Alginomax - antireflux antacid drug

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ALGINOMAX – ANTI-REFLUX ANTACID PREPARATION
Мakarenko М.V.1
, Petrov P.Т.1
, Kazyuchits O.A..2
, Usanov S.А.1
1 Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Minsk, Belarus
2
State Enterprise “AKADEMFARM”, Minsk, Belarus
makarenko@iboch.bas-net.by
Currently, a significant proportion of diseases of the digestive system are
acid-related diseases, which include gastroesophageal reflux
disease (GERD), peptic ulcers of the stomach and duodenum associated
and not associated with Helicobacter pylori, functional dyspepsia, and
symptomatic endocrine ulcers (Zollinger-Ellison syndrome, ulcers in
hyperparathyroidism). The relevance and significance of the problem of treating these diseases
due to the widespread prevalence (40-50%) and the frequent development of serious
complications leading to disability. Pathogenetic basis of diseases –
acidic aggression of gastric juice.
The purpose of this work is to develop and study in vitro properties
combined antacids. Antacid medicines (ALS) are not
affect the production of gastric juice, they reduce the acidity of the gastric
contents by neutralizing the hydrochloric acid of gastric juice in the stomach cavity,
adsorb pepsin, bile acids and lysolecithin (involved in damage
mucous membrane of the stomach and esophagus). Antacids differ from each other in composition and
the ratio of ingredients, which determines their acid-neutralizing activity (KNA),
buffer capacity (BA), the rate of onset of the therapeutic effect, duration and
effectiveness of action Most antacids contain pharmaceutically acceptable
carbonic acid salts of alkali and alkaline earth metals in various compositions or
combinations, aluminum phosphate and the corresponding hydroxides, magnesium trisilicate.
the ingredient has its own pharmacological characteristics. Changing the ratio
ingredients can influence the effectiveness of the drug and reduce side effects,
which can be caused by the use of each of the ingredients separately. Traditionally
all antacids are divided into absorbable and non-absorbable. In modern treatment regimens
less commonly, absorbable antacids are used due to serious adverse reactions: being absorbed,
they affect the exchange of electrolytes and the body as a whole (systemic effects), have
“Ricochet phenomenon” – stimulate the release of hydrochloric acid (secondary
hypersecretion). Nonabsorbable antacids have higher BA and KPA,
the duration of their action reaches 2.5-3 hours. Among antacids, one can conditionally
highlight [1] two groups: monopreparations and combined (binary and compositional)
ALS. Representatives of the first group – aluminum hydroxide (algeldrate) and aluminum
phosphoric acid salt (Phosphalugel, Gefal). Gefal was developed jointly
employees of IBOCH NAS of Belarus and JSC Belmedpreparaty and now widely
used in clinical practice [2]. The second group – aluminum-magnesium antacids
(Maalox, Almagel, Alumag), calcium-magnesium antacids (Rennie, Tams).
aluminum-containing preparations is fraught with the risk of developing serious complications in
in the case of prolonged and uncontrolled use (osteopathy, encephalopathy,
nephropathy), recently clinicians do not recommend long-term use
aluminum-containing antacids (no more than two weeks). Therefore, we have developed
binary pharmaceutical compositions of preparations that do not contain aluminum [3].
A compositional composition of a medicinal product has also been developed, containing
hydroxyapatite, magnesium and aluminum hydroxides [4]. Use as an ingredient
Hydroxyapatite reduces the aluminum content and increases the amount of magnesium.

Which in turn helps to neutralize the blocking effect of calcium and
aluminum due to the laxative effect of magnesium. Magnesium hydroxide provides
rapid onset of acid-neutralizing action, prevents the release of pepsin,
enhances mucus formation and resistance of the gastric mucosa. Testing
antacid properties of binary and composite substances showed a high initial
reaction rate (pH4 ‘in the range of 4.58-6.32 and 4.62-6.81, respectively), which provides
fast therapeutic effect on application and safety of samples (pH20 ‘in
within 4.73-6.89 and 5.93-6.92). Samples of the substance showed high values of the buffer
capacities are the key characteristics of antacids: 10.51-18.90 meq and 13.37-18.74 meq,
accordingly, which exceeds the normative level of BA≥8 meq [5]. Most
the traditional indicator of the effectiveness and duration of action of drugs, their value
KNA, was 15.62-27.81 meq for the best binary samples, for composite samples
22.87-28.51 meq. According to the requirements of the American Pharmacopoeia, the value should be
KNA≥10 meq [6]. In practice, exceeding these values is considered a prerequisite for
further more in-depth study. According to meta-analysis 300
research, a clear link has been established between the effectiveness of a particular
antiulcer drug and the duration of the increase in pH in the lumen of the stomach at
its application: stomach ulcers scar in 100% of cases if the intragastric pH
manages to maintain at a level above 3.0 for 18 hours throughout the day [7].
Composite materials developed by us based on coprecipitated hydrogels
metal phosphates showed high KNA values with pronounced adsorption
properties [8]. Developed a method for obtaining carbonate-substituted hydroxyapatite in the form
highly dispersed nanophase gel with pronounced pH-stabilizing properties in
physiologically acceptable range of pH values as a pH-stabilizing
substances [9]. Some of the specified pharmaceutical substances can be
used as active substances in the creation of new dosage forms
antacids.
In recent years, there has been a reassessment of the role of antacids in the treatment of a number of
gastroenterological diseases, they are experiencing their “rebirth”. In spite of
introduction into the practice of treatment of patients with H2-blockers of histamine receptors and inhibitors
proton pump (PPI), antacids continue to play an important role in
therapy of many diseases of the digestive tract [10]. To a large extent, this
due to both a high percentage of side effects and adverse reactions
when using blockers of gastric secretion, and improving the quality
modern ALS. Antacids are included in almost all treatment regimens
acid-related diseases, which is primarily associated with the mechanism of action
of this pharmacological group. Release of antacids by pharmaceutical
companies all over the world is growing precisely because of the great demand. Most
III generation antacids are in demand for the treatment of peptic ulcers and GERD,
containing alginic acid (A02B X13 in the ATC classification system, 2009) and
possessing a unique pharmacological action. The drugs are effective for
treatment of GERD without esophagitis, as well as with reflux-esophagitis I-II degree, “hungry”
pain, heartburn in practically healthy people. GERD – Chronic Recurrent
a disease characterized by morphological changes in the mucous membrane
esophagus due to retrograde reflux of the gastric or gastrointestinal
contents. Throwing stomach contents into the esophagus can cause a “chemical burn”,
due to three aggressive factors: hydrochloric acid, activated
pepsin (more aggressive than acid), bile acids (active in both acidic and
and in a neutral environment, increase the risk of developing esophageal cancer).
is determined not only by its prevalence, but also by the gradual weighting of the course,
leading to possible complications of GERD: ulcers, strictures, Barrett’s esophagus, cough
and asthma, sore throat and larynx (pharyngeal reflux). GERD is rightfully considered

disease of the XXI century, since in recent years there has been a tendency to decrease
the incidence of gastric ulcer and duodenal ulcer and an increase
incidence of GERD.

The mechanism of action of alginate-containing drugs differs from the mechanisms
inherent in both “classic” antacids (adsorption and neutralization of hydrochloric acid), so
and H2-histamine blockers and proton pump inhibitors (pronounced and
prolonged suppression of acidic gastric secretion). Anti-reflux action
the drug is associated with the formation of a physical barrier in the form of a floating
an alginate-containing gel between the acidic contents of the stomach and the mucous membrane
esophagus. Alginates are polysaccharide polymers from brown marine
algae containing residues of D-mannuronic and L-guluronic acids. The main thing
the advantage of alginate-containing antireflux drugs – alginates do not have
systemic action and specific side effects. Alginate raft acts like
a physical barrier to acid and food reflux. With the same quick action,
as with antacids, the duration of their effect is significantly longer (> 4.5 hours).
Alginates have no significant effect on intragastric pH, mechanisms
production of hydrochloric acid in the stomach and digestion. A combination of immunomodulatory and
the sorbing properties of alginates ensures the success of the antiseptic and sorption
therapy of chronic diseases. A new algorithm for the treatment of GERD [11] takes into account
advances in clinical practice and recommends the use of alginate antacids in
as adjuvant therapy at all levels of treatment, both independently and in
combinations with antisecretory drugs. According to the latest guidelines for
treatment of GERD (Gstaad Guidelines for the Treatment of GERD, 2008) is initially prescribed
drugs from the group of alginates or antacids, and if the therapeutic
effect, switch to combined therapy with PPIs + alginates / antacids.
The most famous drugs of this type are Gaviscon (UK),
containing in one tablet of sodium alginate 250 mg, sodium bicarbonate 133.5 mg,
calcium carbonate 80 mg and double action Gaviscon containing alginate in a tablet
sodium 250 mg, sodium bicarbonate 213 mg, calcium carbonate 325 mg. in a tablet
Alginomax preparation contains the following content of active ingredients: sodium alginate
250 mg, potassium bicarbonate 75 mg, calcium carbonate 125 mg, magnesium hydroxide 45 mg
[12,13]. To optimize the composition of the drug, we experimentally tested
mixtures of a substance with varying amounts of sodium alginate and antacid ingredients
(carbonates and bicarbonates of alkali and alkaline earth metals, oxide or hydroxide
magnesium). As auxiliary substances – macrogol, copovidone, magnesium stearate,
hydroxyapatite, sorbitol, sodium saccharinate and flavor. Ability
alginate / bicarbonate / carbonate formulations to form a floating suspension in
is largely determined by the nature of the polysaccharide, composition and ratio
ingredients, in particular bicarbonate / carbonate salts, which determine
gas-generating properties of the preparation, strength and buoyancy of the resulting raft. V
in the acidic environment of the stomach, the alginate gel becomes buoyant by capturing bubbles
carbon dioxide, which allows the gel to remain on the surface of the contents of the stomach, when
this calcium and magnesium cations “crosslink” the polymers, forming a supramolecular
matrix structure. All active and auxiliary ingredients used
pharmacopoeial quality – meet the analytical specification Ph. Eur, BP, FCC.
The registration of the specified pharmaceutical substances in the Ministry of Health of the Republic of Belarus was carried out. Main raw material
(pharmaceutical substances), as well as auxiliary and packaging materials,
used for the production of tablets of the drug AlginoMAX are supplied to
production after carrying out in accordance with the established procedure incoming control,
confirming the compliance of their quality with all norms and requirements of the current
regulatory documentation. The manufacturing process of a medicinal product includes
the following stages: preparation of raw materials and auxiliary substances (sifting, weighing)

mixing of components by repeated dilution to obtain
homogeneous mixture, tableting. Control is carried out at all stages of production
technological process in accordance with the requirements of VTI No. 37-2013. Pills
packed in blisters – 14 tablets each in a blister strip packaging from a three-layer
films (PVC / PE / PVDC) and flexible packaging based on aluminum foil. By external
form of tablets oval biconvex white with a yellowish and brownish tint
color, tablet weight 1.02 ± 0.02 g. The drug meets the criteria of microbiological
purity: no more than 103 is allowed in 1 g
aerobes, no more than 102 mushrooms, in the absence of Esche richia coli.
Preclinical test results indicate that AlginoMAX does not
toxic to the body of animals in doses up to 5.5 g / kg with a single oral administration (6th
hazard class), does not have negative neurotropic, cardiotropic,
hematropic and organotropic effects when administered daily for 28 days in doses
up to 2 g / kg, does not have a local irritating effect on the gastrointestinal mucosa
tract in doses 4 times higher than those recommended for use in humans.
Methods for monitoring the quantitative content of chemical elements with
using the method of atomic emission spectrometry.
determination of the content of potassium, calcium and magnesium. Validation of methods
determination of cations. The analysis showed the compliance of the tablets with the requirements
of the FSP project.
The determination of the acid-neutralizing properties of the preparation was carried out under the conditions
in vitro models by the method described in the State Pharmacopoeia of Belarus, 2.2.20. In a porcelain mortar, carefully
ground 20 tablets. Weighed a sample equal to the average weight of two tablets and
placed in a glass with a capacity of 250 ml. 70 ml of distilled water was added,
stirred on a magnetic stirrer for 1 min. To the test solution was added
30.0 ml of 1.0 M hydrochloric acid solution. Stirred for 15 minutes, thoroughly
controlling the time. After the end of stirring, the excess
acid with 0.5 M sodium hydroxide solution until stable (at least 10-15 seconds)
pH value equal to 3.5, controlling the pH potentiometrically. The titration period should
take no more than 5 minutes. The results of in vitro studies have shown that, based on
single dose (2 tablets) acid-neutralizing activity corresponds to 10.82 ± 0.14
meq in a physiologically acceptable range of pH.
Method for assessing the weight and volumetric characteristics of the
alginate-containing raft was developed taking into account gelation in the alginate –
metal cations – hydrochloric acid and most fully simulates the behavior of the resulting
antacid-alginate raft in a solution of artificial gastric juice. In porcelain
20 tablets were thoroughly ground in a mortar. A weighed amount equal to the average weight of two tablets,
was added to 50 ml of distilled water with vigorous stirring. Received
the suspension was introduced with gentle stirring into a measuring glass with a capacity of 250 ml,
containing 150 ml of 0.1 M HCl at a water bath temperature of 37 ± 1.0 ° C. The resulting raft
kept in solution for 15 min, dried on filter paper at room temperature
temperature. It was found that the weight of the resulting raft is 27.87 ± 1.13 g, the volume of the raft is
32.80 ± 1.22ml.
Thus, the test results obtained confirm compliance with
pharmacopoeial requirements for the quality of drugs [6] and allow
predict the therapeutic effect in vivo when using an alginate-containing
AlginoMAX for the treatment of acid-related diseases, such as
peptic ulcer and gastroesophageal reflux. The drug can be recommended for
heartburn for pregnant and lactating women, children, as well as practically “healthy” people
and people of the elderly and senile age with the appearance of episodic heartburn. V
currently on the pharmaceutical market of the Republic of Belarus there are no
antireflux alginate-containing antacids. In this regard, the release on the pharmaceutical market
Of the Republic of Belarus of the domestic antireflux antacid drug
funds are highly relevant.

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ALGINOMAX – ANTIREFLUXANTACIDDRUG
Makarenko M.V.1
,Petrov P.T.1
, Kazyuchits O.A.2
, Usanov S.A.1
1
Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Minsk, Belarus
2
SE “Academpharm”, Minsk, Belarusmakarenko@iboch.bas-net.by
Antacid properties of newly synthesized binary and composition substances were studied in
conditions of model in vitro.Development of technology for antireflux antacids AlginoMAX has
been considered. Tablet formulation AlginoMAX contains active ingredients: sodium alginate 250
mg, potassium bicarbonate 75 mg, calcium carbonate 125 mg, magnesium hydroxide 45 mg. As
auxiliary substances – macrogol, copovidone, magnesium stearate, hydroxyapatite, sorbitol, sodium
saccharin and flavoring. Antireflux action of the drug is associated with the formation of a physical
barrier in the form of floating alginate-containing gel between the acidic contents of the stomach
and esophageal mucosa. The methods of monitoring and evaluation of antacid and formation of
alginate raft of drug have been developed