RU2555349C2 - Method for producing pharmaceutical emulsion of lactulose - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and represents a method for producing a pharmaceutical emulsion of lactulose involving the preparation stage of sieving a granular material through a sieve with a mesh size of 0.320 mm and 1.0 mm, filtering the lactulose syrup through a sieve with a mesh size of 0.320 mm and the stage of producing the emulsion with dry admixing of the granular material of the emulsion for 5-10 minutes, homogenisation of the lactulose syrup with Simethicon after the preparation stage for 10-15 minutes at a temperature of 25-30°C and at a rotation speed of 400-600 rpm followed by adding the prepared mixture of the granular material and homogenising the mixture for 30-45 minutes; the prepared emulsion is degasified under vacuum for 10 hours at a temperature of 15-25°C until a homogenous mass having a certain ratio of the ingredients is formed, that is followed by sieve filtration at a mesh size of 0.320 mm.

EFFECT: invention provides the higher physiological quality of the ready dosage form in the form of the stable non-toxic emulsion for normalising the action of the bowels, treating and preventing disbioses of various aetiologies, and recovering the normal intestinal flora following antibiotic therapy.

2 cl, 5 tbl

Description

The invention relates to the pharmaceutical industry, and in particular to a method for producing a pharmaceutical emulsion of lactulose of high physiological, therapeutic and therapeutic value, and can be used in the pharmaceutical industry for the preparation of various medicines on its basis.

A known method of producing lactulose syrup, comprising preparing an aqueous alkaline lactose solution, isomerizing lactose at a temperature of 70-100 ° C, thickening the isomerized solution, crystallizing lactose and separating the lactose alkaline solution from lactulose syrup, using catholyte obtained by electrolysis to prepare the alkaline lactose solution water and having a pH of 10.5-12.5, and the concentration of lactose in the initial solution is 1.0-5.0% (RU 2092563, publ. 10.10.1997 IPC C13K 13/00).

The disadvantage of this method is the length of the process associated with multiple crystallization of the thickened and cooled isomerized solution, which leads to lower productivity and increased costs for additional equipment.

A composition is known combining soluble saccharide, which is poorly absorbed by the body, and a carminative from the siloxane group. The composition of the application is intended to treat constipation without causing side effects such as digestive flatulence and flatulence associated with poor absorption of saccharides. The ratio of components may vary in order to obtain various compositions that are intended for the prevention and treatment of constipation. The composition may contain one or more fillers and / or one or more other active components and may be prepared in the form of a liquid or solid (WO 2004078182, publ. September 16, 2004, IPC A61K 31/695).

The disadvantages of this composition is the instability of the finished form in the form of an emulsion, since the composition of auxiliary components that make it possible to produce a medicinal product in the form of an emulsion is not defined. In addition, the stages of the technological process of industrial production are not optimized, allowing to produce an emulsion of lactulose, because lactulose is capable of epimerization and hydrolysis reactions, and the technology for the production of tablets differs significantly from the technology for the production of emulsions.

The closest analogue of the claimed technical solution is a method for producing a bifidogenic concentrate of lactulose, comprising a preparatory step in the form of the preparation of an aqueous solution of a reducing agent that prevents oxidation of lactulose; introducing into the solution a reducing agent before introducing into the solution dry lactose, a catalyst for the reaction of isomerization and alkali to a pH of 10.5-12.5; isomerization of lactose into lactulose at a temperature of 80-105 ° C until the decrease in the specific rotation rate of the solution, its cooling, demineralization and thickening (RU 2169775, publ. 06/27/2001 IPC C13K 5/00, A23C 21/00) cease.

The disadvantages of this method should recognize the complexity of the process, during which the lactulose solution is subjected to thermal changes, using additional components in the form of a catalyst and alkali. The lack of ready-made food additives with various types of therapeutic effects on humans.

Since lactulose is capable of epimerization and hydrolysis reactions, and in the technological process of emulsion production, it can pass into epilactose and also decompose to galactose and fructose oxidation products, the choice of technological modes for the production of emulsions containing lactulose syrup is important in organizing industrial production.

The technical result of the claimed invention is to increase the physiological value of the finished dosage form in the form of a stable non-toxic emulsion for normalizing intestinal activity, treating and preventing dysbiosis of various etiologies, restoring intestinal normoflora after antibiotic therapy, ensuring optimal emulsion viscosity while optimizing the technological process of industrial production of lactulose emulsion.

The technical result is achieved in that the method for producing a pharmaceutical emulsion of lactulose includes a preparatory step and a step for producing an emulsion. The preparatory phase includes sifting the granular components through a sieve with a mesh size of 0.320 mm and 1.0 mm, filtering the lactulose syrup through a sieve with a mesh size of 0.320 mm. The stage of emulsion preparation includes dry mixing of the loose components of the emulsion for 5-10 minutes, homogenization of the lactulose syrup prepared at the stage of raw material preparation, with semiticon for 10-15 minutes at a temperature of 25-30 ° C and a stirrer speed of 400-600 rpm min followed by the addition of the prepared mixture of granular components and further homogenization of the mixture for 30-45 minutes. After that, the emulsion obtained is degassed under vacuum for 10 hours at a temperature of 15-25 ° C until a homogeneous mass is formed, followed by filtration through a sieve with a mesh size of 0.320 mm. The pH of the finished product is from 2.8 to 4.5. At the following content of components per 100 ml, in g:

lactulose syrup (in terms of the active substance) 66.0 simethicone 0.8 citric acid 0.16-0.198 povidone (polyvinylpyrrolidone) 1.8-2.2 silicon dioxide colloidal (aerosil) 0.405-0.495

Citric acid, povidone (polyvinylpyrrolidone) are sieved through a sieve with a mesh size of 0.320 mm, and colloidal silicon dioxide through a sieve with a mesh size of 1.0 mm.

The method is as follows. Pre-prepared raw materials are sieved. Each component of the emulsion is screened separately: citric acid, povidone (polyvinylpyrrolidone) through a sieve with a mesh size of 0.320 mm, colloidal silicon dioxide (aerosil) through a sieve with a mesh size of 1.0 mm. Lactulose (syrup) is filtered through a sieve with a mesh size of 0.320 mm in a production tank. Filtered lactulose should not contain lumps or mechanical impurities.

The previously prepared raw materials are loaded into the production tank: citric acid, povidone, colloidal silicon dioxide and mixed for 5-10 minutes until the components are evenly distributed. Homogenization is carried out as follows in the reactor load pre-filtered lactulose (syrup), include a stirrer with a rotation speed of 400-600 rpm The prepared simethicone is slowly introduced into the formed funnel with a thin stream and mixed for 10-15 minutes until the simethicone is uniformly distributed at a temperature of no more than 30 ° C. Then, the pre-prepared dry mixture is added portionwise to the reactor with the stirrer switched on and homogenized to obtain a homogeneous stable suspension for 30-45 minutes at a temperature of no more than 30 ° C. With a speed of rotation of the mixer 400-600 rpm Homogenization of the mixture promotes a uniform distribution of viscous simethicone, povidone thickener and stabilizer of a suspension of colloidal silicon dioxide in lactulose syrup. Next, the finished emulsion is degassed in a reactor under a vacuum of 0.04-0.05 MPa and at a temperature of 15-25 ° C for 10 hours. The emulsion is homogeneous, without lumps and mechanical impurities.

As a pH corrector, citric acid is used. The use of citric acid allows you to adjust and maintain the pH value of the finished product within specified limits. The pH of the emulsion should be optimized to minimize solubility and maximize the chemical stability of lactulose susceptible to hydrolysis. In specific embodiments, the pH of the emulsion should be in the range of from about 3.0 to about 7.0, for example, from about 2.8 to about 4.5. The solution can be buffered using pH adjusting agents to maintain the pH of the emulsion in the desired range. Appropriate pH adjusting agents may be present in the suspension in amounts sufficient to provide the desired degree of pH buffering.

PH corrective substances are usually present in the range of from about 0 to about 1 g per 100 ml of syrup. The pH adjusting agent for carrying out the process can be selected from weak organic acids such as citric acid, malic acid, glutamic acid and other similar acids with acceptable palatability for use in tasteful oral syrups.

Citric acid is added to the solution to stabilize the pH of the emulsion from about 2.5 to about 6.5. Citric acid is added since this pH range increases the stability of the product. The corresponding pH for the emulsion when the pharmaceutical active ingredient used is lactulose is from about 3.0 to 7.0, for example from 2.8 to 4.5. Preservatives are selected in terms of their activity precisely within this pH range.

The use in the composition of other excipients capable of performing in the composition of the emulsion of a pH regulator does not allow them to be used in the claimed emulsion. Regulators such as potassium sorbate and ascorbic acid have low stability and are oxidized by light. In experimental samples using these components, an increase in turbidity was observed after 15 days. Lactic acid is very unstable and forms a mixture of derivatives, the result of the presence of which in the finished form is difficult to predict.

The dependence of the pH of the emulsion on the content of citric acid is shown in table No. 1.

Table number 1 The content of citric acid,% 0 0.15 0.18 0.2 pH 4.00 3.67 3.08 2.64

Povidone is used as a thickener for the emulsion (emulsifier). This hydrophilic polymer forms a protective colloidal system, creating at the phase boundary a protective shell with a thickness of one or several molecular layers, lowering the surface tension at the phase boundary, stabilizing and holding uniformly distributed simethicone particles in lactulose syrup. In addition, the use of povidone helps to maintain a certain viscosity and flow rate of the resulting emulsion, providing aggregative stability and a sufficient degree of dispersion, reducing the excess free surface energy to a minimum, since the claimed emulsion has a liquid dispersed phase and a dispersion medium that is prone to the rapid merging of droplets of fragmented liquids ( coalescence).

The functions of the emulsion stabilizer are performed by colloidal silicon dioxide. Its introduction to the composition of the emulsion helps to change the rheological properties of the lactulose syrup and the stabilization of simethicone in it. Aerosil also promotes an even distribution of povidone and citric acid when a dry mixture is introduced into the emulsion.

The speed of mixing the emulsion affects not only the uniformity of the mixing of the components, but also the size of the droplets of immiscible liquids. Observations of the condition of the drug for four weeks under storage conditions confirmed the choice of the correct mode of mixing the emulsion (table No. 2). Samples No. 1, No. 2, No. 3, No. 4, No. 5 were obtained at various mixing speeds at the homogenization stage.

Table number 2 Sample Number Mixing time to visually uniform mixture Mixing speed rpm Result one 3 hours 200 Long process. The emulsion exfoliated after 2 days 2 45 min 400 The emulsion is stable. 3 40 min 600 The emulsion is stable. four 15 minutes 800 The mixture warms up. The mixture has a dark yellow color. 5 - 1000 The experiment was completed based on the results of work with sample No. 4.

The therapeutic efficacy of the claimed emulsion consists of a hyperosmotic laxative effect, stimulation of intestinal motility, improved absorption of phosphates and Ca ⁺ salts, and elimination of ammonium ions. The lactulose that is part of the emulsion is broken down by the intestinal flora of the colon into low molecular weight organic acids, which leads to a decrease in pH and an increase in osmotic pressure and, as a result, an increase in the volume of intestinal contents. These effects stimulate intestinal motility and have an effect on stool consistency. Constipation disappears and the physiological rhythm of colon emptying is restored. With hepatic encephalopathy or hepatic (pre) coma, the effect is attributed to the suppression of proteolytic bacteria by increasing the number of acidophilic bacteria (eg, lactobacilli); the transition of ammonia to ionic form due to acidification of the contents of the colon; bowel movement due to lower pH in the colon and osmotic effect; as well as reducing nitrogen-containing toxic substances by stimulating bacteria utilizing ammonia for bacterial protein synthesis. It inhibits the growth of salmonella in the intestine, reduces the period of bacterial excretion. Simethicone is a hydrophobic polymer substance with a low surface tension that reduces gas formation in the intestine and covers the walls of the digestive canal with a protective film. Reducing the surface tension at the phase boundary, complicates the formation and contributes to the destruction of gas bubbles in the nutrient suspension and gastrointestinal mucus. The gases released in this case can be absorbed by the walls of the intestine or excreted due to peristalsis.

Studies of the emulsion for oral administration, manufactured by the claimed method, showed that the emulsion does not have a general toxic effect at equitherapeutic and exceeding therapeutic doses, does not cause significant disturbances in the biochemical parameters of blood, does not adversely affect internal organs, does not have a local irritant effect on gastrointestinal mucosa.

According to the parameters of acute toxicity, the emulsion for oral administration is a relatively safe substance. LD ₅₀ (the dose of the substance that causes the death of animals in the study group) of the drug for animals was not achieved and amounted to more than 38462 mg / kg according to GLF (corresponding to 25385 mg / kg for the active substance lactulose and 308 mg / kg for the active substance simethicone).

Acute toxicity (died / survived) of the compositions "lactulose + simethicone", "lactulose", "simethicone" with intragastric administration to animals is shown in table No. 3.

Table number 3 Dose mg / kg Groups of animals The control "Lactulose + simethicone" "Lactulose" simethicone " 31 0/6 0/6 0/6 0/6 62 0/6 0/6 0/6 0/6 123 0/6 0/6 0/6 0/6 185 0/6 0/6 0/6 0/6 246 0/6 0/6 0/6 0/6 308 0/6 0/6 0/6 0/6

In experiments on the study of acute and subchronic toxicity using morphological and histological methods, it was shown that the studied drug and comparison drugs do not have an irritating effect on the gastrointestinal tract. Studies have shown that there are no differences in indicators of local irritating effect between the drug made according to the claimed method and the comparison drugs, which indicates that they are equitoxic. The effect of the compared preparations "lactulose + simethicone" with lactulose "and semiticon on the main biochemical parameters of the peripheral blood of rat pups (M ± m) are shown in table No. 4, No. 5.

Table number 4 Research indicators The control The drug, mg / kg "Lactulose + Semiticon" "Lactulose" 2 ETD 10 ETD 2 ETD 10 ETD Males, 30 days Total protein, g / l 66 ± 3 75 ± 3 75 ± 4 77 ± 4 77 ± 4 ACT, E / l 0.73 ± 0.1 0.89 ± 0.03 0.8 ± 0.02 0.80 ± 0.04 0.87 ± 0.02 ALT, E / L 0.35 ± 0.02 0.40 ± 0.03 0.41 ± 0.02 0.42 ± 0.02 0.39 ± 0.01 Alkaline phosphatase, E / L 1.26 ± 0.35 1.11 ± 0.14 1.25 ± 0.14 1.22 ± 0.25 1.22 ± 0.18 Urea, mmol / L 3.70 ± 0.33 3.89 ± 0.37 3.81 ± 0.34 3.68 ± 0.58 3.48 ± 0.51 Creatinine mmol / L 0.10 ± 0.009 0.09 ± 0.009 0.10 ± 0.009 0.09 ± 0.01 0.10 ± 0.01 Glucose, mmol / L 7.1 ± 0.2 6.9 ± 0.1 6.9 ± 0.1 6.6 ± 0.1 6.4 ± 0.09 Total lipids, g / l 2.25 ± 0.40 2.24 ± 0.17 2.31 ± 0.26 2.20 ± 0.29 2.10 ± 0.15 Cholesterol, mmol / L 1.51 ± 0.33 1.20 ± 0.31 1.30 ± 0.25 1.24 ± 0.15 1.34 ± 0.11 Total bilirubin, mmol / l 8.7 ± 0.2 8.4 ± 0.1 8.1 ± 0.1 8.4 ± 0.1 8.3 ± 0.09 K, mol / l 4.9 ± 0.09 5.4 ± 0.09 5.1 ± 0.09 5.2 ± 0.09 5.3 ± 0.1 Females, 30 days Total protein, g / l 75 ± 1 71 ± 2 75 ± 0 71 ± 2 73 ± 1 ACT, E / l 0.61 ± 0.1 0.59 ± 0.03 0.6 ± 0.05 0.90 ± 0.07 0.7 ± 0.03 ALT, E / L 0.45 ± 0.04 0.52 ± 0.03 0.47 ± 0.04 0.51 ± 0.04 0.6 ± 0.03 one 2 3 four 5 6

Alkaline phosphatase, E / L 1.21 ± 0.15 1.28 ± 0.18 1.16 ± 0.18 1.19 ± 0.12 1.24 ± 0.13 Urea, mmol / L 4.15 ± 0.36 3.95 ± 0.25 4.18 ± 0.21 4.02 ± 0.30 4.16 ± 0.24 Creatinine mmol / L 0.09 ± 0.01 0.09 ± 0.009 0.1 ± 0.01 0.1 ± 0.009 0.09 ± 0.01 Glucose, mmol / L 7.6 ± 0.2 7.0 ± 0.09 6.9 ± 0.1 6.8 ± 0.2 7.0 ± 0.09 Total lipids, g / l 2.22 ± 0.11 2.13 ± 0.17 2.14 ± 0.23 2.18 ± 0.22 2.16 ± 0.26 Cholesterol, mmol / L 1.16 ± 0.29 1.29 ± 0.15 1.19 ± 0.35 1.20 ± 0.12 1.20 ± 0.14 Total bilirubin, mmol / l 9.1 ± 0.3 9.2 ± 0.1 9.0 ± 0.4 9.2 ± 0.4 9.1 ± 0.4 K, mol / l 5.0 ± 0.2 5.0 ± 0.2 5.1 ± 0.09 5.1 ± 0.09 5.2 ± 0.1

Table number 5 Research indicators The control The drug, mg / kg "Lactulose + Semiticon" Semiticon 2 ETD 10 ETD 2 ETD 10 ETD Males, 30 days Total protein, g / l 66 ± 3 75 ± 3 75 ± 4 72 ± 4 73 ± 4 ACT, E / l 0.73 ± 0.1 0.89 ± 0.03 0.8 ± 0.02 0.82 ± 0.03 0.80 ± 0.01 ALT, E / L 0.35 ± 0.02 0.40 ± 0.03 0.41 ± 0.02 0.37 ± 0.01 0.39 ± 0.02 Alkaline phosphatase, E / L 1.26 ± 0.35 1.11 ± 0.14 1.25 ± 0.14 1.21 ± 0.20 1.20 ± 0.12 Urea, mmol / L 3.70 ± 0.33 3.89 ± 0.37 3.81 ± 0.34 3.62 ± 0.5 3.41 ± 0.50 Creatinine mmol / L 0.10 ± 0.009 0.09 ± 0.009 0.10 ± 0.009 0.09 ± 0.009 0.10 ± 0.01

Glucose, mmol / L 7.1 ± 0.2 6.9 ± 0.1 6.9 ± 0.1 6.2 ± 0.09 6.0 ± 0.09 Total lipids, g / l 2.25 ± 0.40 2.24 ± 0.17 2.31 ± 0.26 2.0 ± 0.23 2.32 ± 0.14 Cholesterol, mmol / L 1.51 ± 0.33 1.20 ± 0.31 1.30 ± 0.25 1.22 ± 0.16 1.31 ± 0.10 Total bilirubin, mmol / l 8.7 ± 0.2 8.4 ± 0.1 8.1 ± 0.1 8.0 ± 0.1 8.7 ± 0.1 K, mol / l 4.9 ± 0.09 5.4 ± 0.09 5.1 ± 0.09 5.6 ± 0.1 5.4 ± 0.1 Females, 30 days Total protein, g / l 75 ± 1 71 ± 2 75 ± 0 74 ± 2 70 ± 1 ACT, E / l 0.61 ± 0.1 0.59 ± 0.03 0.6 ± 0.05 0.95 ± 0.08 0.6 ± 0.02 ALT, E / L 0.45 ± 0.04 0.52 ± 0.03 0.47 ± 0.04 0.49 ± 0.03 0.6 ± 0.02 Alkaline phosphatase, E / L 1.21 ± 0.15 1.28 ± 0.18 1.16 ± 0.18 1.15 ± 0.11 1.22 ± 0.12 Urea, mmol / L 4.15 ± 0.36 3.95 ± 0.25 4.18 ± 0.21 4.11 ± 0.32 4.26 ± 0.20 Creatinine mmol / L 0.09 ± 0.01 0.09 ± 0.009 0.1 ± 0.01 0.1 ± 0.009 0.09 ± 0.009 Glucose, mmol / L 7.6 ± 0.2 7.0 ± 0.09 6.9 ± 0.1 6.3 ± 0.1 7.2 ± 0.08 Total lipids, g / l 2.22 ± 0.11 2.13 ± 0.17 2.14 ± 0.23 2.11 ± 0.21 2.14 ± 0.20 Cholesterol, mmol / L 1.16 ± 0.29 1.29 ± 0.15 1.19 ± 0.35 1.23 ± 0.11 1.22 ± 0.17 Total bilirubin, mmol / l 9.1 ± 0.3 9.2 ± 0.1 9.0 ± 0.4 9.6 ± 0.3 9.8 ± 0.2 K, mol / l 5.0 ± 0.2 5.0 ± 0.2 5.1 ± 0.09 5.1 ± 0.08 5.2 ± 0.1

The claimed method allows the production of a pharmaceutical emulsion of lactulose with the addition of simetics with increased biological value, enriched with elements necessary for human health and not negatively affecting the biochemical parameters of the blood and the basic physiological functions of the body, which does not cause pathomorphological changes, on standard pharmaceutical equipment on an industrial scale.

Claims (2)

1. A method for producing a pharmaceutical emulsion of lactulose includes a preparatory step and an emulsion receiving step, the preparatory step comprising sieving granular components through a sieve with mesh sizes of 0.320 mm and 1.0 mm, filtering lactulose syrup through a sieve with mesh sizes of 0.320 mm, emulsion receiving step includes dry mixing of the loose components of the emulsion for 5-10 minutes, homogenization of the lactulose syrup prepared at the stage of preparation of the raw material, with semiticon for 10-15 minutes at a temperature of 25-30 ° C and the rotational speed a mixer of 400-600 rpm, followed by the addition of a prepared mixture of loose components and further homogenization of the mixture for 30-45 minutes, after which the emulsion is degassed under vacuum for 10 hours at a temperature of 15-25 ° C until a homogeneous mass is formed, s subsequent filtration through a sieve with a mesh size of 0.320 mm, with the following content of components per 100 ml, in g:
lactulose syrup (in terms of the active substance) 66.0 simethicone 0.8 citric acid 0.16-0.198 povidone (polyvinylpyrrolidone) 1.8-2.2 silicon dioxide colloidal (aerosil) 0.405-0.495 2. The method according to claim 1, characterized in that the citric acid, polyvinylpyrrolidone is sieved through a sieve with a mesh size of 0.320 mm, and colloidal silicon dioxide through a sieve with a mesh size of 1.0 mm.