Central Cavity Of Cyclodextrin Molecules Are Highly Hydrophobic Biology Essay

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The MHRA and Department of Health in the UK have a top 20 priority list for extemporaneous products - Hydrocortisone features as a suspension with a suggested strength 1 or 2 mg/ml (MHRA. 2010). The European Medicines Agency (EMA) have a priority list for studies into off-patent paediatric medicinal products for the 5th call 2011 of the 7th framework programme of the European Commission; hydrocortisone features on this list for an age-appropriate oral formulation, in particular for neonates in the treatment of adrenal insufficiency. (EMA, 2010)

At present, hydrocortisone is used via extemporaneous preparations for use in paediatrics. The preferred preparation is one which contains hydrocortisone tablets that are crushed to a fine powder and prepared with Ora-Plus and Ora-Sweet suspending vehicles to formulate a suspension (Jackson & Lowey, 2010). Other unlicensed uses of hydrocortisone are swallowing injectable solutions and splitting of tablets and mixing with water in smaller preparations.

Cyclodextrins were discovered in 1891 in a bacterial digest isolated from starch. They are cyclic oligosaccharides which contain various numbers of (α-1,4)-linked α-D-glucopyranose units that conform to give a rigid cup-shaped structure. The most common parent cyclodextrins are α-CD, β-CD and γ-CD (Brewster et al., 2007).

The central cavity of cyclodextrin molecules are highly hydrophobic because it is lined with skeletal carbons and ethereal oxygens of the glucose residue (Uekama et al., 1998). It is this cavity that the drug of interest enters and forms an inclusion complex, hydrogen bonds formed from the hydroxyl groups with the water from the aqueous solution resulting in an hydration shell around the dissolved cyclodextrin/drug complex. (Stella et al., 1999)(Brewster et al., 2007). From a pharmaceutical view, these inclusion complexes of drug and cyclodextrin enhance the solubility of poorly soluble drugs and also to mask an unpleasant taste from the palate (Shabir et al, 2010).

Due to extensive investigation into derivatives of parent cyclodextrins, a newer molecule is of great interest, hydroxypropyl-β-cyclodextrin. Not only is this HP- β-cyclodextrin used for its enhanced solubility, it also has a taste masking characteristic.

Cyclodextrin

Number of (α-1,4)- linked α-D-glucopyranose units

Cavity diameter (Å)

Solubility in water (g/100mL)

α-CD

6

4.70-5.30

14.50

β-CD

7

6.00-6.50

1.85

γ-CD

8

7.50-8.30

23.20

HP-β-CD

7

6.00-6.50

60.00

Figure: Comparing the parent cyclodextrins to hydroxypropyl- β-cyclodextrin.

Mady et al evaluated the taste masking of famotidine, a bitter tasting drug with carboxymethyl- β-cyclodextrin. Using a panel of eight volunteers, and a score from zero to four where zero is better and four is worse; they were able to conclude that the formulation of famotidine containing the cyclodextrin had masked the bitterness of of the drug compared to the famotidine formulation without cyclodextrin (Mady et al, 2010). This shows the versatility of cyclodextrins and their derivatives from parent compounds.

Sweeteners:

Sweeteners have been used in pharmaceutical preparations for decades and have a vast array of uses. They are used for flavour enhancement, bitterness suppression, texture, mouth feel and flavour formation (Wilson, R. 2007).

Figure: The NutraSweet Company & LMC International statistics.

Estimates for the global sweetener market has been estimated at $1.2 billion (approx £770 million) by The NutraSweet Company. The chart above shows that aspartame leads the market holding a 27% stake as an intensive sweetener added to products. Neotame holds a 1% share but this could be due to the FDA approving the sweetener in 2002 which is considered relatively recent compared to the other more established sweeteners however it is rapidly on the rise within pharmaceuticals. Neotame claims to be the fastest selling sweetener in the world and there are claims that it is used in 1000 different products. (Web reference http://www.neotame.com/).

The major metabolic pathway is hydrolysis of the methyl ester by esterases that are present throughout the body, which yields de-esterified neotame and methanol. Because only trace amounts of neotame are needed to sweeten foods, the amount of methanol derived from neotame is much lower than that found in common foods, such as fruit and vegetable juices. It has the characteristic aftertaste common to artificial sweeteners.

The selection of sweeteners are considered by many factors including potency, temporal profile and cost. Sweeteners are compared to sucrose as the standard for sweetness intensity, the 'sucrose equivalence' (SE) is when x% of a sweetener is equivalent to the sweetness of x% sucrose in a water solution. The two sweeteners of interest are Neotame and Sucralose; both have the highest potency of sweetness as Neotame is 7000 to 13000 times sweeter than sucrose and sucralose is 600 times sweeter (Wilson, R. 2007).

Neotame (N-[N-(3,3-dimethylbutyl)- -α-aspartyl]- -phenylalanine 1-methyl ester) is a high-potency non-nutritive sweetener with a potency in humans of 7000-13,000 times that of sugar (Mayhew, D.A., et al. 2003). It is a derivative of aspartame hence has very similar qualities; a clean, sweet sucrose-like taste with no undesirable taste characteristics. An important attribute of neotame is that as concentration increases, sweetness increases; there is no bitterness or metallic taste as a result of the increasing concentration (Wilson, R. 2007)(Nofre et al, 2000).

Sucralose is a substituted disaccharide; synthesized by chlorine substitutions at three of the hydroxyl groups in sucrose. It is between 450-1000 times sweeter than sucrose with a clean sugar-like taste (Grotz et al, 2009)(Wilson, R. 2007). At 9% sucrose equivalence, the flavour profile of sucralose compared to sucrose is very similar. It had a very similar response to sucrose with regards to initial sweetness but showed a much larger increase in sweetness aftertaste measured after 60 seconds (Wilson, R. 2007).

Schiffman et al performed an analysis on looking at self-mixture data of sweeteners to interpret the difference in time to the maximum sweetness intensity. The results showed that sucralose had a maximum intensity in an early-to-middle range at both sucrose equivalent levels of 3% and 5%; neotame showed a delay compared to sucralose (Schiffman et al, 2007). This could prove to be highly useful when selecting a sweetener to to mask not only the initial taste of a particular bitter drug, but also the aftertaste that lingers in the mouth afterwards.

Self-mixture

Mean 3% SE

Mean 5% SE

Sorbitol

2.00

2.00

Sucrose

2.00

2.20

Glucose

2.00

2.00

Fructose

2.00

2.00

Saccharin

2.15

2.00

Aspartame

2.15

2.17

Mannitol

2.17

2.00

Acesulfame-K

2.36

2.00

Alitame

2.77

2.31

Sucralose

2.83

3.25

Neotame

3.96

4.54

Thaumatin

5.85

5.27

1 = None, 2 = early, 3 = early-to-middle, 4 = middle, 5 = middle-to-late, 6 = late.

(Cost effectiveness of Neotame over aspartame and sucralose)

Neotame is 30 to 60 times sweeter than asparatame.

Due to high potency, can use low concentrations than any other sweetener on market.

(Discuss intensity of sucralose and Neotame from NutraSweet company graph for aftertaste - correlate to schiffman 2007)

(Find details on extinction times, linger of neotame/sucralose - refer to aftertaste).

(safety factors from NOEL, compare ADI to EDI) - nutrasweet company.

Taste perception:

Definitions:

Taste 'is a chemical sense where an inherent property of a material in solution resulting from contact with sensory receptors of the taste buds. Perception of taste occurs within the first few minutes following ingestion.'

Palatability ' is the sensory and physical attributes of a samples that determine whether and how much will be consumed when no other choice is available.'

Preference ' is the selection of one sample over another when more than one choice is available.'

Humans can detect between 5 different types of taste: sweet, sour, salty, bitter and umami. The first step in taste perception occurs at the taste buds found in the papillae of the tongue; they are also found on the palate and on the walls of the throat. Different types of taste are sensed by particular G-protein-coupled receptors for the particular response. Bitter tastes are received by T2Rs receptors are composed of 25-90% amino acid sequences that vary structurally - this results in various ligand interactions between bitter tastes and thus due to the possibility of many different amino acid chains on the receptors, it gives rise to the ability to taste bitterness of different intensities and types (Montmayeur & Matsunami, 2002). Bitter tastes can remain within the taste buds for many hours after ingesting a strongly bitter product. (Meilgaard et al, 2006). Sweet perceptions are identified by a T1R3 receptor; T1Rs have the seven-transmembrane domains characteristic of G-protein coupled receptors but they differ from T2Rs, the 'bitter receptor' by having a large N-terminal domain (Montmayeur & Matsunami, 2002).

Web reference http://www.cardiff.ac.uk/biosi/staffinfo/jacob/teaching/sensory/taste.html

The current (as of 2008) thinking1 is that sweet, amino acid (umami), and bitter taste converge on a common transduction channel, the transient receptor potential channel TRPM5, via phospholipase C (PLC) (see Figure 2).

Heteromeric receptors made up of a combination of different subunits, coded for by a small gene family - T1Rs - have a look at their structure

T1Rs (3 genes distantly related to mGluRs)

By in situ hybridization, Liao and Schultz (2003) found that all 3 T1R genes are expressed selectively in human taste receptor cells in the fungiform papillae, consistent with their role in taste perception.

T1R1+3 = amino acid receptor (umami)

T1R2+3 = sweet receptor

T1R3 - on its own may be the sweetner receptor

Umami is possibly mediated by both mGluR4 and T1R1+3 receptors

A synthetic derivative of a combination of aspartic acid and

phenylalanine, the same two amino acids that are used to make aspartame.

The bond between the amino acids is harder to break down than aspartame's,

so neotame is more stable.

Why it's low-calorie: Our bodies can't metabolize neotame, and only tiny

amounts are needed to sweeten foods.

Safety: Unlike aspartame, neotame isn't broken down in the body into the

amino acid phenylalanine, which is toxic to people with the rare disorder phenylketonuria

(PKU). Animal and human studies have raised no safety concerns.

Comments: Neotame is so new that it hasn't yet appeared in any foods. It's

always possible that once millions of consumers start eating neotame, some

people may turn out to be sensitive to it.

http://www.cspinet.org/nah/05_04/sweet_nothings.pd

Meilgaard in a study of individual differences of threshold for substances added to beer, found that panels of 20 trained tasters tend to contain two who exhibit a threshold 4 times lower than the median and two who exhibit threshold 5 times higher (Meilgaard, 1993). This shows that there is large variation between subjects thus a larger panel size decreases discrimination. Two major sources of variation are the different perceptions of stimulus by the subjects and the different expression of those perceptions by subjects.

Physiology of a child's tongue

Filiform, fungiform, and circumvallate papillae are visible.

Descriptive Analysis

The technique of descriptive analysis is the optimum strategy for sensory studies (Senn, S, 2009). There are many different measurements of scale that can be adopted with this method of analysis. The most useful scales are ordinal and interval scales as they are interchangeable and have equivalent ranges. Ordinal scales involve a ranking of the score and provides the panelist with a systematic range to assess their preference (Stone & Sidel, 2004). The scale of choice is a 5-point scale ranging from one to five; where one is very bad, two is bad, three is neither good or bad, four is good and five is very good(Mitchell & Counselman, 2003). There is a high level of flexibility with regards to this point scale as it is currently in a rank order but there are equal differences in the scores which allows for the results to be converted into an interval form; this allows for more statistical analysis techniques (Meilgaard et al, 2006).

Statistical Analysis

There are many methods to determine if there is a difference between samples. They are categorised into two types, overall difference tests and attribute difference tests. Overall difference tests are designed to simply show if there is any difference at all between samples. Examples of tests are the triangle test and duo-trio test. However, the limitation is that three samples at the most can be assessed using one reference sample to draw a comparison (Meilgaard et al, 2006).

ANOVA is a multiple hypothesis test, it is a statistical test predominately used to compare three or more samples. It is a very powerful method of analysis but similar to other parametric tests, it can only be used when the conditions of the experiment agree with the assumptions of the test: (Jones D.S, 2008).

The distribution is normal of the populations from which the data have been sampled.

The variance and spread of scores are similar of the populations from which the data have been sampled

The data must be measured on at least an interval scale, with an underlying continuous distribution.

There must be a large number of recorded observations per sample group. Meilgaard et al recommend a sample size of at least 16 to apply ANOVA analysis of variance (Meilgaard et al, 2006)(Jones D.S, 2008).

Due to the nature of the experiment design, it does not allow for the use of a one-way ANOVA or Kruskal- Wallis test.

The design of the experiment is a two-factor analysis without replication hence it has independent variables. The two factors are the different sample formulations and the subjects that are participating in the panel. A one-factor analysis cannot be applied because the single factor would be the different formulations but would result in the subjects having to replicate the test. It would then become a paired experiment design where the subject behaves as a control. Therefore the use of these methods would increase the experimental error (Jones D.S, 2008). An alternative is the two-way ANOVA or the Friedman's Analysis (Meilgaard et al, 2006).

A Friedman analysis uses a randomised block design, it is an ideal method to compare samples between three to six in particular by inexperienced panels. Ranking is the simplest way to perform such comparisons of several samples according to a single attribute e.g. sweetness, preference. However, the data is ordinal and no measure of the degree of difference is obtained from each respondent without further post-hoc testing (Meilgaard et al, 2006).

Epke et al performed a sensory evaluation using a trained panel to determine if nasal occlusion had an effect on the metallic taste of ferrous sulphate and copper sulphate. They used an analysis of variance (ANOVA) to analyse the results and any comparisons across product pairs were tested with a post-hoc test, the least significant difference(LSD) and paired t-tests (Epke et all, 2009).

Mitchell and Counselman led a taste comparison of three different steroid preparations to assess any significance between taste, texture, smell and aftertaste. They analysed data by mean scores and standard deviation followed by a Friedman's test. (Mitchell & Counselman, 2003). This could be further extended by performing a post-hoc test such as the Nemenyi test (Jones D.S, 2008).

Aim

The aim of this project is to assess the taste of various paediatric formulations of hydrocortisone and to determine whether the unpleasant bitter taste and aftertaste have been sufficiently masked. By using various formulations, a comparison can be drawn between samples to determine whether hydroxypropyl-β-cyclodextrin can mask the taste independently or if an additional sweetener is required, used in this investigation will be neotame and sucralose at two different concentrations. If neotame or sucralose are needed to mask the bitter taste and aftertaste then what is the minimum concentration that can be used.

Objectives

To lead a single blind, single dose single centre taste panel.

To perform a statistical analysis to show if there is any difference between formulations.

If there is a statistical difference then to determine to optimum formulation.

Methods

Materials

Method

(Add materials in details and SOP details)

Subjects

Twenty healthy subjects from the School of Pharmacy volunteered to participate in the study. Students or staff were accepted into the study but there was criteria to meet. The age range was limited to young adults (18-28 years old). An attempt was made to keep the ratio of male and female panellists constant. Smokers were permitted but had to forbear smoking one hour prior to test and during test breaks. Participants could not be recruited if they had any deterioration of gustation or olfaction, recent dental care, medicine treatment in the last 15 days prior to test date. Subjects could not be recruited if they had any known allergy or sensitivity of hydrocortisone or other steroidal treatments. All participants were provided with a comprehensive information sheet of the study and were given a verbal talk about the study prior to the test; consent forms were given to all participants to sign and return. The research protocol was approved by the Research Ethics Committee of the university and strictly adhered to.

Stimuli

In total, each panelist tasted 7 samples; 2 control samples and 5 test samples. The negative control was a sample of potable water, the positive sample contained hydrocortisone 0.025%, orange flavour 0.5% in preserved citric acid buffer, no hydroxypropyl-β-cyclodextrin was present. All other samples contained hydrocortisone 0.5%, hydroxypropyl-β-cyclodextrin 12% with orange flavour 0.5% in preserved citric acid buffer as a template. To the formulations shown, one sample contained no sweetener, two samples contained neotame at two concentration of 0.075% and 0.1%, the last two samples contained sucralose at two concentration of 0.075% and 0.1% respectively.

Formulation

1

2

3

4

5

6

Hydrocortisone %

0.025

0.5

0.5

0.5

0.5

0.5

Hydroxypropyl-β-cyclodextrin %

-

12

12

12

12

12

Methylparaben sodium salt

 

 

 

 

 

 

Potassium sorbate

 

 

 

 

 

 

Orange flavour %

0.5

0.5

0.5

0.5

0.5

0.5

Citric acid

 

 

 

 

 

 

Sodium citrate

 

 

 

 

 

 

Sucralose %

-

-

-

-

0.75

0.1

Neotame %

-

-

0.075

0.1

-

-

Test strategy

The strategy was a single blind, single dose, single centre study. All samples were given a three digit randomised code that was applied to the individual 5ml syringes. All panelists were carefully instructed to empty the contents of the syringe onto their tongue then to swirl for 15 seconds. It was emphasised to spit the sample into the spit cup provided and no sample was to be swallowed. On the scoring sheet, they were asked to score the taste, followed by a two minute wait to then score the aftertaste. Before and after each sample, the panelists were given water to rinse their mouth and given unsalted crackers to neutralise their mouth from the previous sample. A 15 minute interval was respected between samples. The first and second sips are the most sensitive and can lead to a lower level of discrimination (Meilgaard et al, 2008). To prevent fatigue, desensitisation of the palate and to reduce the burden on participants, the test was split into two sessions, an hour long each. All syringes were disposed of after a single use.

The test was split into two groups with 10 subjects each; this was to accommodate two subjects per day to participate. The expiry date of the reconstituted formulation is 7 days from the date of reconstitution hence the formulation was made in two batches of 50ml each respectively. The same standard operating procedure was followed in both instances.

Statistical analysis of taste intensity ratings

Taste intensity ratings were kept constant for all participants ranging from one to five where one being very bad and five being very good. The method for analysis is the multisample difference test: rating approach - evaluation by analysis of variance (ANOVA) (Meilgaard et al, 2007) to determine if a significant difference is notable between all samples.

Results:

The null hypothesis for this study is that the different formulations containing hydrocortisone with hydroxypropyl-β-cyclodextrin and varying sweeteners and concentrations show no significant masking of bitterness with regards to the aftertaste.

The alternative hypothesis for this study is that the different formulations containing hydrocortisone with hydroxypropyl-β-cyclodextrin and varying sweeteners and concentrations do show a significant masking of bitterness with regards to the aftertaste.

Table showing the scores achieved for the 20 participants for the assessment of the initial taste.

Participant codes

Paediatric formulation of hydrocortisone

 

 

 

1

2

3

4

5

6

480

1

3

4

5

5

3

419

2

3

5

5

5

5

364

2

2

3

4

3

3

193

2

1

3

3

3

3

147

2

2

4

5

3

3

568

1

2

4

4

1

3

526

2

4

4

5

3

5

639

1

2

5

5

4

4

495

2

1

3

5

4

5

931

2

1

5

4

4

5

995

2

2

4

5

4

4

285

1

4

4

5

1

3

430

2

2

4

2

4

5

591

2

2

5

5

2

4

532

1

3

4

5

2

3

928

1

2

5

4

2

3

858

3

2

5

4

2

4

500

2

2

3

4

5

2

807

1

2

5

4

4

5

656

1

3

4

5

4

5

Mean

1.65

2.25

4.15

4.4

3.25

3.85

Standard Deviation

0.5871

0.8507

0.7452

0.8208

1.2513

0.9881

The results below show good correlation between scores, this is demonstrated by low values of variance. A significantly large variance was seen with formulation 5 containing sucralose at 0.075%.

Anova: Single Factor.

SUMMARY

Groups

Count

Sum

Average

Variance

Column 1

20

33

1.65

0.344737

Column 2

20

45

2.25

0.723684

Column 3

20

83

4.15

0.555263

Column 4

20

88

4.4

0.673684

Column 5

20

65

3.25

1.565789

Column 6

20

77

3.85

0.976316

ANOVA

Source of Variation

SS

df

MS

F

P-value

F crit

Between Groups

121.0417

5

24.20833

30.01359

2.35E-19

2.293911

Within Groups

91.95

114

0.806579

Total

212.9917

119

 

 

 

 

The calculated F statistic was 30.014 whereas the critical F statistic was 2.294. 30.014>2.294 thus rejecting null hypothesis and accepting the alternative hypothesis. A significant difference does exist between the formulations that is not regarded as an occurrence by chance

AFTERTASTE

Participant codes

Paediatric formulation of hydrocortisone

 

 

 

1

2

3

4

5

6

480

2

3

5

4

5

4

419

3

3

5

5

5

5

364

1

1

3

3

2

2

193

1

1

2

3

2

3

147

1

2

4

4

3

2

568

2

3

4

5

4

3

526

2

4

4

3

3

2

639

1

1

5

5

3

4

495

1

1

1

3

1

3

931

1

1

3

2

3

3

995

1

3

3

3

2

3

285

1

4

5

5

2

3

430

1

1

3

2

2

2

591

1

1

1

2

1

1

532

1

1

5

4

3

4

928

1

1

4

3

2

3

858

2

1

4

4

2

3

500

1

1

2

3

3

1

807

1

2

3

4

1

3

656

2

1

4

4

3

3

Mean

1.35

1.8

3.5

3.55

2.6

2.85

Standard Deviation

0.5871

1.1050

1.2773

0.9987

1.1425

0.9881

The table above shows the 20 participants and the score allocated to each formulation for the aftertaste; it is presented on a scale of 1 to 5. The mean shows the average score given by all 20 participants for each formulation where the standard deviation shows the variance in the results from the average score. Formulation 1 shows a small variation from the mean concluding that the population regarded the taste similarly to one another. Larger variances are notable with formulation 3 and 5, the formulations containing neotame and sucralose at their lower concentrations respectively.

Anova: Single Factor

SUMMARY

Groups

Count

Sum

Average

Variance

Column 1

20

27

1.35

0.344737

Column 2

20

36

1.8

1.221053

Column 3

20

70

3.5

1.631579

Column 4

20

71

3.55

0.997368

Column 5

20

52

2.6

1.305263

Column 6

20

57

2.85

0.976316

ANOVA for aftertaste

Source of Variation

SS

df

MS

F

P-value

F crit

Between Groups (6 formulations)

79.54167

5

15.90833

14.73832

3.88806

E-11

2.293911

Within Groups (errors)

123.05

114

1.079386

 

 

 

 

 

 

 

 

 

 

Total

202.5917

119

 

 

 

 

The calculated F statistic is 14.738 whereas the critical F statistic is 2.294. 14.738>2.294 therefore the null hypothesis (H0) is rejected. This means that there is a significant difference in aftertaste between the formulations. However, at present it is not possible to conclude which formulation in particular is significantly different from another, only that a difference exists.

Post-hoc analysis was carried out using Tukey's HSD; this was employed to determine the difference between individual groups to identify where the difference in taste of the formulation lies.

Tukey's HSD:

HSD = q √ MSE / n*

Where q is the studentised range statistic, MSE is the mean square error in ANOVA and n is the number of observations in respective groups.

Q=6.03

Mse=1.079386

N = 20

So HSD = 6.03√ (1.079386/20)

HSD = 1.4008

Discussion

Analysis of results

From the results obtained, some instant conclusions can be drawn.

Firstly, it can be noted that the formulation containing hydrocortisone alone without the hydroxypropyl- β - cyclodextrin or sweetener showed the lowest scores for both taste and aftertaste. This formulation being the control emphasises the need for the taste panel to be conducted because it has the most unpleasant taste. The formulation also had a significantly lower concentration of hydrocortisone; 0.025% compared to all other formulations containing 0.5%. Due to the poor solubility of hydrocortisone, 0.025% was the maximum concentration that could solubilise into water which is also significantly lower than the standard therapeutic dose (1mg/ml).

Secondly, the formulation containing hydrocortisone with hydroxypropyl- β - cyclodextrin showed a marked increase in taste score for both taste and aftertaste. The complexes formed in the ratio of 1:6 show that hydroxypropyl- β - cyclodextrin is capable of masking the taste of the bitter hydrocortisone but still has a highly unpalatable taste.

The formulations containing the sweeteners neotame and sucralose showed a vast improvement in overall taste scores. Neotame had a clear advantage over sucralose in that both concentrations of neotame were preferred rather than the sucralose. There is a significant difference between the two formulations containing neotame for initial taste. The formulation containing neotame at a lower concentration of 0.075% had a mean score of 4.15 whereas the higher concentration of 0.1% had a mean score of 4.4. Both had low levels of variance showing that there was good uniformity of results within the population. With regards to the aftertaste, there was no significant difference found; the difference of the mean scores being 0.05 demonstrates that the aftertaste is perceived relatively similarly.

Sucralose also showed an improved palatability but not to the same extent as the formulations containing neotame. However, they showed a significant difference between both concentrations for taste and aftertaste. The formulation containing sucralose at 0.1% was the more desirable of the two formulations.

The graph above demonstrates that both neotame and sucralose have a late onset of sweetness where it rises gradually and lingers.

Neotame requires the binding site, the N-terminal extracellular domain of T1R2, to bind with the T1R2 + 3 receptor. Studies by Xu et all, 2004 have shown that there are many binding sites located on the receptor which may account for differences found in the temporal profiles. Due to the complex binding process to the receptor, a delayed onset is experienced. However, the results do not show that, if this was the case then the aftertaste would have shown to have a better taste score than the initial taste. All participants rated neotame at both concentrations higher for the initial taste than the aftertaste. Gerna

In a study by Lee et al, the aim was to mask the bitter taste of cetirizine dihydrochloride by using different methods to process the formulation with the β-cyclodextrin. In agreement that β-cyclodextrins and their derivatives such as hydroxypropyl-β-cyclodextrin demonstrate taste masking ability however the method of process has an effect on its efficiency with taste masking. The most effective method of processing was the SAS technique which proved to have the best capability to mask the bitter taste according to the 15 volunteers. 5 volunteers out of the 15 stated that no bitter taste was present. However, the process of physical mixing of cetirizine dihydrochloride and β-cyclodextrin showed that a bitter taste was still present. The reason was that the cetirizine had not penetrated into the hydrophobic cavity of β-cyclodextrin as efficiently as other process resulting in poor palatability. This could be reflective of the results in this experiment as all the reconstitutable formulations were prepared by physical mixing. As a result, the complexes of hydrocortisone with the hydroxypropyl-β-cyclodextrin could have inadequately bound and still showed a bitter taste but to a lesser degree.

Firstly, that taste constantly had a lower score rating for every formulation compared to the respective aftertaste.

Other similar studies supporting this article

Other research has been conducted using the chemicals we have utilised in this study. Studies have shown other B- cyclodextrins to be successful as taste masking ingredients such as carboxymethyl -β-cyclodextrin (Mady et al 2010). This supports our use of hydroxypropyl- B- Cyclodextrin in this study as a taste masking ingredient.

Further evidence of the use of neotame has been provided by studies that aim to test the safety of neotame for consumption. In vitro as well as in vivo studies on dogs, rabbits, mice and rats have been conducted which show that neotame is not genotoxic, teratogenic, carcinogenic neither has it been shown to be associated with any reproductive/ developmental toxicity (Aguilar et al 2007). This evidence suggests that neotame would be safe as an added sweetener on animal models for further research.

Other similar studies not supporting this article

Adult taste perception has been shown to be different to children. Therefore, adult testing panels must take that into account that adult taste testing panels may produce results that may possibly not be accepted by the intended children. Calibration of these panels to adapt for children may be one solution to the differences in taste in adults and children (Davies and Tuleu 2008). Validation of adult taste testing in application to the paediatric population would allow for the transfer of information.

Improvements to method

Perhaps, the one of the main weaknesses of the method of taste tasting is that the points scale may be objective to the individual. Taste perception varies individually yet there were twenty test subjects which cannot be considered a large test group. An example of this variability is that the statistical analysis of the results with respect to the standard deviation suggests that larger variances are notable with formulations 3 and 5. These formulations contain sucralose and neotame at their lower concentrations of 0.075% respectively. These larger variances could be further investigated with a larger group test as well as better trained volunteers. As we had a 5 point assessment scale, the presence of a centre point of point 3 has been found to allow the subject to score indecisively. (Davies and Tuleu 2008). The subject may found for the neutral point in this case score 3.

Development of a novel electronic device, commonly known as E-tongue, has shown great promise in the area of taste testing (Gupta et al 2010). E- tongue is an electrochemical devices that allows for successful analysis of the bitterness intensity of formulations (Zheng and Kheen 2005). Electronic tongues have been shown to offer a safe and objective alternative to the subjective assessment by taste panels (Woertz et al 2010). Taste enhancement technologies that are applied in the food industry may be applicable in the pharmaceutical administration of drugs (Cram et al 2009).

Conclusion

The ideal taste masking formulation should be cost effective, easy to prepare, with as few chemicals/ingredients involved as possible. The safety of the components to the individual should also be considered with toxicity studies carried out on the chemicals, particularly as these formulations will be administered by children. A process which involves fewer steps for preparation before administration is also preferable. The stability of the formulation should be considered too as preparations would be ingested at room temperature.

Statistically, according to Tukey HSD, there is no significant difference for taste and aftertaste between the two different neotame concentrations of 0.075% and 0.1%. Therefore, the lower concentration of 0.075% Neotame would be more cost effective, safer for patients and provide a suitable level of palatability compared to 0.1% of Neotame.

This study has shown the efficacy of Neotane as a better taste masking agent than that of Sucrolase. The results of this study meet the aims of the study. I have shown that for better taste sweeteners added to hydroxypropyl-B-cyclodextrin were significantly better at improving palatability. In particular, Neotane had a better taste and aftertaste compared to sucralose, suggesting it could be an essential component in the administration of hydrocortisone in children. Further research involving children themselves would strengthen our findings and provide a truer sense of palatability, dosage and acceptance of the product.

With paediatric patients a better taste accepted by the children would allow for easier administration and it is more likely that the medicines will be taken as prescribed by the practitioner.

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