidants.

5. Oral solution according to any one of claims 1 to 4, wherein the solution is a pharmaceutical solution.

6. Oral solution according to any of claims 1 to 5, further comprising a viscosity adjusting agent.

7. Oral solution according to any of claims 1 to 6, further comprising a natural sweetener or non-sugar based artificial sweetening agent.

8. Oral solution according to any one of claims 1 to 7, further comprising a flavouring agent.

9. Oral solution according to any one of claims 1 to 5, wherein the solution is a pharmaceutical solution comprising

10 mg/ml folic acid,

600 mg/ml propylene glycol,

200 mg/ml glycerol, and purified water,

and wherein the pH of the solution is 8.0.

10. Oral solution according to any of claims 1 to 5, wherein the solution is a pharmaceutical solution comprising

10 mg/ml folic acid,

500 mg/ml propylene glycol,

200 mg/ml glycerol,

and purified water,

and wherein the pH of the solution is 8.0.