RU2261092C1 - Pharmaceutical composition eliciting anesthetic activity - Google Patents

Abstract

FIELD: medicine, pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition used in stomatology in the topical anesthesia. The pharmaceutical composition comprising articaine hydrochloride and epinephrine hydrochloride and accessory substances, such as sodium metabisulfite, sodium chloride and water for injection involves additionally glycine and pH-regulating substance taken in the definite ratio of components. Invention provides preparing the preparation that is stable, non-toxic and doesn't cause allergic response reactions and elicits highly expressed infiltration and conducting anesthetic activity, good tissue tolerance and activity promoting to accelerated wound-healing in the post-operative period.

EFFECT: improved and valuable medicinal properties of composition.

3 cl, 3 ex

Description

The invention relates to the pharmaceutical industry, namely to pharmaceutical compositions used in dentistry with local anesthesia.

A known drug under the name "Xylonor" [1], which is an anesthetic local-regional action, manufactured by ZAO World Health Systems (WHS), Russia. The drug is available as an injectable solution and contains 1.8 ml per main ingredient 1.8 ml of lidocaine hydrochloride, norepinephrine tartrate, expressed in norepinephrine base 0.036 mg, epinephrine base 0.036 mg, sodium chloride 11.70 mg, disulfate potassium (corresponding to Sox2) 1.24 mg, sodium edetate 0.45 mg, methyl parahydroxybenzoate 1.44 mg, propyl hydroxybenzoate 0.36 mg, hydrochloric acid 0.388 Ml, sodium hydroxide solution as pH of the regulatory substance pH 5.00 ± 0.20 and water for injection. Introduced into the oral cavity through local infiltration anesthesia, lidocaine reaches its peak concentration in the blood approximately 10-15 minutes after the injection. Anesthesia occurs after 2-3 minutes and lasts 90-120 minutes at the level of soft tissues and 5-10 minutes at the level of pulp. The half-life is long and approximately 90 minutes. The drug is an effective anesthetic for any type of classic dentistry intervention. However, the drug has disadvantages, which include a long half-life, various allergic reactions due to high systemic toxicity, an adverse effect on wound healing due to low tissue tolerance.

Known pharmaceutical composition used in dentistry, under the name "Septanest with adrenaline," produced in the form of a solution for injection [2]. The preparation contains 1.8 ml of articaine hydrochloride 72.0 mg in karpul, adrenaline tartrate: epiphedrine bitartrate 0.033 mg, epinephrine base 0.18 mg and excipients such as sodium chloride 2.88 mg, sodium disulfite (sodium metabisulfite) 1, 8 mg, sodium edetate 1.8 mg, sodium hydroxide solution as a pH of a regulatory substance to pH 6.0 + 0.2 and water for injection 1.8 ml. The action of the drug reaches its peak 17 minutes after the injection, the elimination half-life is about 25 minutes, which reduces its toxicity and reduces possible allergic reactions. However, the drug can still cause serious allergic reactions in some patients due to the presence of sodium edetate and a large amount of sodium disulfite in its composition. In addition, the pharmaceutical composition does not have a pronounced infiltration and conductive anesthetic activity.

Closest to the claimed pharmaceutical composition is a pharmaceutical composition for injection with anesthetic activity, called "Ultracain D - C forte" based on articaine and epinephrine [3]. The composition of the components per 1 ml is as follows: articaine hydrochloride 40 mg, epinephrine hydrochloride 12 μg, excipients, such as sodium metabisulfite 0.55 mg, sodium chloride, water for injection. The action of the drug "Ultracain D - C forte" begins after 1-3 minutes, and the duration of anesthesia is 75 minutes. The drug is 2 times stronger than lidocaine, 6 times stronger than novacaine and has high diffusion ability, low toxicity and a small vasoconstrictor effect, which has a more positive effect on wound healing, less side effects due to the absence of sodium edetate in its composition. The half-life is 25.3 minutes. The disadvantages of the drug include some toxicity resulting from the presence of sulfites in the drug, which nevertheless cause serious allergic reactions in some patients.

The basis of the invention is the task to create such a pharmaceutical composition in which by using the main components and auxiliary components taken in a certain ratio, and also thanks to the introduction of an additional component, a significant reduction in toxicity, increased infiltration and conduction anesthetic activity, improved tissue tolerance and accelerated wound healing are achieved.

The problem is solved in that in the known pharmaceutical composition having anesthetic activity containing articaine and epinephrine and auxiliary substances, such as sodium metabisulfite, sodium chloride, pH regulating substance and water for injection, according to the invention glycine is additionally contained in the following ratio of components, g :

Articaine hydrochloride 38.0-42.0 Epinephrine base 0.005-0.12 (in the form of hydrochloride) Sodium metabisulfite 0.25-0.55 Glycine 4.0-20.0 Sodium chloride 0.36-0.8 PH regulatory substance 8.5-12.5 Water for injections up to 1 l

Preferably, the pharmaceutical composition has a content of components, g:

Articaine hydrochloride 40,0 Epinephrine base 0.01 (in the form of hydrochloride) Sodium metabisulfite 0.3 Glycine 8.0 Sodium chloride 0.4 PH regulatory substance 10.0 Water for injections up to 1 l

In addition, a 1 M solution of hydrochloric acid is used as the pH of the regulatory substance.

In this pharmaceutical composition, articaine hydrochloride, an amide type anesthetic belonging to the thiophene group, is used as the active substance. In tissues it undergoes hydrolysis and releases the base, which has lipophilic properties, and easily penetrates through the membrane into the nerve fiber. Ionized and transformed into a cation. Interacting with receptors, inhibits the entry of sodium ions into the cell in the depolarization phase and blocks the conduction of an impulse along the nerve fiber. A high percentage of plasma protein binding in articaine confirms that 95% of the drug reaches the bloodstream in the form of a pharmacologically inactive substance and indicates low systemic toxicity and high efficiency of anesthesia. The composition of the pharmaceutical composition includes a vasoconstrictor - epinephrine (in the form of hydrochloride), which, while exerting a vasoconstrictor effect, inhibits the systemic absorption of articaine and the development of its side effects, and also prolongs the action of the main active substance - articaine for up to 360 minutes.

Due to the introduction of such an amino acid as glycine (aminoacetic acid) into the pharmaceutical composition, the action of the vasoconstrictor, epinephrine, is enhanced and the action of the main active substance, articaine, is prolonged for a longer time. Glycine enhances the action of the main active substance - articaine, which allows the use of the smallest doses of the drug solution. Anesthesia occurs after 0.5-3 minutes and lasts at least 75 minutes. In addition, glycine in aqueous solutions of artecain with epinephrine binds heavy metal ions that are present in sodium metabisulfite, injection water, feedstock, and thus glycine acts as a complexing agent and contributes to the stability of the drug during storage for two years. Glycine also strengthens the cell, protects, nourishes it in a stressful situation, has a sedative effect, which is very important in surgical stomatological intervention. The use of glycine slows the passage of articaine in the general circulation and thus ensures the preservation of active tissue concentration, which in turn contributes to good wound healing in the postoperative period. In addition, the introduction of glycine can reduce the content in the composition of such a stabilizer (antioxidant) as sodium metabisulfite, which in turn reduces the content of sulfites. As medical practice shows, the amount of sulfites in the anesthetic solution should be minimal, since sulfites can cause allergies and provoke an attack of bronchial asthma. Thus, the introduction of glycine reduces the risk of allergic reactions. As a result of preclinical and clinical studies, the optimal amount of glycine content in the pharmaceutical composition was established, which is 4.0-20.0 g per 1 liter. The half-life is 21.9 minutes. Low systemic toxicity of the drug is ensured due to the fact that glycine binds to plasma proteins (up to 95%), as well as due to the fast half-life. This allows you to safely use the pharmaceutical composition for children, pregnant women, nursing mothers and the elderly. The stability of the finished product is ensured by the introduction of a stabilizer (antioxidant) - sodium metabisulfite in a dose that is safe for patients and a complexing agent - glycine, as well as adjusting the pH of the medium to a certain level by introducing a pH of a regulatory substance into the composition, for which a 1 M solution of hydrochloric acid in the amount of 8.5-12.5 g per 1 liter. The optimal pH level at which the maximum resistance of the pharmaceutical composition is achieved is determined in the range of 3.5-4.5.

Thus, a stable and non-toxic pharmaceutical composition was obtained, which has a pronounced infiltration and conduction anesthetic activity, good tissue tolerance and promotes accelerated wound healing.

The pharmaceutical composition is prepared in this way.

Example 1

The solution is prepared in a graduated glass reactor with a capacity of 30 l, equipped with an anchor stirrer. Chilled water for injection with a temperature of 18 ° C is fed into the reactor, passing it through a sterilizing filter, and saturated with filtered nitrogen at a pressure of 0.003 MPa for 20 minutes.

After that, sodium metabisulfite in the amount of 0.01705 kg and pre-calcined sodium chloride in the amount of 0.0108 kg are manually charged through the loading hatch and mixed thoroughly for 10 minutes. Then 0.6 kg of glycine is added to the reactor and the solution is mixed again for 15 minutes.

Then, 1.14 kg of articaine hydrochloride is charged through the hatch into the reactor and stirred until complete dissolution for 15 minutes.

After that, 900 ml of water for injection at room temperature, previously saturated with nitrogen in the reactor, is poured into a separate glass container with a capacity of 1 liter, 0.255 kg of a 1 M hydrochloric acid solution is added and 0.00036 kg of epinephrine base are added. The solution is stirred until complete dissolution of epinephrine within 10 minutes. The resulting solution of epinephrine hydrochloride is quantitatively transferred to the reactor, and then the contents of the reactor are stirred for 10 minutes. A sample is taken through the hatch and the pH of the solution is determined, which should be in the range of 3.5-4.5. The pH adjustment of the solution is carried out with a 1 M solution of hydrochloric acid to the required limits.

At the end of the adjustment, the pH of the solution stops the stirrer of the reactor and adjusts its contents in a label to 25 L, adding water for injection with pre-saturated nitrogen. The solution is stirred for 15 minutes.

At the end of the solution preparation process, a sample is taken for analysis according to the step-by-step control method and the appearance of the solution is determined, the pH of the solution is in the range of 3.5-4.5, the content of articaine hydrochloride in 1 ml of the solution is 0.038 g, the content of epinephrine hydrochloride is from 0.000012 g , sodium metabisulfite content 0.00055 g, glycine content from 0.02 g.

If the quantitative content of the components is deviated, the concentration of the solution is adjusted by adding the calculated amounts of the substance or water for injection pre-saturated with nitrogen.

Then carry out sterilizing filtration of a solution of articaine with epinephrine. The solution from the reactor is pumped to the filters with a pressure of 0.10-0.12 MPa, passed through a preliminary filter with a pore size of 0.45 μm and a finishing sterilizing filter with a pore size of 0.2 μm.

After that, the filtered solution of articaine with epinephrine is fed into a sterile collection of filtered solution.

Then, filling the capsules and capping them is carried out on a special machine for filling and capping the CFV AA capsules by N. STRUNCK + CO (GF-25), 1.8 ml each.

When preparing the solution and filtering, all the equipment is sheathed from light and the whole process is carried out under aseptic conditions, including filling and capping of the capsules.

Example 2

The solution is prepared in a graduated glass reactor with a capacity of 30 l, equipped with an anchor stirrer. Chilled water for injection with a temperature of 19 ° C is fed into the reactor, passing it through a sterilizing filter, and saturated with filtered nitrogen at a pressure of 0.003 MPa for 20 minutes.

After that, sodium metabisulfite in an amount of 0.0093 kg and pre-calcined sodium chloride in an amount of 0.012 kg are loaded manually through a loading hatch and mixed thoroughly for 10 minutes. Then 0.24 kg of glycine is added to the reactor and the solution is mixed again for 15 minutes.

Then, 1.2 kg of articaine hydrochloride is charged through the hatch into the reactor and stirred until complete dissolution for 15 minutes.

After that, 900 ml of water for injection at room temperature, previously saturated with nitrogen in the reactor, is poured into a separate glass container with a capacity of 1 liter, 0.3 kg of a 1 M hydrochloric acid solution is added, and 0.00003 kg of epinephrine base are added. The solution is stirred until complete dissolution of epinephrine within 10 minutes. The resulting solution of epinephrine hydrochloride is quantitatively transferred to the reactor, and then the contents of the reactor are stirred for 10 minutes.

A sample is taken through the hatch and the pH of the solution is determined, which should be in the range of 3.5-4.5. The pH adjustment of the solution is carried out with a 1 M solution of hydrochloric acid to the required limits.

At the end of the adjustment, the pH of the solution stops the stirrer of the reactor and adjusts its contents by label to 25 L, adding water for injection, previously saturated with nitrogen. The solution is stirred for 15 minutes.

At the end of the solution preparation process, a sample is taken for analysis according to the step-by-step control method and the appearance of the solution is determined, the pH of the solution is in the range of 3.5-4.5, the content of articaine hydrochloride in 1 ml of the solution is 0.040 g, the content of epinephrine hydrochloride is 0.000008 g, the sodium metabisulfite content is 0.0003 g, the glycine content is 0.008 g.

If the quantitative content of the components is deviated, the concentration of the solution is adjusted by adding the calculated amounts of the substance or water for injection pre-saturated with nitrogen.

Then carry out sterilizing filtration of a solution of articaine with epinephrine. The solution from the reactor is pumped to the filters with a pressure of 0.10-0.12 MPa, passed through a preliminary filter with a pore size of 0.45 μm and a finishing sterilizing filter with a pore size of 0.2 μm.

After that, the filtered solution of articaine with epinephrine is fed into a sterile collection of filtered solution.

Then, the capsules are filled and corked on a special machine for filling and capping the CFV AA capsules by H. STRUNCK + CO (GF-25), 1.8 ml each.

When preparing the solution and filtering, all the equipment is sheathed from light and the whole process is carried out under aseptic conditions, including filling and capping of the capsules.

Example 3

The solution is prepared in a graduated glass reactor with a capacity of 30 l, equipped with an anchor stirrer. Chilled water for injection with a temperature of 20 ° C is fed into the reactor, passing it through a sterilizing filter, and saturated with filtered nitrogen at a pressure of 0.003 MPa for 20 minutes.

After that, sodium metabisulfite in the amount of 0.0775 kg and pre-calcined sodium chloride in the amount of 0.024 kg are manually charged through the loading hatch and mixed thoroughly for 10 minutes. Then, 0.12 kg of glycine was added to the reactor and the solution was stirred again for 15 minutes.

Then 1.26 kg of articaine hydrochloride is charged through the hatch into the reactor and stirred until it is completely dissolved within 15 minutes.

After that, 900 ml of water for injection at room temperature, previously saturated with nitrogen in the reactor, is poured into a separate glass container with a capacity of 1 liter, 0.375 kg of a 1 M hydrochloric acid solution is added and 0.000015 kg of epinephrine base is added. The solution is stirred until complete dissolution of epinephrine within 10 minutes. The resulting solution of epinephrine hydrochloride is quantitatively transferred to the reactor, and then the contents of the reactor are stirred for 10 minutes. A sample is taken through the hatch and the pH of the solution is determined, which should be in the range of 3.5-4.5. The pH adjustment of the solution is carried out with a 1 M solution of hydrochloric acid to the required limits.

At the end of the adjustment, the pH of the solution stops the stirrer of the reactor and adjusts its contents by label to 25 L, adding water for injection, previously saturated with nitrogen. The solution is stirred for 15 minutes.

At the end of the solution preparation process, a sample is taken for analysis according to the step-by-step control method and the appearance of the solution is determined, the pH of the solution is in the range of 3.5-4.5, the content of articaine hydrochloride in 1 ml of the solution is 0.042 g, the content of epinephrine hydrochloride is 0.000012 g, the content of sodium metabisulfite is 0.00025 g, the glycine content is from 0.004 g.

If the quantitative content of the components is deviated, the concentration of the solution is adjusted by adding the calculated amounts of the substance or water for injection pre-saturated with nitrogen.

Then carry out sterilizing filtration of a solution of articaine with epinephrine. The solution from the reactor is pumped to the filters with a pressure of 0.10-0.12 MPa, passed through a preliminary filter with a pore size of 0.45 μm and a finishing sterilizing filter with a pore size of 0.2 μm.

After that, the filtered solution of articaine with epinephrine is fed into a sterile collection of filtered solution.

Then, the capsules are filled and corked on a special machine for filling and capping the CFV AA capsules by H. STRUNCK + CO (GF-25), 1.8 ml each.

When preparing the solution and filtering, all the equipment is sheathed from light and the whole process is carried out under aseptic conditions, including filling and capping of the capsules.

The resulting preparation has anesthetic activity and meets the requirements of analytical regulatory documentation.

Thus, a pharmaceutical composition is obtained in the form of a drug articaine with epinephrine, which is a stable, less toxic and non-allergic pharmaceutical composition with pronounced infiltration and conduction anesthetic activity, good tissue tolerance and promoting accelerated wound healing.

Sources of information

1. Anesthetic drug "Xylonor" company "World Health Systems" (WHS), www.stomat.ru

2. Anesthetic drug "Septanest with adrenaline", catalog of the company "Septodont", 2003, S. 127-128.

3. Anesthetic drug "Ultracain DS Forte" of the pharmaceutical company "Hoechst Merion Russel", http://medi.ru/doc/f5644.htm

Claims (3)

1. A pharmaceutical composition having anesthetic activity, containing articaine hydrochloride and epinephrine hydrochloride and excipients, such as sodium metabisulfite, sodium chloride and water for injection, characterized in that it additionally contains glycine and pH regulating substances in the following ratio, g: Articaine hydrochloride 38.0-42.0 Epinephrine Hydrochloride 0.005-0.012 Sodium metabisulfite 0.25-0.55 Glycine 4.0-20.0 Sodium chloride 0.36-0.8 pH Regulatory 8.5-12.5 Water for injections Up to 1 liter 2. The pharmaceutical composition according to claim 1, characterized in that it has a content of components, g: Articaine hydrochloride 40,0 Epinephrine Hydrochloride 0.01 Sodium metabisulfite 0.3 Glycine 8.0 Sodium chloride 0.4 pH Regulatory 10.0 Water for injections Up to 1 liter 3. The pharmaceutical composition according to claims 1 and 2, characterized in that a 1 M solution of hydrochloric acid is used as the pH of the regulatory substance.