Encapsulated lyposomal antiviral agent based on human interferon alpha-2b for vaginal application

FIELD: medicine.

SUBSTANCE: invention represents an encapsulated liposomal antiviral agent based on human interferon alpha-2b for vaginal application, characterised by the fact that each capsule is made in the form of a hollow coating, which encloses a powder excipient and liposomes distributed in the excipient, and sodium alginate, a water-soluble polymer gel former; the excipient consists of lactose, sodium chloride, 12-aqueous disodium hydrogen phosphate and sodium dihydrogen phosphate, whereas each of the liposomes represents a hollow coating containing lecithin, cholesterol and alpha-tocopherol, and a nucleus inside the coating and containing recombinant human interferon alpha-2; the ingredients of the agents are taken in a certain ratio, mg.

EFFECT: maintaining the storage activity of recombinant human interferon alpha-2 and prolonged action in vaginal application.

2 cl, 3 dwg, 6 tbl, 6 ex

 

The invention relates to a dry treatment and preventive forms of interferon Alfa-2b human in the form of liposomal particles, placed in capsules with a filler, and can be used in pharmaceutical industry and medicine for vaginal use. The drug is recommended for use in complex therapy of infectious and inflammatory diseases of the urogenital tract: genital herpes, chlamydia, ureaplasmosis, mycoplasmosis, recurrent candidiasis, cannelles, trichomoniasis, human papillomavirus infection, bacterial vaginosis, cervical erosion, cervicitis, vulvovaginitis.

In clinical practice for the treatment of viral infections, in particular hepatitis b, is widely used recombinant interferon Alfa-2b is one of the known leukocyte interferon subtypes.

It is known that the inclusion of recombinant alpha-interferon in liposomes enhances its antiproliferative activity in experimental tumor cells (Eppstein D. A., Stewart W. E. Altered Pharmacological Properties of Liposome-Associated Human Interferon-Alpha. J. Virology, 1982, vol. 41, N 2, p.575-582). Moreover, different ways of Association with the membrane of liposomes, depending on the lipid composition lead to altered pharmacokinetics of interferon preparations in the experiment on mice (Killion J. J., Fan D., C. D. Bucana, D. N. Frangos, J. E. Price, Fidler I. J. Augmentation of the antiproliferative Activity of Interferon Alfa Aginst Human Bladder Tumor Cell Lines by Encapsulation of Interferon Alta Within Liposomes. J. of the Nat. Cancer Inst, 1989, vol.81, N 18 p. 1387-1392).

Known antiviral drug of the local action for intradermal injection on the basis of interferon-alpha, incorporated in liposomes (international application WO No. 91/01719, IPC AC 9/127, publ. 1991). The drug is studied in an experimental model of herpes infection in Guinea pigs. Liposomes derived from lipids, characteristic of the stratum corneum.

Known liposomal dosage form for oral administration containing human alpha-interferon (U.S. patent No. 5503828, IPC AC 38/00, publ. 02.04.1996. However, the specific composition of the dosage form is not specified.

The above drugs are not intended for vaginal use.

Another known antiviral drug based on the recombinant beta-interferon included in liposomes intended for local or parenteral (subcutaneous, intramuscular), application (European patent No. 172007, IPC AC 9/127, publ. 1986). For parenteral use of antiviral drug in liposomal form contains:

recombinant beta-interferon, ME2×108
human serum albumin, g1,25
dextrose,g 1,25
a mixture of garagedoorrepair and
dipalmitoylphosphatidylcholine (7:3), mol2,0
saline solution (0.9%), ml100

The disadvantage of such liposomal drug is content in the composition of human serum albumin, which leads to the possible development of allergic conditions in patients, long-term use interferon. In addition, the composition of this composition is not intended for vaginal use.

Known liposomal antiviral drug for oral administration, containing biologically active ingredient - recombinant interferon Alfa-2, the components forming the liposomes is phosphatidylcholine and cholesterol, the stabilizer is sucrose, antioxidants alpha-tocopherol and ascorbic acid, representing a lyophilisate or isotonic solution (patent RF №2123328, IPC AC 9/127, publ. 20.12.98), with the following ratio of components in a lyophilizate mg:

recombinant interferon Alfa-2, ME(2,5-10)×105
f�statically 60-80
cholesterol6-10
alpha-tocopherol6-10
vitamin C1-2
sucrose40-90

Such liposomal drug provides the manifestation of biological activity characteristic of interferon alpha-2, the oral route of drug administration and therapeutic effect of this medicinal forms without any side effects associated with the parenteral route of administration of interferon.

Specified liposomal drug is not intended and is not effective for vaginal use.

Known oral anti-viral liposomal therapeutic agent (patent RF №2361572, IPC AC 9/127, publ. 20.07.2009), including recombinant interferon Alfa-2 persons, phosphatidylcholine, cholesterol, alpha-tocopherol, lactose, sodium chloride, sodium phosphate disubstituted 12-water, and sodium phosphate odnozameshchenny 2-water, while it is a lyophilisate.

The presence of the liposomal membrane cholesterol and vitamin E in the stated ratios, to provide classifies�optimum stability of liposomes in the gastrointestinal tract to the place of absorption of lipids in the body and, consequently, the preservation of biological activity of interferon, a prisoner in them.

However, such liposomal drug is not intended for vaginal use.

Known suppositories Genferon (manufacturer CJSC "Biocad") as active substances contain three main components (http://www.tiensmed.ru/news/genefron-q2d.html):

- human interferon alpha-2b at a dosage 250000 ME, ME 500000 and 1000000 ME;

- sulfamic acid taurine in an amount of 0.01 g;

- local anesthetic - benzocaine or benzocaine in the amount of 0.055 g

Because the active components of the drug need special environment for rapid penetration into the bloodstream, and fixing on the mucous membranes of the vagina or rectum, as a suitable substance for this purpose, selected solid fat. In the solid fat is evenly distributed active ingredients and other excipients that ensure penetration into the bloodstream, stabilization in the volume of the suppository etc. accessories - exactly the same, and are contained in equal amounts. Vaginal application of suppositories (candles) Genferon. With the introduction Genferon the vagina is achieved locally grown effect with the accumulation of a large part of the dose in the pathological focus. Vaginal mucosa has high�th suction ability, therefore, the penetration of active ingredients into the bloodstream is minimal. As a result vaginal introduction of the drug has a mainly local effect, and only a small system. The maximum concentration in the bloodstream and in inflammation in the mucosa is achieved, on average, 5 hours after the introduction of the candles.

The main disadvantage of candles Genferon is a short time of action of the drug on the mucous membrane of the vagina.

Known oral liposomal agent in the encapsulated form (international patent application WO 94/28876, IPC AC 9/127, publ. 22.12.1994 g), which includes the capsule, made in the form of a hollow shell made of gelatin with an outer film interoperation material Eudragit, wherein the powdery filler and a filler dispersed in the liposomes, wherein the filler comprises lactose, and each of liposomes made in the form of a hollow shell made of a mixture of phosphatidylglycerol and phosphatidylcholine and located inside the shell, the core comprising a biologically active agent.

However, the design of liposomal funds in encapsulated form, is not effective for vaginal use.

The closest analogue (prototype) as intended is a liposomal antiviral agent for about�Novo interferon in the form of suppositories for vaginal use, contains the bean phospholipid, cholesterol, fatty oils, colloidal silicone and recombinant interferon Alfa-2b (China patent No. 1704117, IPC AC 38/21, publ. 07.12.2005).

However, in this suppositories contains fatty oils, which are gradually dissolved during storage of liposomes containing interferon, whereby the drug has insufficient shelf life, and does not provide effective prolonged action for vaginal use.

The technical result of the claimed invention is the creation of such liposomal funds in capsulated form, which would allow a long time to maintain the activity of interferon in liposomes during storage, and during vaginal use - to keep the drug on the mucous membrane of interferon alpha-2 persons to ensure its prolonged action.

Said technical result is achieved in that the liposomal antiviral agent on the basis of interferon Alfa-2b human in encapsulated form for vaginal use is characterized in that each capsule is made in the form of a hollow sheath, wherein the powdery filler and a filler dispersed in the liposomes, wherein the filler comprises a water soluble polymeric gelling agent, lactose, sodium chloride, sodium FD�veil dibasic 12-water, and sodium phosphate onesemester 2-water, while each of liposomes made in the form of a hollow shell containing lecithin, cholesterol and alpha-tocopherol and located inside the shell, the core comprising recombinant interferon-alpha 2 persons at the following content of all components of the capsule (mg):

filler:

lactose90,0-92,0
sodium chloride7,8-8,1
sodium phosphate
dibasic 12-water4,0-5,0
sodium phosphate
odnozameshchenny 2-waterOf 0.5-0.6

membranes of liposomes:

phosphatidylcholine40,0-42,0
cholesterol4,0-5,0
alpha-tocopherolOf 0.5-0.6

core liposomes:

recombinant interferon Alfa-
2, E (1,0-30)105
water-soluble polymer
the gelling agent0,6-8,0

As a water-soluble polymeric gelling agent contains sodium alginate, and the shell of each capsule is made of gelatin and titanium dioxide the next time quantitative content of components of the shell, wt.%:

titanium dioxide2,0
gelatin98,0

Experimental studies have shown that concentrations of 1 capsule of phosphatidylcholine 40,0-42,0 mg, cholesterol of 4.0-5.0 mg, alpha-tocopherol 0.5 to 0.6 mg optimal to include a specified number of recombinant interferon Alfa-2b human in liposomes with an average particle size of from 0.15 to 0.70 µm.

The content of lactose in the range of 90.0-92 mg for the above total lipid composition provides a stable preservation of the liposomal membrane during freeze-drying and subsequent storage, and its higher content provide no additional benefit.

The introduction of components such as sodium chloride, sodium phosphate disubstituted 12-water and sodium �ostronomy odnozameshchenny 2-water in the claimed concentration ensures the preservation of the activity of biologically active substances (recombinant interferon Alfa-2b human) at the stage of preparation of liposomes encapsulated in form.

Vitamin E (alpha-tocopherol) present in the liposome in the claimed proportions, has a sufficient anti-oxidation and stabilizing effect on biologically active substances and lipid components.

When using interferon in an amount of less than 100 thousand IU revealed a lack of clinical efficacy of the proposed dosage form when administered orally, and increasing the amount of interferon in a single dose of more than 3 million ME is impractical because it leads to a further enhancement of therapeutic effect of the drug and may cause unwanted side effects that are typical of high doses of interferon.

In addition, lactose enhances the stability of the formulations during the storage stage. Lactose - nevosstanovlenie disaccharide, and therefore is not subject to oxidation.

Vitamin E (alpha-tocopherol) present in the liposome in the claimed proportions, has a sufficient anti-oxidation and stabilizing effect on the interferon and lipid components.

Improving the sustainability of interferon in the preparation stage of the dosage form is achieved by the introduction of the rehydrated solution of phosphate-saline buffer with characteristics close to those of the substance interferon, which reduces inactivating action�their factors such as the osmolality and acid-base balance.

Water soluble polymeric gelling agent, such as sodium alginate, after introduction into the cavity of the body of the capsule and melt the gelatin swells from environmental moisture, turns into a sticky gel matrix containing uniformly distributed liposomes with interferon. Sticky gel matrix is easily attached to the mucous membrane in the cavity of the body and provides prolonged release of interferon from liposomes.

Fig.1 shows a diagram of a capsule with a liposomal form of interferon. Fig.2 shows a diagram of the liposomes. Fig.3 is a diagram of the capsule after the dissolution of its shell and the formation of a gel matrix with distributed therein a liposome.

Each capsule is made in the form of a hollow shell 1 of gelatin, wherein the powdered filler 2 and distributed in the filler liposomes 3, and a water soluble polymeric gelling agent 4. Filler 2 consists of lactose, sodium chloride, sodium phosphate dibasic 12-water, and sodium phosphate onesemester 2, and each of liposomes 3 is formed of a hollow shell 5 containing phosphatidylcholine, cholesterol and alpha-tocopherol and located inside the shell of the nucleus 6, including recombinant interferon Alfa-2b human.

The weight of one sheath� (1) capsule of gelatin is 90-112 mg. Water soluble polymeric gelling agent 4, for example sodium alginate, after introduction into the cavity of the body of the capsule and melt the gelatin shell 1 swells from environmental moisture, turns into a sticky gel matrix 7 containing uniformly distributed liposomes 3 with interferon.

The following are examples of liposomal formulations means capsules

Example 1. The product with a minimum content of all components of the capsule (mg):

The filler (2):

lactose90,0
sodium chloride7,8
sodium phosphate
dibasic 12-water4,0
sodium phosphate
odnozameshchenny 2-water0,5

membranes of liposomes (5):

phosphatidylcholine40,0
cholesterol4,0
alpha-tocopherol0,5

nuclei� liposomes (6):

recombinant interferon Alfa-
2 people, MEOf 1.0·105
water-soluble polymer
gelling agent (4)0,6

Example 2. The product with the average grade of all components of the capsule (mg):

The filler (2):

lactose91,34
sodium chloride8,01
sodium phosphate
dibasic 12-water4,52
sodium phosphate
odnozameshchenny 2-water0,56

membranes of liposomes (5):

phosphatidylcholine41,18
cholesterolA 4.53
alpha-tocopherol 0,56

core liposomes (6):

recombinant interferon alpha-2
2 people, ME5,0·105
water-soluble polymer
gelling agent (4)1,58

Example 3. The composition of the funds at the maximum content of all the components of the capsule (mg):

The filler (2):

lactose92,0
sodium chloride8,1
sodium phosphate
dibasic 12-water5,0
sodium phosphate
odnozameshchenny 2-water0,6

membranes of liposomes (5):

phosphatidylcholine42,0
cholesterol5,0
alpha-tocopherol0,6

core liposomes (6):

recombinant interferon Alfa-
2 people, ME30·105
water-soluble polymer
gelling agent (4)8,0

Example 4. The technology of producing liposomal interferon capsules

In a round bottom flask (V=20 l) containing 400 ml of ethanol make lecithin, dissolved with stirring, add cholesterol, dissolved in a mixture of chloroform with ethanol in a volume ratio of 1:2, mix, add alpha-tocopherol and evaporated under vacuum to obtain a dry lipid film on the flask walls. After evaporation lipid film was purged with inert gas to prevent oxidation of lipids. Add to the flask a solution of the substance is recombinant interferon Alfa-2b human. The content was stirred until complete hydration of the lipid film for 30 min at room temperature. The obtained liposomal suspension was subjected to successive forming and sterilizing filtration through polycarbonate membranes of the firm "Nuclepore�' (pore diameter of 0.4; 0.2 and 0.1 μm) under pressure of an inert gas (nitrogen, argon). Next, the resulting intermediate is administered following components: sodium chloride, sodium phosphate disubstituted 12-water, sodium phosphate odnozameshchenny 2-water, lactose, gelling agent, distilled water.

Under aseptic conditions, the slurry is poured into trays, freeze at 40°C and perform lyophilic drying of the drug to achieve a residual humidity of (7±1) wt.%. 50 l of the intermediate product 8 kg of dried powder which is passed on packing in solid opaque gelatin capsule machine-ZIBO 40F for automatic filling product. The liposomal composition tools interferon capsules obtained according to the above technology, presented in examples 1-3.

The average diameter of liposomes obtained by extrusion multilamellar vesicles through polycarbonate membrane and having the inventive composition is from 0.15 to 0.70 µm.

In the analysis of antiviral activity of liposomal suspension is established that no more than 25% of interferon is not encapsulated.

Example 5. For in vitro testing of antiviral activity of liposomal interferon obtained as described in example 1 using the method of suppression cytopathogenic steps of vesicular stomatitis virus (BBC) �Tamm "Indiana" in the culture of diploid lung fibroblasts of the human embryo (L-68), grown in monolayers in 96-well microplates firm "Linbro" (Reaferon for injection dry. Pharmacopoeial article. VFS-42-227 TH-89). Pre-BBC saute in chicken embryos beyond 42-14-97-79, not less than 3 passages (infecting dose of 102-106TCD50/0.1 ml in infectious activity of 105-106TCD50/0.1 ml). To control the degree of oxidation of the lipids used a method based on measuring the concentration of products of lipid peroxidation by reaction with thiobarbituric acid (Yagi K. Lipid peroxidation. Assay for blood plasma and serum. Methods Enzymol, 1984, vol. 105, p.328-333).

Prior to determination of antiviral activity of liposomal suspension were incubated (20±2) minutes at a temperature of (22±1°C) in the presence of 1% (V/V) Triton X-100 for the destruction of liposomes. To determine the activity prepare two-fold dilutions (above and below the estimated titer) of the studied drugs and CCA activity (activity which is expressed in international units - IU-CCA activity, FS 42-28-90-87) in medium 199 or Needle with 2% serum fruits cows in a 42-7 FS SU-85 (supportive environment) and antibiotics. At each dilution not use less than 4 holes with monolayer cell culture. Removed from the wells environment and contribute to 0.1 ml of the alleged dilutions of liposomal interferon. 4 wells with cell culture leave as a control. Except �wow, 16 holes left to control the dose indicator of the virus. In these wells contribute to 0.1 ml of a supportive environment. Inoculated and control cultures were incubated for 1 h at (37±1)°C in an atmosphere of (5,0±0,5)%CO2then in each of the test materials substantially predetermined dose of the air force, corresponding to 100 TCD50in 0.1 ml. at the same time control is taken as the dose of virus on designed for this purpose 16 wells with culture. Use the 4 wells for each dilution of the virus, since dilution corresponding to 100 TCD50before breeding, corresponding to 0.1 TZD50with a dilution rate equal to 10. After introduction of the indicator virus and titration of the dose, the cell culture was incubated for 2 days at a temperature of (37±1)°C, in an atmosphere of (5,0±1)% CO2under the supervision of a dose of the virus.

Records of the results of antiviral activity of liposomal interferon carried out, when the dose of the introduced virus corresponds to 100 TCD50. If the dose of virus corresponding to 100 TCD50count on the basis of the results after 24 h after infection, and account for the titration of the drug is carried out after 24 h. results analysis of experience is possible, if there are no signs of degeneration in the control culture. The titer of liposomal interferon take of magnitude, about�atna dilution of the drug, wherein the cell culture in 50% of the holes is completely protected from the cytopathic action of the virus. Recalculation of activity in ME performed by the formula

As is known, pharmaceutically acceptable shelf life of the drug at least 6 months, preferably for at least 1 year.

To confirm the stability of freeze-dried liposomal dosage forms of recombinant interferon alpha-2 capsules composition claimed within 36 months were studied antiviral activity of the drug. The drug was stored in the refrigerator at 4°C. throughout the period of observation the degree of oxidation of the lipids remained unchanged.

As the research showed, within 36 months of storage is not detected a significant reduction in the antiviral activity of the claimed medicinal product (tab.1). Compared with the prototype of the shelf-life of the drug increased in 2 times.

Example 6. Study capsules for vaginal use with recombinant interferon Alfa-2b in liposomes

Materials and methods. Study capsules for vaginal use with recombinant interferon Alfa-2b was carried out on laboratory animals. Used 12 female rabbits breed "Chinchilla" with Mas�Oh 1,5-2 kg.

Rabbits were divided into 2 groups of 6 animals. Rabbits of group 1 was administered vaginal capsules with recombinant interferon Alfa-2b 500 thousand ME, the rabbits of the control group (group 2) received the candles Genferon 500 thousand ME. In both groups, the drugs were used 1 time in a day for 7 days (table.2).

A study of clinical and laboratory parameters was performed immediately before the first injection of the capsules/suppositories, and on the 7th day after injection.

The following studies were undertaken:

1. Microscopic examination of vaginal smears (the number of cells in field of view, the number of squamous epithelium in the field of view, the presence of microflora).

2. Activity of neutrophils in the test with nitroblue tetrazolium (NBT-test).

3. Peripheral blood parameters (total number of cells, the content of Palocco-nuclear neutrophils, segmented neutrophils, eosinophils, lymphocytes, monocytes).

4. The study of immunological indexes (the total number of T-lymphocytes CD3, the number of T-helpers CD4, the number of T-killer cells CD8, immunoregulatory index CD4/CD8).

All digital data obtained by the groups in the study were subjected to statistical analysis using student's criterion. The difference of mean values before the beginning of the study and on day 7 was considered dostave�tion at P≤0.05.

Results

On microscopic examination of vaginal smears detected a significant reduction in the number of cells on the 7th day from 4.5 to 0 in the field of view in group 1(P≤0.05) and from 3.5 to 0.75 in the control group (P≤0.05). The number of squamous epithelium was also significantly decreased from 5 to 2 in group 1(P≤0.05) and from 4.5 to 2 in the control group (P≤0.05). Non-pathogenic Bacillus was discovered and before the beginning of the study and on day 7 in both groups (tab.3).

The research activity of neutrophils in the test with nitroblue tetrazolium (NBT-test) showed a significant increase in activity on day 7 in 4,06 time in the group treated with vaginal capsules (P≤0.05), and in about 3.26 times in the control group (treated with Genferon) (P≤0.05) (tab.4).

Peripheral blood indices in both groups were within normal values throughout the study period. It was noted the increase in the total number of leukocytes (P≤0.05 in both groups), the number of lymphocytes (P≤0.05 in group 1) and a decrease in the number of eosinophils (P≤0.05 in group 1). More pronounced changes in all the above mentioned parameters occurred in the group of rabbits treated with vaginal capsules (PL.5).

Indicators of immunological indexes in both groups also found�camping within normal values throughout the study period. In the immunological study showed an increase in the total number of T lymphocytes (CD3) in group 1(P≤0.05) and tended to decrease in their number in the control group on the 7th day. The number of T-helpers (CD4) increased significantly in group 1 (P≤0.05) and remained virtually unchanged in the control group. Slightly decreased the content of T-killer cells (CD8) in both groups (differences statistically insignificant). Immunoregulatory index (CD4/CD8) significantly increased in group 1(P≤0.05) (tab.6).

Conclusions

1. Significantly (P≤0.05) decreased the number of leukocytes and squamous epithelium on the research results of vaginal smears in both groups. The more pronounced decrease occurred in the group of rabbits treated with vaginal capsules.

2. Was significantly (P≤0.05) increase in activity of neutrophils on day 7 in both groups of animals, with a more pronounced increase was observed in the group treated with vaginal capsules, compared with the group receiving Genferon (4,06 and about 3.26 times respectively).

3. According to the analysis of peripheral blood revealed a significant (P≤0.05) increase in total number of leukocytes in both groups, more pronounced in group 1. The number of lymphocytes significantly (P≤0.05) increased in group 1 and had a tendency to increase in the control group. In both groups occurred� decline in the number of eosinophils, moreover, in group 1 significantly (P≤0.05).

4. Indicators of immunological indexes indicate the activation of T-cell components of the immune system on the 7th day of the study in group 1 (significantly increased the total number of T lymphocytes (CD3), T-helper cells (CD4), immunoregulatory index (CD4/CD8)). Indicators of immunological indexes in the control group varied slightly.

Thus, according to the analysis of vaginal smears confirmed by comparable local effect of vaginal administration of capsules with interferon and candles Genferon (significant decrease in the number of leukocytes and squamous epithelium).

According to the results of the research activity of neutrophils on day 7 of the study also revealed comparable stimulatory effect on the General immunity system, more pronounced in capsules with interferon than candles Genferon.

The results of immunological analysis indicate a significant influence of capsules with interferon on the immune system (activation of T-cell components of the immune system). Thus when using candles Genferon similar effects were observed.

Industrial applicability

Created liposomal formulated with recombinant alpha-2 interferon person in encapsulated form for vaginal use, which allows for a long time (up to 36 months, tab.1) save �aktivnosti interferon in liposomes during storage. Known closest analogue, pharmaceutically produced, candles with interferon Genferon has a shelf life of 1 year. Storage conditions of candles Genferon - at a temperature of 2-8°C (http://site-zdorovie.ru/lekarstvennie-sredstva/genferon-svechi-instrukciya.htm). Drug-prototype (liposomal form of interferon in the candlelight) has a shelf life of more than 18 months.

Vaginal application of the proposed drug is prolonged the effective action, which is confirmed by the data presented in tables 2-6, due to the retention on the mucosa of liposomal drug interferon alpha-2 through a gel matrix on the basis of sodium alginate.

1. Liposomal antiviral agent on the basis of interferon Alfa-2b human in encapsulated form for vaginal use, characterized by the fact that each capsule is made in the form of a hollow sheath, wherein the powdery filler and a filler dispersed in the liposomes and water-soluble polymeric gelling agent sodium alginate, wherein the filler comprises lactose, sodium chloride, sodium phosphate dibasic 12-water, and sodium phosphate onesemester 2, and each of liposomes made from the husks, lecithin, cholesterol and alpha-tocopherol, and located inside the shell, the core comprising recombinant interferon Alfa-2 persons at the following content of all components of the capsule (mg):
filler:

lactose90,0-92,0
sodium chloride7,8-8,1
sodium phosphate
dibasic 12-water4,0-5,0
sodium phosphate
odnozameshchenny 2-waterOf 0.5-0.6

membranes of liposomes:
phosphatidylcholine40,0-42,0
cholesterol4,0-5,0
alpha-tocopherolOf 0.5-0.6

core liposomes:
recombinant interferon alpha-2
man, ME(1,0-30)·105
water-soluble polymer
the gelling agent sodium alginate0,6-8,0

2. Liposomal anti�everynoe remedy based on interferon Alfa-2b human in encapsulated form for vaginal use according to claim 1, characterized in that the shell of each capsule is made of gelatin and titanium dioxide the next time quantitative content of components of the shell, wt. %:

Titanium dioxide2,0
Gelatin98,0



 

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4 cl, 13 tbl, 8 ex

FIELD: medicine.

SUBSTANCE: composition includes glutaryl histamine in an amount of 18.0-75.0 wt % as an active substance, and as auxiliary substances: microcrystalline cellulose in an amount of 18.0-71.0 wt %, sodium croscarmellose in an amount of 0.25-1.0 wt %, colloidal silicon dioxide in an amount of 0.5-2.0 wt %, calcium stearate in an amount of 0.5-2.0 wt % and lactose monohydrate. The invention also relates to a method of obtaining the said composition.

EFFECT: invention is characterised by the high bioavailability of the active component and high pharmacological activity.

4 cl, 6 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: therapeutic agent contains recombinant interferon specified in a group of: recombinant interferon alpha, recombinant interferon beta, recombinant interferon gamma, metronidazole, fluconazole and/or voriconazole, and a pharmaceutically acceptable base in the following proportions, g per 1 ml of the mixture: recombinant interferon, international units 100-10,000,000; metronidazole 0.00001-0.5; fluconazole and/or voriconazole 0.00001-0.5; pharmaceutically acceptable base - the rest. Besides, the therapeutic agent contains boric acid in an amount of 0.00001-0.5 g and hypromellose in an amount of 0.00001-0.5 g. As a pharmaceutically acceptable base, it contains macrogol 400 or macrogol 1500, or macrogol 4000.

EFFECT: higher efficacy of the compound.

2 cl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula:

,

wherein: each D and Z is independently absent or represents an optionally substituted linear aliphatic group containing zero to eight carbons, wherein 'aliphatic' refers to an alkyl, alkenyl or alkynyl group, and 'optionally substituted' refers to substituting by replacing independently one, two or more hydrogen atoms by substitutes specified in -F, -Cl, -Br, -I, -OH, -NO2, -N3, -CN, -NH2, -NH-C1-C12-alkyl, -NH-C2-C8-alkenyl, -NH-C2-C8-alkynyl, -NH-C3-C12-cycloalkyl, -dialkylamino, -O-C1-C12-alkyl, -NHC(O)-C1-C12-alkyl, -NHC(O)-C2-C8-alkenyl, -NHC(O)-C2-C8-alkynyl, -NHC(O)-C3-C12-cycloalkyl; each A and E is independently absent or represents a cyclic group with the above cyclic group is independently specified in a group consisting of aryl or heteroaryl, each of which is optionally substituted; 'aryl' refers to phenyl, naphthyl, tetrahydronaphthyl, indanyl or idenyl; 'heteroaryl' refers to pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl or quinoxalinyl; 'optionally substituted' refers to substituting by replacing independently one, two, three or more hydrogen atoms by substitutes specified by -F, -Cl, -Br, -I, -OH, -NO2, -N3, -CN, -NH2, -NH-C1-C12-alkyl, -NH-C2-C8-alkenyl, -NH-C2-C8-alkynyl, -NH-C3-C12-cycloalkyl, -dialkylamino, -O-C1-C12-alkyl, -NHC(O)-C1-C12-alkyl, -NHC(O)-C2-C8-alkenyl, -NHC(O)-C2-C8-alkynyl, -NHC(O)-C3-C12-cycloalkyl; T is absent or represents an optionally substituted aliphatic group containing 1 to 24 carbons; 'aliphatic' refers to an alkyl, alkenyl or alkynyl group; 'optionally substituted' refers to substituting substituting by replacing independently one, two, three or more hydrogen atoms by substitutes specified in -F, -Cl, -Br, -I, -OH, -NO2, -N3, -CN, -NH2, -NH-C1-C12-alkyl, -NH-C2-C8-alkenyl, -NH-C2-C8-alkynyl, -NH-C3-C12-cycloalkyl, -dialkylamino, -O-C1-C12-alkyl, -NHC(O)-C1-C12-alkyl, -NHC(O)-C2-C8-alkenyl, -NHC(O)-C2-C8-alkynyl, -NHC(O)-C3-C12-cycloalkyl; one to four of A, D, E, T and Z are absent; the ring B is specified in imidazolyl, pyrazolyl, 1,3,4-thiazolyl, and 1,3,4-oxadiazolyl, and the ring B is bound to J through atom C and bound to Z, E, T, A and D through atom C; in each specific case, R1 is independently specified in a group consisting of hydrogen, halogen, cyano optionally substituted by C1-C4alkyl, -O-R11, -NRaRb, -C(O)R11, -CO2R11 and -C(O)NRaRb; in each specific case, R11 independently represents hydrogen or optionally substituted C1-C8alkyl; in each specific case, each Ra and Rb are independently specified in hydrogen, C1-C8alkyl and C2-C8alkenyl; u is independently equal to 1, 2 or 3; Q and J represent R6 is specified in a group consisting of -C(O)-R12, -C(O)-C(O)-R12, -S(O)2-R12, and -C(S)-R12; in each specific case, R12 is independently specified in a group consisting of -O-R11, -NRaRb, and -R13; and in each specific case, R13 is independently specified in a group consisting of: hydrogen, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C8cycloalkyl and C3-C8cycloalkenyl, each of which is optionally substituted; 'optionally substituted' refers to substituting independently by replacing one, two, three or more hydrogen atoms by substitutes specified in -F, -Cl, -Br, -I, -OH, -NO2, -N3, -CN, -NH2, -NH-C1-C12-alkyl, -NH-C2-C8-alkenyl, -NH-C2-C8-alkynyl, -NH-C3-C12-cycloalkyl, -dialkylamino, -O-C1-C12-alkyl, -NHC(O)-C1-C12-alkyl, -NHC(O)-C2-C8-alkenyl, -NHC(O)-C2-C8-alkynyl, -NHC(O)-C3-C12-cycloalkyl, which inhibit an RNA-containing virus, particularly hepatitis C virus (HCV).

EFFECT: preparing hepatitis C inhibitors.

38 cl, 22 tbl, 516 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of structural formula (I), which possess the properties of HCV polymerase inhibitors. In formula , is specified in a group consisting of a single carbon-carbon bond and a double carbon-carbon bond; R1 and R3 are specified in hydrogen and methyl; R2 represents hydrogen; R5 is specified in a group consisting of hydrogen, hydroxy, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C2-C6alkenyloxy, C3-C6alkynyloxy and halo; L represents a bond, and R6 represents a condensed 2-ring carbocyclyl, wherein each substitute is optionally substituted by one or more substitutes independently specified in a group consisting of RE, RF, RG, RH, RI, RJ and RK; or L is specified in a group consisting of a bond, C≡C, C(O)N(RC), N(RD)C(O), C1-C2-alkylene, C(H)2O, OC(H)2, cyclopropyl-1,2-ene, C(H)2N(RL), N(RM)C(H)2, C(O)CH2 and CH2C(O), and R6 is specified in a group consisting of C5-C6-carbocyclyk and 5-6-merous heterocyclyl, wherein each substitute is optionally substituted by one or more substitutes independently specified in a group consisting of RE, RF, RG, RH, RI, RJ, RK, RL and RM; the R4, RE, RF, RG, RH, RI, RJ, RK, RL and RM values are presented in the patent claim.

EFFECT: invention refers to a pharmaceutical composition containing the above compounds, to using the compounds for producing a drug preparation for HCV RNA polymerase inhibition and hepatitis C treatment, and to a method for preparing the above compounds.

21 cl, 46 dwg, 42 tbl, 140 ex

Abt-263 capsule // 2550956

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutics, in particular, described is a capsule, containing a capsule envelope, which includes an encapsulated liquid solution of N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)3-(morpholin-4-yl)-1-(phenylsulphanyl)methyl)propyl)-amino)-3-((trifluoromethyl)sulphonyl)benzenesulphonamide (ABT-263) or its bis-hydrochloride salts in a non-ethanol carrier. As filling agents used are: a phospholipid, a solubilising agent for the phospholipid, selected from glycols, glycolides, glycerides and their mixtures, a surface-active substance of a non-phospholipid type and a sulphur-containing antioxidant in an amount, effective for the reduction of oxidising ABT-263 degradation in storage. The sulphur-containing antioxidant is selected from sulphites, bisulphites, metabisulphites and thiosulphites and their mixtures. A method of the capsule obtaining is also described. The capsule is used for treating a disease, characterised by the overexpression of one or several anti-apoptotic proteins of the Bcl-2 family, for instance, cancer.

EFFECT: invention provides a long storage term for the said capsule.

33 cl, 3 dwg, 20 tbl, 14 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to the pharmaceutical industry, namely to a formulation of a cough medical composition. The formulation of the cough medical composition contains an active substance presented by thermopsis herb powder or a dry extract of thermopsis and sodium hydrocarbonate, as well as an excipient, a granulating agent and a lubricant taken in certain relations (versions).

EFFECT: composition of the cough medical composition possesses improved pharmaceutical (appearance, taste) and technological characteristics (hardness, disintegration).

11 cl, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a storage-stable pharmaceutical composition and a pharmaceutical formulation containing at least one active pharmaceutical ingredient presenting a nitrocatechol derivative, 2,5-dichlor-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide, at least one excipients and at least one binding agent, wherein at least one excipient is other than a phosphate derivative, wherein at least one binding ingredient is other than a polyvinylpyrrolidone compound, and wherein the above active pharmaceutical ingredient is present in the granulated form.

EFFECT: compositions and/or formulations according to the invention are stable for a long period of time and show a high stability if stored in the high temperature and moisture environment.

26 cl, 8 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: therapeutic agent contains anastrozole, poly(lactic-co-glycolic acid), polyvinyl alcohol and D-mannitol. The therapeutic agent represents sub-micron particles and can be presented in the form of capsules, granules, powder, as well as a suspension for injections.

EFFECT: using the developed therapeutic agent enables achieving the therapeutic effect with lower therapeutic doses and making the antitumour therapy more comfortable for the patient.

2 cl, 1 tbl, 2 dwg, 3 ex

FIELD: medicine.

SUBSTANCE: pharmaceutical composition for producing soft capsule coatings contains corn starch, carrageenan, water and a softening agent in certain proportions.

EFFECT: composition prolongs the shelf life of the soft capsule coatings without usability deterioration.

2 cl, 4 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: invention refers to a pharmaceutical composition with anti-ischemic and antioxidant activity in the form of tablets or capsules, and a method for preparing it. The composition contains 4-((3-oxo-3-ethoxypropanoyl)amino)benzoic acid in an amount of 40 to 80 wt %, an amino-containing compound and pharmaceutically acceptable excipients. The amino-containing compound is specified in a group of trometamol, methyl glucamine and L-lysine; 1 mole of 4-((3-oxo-3-ethoxypropanoyl)amino)benzoic acid is accounted for 0.05 to 0.25 mole of the above amino-containing compound. The composition also contains lactose, microcrystalline cellulose, calcium stearate and other pharmaceutically acceptable excipients. According to the method for preparing the composition, taking 4-((3-oxo-3-ethoxypropanoyl)amino)benzoic acid and amino-containing compound in molar ratio 1:0.05 to 1:0.25, pre-mixing, moisturising with a aqueous or alcohol solution of a binding agent, adding pharmaceutically acceptable excipients in such an amount to provide the content of 4-((3-oxo-3-ethoxypropanoyl)amino)benzoic acid from 40 to 80 wt %, granulating the mixture, drying and producing tablets or capsules according to the known technique.

EFFECT: implementing the above application.

6 cl, 7 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutics, in particular a pharmaceutical composition in the form of a peroral drug form is described. The composition includes rebamipide as an active ingredient and a pharmaceutically acceptable carrier. Rebamipide is contained in an amount from 0.5 to 50 mg/kg, preferably from 0.6 to 6 mg/kg.

EFFECT: application of the rebamipide-based pharmaceutical composition for the prevention and treatment of arthrosoarthritis.

5 cl, 3 dwg, 1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to the chemical-pharmaceutical industry and represents a composition in the form of a gelatine capsule possessing the antihypertensive action, containing lisinopril dihydrate granules and verapamil hydrochloride tablets in a ratio of 1:5 to 1:20.

EFFECT: invention refers to a method for preparing this composition, consisting in encasing the lisinopril granules and verapamil tablets into the gelatine capsule that provides the ease of preparing the dosage form, and an acceptable profile of the therapeutic substance release.

2 cl, 2 ex, 4 tbl, 2 dwg

FIELD: chemistry.

SUBSTANCE: coagglomerates of crystalline mannitol and granular starch in the ratio mannitol/starch from 99.5/0.5 to 50/50 have compressibility of 200 N to 450 N, flow time of 3 to 15 s and volume mean diameter D4.3 of particles based on laser granulometry of 60 to 500 mcm. The coagglomerates are intended for producing tablets or solid gelatin capsules for use in pharmaceutics. The method of producing said coagglomerates includes preparing, at 45-65°C, a solution of mannitol and granular starch or a mannitol solution only, where content of solid substance ranges from 25% to 45%, holding said solution at 45-65°C, spray-drying said solution in an MSD-type dryer equipped with a high pressure spray-drying nozzle with recycling of the fine particles at the spray-dryer top and, if necessary, adding dry starch, separating the obtained the coagglomerates of mannitol and of starch. The method can also include granulating the solution of mannitol and starch by spraying in a circular continuous fluidised-bed granulator with a discharge pipe or plug-flow rectangular continuous fluidised-bed granulator.

EFFECT: obtaining coagglomerates with good compressibility and good fluidity.

9 cl, 12 tbl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, particularly to pharmaceutical industry, and describes a dosage form of Clopidogrel presented in the form of a solid gelatine capsule. The dosage form contains Clopidogrel hydrogen sulphate, lactose anhydride, microcrystalline cellulose, sodium croscarmellose, colloidal silicon dioxide and magnesium stearate.

EFFECT: according to the invention, the dosage form of Clopidogrel contains a high amount of the active ingredient; it is prepared without the use of a wet granulation technique, and provides the more accurate dosage of the ingredients and the stability of the substances used.

9 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and represents a method for reducing extracellular matrix producing cells in lungs or suppressing an increase of the extracellular matrix producing cells in lungs, involving administering into an individual a composition containing (i) a carrier containing retinoid as a targeting agent, and (ii) a pro-drug specified in a group consisting of siRNA, RNA enzyme, anti-sense nucleic acid and DNA/RNA chimeric polynucleotide, which is targeted on HSP47, and vectors expressing said siRNA, RNA enzyme, anti-sense nucleic acid and/or DNA/RNA chimeric polynucleotide.

EFFECT: invention provides using retinoic acid as a targeting agent for the drug delivery to the extracellular matrix producing cells in the lungs.

8 cl, 6 dwg, 3 ex

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