Резюме
Портянко В.С., Коваленко Св.М. Розробка технології гелю для лікування гінгівітів.
За допомогою проведених технологічних досліджень обґрунтовано параметри приготування стоматологічного гелю комплексної дії для лікування гінгівітів. Обрано оптимальні умови, послідовність змішування, температурний режим тощо. На підставі цих досліджень було розроблено технологічну схему виробництва гелю, що включає сім стадій. Дана технологія була опробована у промислових умовах.
Ключові слова: стоматологія, гель, технологія, амінокапронова кислота, триклозан, лавандова олія.
Резюме
Портянко В.С., Коваленко Св.Н. Разработка технологии геля для лечения гингивитов.
С помощью проведенных технологических исследований обоснованы параметры приготовления стоматологического геля комплексного действия для лечения гингивитов. Выбрано оптимальные условия, последовательность смешивания, температурный режим и т.д. На основании этих исследований была разработана технологическая схема производства геля, состоящая из семи стадий. Данная технология была апробирована в промышленных условиях.
Ключевые слова: стоматология, гель, технология, аминокапроновая кислота, триклозан, лавандовое масло.
Summary
Portyаnko V.S., Kovalenko Sv.N. Development of gel technology for treatment of gingivitis.
With technological research conducted reasonably parameters dental gel preparation of comprehensive treatment for gingivitis. Selected optimal conditions, the sequence of mixing, temperature and etc. Based Tsikh studies were developed technological scheme of the gel, which includes seven stages. This teсhnology was of approbation of the in the industrial environments.
Key words: dentistry, gel, teсhnology, aminocaproic acid, triclosan, essential oil of lavena.
Рецензент: д.фарм.н., проф. Є.В. Гладух

УДК 615.242:615.014.22:615.454.1

Національний фармацевтичний університет (Харків)

Национальный фармацевтический университет (Харьков)

61002, г. Харьков, ул. Пушкинская, 53

National University of Pharmacy (Kharkov)

Ukraine, 61002, Kharkov, 53, str. Pushkinska

lana_koval@mail.ru

Introduction. Gingivitis is an inflammatory disease of the gums, characterized by hyperemia, swelling and bleeding gums with minimal trauma. The most common cause of gingivitis is inappropriate oral hygiene, resulting in the formation of dental plaque (colonies of microorganisms closely connected with the tooth surface) [8,9,10,17,18,19]. Gingivitis can also occur because of pathological occlusion, dental tartar (calcified dental plaque). For these categories of patients the disease is usually more severe due to the hormonal changes in the body. Gingivitis can also be a sign of a systemic disease (e.g., herpes, allergies, vitamin deficiency, leucopenia, which depletes patients) [11,12,13,14].

Development of modern external action medicines for the treatment of inflammatory periodontal diseases - gingivitis - is an urgent problem in dentistry [1,3,4].  This is due to the massive spread of this disease, especially among young people. Gingivitis always preceds a more severe inflammatory and destructive periodontal damage - chronic periodontitis [15,16,17].  Therefore, the prevention of the later is based on the effective treatment of inflammatory periodontitis – gingivitis [18,19,20]. 

To develop a contemporary local action gel for the treatment of gingivitis, we chose the following active substances: a famous antibacterial ingredient - triclosan [8], aminocaproic acid (the main action - hemostatic) and essential oil of lavender, which exhibits high anti-inflammatory, antibacterial, regenerative activity [5,6,7].

As the dental preparation of local action is planned to be used in dentistry, therefore, there is a certain number of requirements for the properties of the base vehicle [2,21]:

• necessity to provide a pH level close to the oral mucosa and moderate osmotic activity;
•  absence of irritating and sensitizing action, the base must not contain any allergenic ingredients not to provoke exacerbation;
• painless application to the mucosa and providing the uniform distribution, completeness and release of active substances rate;
• storage stability, satisfactory consumer characteristics.

In the development of experimental some samples standard equipment, necessary for the production of soft medicinal forms was used.

Connection of the work with academic programs, plans, themes. This work was performed in accordance with the research work plan of National University of Pharmacy ("Technology of obtaining of original and combined pharmaceuticals in various dosage forms", state registration number 0108U009174) and the Problem Commission "Pharmacy" of Ministry of Health and Medical Sciences Academy of Ukraine.

Aim of work. Development of a rational gel technology for the treatment of gingivitis, step-by-step description of each technological operation (temperature regime, stirring regime, time of the process etc.).

Materials and methods of research. As objects of study while processing the technology experimental gel samples with the chosen substances were taken: carbomer "Ultrez 10", sorbitol, aminocaproic acid, triclosan and lavender oil. To determine the optimal technological parameters some laboratory equipment (mini reactor with agitators, homogenizer etc.) was used. The technology was tested under industrial conditions.

Research of indicators (structural viscosity ŋ (mPa·s), shear stress τ_r (Pa), shear rate Dr or γ (s^-1) was performed on the viscometer BROOKFIELD DV-II + PRO (USA). PH indicators of the gel samples were determined by potentiometric method using the device "pH Meter Metrohm 744" (Germany). For quality control of the developed samples the recommendations and methodologies given in the 1 edition of SPhU "Soft drugs for topical application," p. 507 – 511were followed.

Results and Discussion. During the first stage some gel base was prepared according to the classical scheme: carbomer "Ultrez 10" powder was dispersed in particles of purified water at a room temperature. This process (dispersion) occurred within an hour. In order to neutralize the carbomer the freshly prepared10% solution of sodium hydroxide (to the desired pH and thus structural viscosity) was added. As a result, a clear gel base was received to which some sorbitol was added.

At the same time some active substances and a preservative were dissolved in solvents. Aminocaproic acid, Nipagin were dissolved in purified water, triclosan and lavender oil were dissolved in ethyl alcohol 96%. All the solutions were prepared at a room temperature with constant stirring until homogeneous clear ones, which were then added to the produced gel base.

The technological process of gel obtaining consists of:

• an auxiliary work stage;

• a main technological process stage;

• a packaging, labeling and shipping of finished products to the warehouse stage.

The results of experimental studies were used in development of technological regulations of the gel for the treatment of gingivitis.

The manufacture of the developed drug consists of seven stages of the main technological process and three stages of packing, a brief description of which is given below.

Figure 1 shows critical parameters and critical stages, the parameters that are directly controlled and are related to the control of the developed gel production.

Manufacture preparation (is not shown in the diagram). It consists of preparation of the premises, equipment and facilities, personnel, raw material and other materials, inspection of the required documentation.

Stage 1. Weighing of the gel components

Raw material for the gel preparation undergoes the incoming inspection.

After passing the incoming inspection the raw material is delivered to the place by transporting carriages.

With the help of scales all the components are consistently weighed into the collectors and transferred by transporting carriages during stages 2-6.

Stage 2. Preparation of aminocaproic acid and Nipagin solution.

From a measuring tank, the required amount of purified water is measured into the reactor. With the help of scales in the collector the required amount of aminocaproic acid and Nipagin is weighed and manually loaded into the reactor. Then the mixture is stirred until aminocaproic acid and Nipagin powders are completely dissolved.

The aminocaproic acid solution is then passed to stage 6 using compressed air. Visual control is used. The solution must be completely transparent and have no undissolved particles.

Stage 3. Preparation of triclosan and lavender oil solution in ethanol

On scales the required amount of triclosan, lavender oil and ethanol are weighed into the collectors. Into the reactor with a propeller stirrer the ethanol is loaded at a room temperature and then triclosan and lavender oil being constantly stirred until complete dissolution are dissolved in it. The solubility is checked visually. The solution must be completely transparent and have no undissolved particles.

Stage 4. Preparation of sodium hydroxide solution

In order to obtain a carbomer based gel system the neutralizer solution - sodium hydroxide is prepared. The required amount of sodium hydroxide is weighed in the collector, and the required amount of purified water is transferred from a measuring tank. The solution of neutralizer is stirred with agitators until the substances are completely dissolved.

Stage 5. Obtaining the gel base.

To obtain a base the required amount of purified water is measured into the reactor and a preservative is added from a collector, then the stirrer is turned on and the mixture is stirred for 3 minutes. Preservative dissolution is performed at a room temperature. The same reactor is then gradually loaded with small portions of gelling agent powder - carbomer and left for an hour. An hour later the dispersed solution is stirred with the turned on reactor stirrers until a homogeneous dispersion which is visually controlled. It must be homogenous, and have no lumps.

For gel preparation the neutralization of carbomer dispersion is carried directly in the reactor with constant stirring (rotation speed 800 r / min). With the help of vacuum the required amount of the neutralizer solution (sodium hydroxide) is loaded in several steps – as a result the process of gelation occurs.

In order to prevent the formation of areas with a high content of alkali thickener, which in turn may contribute to carbomer sedimentation and gel destabilization, as well as to achieve the most complete uniformity and gradually increase of the gel viscosity the solution of sodium hydroxide is introduced gradually. After introduction of each portion of sodium hydroxide solution the mixture in the reactor is stirred with a gate and blade stirrers for 2-3 minutes.

The obtained mass is stirred for 20 minutes with simultaneous addition of vacuum until a homogeneous transparent colorless gel base is formed. The gel is controlled for homogeneity and pH value.

Stage 6. Gel obtaining

Into the reactor with the previously prepared at stage 4 gel base the solution of aminocaproic acid, Nipagyn from stage 2 are sequentially introduced, mixed thoroughly, then the alcoholic solution of triclosan and lavender oil from stage 3 is added. Gate stirrer is then turned on and the mixture is stirred for 30 minutes until it is homogeneous.

Stage 7. Homogenization of the gel

Homogenization is carried out in a reactor with a gate stirrer for 20 minutes with simultaneous vacuuming to avoid an aeration process in the gel.

After homogenization some control samples from different zones of the reactor are selected and the analysis of the intermediate product - finished gel - is carried out. The gel must be a homogeneous translucent mass with a smell peculiar to lavender oil and must meet all the requirements of Quality Control Techniques.

Stage 8. Packing gel into tubes

The obtained gel is pumped into the hopper of a tube filling machine GF-12, whereby the gel is packed in aluminum tubes with Bushonnes. The dosing accuracy, producing ability of the machine and tube labeling (batch number and expiration date) are controlled.

Stage 9. Packaging tubes into packets.

Tubes with instructions for use are packaged into packets. The package content (tube, instructions, Bushonnes) is controlled.

Stage 10. Packaging packs into a group container.

On the packing table packaging packs into boxes is carried out manually. The series of finished product is formed at one load of the reactor-homogenizer.

Critical parameters: the amount of raw material, rotating speed of gate and blade stirrers.

Critical operations: raw material weighing, aqueous phase components dissolution, homogenization.

Parameters monitored: raw material weight, stirrers rotating speed, gel components dissolution, the appearance of the gel, the unpacked gel compliance to the requirements of Quality Control Techniques.

Measuring techniques: weighting, physical, visual, physico-chemical.

Сonclusions

1. With the help of the technological research conducted we have grounded the technological parameters of preparation of a dental gel with a number of active substances: aminocaproic acid, triclosan and lavender oil. Conclusions

 2. The conditions of preparation, sequence of mixing and temperature regime of the developed drug were determined as well. Based on these research the manufacturing block diagram of a new drug - gel for the treatment of gingivitis was made. The technology of the dental gel was tested under industrial conditions.

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