Implanted drug preparation of naltrexone for treating alcohol- or opioid-dependent patients

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and represents a drug preparation containing 97.0-59.5 wt % of naltrexone base, 0.5-3.0 wt % of corticosteroid specified in triamcinolone, betamethasone or dexamethasone, 2.0-37.0 wt % of a nitrogen-containing polymer composition and 0.2-0.5 wt % of stearic acid or magnesium stearate. The nitrogen-containing polymer composition contains N-vinylpyrrolidone and 2-methyl-5-vinylpyridine copolymer or a salt of branched oligomers hexamethylene diamine and guanidine, and polyvinylpyrrolidone. The drug preparation may be used in addictology for treating the alcohol- or opioid-dependent patients.

EFFECT: invention provides prolonged and uniform naltrexone release with a lower probability of the implant rejection caused by an inflammatory response.

2 cl, 3 ex, 2 tbl

 

The technical field

The invention relates to addiction and can be used for the treatment of patients dependent on alcohol or opiates. Implantation medicines prolonged action in accordance with the invention improves the effectiveness of treatment and reduce the severity of side effects by eliminating the daily peaks of naltrexone, reduce the formation of its metabolites when administered parenterally, especially in the case of the inflammatory response.

Information about prior art

Alcohol dependence (alcoholism) is a chronic disease that poses a significant threat to the health and well-being of the population. According to experts, currently in Russia up to 10 million people dependent on alcohol and up to 30 million people abuse them systematically.

Opioid addiction is also common in Russia. According to official data, the registered about 2.5 million people are dependent on natural and synthetic drugs, and the proportion of opiates is up to 80%. Due mainly intravenous route of administration of drugs is a disease characterized by high mortality due to acute intoxication (overdose), and comorbidities (severe viral and bacterial in the eccii, embolism, thrombosis, abscesses, gangrene etc). Convalescence among injecting opiates, does not exceed 10%, however, they need help, especially when there is threat to their lives.

Treatment of alcohol and drug dependence includes phases of detoxification and rehabilitation. Detoxification, especially when the degrees of intoxication, threatening the life and health, eliminates the influence of alcohol or a drug and its metabolites, but also makes it easier for subsequent withdrawal syndrome. Rehabilitation is aimed at the full restoration of normal functioning of body systems, as well as psycho-emotional and behavioral spheres of the patient.

Traditionally for rehabilitation use of psychological impact, for example, hypno-suggestive therapy, sociotherapy, auditory training, etc. recently, However, there were credible evidence that the rehabilitation of patients can be successfully applied and therapeutic tools.

High enough efficiency to help patients dependent on alcohol, drugs and toxic substances received preparations containing naltrexone as an active substance.

In the application WO 1998/030171 (publ. As of 16.07.1998 entitled) declared implant containing a mixture of opiate antagonist and a pharmaceutically acceptable carrier, JV is essoungou in pellets, for subcutaneous implantation, where these pellets can release the specified opiate antagonist over a long period of time. In preferred embodiments, the time period is approximately 30 days, the opioid antagonist is naltrexone, a pharmaceutically acceptable carrier represented by magnesium stearate, wood pellets are in the form of cylinders with a length of approximately 8 mm and a diameter of approximately 13 mm, and the content of opiate antagonist is from 0.01 up to 99.0 wt.%. From the description of the invention should not be the need and possibility of use of other assistive devices, except magnesium stearate.

In the application WO 2010/039821 (publ. 08.04.2010) the claimed device for controlled release of naltrexone for extended period of time to achieve local or systemic pharmacological effects, including polymer-based polyurethane, molded so as to restrict the hollow space, and a solid pharmaceutical composition comprising a compound of naltrexone and, optionally, one or more pharmaceutically acceptable carriers, where the specified solid pharmaceutical composition is enclosed in the hollow space and where the device provides the desired rate of release of naltrexone after implantation. In preferred embodiments, the naltrexone is released the C device with a speed of from about 5.5 to 883 µg/(cm 2·day).

In the patent RU 2147879 (publ. 27.04.2000) revealed the drug to treat patients with opium addiction, containing 50-100 parts of naltrexone and 4-8 parts of corticosteroid, such as triamcinolone, which can be represented in implantable form. In the patent RU 2147880 (publ. 27.04.2000) revealed the same drug for the treatment of patients with chronic alcoholism. Descriptions of inventions to the aforementioned patents do not disclose the nature of the components that make up the rest of the implantable dosage forms, i.e. do not give grounds to assume that the introduction of polylactide and/or polyethyleneglycole polymers will contribute to the achievement of the claimed technical result. In addition, relatively high levels of corticosteroids can cause typical for these drugs long term side effects, the probability of which is compounded by lesions of the organs (kidney, liver, pancreas), usually present in patients with drug addiction and alcoholism.

In the application US 20010036469 (publ. 01.11.2001) disclosed implant comprising a mixture of opiate antagonist and a pharmaceutically acceptable carrier, said mixture compressed into pellets implanted subcutaneously, and these pellets can release opiate antagonist during the entire time the new location of the implant in the patient's body. In preferred embodiments of the opiate antagonist is represented by naltrexone in the form of the hydrochloride, which is 95% of the mass of cylindrical pellets with a length of about 8 mm and a diameter of about 13 mm Pharmaceutically acceptable carrier is magnesium stearate, and the time of the release of an effective amount of naltrexone hydrochloride of the implant is about 30 days. Described product does not contain anti-inflammatory ingredients that can cause adverse effects, particularly poor tolerance in case of inflammation.

Thus, there is a need to expand the Arsenal of implantable means for the treatment of patients addicted to alcohol and opiates.

Description of the invention

The authors of the present invention have conducted extensive studies and unexpectedly found that the above disadvantages of the prior art can be overcome by the creation of implantable drug on the basis of naltrexone, optionally containing corticosteroid, as well as the composition of nitrogen-containing polymers and magnesium stearate or stearic acid as auxiliary components.

More specifically, the present invention provides an implantable drug on the basis of naltrexone for the treatment of patients suffering from dependence on alcohol is Olya or opiates optionally containing corticosteroid, characterized in that it contains 97,0 is 59.5 wt.% naltrexone in the form of the base, 0.5 to 3.0 wt.% corticosteroid selected from triamcinolone, betamethasone, beclomethasone, or dexamethasone, 2,0 is 37.0 wt.% the composition of nitrogen-containing polymers and 0.2-0.5 wt.% stearic acid or stearate, where the composition of the nitrogen-containing polymer contains from 5 to 10 wt.% copolymer based on N-vinylpyrrolidone with srednevozrastnoe molecular weight 46-90 kDa represented by the General formula (I):

where Monomeric link M is the fragment of 2-methyl-5-vinylpyridine) - derivatives (IMP):

and the content of monomer units n is 25-90 mole% and 95-90 wt.% polyvinylpyrrolidone or 0.5-2.5 wt.% branched oligomer diamine and guanidine of the formula (II) in the form of their cleaners containing hydrochloride, phosphate or succinate salts with mass-average molecular weight of 3800 to 6300 and srednetsenovoj molecular weight of from 600 to 1100 with the mass-average molecular weight of 3800 to 6300 and srednetsenovoj molecular weight of from 600 to 1100

where R representsor,

a n1n2and n3equal 1-3, a z is equal to 0.15-1,10 molecular weight distribution Mw/Mn from 5.4 to 9.3 and 99.5-97.5 wt.% polyvinylpyrrolidone.

The technical result of the invention to prolonged and steady release of naltrexone in reducing the risk of implant rejection due to inflammatory response, is achieved through the use of naltrexone in the form of a Foundation, as well as the introduction of the steroid or its synthetic analogue. The preferred corticosteroid is triamcinolone, betamethasone, beclomethasone, or dexamethasone. More preferred triamcinolone or dexamethasone, the most preferred triamcinolone in amounts of from 1.0 to 2.5 wt.%.

The achievement of the technical result is also conducive to the introduction of the implant branched oligomer diamine and guanidine of the formula (II)described above, which possess moderate antibacterial activity against a wide range of pathogenic bacteria, which reduces the risk of inflammation at the implantation site.

Alternatively, the introduction of a copolymer of formula (I) based on N-vinylpyrrolidone, which is an immunomodulator and as an activator of phagocytosis also reduces the risk of the inflammatory response.

Implants in accordance with the present invention may be compressed into tablets having a suitable size and containing from 100 to 1500 mg of the naltrexone, for example 100, 200, 300, 500, 1000 or 1500 mg of base personnel who Rexona. The size of the tablets can be from 7 to 13 mm. Thus, depending on the patient's medical history, the psychiatrist gets a choice of tablets with different contents of naltrexone implant is most suitable for treatment combinations.

Hereinafter the invention will be illustrated by examples of preparation and use of implants.

Examples 1-3. A General method of obtaining implants in the form of a biconvex tablets

Sifted the basis of naltrexone, a corticosteroid, stearic acid or magnesium stearate are mixed in a high speed mixer with a polyvinylpyrrolidone, a copolymer based on N-vinylpyrrolidone or branched oligomers diamine and guanidine in the form of their cleaners containing hydrochloride, phosphate or succinate salts with mass-average molecular weight of 3800 to 6300 and srednetsenovoj molecular weight of from 600 to 1100. The resulting homogeneous mass force serves to press tablet press, which produces the pressing of 100 implants in the form of a biconvex tablets.

In the following table 1 shows the composition of the implants (mass components are based on 100 tablets).

Table 1
ComponentContent Example (Dose naltrexone, mg)
1 (500)2 (200)3 (1000)
Naltrexone baseMass, g50,00020,00100,000
Wt.%97,0059,50the sideways range between 77.90
CorticosteroidNameTriamcinoloneTriamcinoloneDexamethasone
Mass, g0,261,001,93
Wt.%0,503,001,50
PolymerNameN-PGN-PGPgmg
Mass, g0,100,640,13
Wt.%0,201,90 0,10
PVPMass, g0,9311,925,68
Wt.%1,8035,4020,00
Magnesium stearateMass, g-0,060,65
Wt.%-0,500,50
Stearic acidMass, g0,26--
Wt.%0,20--
The weight of one tablet mg5153351285
PVP - polyvinylpyrrolidone;
N-VP - copolymer based on N-vinylpyrrolidone;
Pgmg - branched Oli the Windows diamine and guanidine.

Example 4. Test implants in vivo

Testing of the implant in accordance with example 1 were performed on adult animals fur-bearing animals (mink) of both sexes, divided into 3 groups of 4 animals. Each animal under General anesthesia through an incision in the skin of the back is implanted two tablets subcutaneously below the incision. The wound is treated with antiseptic and cover with surgical glue.

The effectiveness of implants judged by the content of naltrexone in blood, determined by HPLC, 1, 7, 14, 20, 45, 60, 80, 100 and 120 day observation. In parallel to assess the General condition of the animals, as well as the condition of the skin and soft tissues in the region of implantation.

The results of the determination of naltrexone in the blood of holes at different points in time after the introduction of the implant, as well as the total percentage released of naltrexone are shown in table 2.

td align="center"> 4,03
Table 2
Time, dayThe percentage released of naltrexone per dayAverageThe total percentage of free naltrexone
Group 1Group 2Gruppe
11,502,021,751,761,76
78,519,8011,09,7711,53
14of 7.489,01compared to 8.268,2519,78
205,496,537,516,5126,29
454,505,525,035,0231,30
604.09 to5,114,474,5635,86
804,064,824,424,4340,29
1004,58or 4.31or 4.3144,60
120a 3.874,604,224,2348,83

From these data suggest that the implantation of the medicinal product in accordance with the present invention allows already to the end of the first week of treatment to reach maximum concentration of naltrexone. This is possibly due to accelerated desorption of the active substance from the upper layer of the implant having the greatest surface area in this period of time. Further dimensions of the implant decreases in time because of its dissolution, which reduces the rate of release of naltrexone. However, the concentration of naltrexone in the blood of animals is reduced in 2 times in comparison with the maximum only after 60 days. Therapeutically effective concentration of naltrexone in the blood is maintained within 120 days.

For all the time observing changes in behaviour, appearance, feces, and skin and subcutaneous fat at the site of implantation of the medicinal product was not detected. Morphological changes of the kidneys, liver, stomach, spleen, light is after opening the dead animals at the end of the observations is not marked.

Thus, the conclusions based on the analysis of the obtained data confirm the achievement of the technical result and illustrate the advantages of the present invention compared with the prior art.

1. Implantable drug on the basis of naltrexone for the treatment of patients suffering from dependence on alcohol or opiates, optionally containing corticosteroid, characterized in that it contains 97,0 is 59.5 wt.% naltrexone in the form of the base, 0.5 to 3.0 wt.% corticosteroid selected from triamcinolone, betamethasone, beclomethasone, or dexamethasone, 2,0 is 37.0 wt.% the composition of nitrogen-containing polymers and 0.2-0.5 wt.% stearic acid or stearate, where the composition of the nitrogen-containing polymer contains from 5 to 10 wt.% copolymer based on N-vinylpyrrolidone with srednevozrastnoe molecular weight 46-90 kDa represented by the General formula (I)

where Monomeric link M is the fragment of 2-methyl-5-vinylpyridine) - derivatives (IMP)

and the content of monomer units n is 25-90 mole% and 95-90 wt.% polyvinylpyrrolidone or 0.5-2.5 wt.% branched oligomer diamine and guanidine of the formula (II) in the form of their cleaners containing hydrochloride, phosphate or succinate salts with mass-average molecular weight of 3800 to 6300 and srednetsenovoj m is molecular weight of from 600 to 1100

where R representsor,
and n1n2and n3equal 1-3, a z is equal to 0.15-1,10 molecular weight distribution Mw/Mnfrom 5.4 to 9.3 and 99.5-97.5 wt.% polyvinylpyrrolidone.

2. Implantable drug according to claim 1, wherein the corticosteroid is selected from triamcinolone or dexamethasone.



 

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