RU2600924C1 - Method of producing a pharmaceutical erythromycin composition - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to medicine and chemical-pharmaceutical industry and a method of producing a new pharmaceutical erythromycin composition in the form of capsules for use as a broad-spectrum antibiotic. Method of producing a pharmaceutical composition for treating bacterial and protozoal infectious diseases in the form of enterosoluble erythromycin-based capsules comprises mixing erythromycin base or its pharmaceutically acceptable salt with pluronic at a ratio of 70:30, micronization of produced mixture, addition of auxiliary substances, repeated micronization and filling gelatine capsules with the produced mixture. Kolliphor P 188, Kolliphor P 407 or their mixture are used as a pluronic.

EFFECT: method is high-tech, and the produced composition and dosage form have high bioavailability of about 70 %, sufficient for considerable reduction of preparation dose (up to 2 g a day) and maintaining a stable erythromycin concentration in blood.

6 cl, 3 ex, 2 tbl

Description

Technical field

The invention relates to the field of medicine and the pharmaceutical industry and relates to a method for producing a new pharmaceutical composition of erythromycin in the form of capsules for use as a broad-spectrum antibiotic.

State of the art

Six varieties of erythromycin are known, which are indicated in Latin letters from A to F. Of these, only erythromycin A is used in clinical practice. The chemical structure of the drug includes a macrocyclic lactone ring containing 14 carbon atoms, to which are attached two carbohydrate residues - desosaminosis and cladinosis. Erythromycin is a weak base, poorly soluble in water (HF XII, part 1, p. 92), which is rapidly destroyed by the action of hydrochloric acid.

Erythromycin has a wide spectrum of antimicrobial activity, which includes many gram-positive cocci (streptococci, staphylococci) and rods, some gram-negative microorganisms, spirochetes, chlamydia, mycoplasmas, legionella, anaerobes.

Erythromycin is highly active in vitro against most strains of group A β-hemolytic streptococcus (S.pyogenes), group B streptococcus (S.agalactiae) and pneumococcus. Verdant streptococcus (S.viridans) is moderately sensitive to this antibiotic.

Staphylococcus aureus (S. aureus) and epidermal (S.epidermidis) are sensitive to erythromycin, including penicillin-resistant strains.

Erythromycin acts on corynebacteria (C. diphtheriae, C.haemolyticum, C.minutissimum), listeria (L.monocytogenes), and anthrax (B.antracis).

Gonococci, meningococci and M. catarrhalis are sensitive to erythromycin. Erythromycin is active against the causative agent of pertussis (B.pertussis), legionella (L. pneumophila, L.micdadei), the causative agent of soft chancre (H.ducreyi). More than 90% of Campylobacter (C.jejuni) strains are sensitive to it. Erythromycin is slightly weaker on H. influenzae. Erythromycin is moderately active against pale spirochete (T. pallidum) and borrelia (B.burgdorferi). Erythromycin is 50 times more active against M. pneumoniae than tetracycline. Among chlamydia, C.trachomatis and C. pneumoniae are the most sensitive to erythromycin. Its activity against C.psittaci is somewhat lower. Erythromycin is moderately active against certain clostridia (C.perfringens) and non-spore-forming anaerobes, including anaerobic streptococci and bacteroids, including individual B.fragilis strains. In addition, erythromycin acts on P. acnes. Erythromycin has a post-antibiotic effect against S. pneumoniae, S. aureus and L. pneumophila. With prolonged maintenance of sub-MPC concentrations, erythromycin has a bactericidal effect on P. aeruginosa.

Initially, erythromycin was produced only in the form of a base. As mentioned above, it is an acid labile compound and, when ingested, can be inactivated to varying degrees under the influence of hydrochloric acid of the stomach. Erythromycin absorption is affected by the rate of gastric emptying and food. Therefore, the bioavailability of the drug with oral administration is low and its degree can vary in various patients, resulting in variability in the concentration of the antibiotic in the blood.

To increase stability in the gastrointestinal tract and improve absorption, special enteric-soluble dosage forms of the erythromycin base, as well as its salts, esters and ester salts, were subsequently developed and introduced into clinical practice. In total, there are more than 15 different erythromycin preparations for oral administration.

It should be borne in mind that only erythromycin base has antibacterial activity. The stearate salt and erythromycin esters are microbiologically inactive. When ingested erythromycin stearate in the duodenum, salt dissociation occurs and erythromycin is absorbed as a base. Erythromycin estolate and ethyl succinate are absorbed in an inactive state, after which esters are hydrolyzed with the gradual release of erythromycin base. Erythromycin esters can be taken during and after meals, and the bioavailability of estolate even increases under the influence of food.

Recently developed esters and erythromycin salts (acistrate, stinoprat) are known, which have increased acid resistance, improved bioavailability and the ability to create higher concentrations in the blood, but they, like other esters, have limited use due to adverse effects on the body.

Also described is the use of erythromycin base in the form of pellets (enteric spheres with a diameter of 0.5-1.5 mm), antibiotic absorption is more stable than when taking enteric tablets, and higher concentrations of erythromycin in the blood are noted. This may be due to the fact that pellets, unlike tablets, do not linger in the pyloric stomach.

Accelerated absorption and increased bioavailability are characterized by enteric-soluble granules of erythromycin base - the domestic drug "erigran", which was developed by the State Scientific Center for Antibiotics.

And although all dispersible forms of erythromycin provide its rapid release, the potential capabilities of the drug (compared with in vitro activity) in terms of its effectiveness are used by only 30-50%. In this regard, it is necessary to use it in large doses up to 4 g per day.

Description of the invention

The objective of the present invention is to provide a technologically advanced method for producing a solid dosage form of a pharmaceutical composition of erythromycin with high bioavailability, sufficient to significantly reduce the dose of the drug and a stable concentration of erythromycin in the blood.

The problem is solved by a method of obtaining a dosage form of erythromycin in the form of enteric capsules, inside which is a pharmaceutical composition with innovative qualitative and quantitative composition.

The technical result is achieved by a method of obtaining a pharmaceutical composition for the treatment of bacterial or protozoal infectious diseases in the form of enteric erythromycin capsules, in which erythromycin is mixed with pluronic in a ratio of 70:30, the resulting mixture is micronized, auxiliary substances are added, after which micronization is repeated and the resultant is filled a mixture of gelatin capsules.

As Pluronic, Colifor P 188 (Lutrol F 68), Colifor P 407 (Lutrol F 127) or a mixture thereof are used.

In this case, the base or its pharmaceutically acceptable salts are preferably used as erythromycin.

As auxiliary substances, lactose, starch, stearic acid and / or its calcium or magnesium salts, microcrystalline cellulose are used.

The 0.5 mg gelatin capsule for the treatment of bacterial or protozoal infectious diseases preferably has the following composition, in g / capsule:

Erythromycin base 0.147-0.189 Colifor P 188 (Loutrol F 68) 0,063-0,081 Lactose 0.11-0.14 Modified corn starch 0,065-0,095 Microcrystalline cellulose 0,054 Magnesium stearate 0.001

Preferably, all components of the mixture are subjected to micronization prior to homogenization with sieving on a 0.5 mm sieve.

The oral route of administration of the drugs is most preferable because it contains a number of advantages over other dosing methods, such as the greatest comfort for the patient, the possibility of using flexible treatment regimens, and the low cost of treatment. However, the oral bioavailability of many drugs is severely limited due to their very low solubility and low absorption in the small intestine. The release of a biologically active substance is determined by the rate of disintegration of the dosage form and the time of dissolution of the substance in biological fluids.

Evaluation of bioavailability is one of the most important steps in the development and implementation of new dosage forms of biologically active compounds. The main attention when creating dosage forms is focused on creating conditions that increase the bioavailability of the drug.

Capsules are intended for oral, less often rectal, vaginal routes of administration.

Depending on the location, oral capsules are divided into sublingual, gastro-soluble and enteric-soluble (resistant to the action of gastric juice, but easily destroyed in the environment of the small intestine).

Modified-release capsules contain special excipients in the contents or shell to change the rate or place of release of the active substances. Enteric capsules also relate to modified release agents that must be stable in the gastric juice and release the active substances in the intestines. They can be made by coating hard or soft capsules with an acid-resistant shell or by filling the capsules with granules or pellets coated with acid-resistant shells.

Currently, the gelatin capsule dosage form has become very popular with pharmaceutical manufacturers, consumers and doctors due to a number of advantages and positive characteristics. These include, but are not limited to:

- high precision dosing placed in them medicinal substances. Modern equipment provides high accuracy of filling capsules with filler (with a tolerance not exceeding ± 3%) and minimal losses;

- high bioavailability. Studies have shown that capsules often disintegrate faster in the human body than tablets or dragees, and their liquid or non-compressed solid contents are faster and easier to absorb. The pharmacological effect of the drug appears after 4-5 minutes;

- high stability. Medicinal substances in capsules are protected from various adverse environmental factors - exposure to light, air, moisture, mechanical stress - thanks to the shell, which provides a sufficiently high tightness and insulation of the components. Therefore, in the manufacture of capsules, you can avoid the need to use antioxidants or stabilizers or reduce their number;

- corrective ability - eliminates the unpleasant taste and smell of medicinal substances, which is especially important in pediatrics;

- high aesthetics - achieved through the use of various dyes in the preparation of capsule shells. Today, leading pharmaceutical companies apply up to 1000 different colors and shades for coloring capsule shells;

- the ability to set certain properties for medicinal substances - the creation of enteric-soluble capsules, as well as retard capsules (with prolonged release of the drug), which can be achieved by various technological methods;

- fewer excipients in the manufacture of capsules than, for example, in the manufacture of tablets.

In addition, for the manufacture of capsules, fewer machinery is required due to a decrease in production steps, fewer analytical techniques used in the necessary analyzes, and fewer licensing procedures and documents than in tablet manufacturing.

The capsules can be packaged preparations unchanged, without exposing them to wet granulation, heat, pressure, as in the manufacture of tablets. In addition, the number of factors affecting the processes of drug release and absorption from capsules is significantly less than for other dosage forms.

Biopolymers (widely used in medicine and pharmaceuticals and can provide intracellular delivery of the necessary drugs (active pharmaceutical substances) for the treatment of various diseases.

The method of obtaining a new type of biodegradable materials is not difficult, and the decomposition products can be freely transported through cell membranes, which allows the use of polymers as drug delivery vehicles.

The block copolymers of oxyethylene and oxypropylene are also known as Pluronic. The hydrophobic-hydrophilic properties of pluronics and their ability to solubilize water-insoluble compounds are determined by the size and ratio of polyoxyethylene (hydrophilic) and polyoxypropylene (hydrophobic) blocks.

Despite the fact that these block copolymers are widely used in pharmaceutical and cosmetic compositions, including, and to increase the solubility of hydrophobic water-insoluble compounds, an individual solution is required when using them for each specific drug. The exact mechanisms of interaction of different surface-active polymers with different transporters and their combinations that limit the bioavailability of different drugs are not currently established, and a composition that has a positive effect on the bioavailability of one active substance may be ineffective for another and vice versa.

Higher bioavailability is provided by block copolymers of oxyethylene and oxypropylene, in which the content of the hydrophobic block is less than 50 mass. %, and the molecular weight of the hydrophilic block is 2250 Yes or more. It was experimentally found that the best results in increasing the solubility of erythromycin were shown by surface-active polymers, the so-called pluronics or poloxamers, namely currently available products of the Kolliphor P (BASF) brand are available in granular form with an average particle size of about 1000 microns: Kolliphor P 407 (Colifor P 407) and Kolliphor P 188 (Colifor P 188) or their old names, respectively, LUTROL F 68 (Lutrol F 68) and LUTROL F 127 (Lutrol F 127), which were used to create a new pharmaceutical composition of erythromycin.

Used lactose and starch are fillers that provide the necessary rate of dissolution and absorption.

Stearic acid and / or its calcium or magnesium salts are used according to their traditional purpose as dusting and lubricating agents.

It is essential to improve the process in this invention is to obtain a particle size distribution with certain sizes from micronized powders of substances of both active and auxiliary substances.

It is known that grinding (or micronization) of substances affects bioavailability. However, it also leads to an increase in free energy and, accordingly, can cause a decrease in storage stability. We found that if you use both the active principle and all auxiliary substances with the stated average particle sizes, a significant improvement in fluidity, an optimal bulk density and an increase in the bioavailability of erythromycin are possible.

Illustration of the process of dissolution of erythromycin base in water with the addition of Kolliphor P 407 (LUTROL F 127) and Kolliphor P 188 poloxamers (LUTROL F 68).

Examples of specific embodiments of the invention

Implementations of the claimed invention is shown in examples of specific performance, but is not limited to these examples.

Example 1

Hard gelatin capsules are filled with the technological mixture obtained using the following ingredients in mg per capsule:

Erythromycin base 147 Colifor P 188 (Loutrol F 68) 63 Lactose 140 Modified corn starch 95 Microcrystalline cellulose 54 Magnesium stearate one

Erythromycin (base) and Colifor P 188 are poured into the mill hopper and crushed to the size of particles passing through a sieve with a hole diameter of 0.5 mm. Then the resulting substance is overloaded into a homogenizing mixer, lactose is added and thoroughly mixed for 5 minutes. Next, corn starch and microcrystalline cellulose are added to the resulting mass and mixed again for 5 minutes at the same rotation speed. At the end of the process, magnesium stearate is added and mixed again for 3-4 minutes. The resulting process mixture is micronized using a mill while sifting through a sieve with a hole diameter of 0.5 mm mounted on the mill. Check the moisture and flowability of the obtained powder and fill them with hard gelatin capsules.

Hard gelatin capsules are filled with the technological mixture obtained using the following ingredients in mg per capsule:

Erythromycin base 147 Colifor P 188 (Loutrol F 68) 63 Lactose 140 Modified corn starch 95 Microcrystalline cellulose 54 Magnesium stearate one

Example 2

All components of the mixture are subjected to micronization prior to homogenization with sieving on a 0.5 mm sieve. Next, as in example 1, a mechanochemical mixture of the composition below is obtained, micronized and the moisture content and flowability of the obtained powder are additionally checked, then hard gelatin capsules are filled with it. The composition for filling the capsules is as follows, in mg / capsule:

Erythromycin base 189 Colifor P 407 (Loutrol F 127) 81 Lactose 110 Potato starch 65 Microcrystalline cellulose 54 Magnesium stearate one

Example 3

Hard gelatin capsules receive, as in example 1, using the following ingredients in quantities, mg / capsule:

Erythromycin base 189 Colifor P 188 (Loutrol F 68) 10 Colifor P 407 (Loutrol F 127) fifty Lactose 130 Modified corn starch 65 Microcrystalline cellulose 54 Magnesium stearate 2

Claims (6)

1. A method of obtaining a pharmaceutical composition for the treatment of bacterial or protozoal infectious diseases in the form of enteric capsules based on erythromycin, characterized in that erythromycin is mixed with pluronic in the ratio of 70:30, the resulting mixture is micronized, auxiliary substances are added, after which micronization is repeated and filled the resulting mixture is gelatin capsules, and as Pluronic use Colifor P 188, Colifor P 407 or a mixture thereof. 2. The method according to p. 1, characterized in that as the erythromycin use the base or its pharmaceutically acceptable salts. 3. The method according to p. 1, characterized in that as auxiliary substances use lactose, starch, stearic acid and / or its calcium or magnesium salts, microcrystalline cellulose. 4. The method according to p. 1, characterized in that the 0.5 mg gelatin capsule for the treatment of bacterial or protozoal infectious diseases preferably has the following composition, in g / capsule:
Erythromycin base 0.147-0.189 Colifor P 188 0,063-0,081 Lactose 0.11-0.14 Modified corn starch 0,065-0,095 Microcrystalline cellulose 0,054 Magnesium stearate 0.001 5. The method according to p. 1, characterized in that the micronization is carried out by grinding while sifting on a sieve of 0.5 mm 6. The method according to p. 1, characterized in that previously all the components of the mixture are subjected to micronization with sieving on a sieve of 0.5 mm