INTRODUCTION:

For most of the people the type of the liquid they use to administer the drug is with no significance at all. In turn this presents the possibility for altering drug concentration due to various interactions between the drug or dosage form excipients with different ingredients in the liquid that differs from potable water. It is also very typical for patients that they rarely use sufficient amount of liquid for swallowing the tablets or capsules. This can without a doubt affect drug release and absorption¹

Worldwide a lot of researchers investigate and evaluate the influence of food and drinks on pharmacokinetic behavior of drugs^2-5. Drug absorption depends on many factors such as type and properties of the dosage form, physico-chemical properties of the drug itself and also the physiological conditions present in the gastro-intestinal tract⁶.

The interaction between different components of the formulation and food or drinks can lead to inhibition of the active pharmaceutical ingredient (API) transport through the mucosa and the respective change in drug absorption⁴.

It is also well known that different furanocoumarins, found in the grapefruit juice can affect the metabolism of some drugs for example Calcium-channel blockers^7,8.

Drug-food or drug-beverage interactions can influence as well the dosage form disintegration as the API release⁹. Foodstuffs and drinks affect the gastro-intestinal conditions. Changes in the motility, volume and pH of the liquid are established in the presence of such substances. These changes can entail changes in the release characteristics, e.g. especially for dosage forms with pH-dependent modified release. The physiological gastric pH in fasted state is in the range of 1.0-2.5 and alongside the small intestine it varies reaching values of 7.0±0.5^10,11.

Postprandial pH is susceptible to variations in each area of the gastro-intestinal tract and depends as well on the type of administered food or liquid as on the intra-individual variations¹².

All those interactions and influences are a prerequisite for the need of study and evaluation of the potential effect foodstuffs can render to drug action. Hence it is not without concern whether the patient takes his medications with a glass of water or with a glass of orange juice or another liquid.

Furthermore, some statistical analyses show increase in the consumption of soft-beverages^13,14.

People drink more frequently such beverages and patients in particular sometimes use them for solid dosage form administration. According to our studies (not present here) this phenomenon is becoming more persistent. The need of additional liquids for the ease of swallowing is very typical for elderly patients and for the ones with dysphagia¹⁵.

Investigation of the in vitro release profiles is an easily available method which can be very useful for probability estimation of in vivo interaction manifestation. The dissolution test is a physical method used for characterization of API release from different dosage forms in vitro. It is a basic pharmacopoeia method since 1970 for the purposes of dosage forms design and also quality control. Because the method is non-invasive and in the presence of appropriate operating conditions it can be ground for determining in vivo-in vitro correlation it is one of the most frequently used methods for biopharmaceutical characterization of medicinal products^16,17. Due to its specificity and excellent sensitivity, HPLC is often used to separate and quantify different target compounds, both in dissolution testing procedures^18-20 and in various other studies^21-27.

According to World Health Organization (WHO) data for 2016 there are four major causes of death worldwide- cardio-vascular diseases, cancer, diabetes and chronic lung conditions²⁸.

Therefore, the cardio-vascular risk prophylaxis is of significant importance. Prophylaxis and prevention can be related to different means including changes in the patient’s lifestyle and also pharmacological therapy. According to WHO the prophylaxis can be classified in two groups- primary (without previous manifestation) and secondary (in patients with cardio-vascular conditions). Acetylsalicylic acid is considered as suitable for all cases of secondary prophylaxis and for some cases of primary one when the benefits overweight the risks²⁹.

Acetylsalicylic acid (ASA) belongs to the group of Non-steroid anti-inflammatory drugs (NSAIDs), possess pronounced anti-inflammatory activity and can affect pain with different origin and in addition it is widely used in the symptomatic treatment of fever³⁰.

Its activity is due to the irreversible non-selective inhibition of the COX-1 and COX-2 (isoforms of the Cyclooxigenase family)^31,32. The hindering of COX-1 activity in platelets with administration of low-dose ASA leads to inhibition of Thromboxane A2 production³³ which in turn leads to inhibition of platelet aggregation³⁴.

Due to this anti-aggregation potential low-dose ASA is indicated both for primary and secondary prophylaxis of acute coronary syndromes and ischemia³⁵.

According to different authors the dose of low-dose acetylsalicylic acid formulation which is sufficient for an adequate therapeutic efficacy lies between 30-325mg/day^36-40.

The low dose is recommended due to the fact that higher doses are more commonly related to manifestation of side effects such as hypersensitivity, gastro-intestinal discomfort and even bleeding⁴¹.

For adequate cardio- vascular risk prophylaxis long duration of treatment is required. It depends on the type of the co-morbidity and the presence of previous manifestation and usually is between 18 months and 4 years or longer⁴². This systemic or chronic drug administration can be accompanied by patient’s non-compliance and discontinuation of treatment. Patients are also very susceptible to spontaneous changes of therapy or they very often do not follow exactly the prescription and the instructions for drug administration⁴³. The strict following of the therapy is a prerequisite for its success and respectively for increasing the quality of life (QALY)⁴⁴.

Regarding all the issues related to chronic drug therapy and the application of liquids other than water as means to ease up swallowing in the present work the influence of different commercial soft beverages and orange juices on the in vitro release of low-dose acetylsalicylic acid from gastro-resistant tablets was investigated in order to evaluate possible interactions.

MATERIALS AND METHODS:

Materials:

Aspirin protect^® (100mg acetylsalicylic acid (PubChem CID:10745), gastro-resistant tablets, Bayer Schering Pharma, batch number: BTADR11) (containing 100mg acetylsalicylic acid cellulose powder, maize starch with film coating containing: methacrylic acid-ethyl acrylate copolymer 1:10 dispersion 30% (Ph. Eur.) talc, triethyl citrate) was purchased from a local Pharmacy.

Soft beverages: Coca-Cola^®, Coca-Cola Bulgaria (containing water, glucose-fructose syrup, carbon dioxide, coloring agent E150d, phosphoric acid, natural flavors including caffeine); Coca-Cola Zero^®, Coca-Cola Bulgaria (containing water, carbon dioxide, coloring agent E150d, Sodium cyclamate, Acesulfam Potassium, Aspartame, phosphoric acid, natural flavors including caffeine, sodium citrate) were purchased from a local store.

Different commercial orange juices were purchased also from a local store. Orange juice Pfanner^®(100% orange juice, 25mg/100ml ascorbic acid, 9% sugar, 0.7% proteins, 0.2g% fats, Sodium <0.01%), Orange juice Rauch^® (100% orange juice, 32mg/100ml ascorbic acid, 9.4% sugar, 0.7g% proteins, 0.2% fats, salt 0.005%) and Orange juice Cappy^®(51% orange juice from concentrate containing fructose- glucose syrup, citric acid and ascorbic acid with 22% sugars).

Disodium hydrogen phosphate (PubChem CID:24203) extra pure, Ph. Eur. grade and Sodium-dihydrogen phosphate- dodecahydrate (PubChem CID:21902471) extra pure, Ph. Eur. grade; Hydrochloric acid 37% (PubChem CID:313), pure for analysis; Sodium 1- heptanesulfonate (PubChem CID:23672332) were purchased from Merck, Germany.

Acetonitrile (PubChem CID:6342), Formic acid (PubChem CID:284) were purchased from Sigma Aldrich, Germany.

Purified water was prepared in house by distillation with Boeco Water Still WS 7500, Boeco, Germany.

Methods:

Determination of the pH of commercial non-alcoholic beverages:

For the pH measurement 713 pH Meter was used (Metrohm, Germany). The pH was evaluated as well for the pure soft drink as for the mixtures imitating the physiological conditions. The pH was measured at 22.0±0.5⁰C until a constant value is displayed.

Dissolution test:

The dissolution test was carried out with RC-8D Dissolution tester, Minhua Pharmaceutical Machinery Co, Limited, Shanghai, China. The Paddle apparatus (dissolution test 2) was used as described in the European Pharmacopoeia (Ph. Eur., 2010). The process parameters included temperature 37^°C ± 0.5°C; 100rpm for paddle rotation. The dissolution media consisted of 200ml soft beverage and 700 ml simulated gastric fluid (pH=1.2, 1M Hydrochloric acid), simulated duodenal fluid (pH=4.5 0.1M acetate buffer) or simulated intestinal fluid (pH=6.8 0.1M phosphate buffer, Ph. Eur).Samples were taken at predetermined time intervals. As a reference dissolution test was performed also in 900ml media containing only simulated gastric, duodenal or intestinal fluid.

Dissolution media containing phosphate buffer with pH 6.8 and different soft beverages for facilitation were coded as shown in Table 1.

Table 1: Composition of different dissolution media.

Medium composition	Coding
Phosphate buffer with pH 6.8, 900ml	Medium A
Phosphate buffer with pH 6.8, 700ml + orange juice Cappy, 200ml	Medium B
Phosphate buffer with pH 6.8, 700ml + orange juice Pfanner, 200ml	Medium C
Phosphate buffer with pH 6.8, 700ml + orange juice Rauch, 200ml	Medium D
Phosphate buffer with pH 6.8, 700ml + Coca Cola, 200ml	Medium E
Phosphate buffer with pH 6.8, 700ml + Cola zero, 200ml	Medium F

HPLC analysis:

Before being injected into the HPLC system the samples were initially filtered through a Glass 0.45 µm. Diluent of the samples was acetonitrile and formic acid in the ratio of 99:1. The samples were centrifuged and the supernatant was used for the HPLC assay.

For the analysis of the dissolution samples an HPLC system consisted of a Shimadzu DGU-20A₅vacuum degasser, a Shimadzu LC-20AD quaternary pump, a Shimadzu SPD-20AUV/VIS detector and SIL-20A auto sampler was selected. A chromatography data system was used to record and evaluate the data collected during and following chromatographic analysis. The separation was achieved on a LiChrospher^®RP-18 column packed with octadecylsilyl silica gel 10 µm, 250x4 mm. The mobile phase was acetonitrile – water, containing 1 g of sodium 1-heptanesulfonate, the pH was adjusted to 3.4 with glacial acetic acid (85:15) and pumped at a constant flow rate 2.0 mL per minute. The eluent was monitored using UV/VIS detector at a wavelength of 280 nm. The column was maintained at room temperature and volume of 20 µl was injected. Under these conditions, the retention times (t_R) of Salicylic acid and Acetylsalicylic acid were approximately 5 and 8 min.

RESULTS AND DISCUSSION:

pH determination:

The pH of each of the commercial soft drinks was measured in order to evaluate its potential role in the acetylsalicylic acid dissolution from gastro-resistant tablets. From the data presented in Table 2 it can be seen that these liquids are acidic. This may influence the release rate of gastro-resistant tablets due to change in the pH.

Table 2: pH values of the different commercial beverages

Soft drink	pH
Coca-Cola	2.700
Coca-Cola Zero	2.710
Orange juice (Pfanner)	3.817
Orange juice (Rauch)	3.876
Orange juice (Cappy)	3.682

The pH values of dissolution media consisted of 200ml soft beverage and 700ml of pH=1.2, 1M Hydrochloric acid, pH=4.5 0.1M acetate buffer or pH=6.8 0.1M phosphate buffer, Ph. Eur. were also measured. The values are given in Table 3.

Table 3: pH values in dissolution media consisted of 200ml soft beverage and 700ml of buffers.

Soft drink 200 ml /Buffer 700 ml	pH (1.2)	pH (4.5)
Coca-Cola	1.781	4.568
Coca-Cola Zero	1.786	4.573
Orange juice (Pfanner)	3.555	4.462
Orange juice (Rauch)	3.515	4.416
Orange juice (Cappy)	3.565	4.496

As it can be seen in Table 3 the pH in simulated gastric fluid without enzymes is changed to higher pH values due to the fact that it is not a buffered medium. Slight but not significant decrease is noticed in the other media in the presence of a soft beverage (Table 3 and Table 4).

Table 4: pH values in dissolution media consisted of 200ml soft beverage and 700ml of buffers

Soft drink 200 ml /Buffer 700 ml	Medium	pH (6.8)
Coca-Cola	B	7.019
Coca-Cola Zero	C	7.025
Orange juice (Pfanner)	D	6.793
Orange juice (Rauch)	E	6.786
Orange juice (Cappy)	F	6.801

Release profiles from dissolution of ASA in different media:

In the release media with pH 1.2 1 M Hydrochloric acid and pH 4.5 0.1 M acetate buffer either without or with the addition of a soft beverage no release was detected. The represented profiles (Fig. 1) are for the samples in pH 6.8 0.1M phosphate buffer. A slight difference is observed in the dissolution profiles in the presence of additional liquid to the release medium.

Fig. 1: Release profile of % Acetylsalicylic acid released with time (Zero order kinetics).

The release kinetics of the dissolution data were considered by various models such as Zero Order (Fig. 1), First Order (Fig. 2a), Higuchi (Fig. 2b), Hixon-Crowell (Fig. 2c), and Korsmeyer-Peppas (Fig. 2d).

Fig. 2: Release kinetic plots for: (a) First order model; (b) Higuchi model; (c) Hixon-Crowell model; (d) Korsmeyer-Peppas model.

The data obtained from the in vitro drug release study in 700ml media with the presence of 200ml various soft beverages were fitted to different kinetic models. The resulting coefficients are presented in Table 5.

Table 5: Correlation coefficient (R²) and dissolution constant (k) received in intestinal dissolution media A-F in presence of different soft beverages.

Medium

Zero order

First order

Higuchi

Hixon - Crowell

Korsmeyer-Peppas

R² = 0.62316

k = 1.23309

R² = 0.755

k = -0.10516

R² = 0.89651

k = 11.9414

R² = 0.26251

k = 0.04453

R² = 0.99847

n = 0.26086

R² = 0.88448

k = 1.59292

R² = 0.97648

k = -0.03353

R² = 0.84981

k = 13.034

R² = 0.63961

k = 0.08147

R² = 0.97162

n = 0.68712

R² = 0.75899

k = 1.5273

R² = 0.97375

k = -0.04351

R² = 0.88414

k = 13.54015

R² = 0.46302

k = 0.06771

R² = 0.95323

n = 0.43003

R² = 0.76849

k = 1.54274

R² = 0.97589

k = -0.04395

R² = 0.88879

k = 13.63745

R² = 0.47075

k = 0.06807

R² = 0.94868

n = 0.43961

R² = 0.91694

k = 1.55748

R² = 0.98777

k = -0.03394

R² = 0.89772

k = 12.84395

R² = 0.63918

k = 0.07198

R² =0.81675

n = 1.05325

R² = 0.61579

k = 1.2365

R² = 0.91023

k = -0.06546

R² = 0.89429

k = 11.98061

R² = 0.26602

k = 0.04475

R² = 0.97315

n = 0.27695

Table 6: pH values in different dissolution mediа

Medium	K	L	M	N	O	P	Q
pH	6.719	6.725	6.793	6.786	6.801	6.668	6.604

Table 7: Correlation coefficient (R²) and dissolution constant (k) received in intestinal dissolution media K-Q in presence of different concentration of sucrose solution

Medium

Zero order

First order

Higuchi

Hixon - Crowell

Korsmeyer-Peppas

R² = 0.88464

k = 1.59278

R² = 0.97677

k = - 0.03351

R² = 0.84987

k = 13.03224

R² = 0.63961

k = 0.08147

R² = 0.91493

n = 0.50511

R² = 0.75899

k = 1.5273

R² = 0.97374

k = - 0.04351

R² = 0.88414

k = 13.54015

R² = 0.46302

k = 0.06771

R² = 0.94871

n = 0.32008

R²= 0.76849

k = 1.60281

R² = 0.97589

k = -0.04395

R² = 0.88879

k = 13.63745

R² = 0.47075

k = 0.06807

R² = 0.94193

n = 0.33416

R² = 0.8895

k = 1.38553

R² = 0.97683

k = - 0.03442

R² = 0.85158

k = 13.09502

R² = 0.63929

k = 0.08152

R² = 0.95859

n = 0.49822

R² = 0.89752

k = 1.38553

R²= 0.94317

k = - 0.02297

R² = 0.76779

k = 10.80315

R² = 0.73145

k = 0.08445

R² = 0.89767

n = 0.55986

R² = 0.96985

k = 0.9036

R² = 0.9531

k = - 0.01215

R² = 0.76409

k = 6.80413

R² = 0.84209

k = 0.06894

R² = 0.9353

n = 1.22722

R² = 0.96306

k = 0.54397

R² = 0.9583

k = - 0.00653

R² = 0.74779

k = 4.0722

R² = 0.85744

k = 0.05826

R² = 0.93709

n = 1.30159

The release kinetics of the dissolution data were considered by various models such as Zero Order (Fig. 3а), First Order (Fig. 3b), Higuchi (Fig. 3c), Hixon-Crowell (Fig. 3d), and Korsmeyer-Peppas (Fig. 3e). The pH values of dissolution media consisted of 200ml imitatingsoft beverage and 700ml of pH=6.8 0.1M phosphate buffer, Ph. Eur. were also measured. The values are given in Table 6.

The data obtained from the in vitro drug release study in 700ml media with the presence of 200ml sucrose solution imitating soft beverages were fitted to different kinetic models. The resulting coefficients are presented in Table 7.

The obtain results correlate with the results of dissolution test with original beverages.The release begins at 10^th minute in medium with added imitation beverage with the lowest sucrose concentration (9% and 9.4%).At a concentration of sucrose above 10%, the release of the active substance begins at the 15^th minute, at 20% - on the 20^th minute and the released active substanceis about 30% of the declared on the label. At a concentration of 32 and 64%of sucrose in the medium, release starting at 15^th minute but the released ASA is respectively 4.92% and 2.74%. In a medium with added sucrose the release profile follows a first order kinetics, like in a medium with added original beverages. The obtained results give us reason to suppose that the concentration of sugars in soft drinks is one of the factors that influence the release of ASA from Aspirin protect^®. Due to the direct relationship between sugar concentration and the viscosity of the medium, we intend to investigate how the change of viscosity affects the release of the active substance in our next study.

CONCLUSION:

This study was carried out to determine if there is an alteration of in vitro dissolution release of gastro-resistant tablets when co-administered with soft beverages. The study showed reduction of the release rate in case of glucose-fructose syrup presence. Release rate depended on the concentration of sugar content in soft beverage. When the soft beverage does not contain sugar or glucose-fructose syrup no change in rate of release was observed. The presence of sugar or glucose-fructose syrup in soft drinks, which are often used by patients to swallow tablets, changes the kinetics of release of acetylsalicylic acid from the gastro-resistant tablets, compared to beverages with sweetening agents in vitro. The most significant change that we observed in vitro for the release of ASA from gastro-resistant tablets was the change in release kinetics in the presence of soft drinks containing sugar or glucose-fructose syrup, compared to those with artificial sweeteners. The release kinetics of the active substance in the medium with added beverage with sweeteners followed Korsmeyer-Peppas model release, the same model of release like in simulated intestinal fluid, while the model that best described the release from the medium with added soft drink with sugar content is First order. The habit of swallowing the drug with liquids other than water must be done with caution although differences in the amount released aspirin was not significant, change in release kinetic is sufficient reason.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

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Received on 30.07.2020 Modified on 17.02.2021

Research J. Pharm.and Tech 2021; 14(12):6345-6352.

DOI: 10.52711/0974-360X.2021.01097