*120164*
N. Zayarnyuk1,
O. Fedorova1,
B. Sobetov1, A. Komar2,
G. Zagoriy2, M. Ponomarenko3, V. Novikov1
1 Department of Technology
of Biologically Active Substances, Pharmacy and Biotechnology, National
University "Lviv Polytechnic", 79013, Ukraine, Lviv,
Bandera Str., 12; e-mail: vnovikov@polynet.lviv.ua
2 PJSC “Pharmaceutical
company” Darnitsa”, 02093, Ukraine, Kyiv, Borispilska Str., 13
3P.L. Shupyk National
Medical Academy of Post-Graduate Education, 04112, Ukraine, Kyiv, Dorogozhytska
Str., 9
Development
of new injection prolong of disulfiram with biodegradable polymers
The
prevention of recurrence of drug dependence, especially in the early stages of
treatment, is the topical task of its therapy. The lack of motivation of patients for the long-term
use of fixed
dose of
the drug is a major problem in this period. The
drug
with prolonged action can improve the adherence to the therapeutic regimen. One of the ways of the
improvement of the drugs is the creation of combined drugs, containing the complex
medicinal substances (MS) and capable of influencing different components of
the pathogenesis of the disease and realize the therapeutic effect covering all
patient groups. The use of a combination of several drugs allows
reducing total doses and the side effects of the treatment. The use of naltrexone and disulfiram is widespread
in long-term therapeutic programs in combination with psychopharmacological,
psychotherapeutic and rehabilitative methods. These drugs are licensed in most
European countries, Canada, USA, India and Australia. The studies in the last
decade have shown the effectiveness of the combined use of both naltrexone and
disulfiram in the treatment of alcohol and drug dependencies. The use of combined
injecting drug based on disulfiram and naltrexone for treatment of patients
with alcohol and opioid dependence will provide the necessary dose for a long
time.
We studied
the physico-chemical properties of disulfiram and naltrexone, based on which
the rational pharmaceutical form and adjuvants was chosen: solvent - dimethyl
sulfoxide (DMSO) and biodegradable polymers (BP) - polyvinyl alcohol with the
molecular weight of 30000 and polyvinylpyrrolidone with the molecular weight of
10000. DMSO is allowed in
medical practice being excellent solvent and a carrier for the transfer of
drugs into the body, providing fast and higher concentration of disulfiram in
biological media which is necessary to achieve a therapeutic effect. Anti-alcohol activity of
the solvent is also known, and its therapeutic effect on patients with opioid
addiction was recently discovered.
Based on the
study of the dynamics of the naltrexone release from the prolonged form by
dialysis, it was determined that the predicted effect of the prolonged action
drug (PAD) makes 30 days.
The
biocompatibility of drug adjuvants was tested. Ovules and embryos of loach (Misgurnus
fossilis L.) during early embryogenesis, prepared and fertilized by the
Neifach method, were used as a biological model. The results have shown that the number of hatched
larvae in the studied solutions with DMSO has increased when adding BP. Thus,
the pathological effect of the joint application of DMSO and BP was missing.
The component
compatibility has been confirmed by differential thermal analysis, which showed
no adverse interactions between the components of the drug.
The shape and
size of the particles in the developed drug was identified by scanning electron
microscopy. Sediment in the form of individual spherical particles ranging in
size from 100 nm to 1 μm with uniform size distribution, thus providing
the prolonged effects of drugs, was observed in micrographs.
Based on the
studies the PAD composition was determined and the technology of the production
of new PAD "Naltetlong" was developed and tested in the industrial
conditions. The main quality indicators were determined; the methods of
identification and quantitative determination of active substances were
developed. The PAD composition and technology were protected by the patents of Ukraine.
Based on the
PAD stability studies the storage mode was selected – 5-15ºC. The
preservation of the structure of components of drugs in the selected
temperature range was confirmed by high performance liquid chromatography,
infrared spectroscopy, nuclear magnetic resonance and differential thermal
analysis.
The
pharmacological studies on male and female rats of Wistar line and white mice
with Balb/c line have shown that the expressed anti-narcotic activity of
"Naltetlong" has similar effect to the reference drug naltrexone,
while the anti-alcohol activity exceeded the activity of the reference drug
disulfiram, LD50 of the drug makes 58.0 mg/kg which corresponds to
toxicity class III. Based on the conclusion of pre-clinical studies at the
State University "Institute of Neurology, Psychiatry and Addiction"
(Kharkiv, Ukraine), together with the Ukrainian Association for Alcohol and
Drug Abuse (Lviv, Ukraine), the clinical trials of an experimental batch drugs
were started and have shown the prospects of the “Naltetlong” use as a means of
anti-recurrence therapy in patients with opioid addiction and chronic
alcoholism.
The
introduction of this development into clinical practice will make it possible
to refuse the oral administration of disulfiram and naltrexone, and will
provide persistence of long-term treatment effect.