RU2471478C1 - Pharmaceutical composition for treating alcoholism, drug addiction and chemical abuse with improved naltrexone release profile - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and pharmacy, namely addictology and may be used for treating human addiction to alcohol, drugs and toxic substances. An intramuscularly injected prolonged-release pharmaceutical composition contains naltrexone as an active substance. Additionally, the composition contains a pharmaceutically acceptable solvent and excipients differing by the fact that the active substance is included in first and second microsphere fractions of polylactide coglycolide. The first microsphere fraction is characterized by the relation of lactide and glycolide monomer links 50 mole %:50 mole % and microsphere size 0.4 to 7 mcm. The second microsphere fraction is characterized by the relation of lactide and glycolide monomer links 75 mole %:25 mole % and microsphere size 20 to 90 mcm. A weight ratio of the first fraction of 0.01 to 0.15, while a weight ratio of the second fraction is 0.99 to 0.85.

EFFECT: preparing the composition for treating human addition to alcohol, drugs and toxic substances.

3 cl, 1 tbl, 9 ex

Description

Technical field

The invention relates to narcology and can be used to treat a person’s addiction to alcohol, drugs and toxic substances. The use of a prolonged-action composition in accordance with the invention improves the effectiveness of treatment and reduces the severity of side effects by eliminating daily peaks of naltrexone and reducing the formation of its metabolites upon parenteral administration.

Prior Art Information

Alcohol addiction (alcoholism) is a progressive chronic disease that arises as a result of numerous factors: genetic predisposition, environmental influences, including society, etc. Alcoholism in Russia poses a significant threat to the health and well-being of the population: according to experts, up to 10 million people are addicted to alcohol and up to 30 million people abuse it systematically.

Drug addiction, especially the abuse of opioids, also poses a significant problem: according to official figures, about 2.5 million people are dependent on natural and synthetic drugs in Russia. According to experts, convalescence among drug addicts is approximately 10%. Nevertheless, drug addicts require palliative care, especially when there is a threat to their life.

Treatment for alcohol and drug addiction includes phases of detoxification and rehabilitation. Detoxification, especially in cases of intoxication, threatening life and health, eliminates the effects of alcohol or the drug and its metabolites, and also facilitates the course of subsequent withdrawal symptoms. Rehabilitation is aimed at the most complete restoration of the normal functioning of the body systems, as well as the psychoemotional and behavioral areas of the patient.

Traditionally, for the purpose of rehabilitation, psychological influences are used, for example, hypno-suggestive therapy, sociotherapy, auto-training, etc. However, recently reliable evidence has been obtained that therapeutic agents can also be successfully used for the rehabilitation of patients. The selection of such funds can be carried out individually, in particular - on the basis of genotyping for the genes of dopamine, serotonin, noradrenaline and gamma-aminobutyric acid systems of neurotransmitter metabolism and psychodiagnostic testing, as described in patent RU No. 2402974 (publ. 10.11.2010). Drugs containing naltrexone as an active substance received sufficiently high efficacy to alleviate the condition of patients dependent on alcohol, narcotic and toxic substances.

US Pat. No. 6,264,987 (published July 24, 2001) discloses a method for producing microparticles comprising (a) providing a polymer having an initial molecular weight, (b) dissolving the polymer and the nucleophilic compound in a solvent to form a first phase, (c) combining the first phase with the second phase under the action of mixing devices to form an emulsion, (d) combining the emulsion and the extraction medium with the formation of microparticles, and (e) keeping the first phase at the holding temperature for the holding time before step (c), where the holding time is selected in such a way as to reduce the initial molecular weight so that as a result, the selected molecular weight of the microparticle polymer is achieved. In a preferred embodiment, the nucleophilic compound is naltrexone. Microparticles obtained by this method are also disclosed.

In the international application WO 2001/089482 (publ. 11.29.2001) a method for producing microparticles having a selected molecular weight of a polymer is disclosed, including

(a) preparing a first phase comprising a nucleophilic compound, a polymer having an initial molecular weight, and a polymer solvent,

(b) combining the first phase with the second phase under the action of mixing devices to form an emulsion,

(c) combining the emulsion and the extraction medium to form microparticles and

(d) keeping the first phase at a holding temperature for a holding time before step (b) for a holding time sufficient to reduce the initial molecular weight so that a selected molecular weight of the microparticle polymer is achieved. In a preferred embodiment, the nucleophilic compound is naltrexone. Microparticles obtained by this method are also disclosed. In a preferred embodiment, the nucleophilic compound is naltrexone. Microparticles and a microencapsulated active agent obtained by this method are also disclosed.

The closest analogue is Vivitrol, an extended-release drug for intramuscular injection (manufacturer - Alkermes Inc., USA) containing naltrexone encapsulated in a copolymer of lactic and glycolic acid (the ratio of lactide and glycolide monomer units in the copolymer is 75 mol%: 25 mol%). The solvent is water for injection, containing pharmacologically determined amounts of sodium chloride, sodium carboxymethyl cellulose and Polysorbate 20. According to the manufacturer of the drug, after intramuscular administration, the change in the concentration of naltrexone in the blood plasma is characterized by an initial peak with a maximum of about 2 hours after administration and a second peak after 2-3 days. Starting from approximately 14 days after administration of the drug, its plasma concentration gradually decreases, but a measurable concentration persists for more than 1 month.

The given release profile has disadvantages. Firstly, the rapid release of the drug when it is administered at the initial peak is unsafe for young patients, as well as for those whose body is weakened by diseases caused by alcoholism and / or drug addiction (for example, moderate renal and / or liver failure). Secondly, a decrease in the concentration of naltrexone on the second or third day worsens the quality of treatment. In particular, to equalize the concentration profile, it is necessary to introduce an immediate release form, which is not always safe and justified. If such an introduction is impossible, the patient’s stay in the hospital is unproductive, because does not bring the required relief of withdrawal symptoms. In addition, a two-week period of maintaining an effective plasma concentration of naltrexone is insufficient to assist in severe cases of drug addiction.

Therefore, there is a need to expand the arsenal of injectable drugs with prolonged release of naltrexone, to increase the duration of their effective action, as well as to reduce the severity of their side effects.

Description of the invention

The authors of the present invention conducted numerous studies and unexpectedly found that the above-mentioned disadvantages of the prior art can be overcome by the creation of an injectable intramuscularly pharmaceutical composition with prolonged release of naltrexone, intended for the treatment of alcoholism, drug addiction or substance abuse, in which naltrexone is included in two fractions of polylactide-co microspheres -glycolide.

The first fraction of microspheres is characterized by a size of 0.4 to 7 μm, while the ratio of lactide and glycolide monomer units in the polylactide-co-glycolide of the first fraction is 50 mol.%: 50 mol.%. The specified fraction provides an accelerated release of the active substance in the first days after administration.

The second fraction of microspheres is characterized by a size of 20 to 90 μm, while the ratio of lactide and glycolide monomer units in the polylactide-co-glycolide of the second fraction is 75 mol.%: 25 mol.%. The specified fraction provides a longer release in the following days, providing a detectable concentration of naltrexone for 1-1.5 months.

The authors found that achieving the initial peak in plasma naltrexone can be avoided with a mass fraction of the first fraction from 0.01 to 0.15 and a mass fraction of the second fraction from 0.99 to 0.85, respectively. Higher values of the mass fraction of the first fraction provide better alignment of the release profile at the initial stage of treatment, while higher values of the mass fraction of the second fraction ensure the maintenance of an effective plasma concentration of naltrexone for a longer time.

Thus, the present invention provides an intramuscularly injectable pharmaceutical composition for the treatment of alcoholism, drug addiction or substance abuse with prolonged release of an active substance, further comprising a pharmaceutically acceptable solvent and excipients, characterized in that the active substance is naltrexone, the active substance is included in the first and second fractions of the microspheres polylactide-co-glycolide, where the polylactide-co-glycolide of the first fraction of microspheres is characterized by the ratio l ctide and glycolide monomer units of 50 mol.%: 50 mol.% and the size of the microspheres of the first fraction is from 0.4 to 7 μm, and polylactide-co-glycolide of the second fraction of the microspheres is characterized by a ratio of lactide and glycolide monomer units of 75 mol.%: 25 mol% and the size of the microspheres of the second fraction is from 20 to 90 μm, while the mass fraction of the first fraction is from 0.01 to 0.15, and the mass fraction of the second fraction is from 0.99 to 0.85, respectively.

Comparative studies of the release profiles of naltrexone from the drug "Vivitrol" and from the drug in accordance with embodiments of the invention showed that the proposed drug shows a higher release rate in the initial period and has a longer duration of action (table 1).

Table 1 Day The concentration of naltrexone transferred to the dissolution medium,% Vivitrol The drug 1 * The drug 2 ** 0 0 0.2 one one 3.3 7.6 12.9 7 40.6 37.8 46.3 fourteen 58.6 52,2 56.9 28 55,2 58.4 56.3 * The drug obtained in accordance with Example 7 ** The drug obtained in accordance with Example 8

Further, the invention will be illustrated by examples representing options for its implementation with the achievement of the specified technical result.

Example 1. Obtaining microgranulate with prolonged release of naltrexone (option 1)

Polylactide-co-glycolide with a molar ratio of monomers of 75:25 (1.5 g) was dissolved in methylene chloride (6.7 ml), then naltrexone in the form of a base (1.5 g) was added to the resulting organic solution and stirred until complete dissolution . The resulting organic solution is added in portions with constant stirring into a 2% aqueous solution of polyvinyl alcohol with a molecular weight of 40 kDa (1.02 g) to obtain a suspension of microgranulate. The obtained micro granulate is transferred to the washing stage in a reactor, where it is washed for 18 hours using 1 liter of purified water per 1.0 g of micro granulate. Toxic methylene chloride is removed by diffusion of the solvent with a gradual increase in temperature and purging with an inert gas (nitrogen, argon). After washing, the microgranulate is freeze dried and sterilized using ionizing radiation.

1.9 g of lyophilized microgranulate are obtained with an average particle size of 70 μm.

Example 2. Obtaining microgranulate with prolonged release of naltrexone (option 2)

Polylactide-co-glycolide with a molar ratio of monomers of 75:25 (1.5 g) was dissolved in methylene chloride (6.7 ml), then naltrexone in the form of a base (1.5 g) was added to the resulting organic solution and stirred until complete dissolution . The resulting organic solution was added in portions with constant stirring into a 2% aqueous solution of polyvinyl alcohol (1.02 g) with a molecular weight of 40 kDa and a 2% aqueous solution of methylcellulose (dynamic viscosity of the solution 92 cP) (1.02 g) to obtain a microgranulate suspension. The obtained micro granulate is transferred to the washing stage in a reactor, where it is washed for 18 hours using 1 liter of purified water per 1.0 g of micro granulate. Toxic methylene chloride is removed by diffusion of the solvent with a gradual increase in temperature and purging with an inert gas (nitrogen, argon). After washing, the microgranulate is freeze dried and sterilized using ionizing radiation.

Obtain 2.1 g of lyophilized microgranulate with an average particle size of 50 μm.

Example 3. Obtaining microgranulate with a sustained release of naltrexone (option 3)

Polylactide-co-glycolide with a molar ratio of monomers of 75:25 (1.5 g) was dissolved in ethyl acetate (11 ml). Separately, in the form of a base (1.5 g), naltrexone is dissolved in benzyl alcohol (2.5 ml). Both organic solutions are mixed to obtain a slightly opalescent solution. The resulting solution was added in portions with constant stirring into a 2% aqueous solution of polyvinyl alcohol with a molecular weight of 40 kDa (1.02 g) and a 2% aqueous solution of methyl cellulose (1.02 g) (dynamic viscosity of the solution 92 cP) to obtain a microgranulate suspension. The obtained micro granulate is transferred to the washing stage in a reactor, where it is washed for 18 hours using 1 liter of purified water per 1.0 g of micro granulate. Toxic methylene chloride is removed by diffusion of the solvent with a gradual increase in temperature and purging with an inert gas (nitrogen, argon). After washing, the microgranulate is freeze dried and sterilized using ionizing radiation.

Obtain 1.9 g of lyophilized microgranulate with an average particle size of 85 microns.

Example 4. Obtaining microgranulate with prolonged release of naltrexone with a low content of methylene chloride in microcapsules

Polylactide-co-glycolide with a molar ratio of monomers of 75:25 (1.5 g) was dissolved in methylene chloride (6.7 ml), then naltrexone in the form of a base (1.5 g) was added to the resulting organic solution and stirred until complete dissolution . The resulting organic solution was added in portions with constant stirring into a 2% aqueous solution of polyvinyl alcohol (1.02 g) with a molecular weight of 40 kDa and a 2% aqueous solution of methylcellulose (dynamic viscosity of the solution 92 cP) (1.02 g) with constant heating (40 -60 ° C) and stirring for a long time to obtain a suspension of microgranulate. The obtained micro granulate is transferred to the washing stage in a reactor, where it is washed for 18 hours using 1 liter of purified water per 1.0 g of micro granulate. Toxic methylene chloride is removed by diffusion of the solvent with a gradual increase in temperature and purging with an inert gas (nitrogen, argon). After washing, the micro-granules are fractionated by passing through a system of glass filters with an average pore size of 120-180 microns (primary filter to separate the unused fraction) and 14-16 microns (filter to separate the main fraction). Next, the main fraction is subjected to freeze drying and sterilized using ionizing radiation.

Obtain 1.8 g of lyophilized microgranulate with an average particle size of 60 microns.

Example 5. Obtaining microgranulate with accelerated release of naltrexone (option 1)

Polylactide-co-glycolide with a molar ratio of monomers of 50:50 (1.5 g) was dissolved in methylene chloride (5.0 ml), then naltrexone in the form of a base (1.5 g) was added to the resulting organic solution and stirred until complete dissolution . The resulting organic solution with constant stirring is introduced in portions into a 2% aqueous solution of polyvinyl alcohol with a molecular weight of 40 kDa and a 2% aqueous solution of methylcellulose (dynamic viscosity of the solution 92 cP) to obtain a microgranulate suspension. Next, the microgranulate is transferred to the washing stage in a reactor, where it is washed for 18 hours using 1 liter of purified water per 1.0 g of microgranulate. Toxic methylene chloride is removed by diffusion of the solvent with a gradual increase in temperature and purging with an inert gas (nitrogen, argon) and freeze-drying and sterilizing using ionizing radiation.

Obtain 1.5 g of lyophilized microgranulate with an average particle size of 5 μm.

Example 6. Obtaining microgranulate with accelerated release of naltrexone (option 2)

A polylactide-co-glycolide with a 50:50 molar ratio of monomers (0.5 g) was dissolved in methylene chloride (12 ml), then naltrexone in the form of a base (0.2 g) was added to the resulting organic solution and mixed until completely dissolved. The resulting organic solution with constant stirring is introduced in portions into 120 ml of a 2% aqueous solution of polyvinyl alcohol with a molecular weight of 40 kDa containing 2% methylcellulose to obtain a suspension of microgranulate. Next, the microgranulate is transferred to the washing stage in the reactor, where it is washed for 18 hours using 1 liter of purified water per 1.0 g of microgranulate. Toxic methylene chloride is removed by diffusion of the solvent with a gradual increase in temperature and purging with an inert gas (nitrogen, argon) and freeze-drying and sterilizing using ionizing radiation.

Obtain 1.4 g of lyophilized microgranulate with an average particle size of 3 μm.

Example 7. Obtaining a pharmaceutical composition (option 1)

The accelerated-release micro granulate obtained in accordance with Example 5 (0.800 g, 5% by weight) and the sustained-release nano-granule obtained in accordance with Example 1 (1.805 g, 95% by weight) were added under continuous stirring to 60 ml of purified water. The resulting mixture is placed in 5 vials (600 μl / vial), subjected to freeze drying and final sterilization by ionizing radiation. The dose of naltrexone contained in each vial is 380 mg.

Example 8. Obtaining a pharmaceutical composition (option 2) microgranules with accelerated release of naltrexone obtained in accordance with Example 5 (2,400 g, 15 wt.%), And microgranules with prolonged release of naltrexone obtained in accordance with Example 1 (1,615 g, 85 wt.%), added with constant stirring in 60 ml of purified water. The resulting mixture is placed in 5 vials (600 μl / vial), subjected to freeze drying and final sterilization by ionizing radiation. The dose of naltrexone contained in each vial is 380 mg.

Example 9. In vitro study of the kinetics of the release of naltrexone from microgranulate

The amount of naltrexone transferred to the solution is determined spectrophotometrically in accordance with the following procedure. The contents of the vial are resuspended in a medium containing amounts of sodium dihydrogen phosphate monohydrate (Fluka, cat. No. 71504 or similar quality), sodium hydrogen phosphate (Fluka, cat. No. 71640), sodium chloride (chemically pure, GOST 4233-77), Tween 20 (J.T. Baker, No. X251-07) and sodium azide (Fluka, Cat. No. 71290), sufficient to ensure isotonicity, physiological blood pH and bacteriostatic action. The volume of the suspension is adjusted to 500 ml. The osmolality of the resulting suspension should be in the range from 250 to 290 mOsm.

Throughout the study, the suspension is kept in a water bath at a temperature of 37.0 ± 0.3 ° C. On days 1, 7, 14, and 28, 5.00 ml aliquots were taken, filtered through a membrane filter from regenerated cellulose with a pore diameter of 0.45 μm, discarding the first 1 ml of the filtrate. The remaining cooled filtrate is photometrified at wavelengths of 283 and 450 nm using a dissolution medium as a reference solution. The amount of naltrexone transferred from the microspheres to the solution is determined by the absorption ratio method using standard naltrexone solutions with concentrations from 0.01 wt.% To 0.1 wt.% For calibration. The determination results are presented as a percentage of the initial content.

Claims (3)

1. Injectable intramuscularly pharmaceutical composition for the treatment of alcoholism, drug addiction or substance abuse with prolonged release of the active substance, additionally containing a pharmaceutically acceptable solvent and excipients, characterized in that the active substance is naltrexone, the active substance is included in the first and second fractions of polylactide-co- microspheres glycolide, where the polylactide-co-glycolide of the first fraction of microspheres is characterized by a ratio of lactide and glycolide monomer units of 50 mol.%: 50 mol% and the size of the microspheres of the first fraction is from 0.4 to 7 μm, and the polylactide-co-glycolide of the second fraction of the microspheres is characterized by a ratio of lactide and glycolide monomer units of 75 mol%: 25 mol% and the size of the microspheres of the second fraction is equal to 20 to 90 μm, while the mass fraction of the first fraction is from 0.01 to 0.15, and the mass fraction of the second fraction is from 0.99 to 0.85, respectively. 2. Injectable intramuscularly the pharmaceutical composition according to claim 1, characterized in that the mass fraction of the first fraction is from 0.01 to 0.05, and the mass fraction of the second fraction is from 0.99 to 0.95, respectively. 3. The injectable intramuscularly pharmaceutical composition according to claim 1, characterized in that the mass fraction of the first fraction is from 0.10 to 0.15, and the mass fraction of the second fraction is from 0.90 to 0.85, respectively.