Pharmaceutical composition for transdermal application for increase of drug activity and decrease of side effects

FIELD: medicine.

SUBSTANCE: phospholipid emulsion contains lecithin with the phosphatidylcholine content min. 60%, ethanol, water and diclofenac sodium in the amounts specified in the patent claim. The phospholipid emulsion represents liposomes (nanosomes) of a mean diameter of 20 to 500 nm. The composition is used for the liposomal introduction of biologically active substances and/or drugs into a human body. The emulsion nanosomes may additionally contain one or more substances specified in a group: carotinoids, flavonoids, vitamins, resveratrol, vitamin-like substances, cartilage protectors, amino acids, preserving agents.

EFFECT: emulsion provides selectivity of the effect of the active compound on body tissues, enables adjusting skin penetration rate of the active substance, dosing the active ingredients, increasing bioavailability of the active substances, reducing their negative effect of the body.

13 cl, 7 dwg, 1 tbl, 11 ex

The invention relates to chemical-pharmaceutical industry, particularly compositions that enable the composition of the liposomes (nanos) medicinal substances and/or biologically active substances intended for transdermal use. The proposed composition constituting the liposomes (nanosomes) with a double layer of membranes, the average diameter of the liposomes (nanos) is from 20 to 500 nm at the following best-chosen ratio of the components of liposomes (nanos). The liposomal composition is intended for introduction into the body of biologically active substances and/or drugs.

Appearing at the dawn of civilization dosage forms have been long and difficult path of evolution, during which some have disappeared or changed, others appeared. Optimally matched dosage form for a particular pharmaceutical substance to maximize the effect of drugs with minimal side effects, change the nature of the substance to accelerate or prolong it, to reduce allergic action, if necessary, to improve organoleptic characteristics.

One of the modern trends modification of the traditional dosage forms is the use of directional transport Le is arctonyx and biologically active substances. The media used for the targeted transport of biologically active compounds, divided into 3 groups:

1st generation - microcapsules, microspheres;

2nd generation - passive colloidal carriers: liposomes, nanocapsules, and others;

3rd generation - colloidal carriers with monoclonal antibodies as a vector, with a molecular substrate.

Dosage forms with native 1st generation are introduced into the bloodstream near the target. Biodegradable microspheres or microcapsules are used for sustained release of proteins with injections of peptide hormones, small doses of steroids used as contraceptives for prolonging the actions of the antagonists drugs used in Oncology.

Media 2nd generation (sizes less than 1 micron) - liposomes are numerous advantages, they can include various medicinal substances. Liposomal dosage forms can be controlled by acting externally locally in the area of the site of the pathological process, providing targeted delivery. Liposomes are introduced in different ways: they are used for the treatment of intracellular infections, liver, ophthalmology and externally.

Today, the transdermal route of administration of the drug is important for the treatment of skin diseases, diseases of the soft tissue is her varicose veins, musculoskeletal system of the person and others By improving this way the delivery of active substances in the human body developed a transdermal therapeutic system (TTS).

For example, a known system for transdermal delivery for local application of one or more active agents contained in one and/or more layers of a polymeric and/or adhesive media, directly adjacent to contain no drug polymer and/or adhesive coating, which is applied either on the carrier basis or on a removable strip transdermal system. This device for transdermal delivery is made when optimizing boot medicines while ensuring obtaining the desired adhesion to the skin or mucous membrane, as well as the possibility to modulate the delivery of the medicinal product and its profile (Patent RU 2356580).

The use of liposomes as a delivery path of biologically active substances received practical application in the cosmetic field.

Known antimicrobial liposomal composition and shower gel, including liposomal composition is a detergent for skin care. Antimicrobial liposomal composition as biologically AK is positive component contains dioxidine, as a component constituting the liposomes of phospholipids and/or cyclodextrins, preservative, selected from a number of parabens, and water (Patent RU 2371166).

As the method of delivery, liposomal transport way for medicinal substances known for oral and aerosol routes of administration. Leading positions in research and development of liposomal forms of administering drugs belong to three American companies: The Liposome Company (TLC), Liposome Technology Inc. (LTI), Vestar. Through their research on the market already entered liposomal amphotericin b for the treatment of systemic mycoses, liposomal antitumor drugs daunorubicin, doxorubicin, cisplatin. Final stages of clinical trials are drugs such as liposomal influenza vaccine and melanoma, antidiabetics complex insulin-liposomes, antiviral nucleosides for the treatment of AIDS, a series of liposomal bronchodilatory drugs and other

Described high-dose liposomal aerosol composition containing 12-30 mg/ml cyclosporine a or budezonida and 130-375 mg/ml of phospholipid in the ultrapure water held in the tank of the sprayer, where the size of particles called liposomes is in the range from about 1 μm to about 3.0 mm (Patent RU 2174390).

Renowned pharmaceutical composition for prevention and/or treatment of cancer is of deseases, to increase the activity of anticancer drugs and reduce side effects of anticancer drugs, containing nanoparticles with high affinity to degenerate cells. This composition was proposed to use oral (application for invention EN 2008110324/15 from 21.08.2006).

Known dental transdermal elixir containing liposomes, which do not have General toxic, irritant and allergic action, has a homogeneous consistency, evenly distributed when rinsing on the mucous membrane of the oral cavity, has anti-inflammatory and keratoplasticheskie action (Patent RU 2327445).

Liposomes as efficient transport of biologically active substances of plant and natural origin, has received recognition and application especially in the cosmetic industry.

Known gel for the treatment, prevention of the formation of keloid and hypertrophic scar skin containing biologically active additive in the form of a suspension of liposomes from phospholipids and lipids of animal and vegetable origin include chloroform extract of medicinal herbs, which is included in the gel structure (Patent RU 2008110804).

Described cosmetic remedy for aging skin, as well as burns and antiherpetic means, to the m used liposomes for targeted transport of drugs (DNA molecules) (Patent RU 95102712).

Known cosmetic treatment for problematic skin, which as liposomes contains a suspension of liposomes of plant and animal origin (Patent RU 2241440).

Described phospholipid emulsion, containing dihydroquercetin, and the method of its production, in particular liposomal biologically active form of dihydroquercetin and how you can get it. Phospholipid emulsion contains dihydroquercetin, one of membranebased substances: a phospholipid, glycine and an aqueous solution of ethyl alcohol when the alcohol content of from 0.05 to 20% (Patent RU 2369383).

This composition to the technical nature and the subject is closest to the proposed invention.

The disadvantages of this tool include the following:

the composition is not intended for inclusion in the composition of medicinal substances (media only biologically active vegetable substances);

- the area of practical use of the composition is limited to food SUPPLEMENTS and cosmetic products;

- insufficient bioavailability through the skin (the structure of liposomes single layer, in contrast to the membranes of the skin with double layer);

the composition does not provide for the selective action of the active compounds in the tissues of the body;

the composition does not allow you to adjust the speed of penetration of the active substances is STV through the skin;

the composition does not provide for dispensing of active components;

The aim of the invention is to provide a composition, the design of which takes into account all the shortcomings of the previously described products and which is intended for use in pharmaceutical practice for transdermal use. The proposed composition constituting the liposomes (nanosomes) with a double layer of membranes, the average diameter of the liposomes (nanos) is from 20 to 500 nm, the next time optimally selected ratio of the components of liposomes, in wt.% (100 wt.%):

In this composition include pharmacologically active agent in an amount of from 0.001 to 30% depending on the recommended dosage and concentration, planning to get in the final dosage form. The composition is designed for direct human consumption and/or for preparation for external or internal use.

As the active components which may be biologically active component of plant origin and/or drug(s) substance(s).

The composition is designed for direct human consumption and/or for preparation for external or internal application, for example:

The composition can be contained in the emulsion (based on 100 wt.%):

As the active component may be biologically active component of plant origin and/or drug(s) substance(s).

The composition of the drug substance may be contained in the composition of the ointment bases (based on 100 wt.%):

Composition with biologically active component may be contained in the composition of the gel (based on 100 wt.%):

Nanosomes compositions may contain one or more pharmaceutically and pharmacologically compatible active substances selected from groups: carotenoids, flavonoids, vitamins, polyphenols, phytoalexins (preferably resveratrol, vitamin-like substances, volatile substances, amino acids, proteins, minerals, inhibitors of angiotensin-converting enzyme; α-adrenergic agonists; β-adrenergic agonists; alpha adrenergic blockers; beta adrenergic blockers (beta blockers); inhibitors of alcohol; inhibitors alsoreported; aldosterone antagonists; amino acids, anabolics, analgesics (both narcotic and non-narcotic); anesthetics; anorexics; antacids; anthelminthic drugs; agents against acne; antiallergic drugs; anti-androgens; antianginal agents, sedative agents; antiaritmikov; anti-asthmatic agents; antibacterial agents and antibiotics; drugs against alopecia and baldness, protivozobnyj means; antibodies; anticholinergic drugs, anticoagulants and blood thinners; antiaritmichesky drugs; anticonvulsants; antiishemiceski drugs; antidepressants; antidiabetic agents; antidiarrheal means; antidiuretics; antidotes; antiemetics; antiestrogens; antiflatulents; antifungal agents; antigens; antiglaucoma agents; antihistamine drugs; antigipertion means; antihyperlipidemics means; antihypertensive agents; antihypertrophic; antihypotensive means; antiseptirovannyh funds; anti-infective funds; anti-inflammatory (both steroidal and non-steroidal) funds; antimalarial agents; agents against migraine; antineoplastics; anti-obesity; anti-Parkinson agents and antidyskinetics; antipneumococcic agents; Antiprotozoal agents; antipruritic agents; antipsoriatic; antipsychotics; antipyretics; Antirheumatic means; antisecretory agents; antishock drugs; antispasmodics; antithrombotic means; anticancer agents; antitussives means; antiulcer means; antiviral agents; anxiolytics; microbicides; seals bones; bronchodilators; calcium channel blockers, carbonic anhydrase inhibitors; cardiotonics and pacemakers; chemotherapeutic means; cholagogue; cholinergic means; means for the treatment of chronic fatigue syndrome; CNS stimulants; coagulants; contraceptives; agents for the treatment of cystic fibrosis; decongestants means; diuretics; agonists of dopamine receptor; receptor antagonists dopamine; enzymes; estrogen; face means; means for the treatment of gastric hyperactivity; glucocorticoids; hemostatics; inhibitors of the reductase the coenzyme And ilovecosmo menopausal gonadotropin; hormones; hypnotics; immunomodulators, immunosuppressants; laxatives; agents for treating diseases of the oral cavity and periodontal diseases; miotikov; monoamine oxidase inhibitors; mucolytic means; means for the treatment of multiple sclerosis; muscle relaxants; Mydriatics; narcotic antagonists; antagonists of the NMDA receptor; oligonucleotides; ophthalmic preparations; rodoslovnaya means; peptides, polypeptides and proteins; polysaccharides; POCs; prostaglandins; protease inhibitors; promoters of breath; sedatives; inhibitors of serotonin uptake; sex hormones, including androgens; drugs used for Smoking cessation; smooth muscle relaxants, stimulants smooth muscles; thrombolytics; tranquilizers; pagkikita urine; medicines for the treatment of urinary incontinence; vasodilators; vasoprotective; chondroprotective (chondroitin, glucosamine and its salts, hyaluronic acid and its salts), and combinations thereof.

The composition may further contain at least one vitamin selected from the group comprising vitamin E, vitamin C, vitamin D, folic acid, vitamin B, vitamin A, Biotin, vitamin PP, Pantothenic acid or its salts, vitamin K, and/or vitamin-like substance.

As recognize the aqueous raw material for the nanos uses highly purified lecithin content of phosphatidylcholine at least 60%, because of this connection, as a component of the cell membrane of the skin and gives the received nanosomal increased flexibility, mobility, penetration and stability by participating in the formation of a stable liposomal system.

Claimed the drug differs from prototype qualitative and quantitative composition, and has an original circuit and receiving over a wide area of practical use.

This goal is achieved by obtaining liposomes (nanos) of high-purity lecithin containing nanoparticles pharmacologically active(CSOs) substances(a). To obtain a phospholipid emulsion, in terms of phosphatidylcholine, prepare a solution of lecithin in ethanol and dispersed environment, including deionized water, untwist the dispersion medium before the formation of a stable gradient rotation. Make a pharmacologically active ingredients according to the recipe, while continuing the stirring. The technical result are liposomes (nanosomes) with / or without the active component, the size of liposomes from 20 to 500 nm, having the dual structure (multi-layer) layer around the liquid core, which allows to encapsulate them as lipophilic active substances and hydrophilic active substances.

The advantages of the present invention include the fact that:

Composers who I can be a carrier of drugs, which is in direct contact with the skin causes irritation.

Shell and structure of liposomes (nanos) allows you to encapsulate biologically active substances and medicinal substances of different chemical structure and physical properties, as lipophilic and hydrophilic given pharmaceutical compatibility at the same time.

High bioavailability of the compositions and preparations on its basis, taking into account the approximate structure of the membranes sediment and cell membranes.

Shell liposomes (nanos) increases the stability of the active substances encapsulated inside liposomes to adverse environmental factors and ensures their activity, increasing the shelf life of the drug based on the composition.

Themselves liposomes (nanosomes), or not containing the active ingredient, do not cause irritation to the skin, so you can use them to obtain a transdermal preparations.

Themselves liposomes without encapsulated active component, adding a moisturizing and soothing effect on the skin.

The composition provides for the selective action of the active compounds in the tissues of the body.

Composition allows you to adjust the speed of penetration of the active substance through the skin by affecting the flexibility of memb the Ana nanosomes. More flexible liposomes are characterized by a faster penetration rate. The management flexibility of liposomes is achieved by the location of liposomes in a relevant environment: in an environment with a high content of water (spray, lotion, tonic, gel, etc.) nanosomes penetrate faster; liposomes in an environment with increased content of lipid fraction (ointment or gel base, including the introduction of additional oils) slows down the rate of penetration of liposomes through the cell membrane of the organism, and this property can be used for drugs intended for long term ingestion by adjusting the exposure time on the fabric.

Composition allows you to dispense the active components and to limit their upper limit, which is important for potent substances. For active substances with hydrophilic properties of the maximum concentration of the substances included in liposomes (nanosomes), up to 30%, for active substances with lipophilic properties up to 25%.

The composition is designed for direct human use and/or for the preparation of medicines, cosmetics, specialized food product or biologically active food supplements. The most optimal use of the composition for the preparation of dosage forms for external use (gels, BAP is s, ointments, emulsions, sprays etc). To this end, the composition may act as a pre-prepared semi-finished product that simplifies the design of the final product. So, in the composition of ointments composition is introduced at the final stage of production under continuous stirring at a temperature not exceeding 30°C.

For drugs emulsion type with the introduction of liposomes (sediment) in the formula can be used emulsifier. The most optimal use of non-ionic emulsifiers of the type M/B, anionic emulsifiers of the type M/B, non-ionic emulsifiers of the type B/M, anionic emulsifiers of the type B/M.

The main feature of the proposed structure is the presence in the composition of liposomes (sediment) with a double layer of membranes (multilayer), and the possibility of inclusion in liposomes (nanosomes) biologically active substances and medicinal substances, regardless of their properties and solubility, the average diameter of the liposomes (nanos) is from 20 to 500 nm.

The invention is illustrated below by examples of industrial application in the production environment.

Examples of specific performance.

Example 1

Ready-to-eat form a composition of liposomes (nanos) without filler (based on 100 wt.%):

Prepare a solution of lecithin in ethanol solution and deionized water are placed in a reactor with a stirrer, untwist a lot to the formation of a stable gradient rotation. The resulting preparation examined for compliance with the basic criteria of quality (particle size, description, odor, pH of the medium and microbiological purity). A lot of liposomes (nanos) stored in appropriate sealed containers, protected from light at a temperature of +4°C, avoiding microbiological contaminatio. The resulting composition is used as a material for obtaining medicinal, cosmetic and food products.

Example 2

Ready-to-eat form a composition of liposomes (nanos) without filler (based on 100 wt.%):

Prepare a solution of lecithin in ethanol solution and deionized water are placed in a reactor with a stirrer, untwist a lot to the formation of a stable gradient rotation. The resulting preparation examined for compliance with the basic criteria of quality (particle size, description, odor, pH of the medium and microbiological purity). A lot of liposomes (nanos) stored in appropriate sealed containers, protected from light at a temperature of +4°C, avoiding microbiological contaminatio. The resulting composition is used as a material for obtaining medicinal, cosmetic and food products.

Example 3

Ready-to-use emulsion-based compositions of liposomes with coenzyme Q10 (based on 100 wt.%):

Prepare a solution of lecithin in ethanol, separately dissolved coenzyme Q10 in the lipid fraction (triglycerides of fatty acids), separately prepare the environment - deionized water, all placed in a single reactor with a stirrer, untwist a lot to the formation of a stable gradient rotation, emuleret 30-40 minutes Received the drug is examined for compliance with the basic criteria of quality (particle size, description, odor, pH value of the environment, microbiological purity, the quantitative content of the active component). Received the tool does not have General toxic, irritant and allergic action, has a homogeneous consistency, evenly applied to the skin, has an antioxidant effect. The technical result is improved stability and increased shelf life of the emulsion for external use, as well as improving bioavailability and selectivity of the impact of active connections.

Example 4

Ready-to-eat form a gel containing composition of liposomes (nanos) with the active substance in a concentration of 0.001% (based on 100 wt.%):

Prepare a solution of lecithin in ethanol, separately dissolved resveratrol in water, all placed in a single reactor with a stirrer, untwist a lot to the formation of a stable gradient rotation, emuleret within 30-40 minutes the resulting mass is injected into the gel base at a temperature not exceeding 30°C, add preservatives (nipagin and nipazol) and stirred for 10-20 minutes

Received the tool does not have General toxic, irritant, has a homogeneous consistency, evenly applied to the skin, has anti-oxidant and moisturizing effects.

Example 5

Ready-to-eat form a gel containing composition of liposomes (nanos) with active substances is the your at a concentration of 30% (based on 100 wt.%):

Prepare a solution of lecithin in ethanol, separately dissolved resveratrol in water, all placed in a single reactor with a stirrer, untwist a lot to the formation of a stable gradient rotation, emuleret within 30-40 minutes the resulting mass is injected into the gel base at a temperature not exceeding 30°C, add preservatives (nipagin and nipazol) and stirred for 10-20 minutes

Received the tool does not have General toxic, irritant, is homogeneous to the Silencio, evenly applied to the skin, has an antioxidant effect.

Example 6

Ready-to-use ointment on the basis of the composition of liposomes with diclofenac sodium (based on 100 wt.%):

Prepare a solution of lecithin in ethanol,separately dissolve diclofenac sodium in water, all placed in a single reactor with a stirrer, untwist a lot to the formation of a stable gradient rotation, emuleret within 30-40 minutes the resulting mass is injected into the ointment base at a temperature not exceeding 30°C, add preservatives (nipagin and nipazol) and stirred for 10-20 minutes

Received the tool does not have General toxic, irritant, has a homogeneous consistency, evenly applied to the skin, has anti-inflammatory action. The technical result - ointment for external use with improved bioavailability and selectivity effects of diclofenac, improving the safety of the drug.

In practice, you can make changes and modify described the preferred embodiments of the present invention, without departing from the scope and aims of the present invention, within the stated claims.

Studies have been conducted to study the specific activity of the preparation according to example 6.

Anti-inflammatory activity of the ointment on the basis of liposomes of diclofenac sodium was studied on the model of kaolin swelling of the paws of rats. The experiments were carried out on outbred rats contained in vivarium in a hospital on a standard diet. Each group of animals in the experiment consisted of 6 rats weighing 170±20,0. The inflammation caused in the introduction under the aponeurosis of the hind legs of 0.1 ml of 10% suspension of kaolin. We determined the effect of the ointment with liposomes of diclofenac sodium on the second stage of the inflammatory exudation. Edema was assessed ecometrics, its value was determined from the change in volume of the paws, which were measured before the introduction of flaggen and after 5, 24 and 48 h after injection of a suspension of kaolin. The effectiveness of the studied compositions were compared with the efficiency of classical ointment diclofenac sodium 1% (Mashkovsky PPM Medicines. M., 2005. So 1, 2; composition: 1 g ointment contains 10 mg of diclofenac sodium, an excipient is a polyethylene oxide-400, polyethylene oxide-4000, 1,2-propylene glycol, nipagin, nipazol).

The first group animals treatment is not received, the second group applied the ointment diclofenac 1%, the third - gel-based, fourth - ointment composition with liposomes of diclofenac sodium 1%. The results obtained are presented in table 1. As follows from the obtained results, the ointment with liposomes of diclofenac sodium on pharmacological activity was found to be more effective prototype (classical ointment diclofenac 1%).

Based on the above we can conclude that the proposed arrangement has a number of advantages in comparison with the prototype and will find wide application in obtaining effective means.

Example 7.

Prepare a solution of lecithin in ethanol, separately dissolved fucoidan, escin and caffeine in the water, all placed in a single reactor with a stirrer, untwist a lot to the formation of a stable gradient rotation, emuleret for 30-40 minutes resulting mass is collected in a container and further used for finished dosage forms by adding calculated amounts in the compositions. This phospholipid composition with precise amounts of active substance allows to dose of the pharmacologically active component in effective amounts (example 8).

Example 8.

Thus, the resulting mass in example 7 in an amount of 5% is introduced into the gel base at a temperature not exceeding 30°C, add preservatives (nipagin and nipazol) and stirred for 10-20 minutes

This composition was subjected to in vivo. The study involved 5 volunteers aged 30 to 50. The composition of the nanos who stayed around the eye area daily 1 time per day. The course duration is 14 days. Study target parameter: skin color (chromameter). Upon completion of the study tested the condition of the skin. On day 14 all 5 participants eye area turned out to be much lighter compared to the beginning of the study. Figure 1 shows a photograph of the eye of one of the study participants.

Average data after aggregation are presented graphically in figure 2.

Example 9.

Prepare a solution of lecithin in ethanol, separately dissolved linoleic acid, vitamin E and D-panthenol in the water, all placed in a single reactor with a stirrer, untwist a lot to the formation of a stable gradient rotation, emuleret within 30-40 minutes the resulting mass is injected into the emulsion-base at a temperature not exceeding 30°C and stirred for 10-20 minutes

This example is used to assess the ability to regulate the flexibility, mobility, penetration and stability of the composition that has been confirmed by studies in the treatment of hair loss.

Due to the structure of liposomes was achieved the highest degree of penetration of the active substances and delivering them to the follicles, which ensured stop hair loss and restore problem areas. The study involved 11 volunteers (6 men and 5 women). Within 24 weeks 4 person daily inflicted in the form of a mask for hair product that contains vitamin E, linoleic acid and D-panthenol in concentrations of 1%, 2.5% and 3%, respectively.

Other participants used topically emulsion for hair that was done on the scalp for 20 min, after which the emulsion was washed off enough what kolichestvo water.

At the beginning and end of the study calculated the average number of hairs on problem areas (the number of hairs/cm²and the condition of the hair.

At the end of the study showed that patients using known means, not containing active substances in liposomal form, visible changes to improve the condition of the hair has not occurred. The participants using liposomal composition, a marked improvement and recovery of problem areas (Fig.3.)

The obtained composition according to example No. 6, containing diclofenac, used for studies of the stability of the structure.

Diclofenac enclosed in liposomes, was placed in the form of a gel. To speed up the determination of ESR additionally placed in the liposomes of vitamin E. the Penetrating ability of the composition (blue curve) was compared with commercially available ointment (blue curve).

The natural antioxidant capacity of the skin was taken as 100%. The rising curve shows increased penetration. Interesting fact is that commercially available ointment not only demonstrates the penetrating ability (to be described by a straight line at 100%), but also acts oxidant (damage skin).

The composition according to example No. 6 shows excellent penetration after 30 minutes after application.

The host system (liposomes) was added 14C-marking and diclofenac sodium was used for the biopsy to the LM. After 8 hours the skin was removed the top layer 16 times, and counting of radioactive indicators were measured in the skin layers, as well as in adipose tissue and fluid. Using commercially available ointments, conducted comparison studies.

The host system shows very good penetrating ability, whereas commercial ointments mainly found in the upper 4 strips.

Based on the proposed phospholipid composition is a big part of the applied diclofenac was directed into the skin.

Moreover, diclofenac entered in the adipose tissue, which shows the TRANS-dermal penetration ability of a carrier system. This in turn may facilitate the accumulation of diclofenac in the joints.

Conducting tests on animals, compared liposome encapsulated diclofenac (sample experience under the code name Cutisome No Pain) with commercially available ointments and tablets with diclofenac. It was shown that the proposed system-media ensures superior supply muscles and kneecap diclofenac, which exceeds more substantial dose of diclofenac for oral use.

Moreover, it was shown that the penetrating power of a carrier system is also superior to commercially available creams and pills, despite the fact that the concentration of the drug in the carrier system 10 times less (ri is .4).

Example 10.

Liposomes containing extract Lutein:

Prepare a solution of lecithin and lutein in ethanol, separately added water, all placed in a single reactor with a stirrer, untwist a lot to the formation of a stable gradient rotation, emuleret for 30-40 minutes

We obtained 4 prototype nanosystems extract lutein in this example using lutein with different variacijami content of phosphatidylcholine. Biopharmaceutical properties of nanosystems was estimated by the rate and completeness of the dissolution test in vitro.

At the first stage, we estimated the rate of release into the environment dilution water:ethanol (7:3 by volume)recommended in the Pharmacopoeia requirements for substances that are poorly soluble in aqueous media.

Evaluation of the speed of release was performed using a test "Dissolution" device type "rotating cor the Inca" (Type DT 600, Erweka, Germany) at a temperature (37±1)°C. the Speed of rotation of 100 rpm installation of the product, equivalent to 20 mg of extract lutein, were placed in the basket and at the expiration of the specified time intervals(5, 15, 30, 45, 60, 90 min and 2, 3, 4 h) samples were taken.

For the quantitative analysis of lutein in the environment release of used HPLC method. The analysis is performed on the chromatograph, high pressure, Shimadzu (Japan) with column Luna C18 (4.6×150 mm, 5 µm) and precolonial (2.0 mm), filled with the same sorbent (Phenomenex, USA), isocratic elution with a mixture of methanol:acetonitrile 5:95 (by volume), the flow rate of eluent, 1 ml/min, dosing volume of sample 20 ál of the wavelength detection at 450 nm.

Registration and processing of chromatograms performed using LCSolution software (Shimadzu, Japan).

Dosing of all samples was repeated at least twice the frequency. The calculation was performed according to the calibration curve, constructed by a methanol solution of the extract lutein. Expected number of lutein, passed into the solution, in % of the maximum possible.

Statistical processing of chromatographic data was performed using software Origin 4.1.

The results of the experiment shown in Fig.5.

During the experiment it was found that administration of the extract lutein part L3 virtually no effect on the speed vysvobozhdeny is. Of dispersed systems L4 number of free lutein reached 38% to 30 minute experiment, however, further release is not observed. Disperse system L2 allows you to free up to 2 hours of the experiment, about 50% of lutein. The best release of lutein observed from the system L1: 60 minute experiment released about 65%.

The rate constants of dissolution, calculated by the least squares method, were as follows:

L1 composition 0,5012 min^-1

L2 composition 0,3435 min^-1

L3 part - 0,0449 min^-1

L4 part - 0,2234 min^-1

extract lutein - 0,02798 min^-1

Thus, the highest weight and the rate of release of lutein observed with the compounds L1 and L2.

For these samples was studied the rate of release in a two-phase medium of dissolution, which simulates conditions of the gastrointestinal tract for lipophilic, water-insoluble substances and correlates well with the data of pharmacokinetics in vivo.

Evaluation of the speed of release in vitro was performed using a test "Dissolution" device type "rotating mixer (Type DT 600, Erweka, Germany) at a temperature (37±1)°C. the Speed of rotation of 100 rpm, the dissolution of the two - phase system water:octanol 3:1, the total environment dissolving 400 ml.

For the quantitative analysis of lutein in the environment of the release used is ovali method direct spectrophotometry in the UV region. The optical density of the resulting solutions was measured on a spectrophotometer Shimadzu" when the wavelength of maximum (450 nm) in a cell with a layer thickness of 1 cm

The amount of lutein, passed into the solution (in % of maximum possible), was calculated using the extinction coefficient E1% 1 cm = 2560.

The results are shown in Fig.6.

The most fast and complete release of flows from a disperse system L1: 30 minutes of the experiment at which the maximum release, which is about 43%, which is 14 times more in comparison with pure extract lutein (about 3%). The maximum concentration at the release of part L2 is achieved by 2 hours and does not exceed 26%. The rate constants of dissolution, calculated by the least squares method, were as follows:

L1 composition 0,4450 min^-1

L2 composition 0,3499 min^-1

extract lutein - 0,0424 min^-1

The data obtained allow us to conclude that the introduction of the extract lutein in nanosystems can significantly increase its bioavailability in vitro. From the obtained nano highest bioavailability is characterized by a dispersed system L1.

The average particle size, determined by the method of photon-correlation spectroscopy instrument Malvern Zetasizer 3000HSA (Malvern instruments, Worcestershire, UK)was 152±2 nm.

Example 11.

Liposomes containing blueberry extract:

Prepare a solution of lecithin in ethanol, separately added water and blueberry extract, all placed in a single reactor with a stirrer, untwist a lot to the formation of a stable gradient rotation, emuleret for 30-40 minutes

We received 2 of the prototype of nanosystems with blueberry extract with the use of lecithin with different content of phosphatidylcholine. The content of bilberry extract in nanosystems was 20 wt%.

For the samples was studied the rate of release in the dissolution test (in vitro) on the device type "rotary basket" (Type DT 600, Erweka, Germany) at a temperature (37±1)°C. the Speed of rotation of 100 rpm, the dissolution - 0.1 N. hydrochloric acid, the volume of medium dissolving 250 ml. Sample of the test product (20 mg, calculated on the blueberry extract) were placed in the basket. After the specified periods of time(3, 5, 10, 15, 20, 30, 40, 50, 60 min) samples were taken in 1 ml volume vos is anali the same solvent.

For the quantitative analysis of anthocyanins used the method of direct spectrophotometry. The optical density of the resulting solutions was measured on a spectrophotometer Shimadzu" when the wavelength of maximum (510 nm) in a cell with a layer thickness of 1 cm was Calculated amount of anthocyanins, passed into the solution, in % of the maximum possible.

The results of the experiment shown in Fig.7.

The data obtained allow us to conclude that the release of the extract and composition B1 virtually no difference: 5 minute experiment reaches its maximum concentration in the environment of the release, the number of free anthocyanins is about 90%. System B2 is characterized by a slower release: the maximum release is achieved by the 30th minute of the experiment and is about 95%.

The rate constants of dissolution, calculated by the least squares method, were as follows:

B1 part - 7,6900 min^-1

B2 part - 2,9746 min^-1

blueberry extract - 8,3207 min^-1

The data obtained allow us to conclude that the introduction of bilberry extract in a disperse system B1 does not affect its bioavailability in vitro system B2 provides a more prolonged release while maintaining a high level of bioavailability. The models in vitro experiments do not allow us to show pre is the property of nanosystems with blueberry extract because of the high bioavailability of the extract. More adequate data to improve the bioavailability of the products on the basis of blueberry extract can be obtained only after pharmacokinetic studies in vivo, for example in rabbits.

The average particle size, determined by means of photon correlation spectroscopy, was 268±15 nm.

During the crystallization of a solid from a solution or melt of the first forms the least stable phase, which is the largest free energy is closest to the solution (rule Westward).

It is therefore metastable modifications have less internal adhesion molecules, resulting in their increased solubility. The solubility of drug substances in the water seems to be the most important physical property.

Dissolution plays the role of the rate-limiting step and the absorption of drug substances from the gastrointestinal tract. That's why metastable forms are of particular interest when creating a pharmaceutical substance.

Comparing the rate constants of dissolution of lutein, we can conclude that the nanosystems are characterized by a more rapid release of water insoluble lutein compared with the substance. So the rate of release of lutein from nanosystems increases of 10.5 times. Thus, administration of the extract lutein part of nanosystems shows the substantial improvement release it in the aquatic environment. This effect can be explained by the reduction of particle size and stabilization of the particles in the composition nanosystems.

Thus, the introduction of plant extracts in the composition of the metastable form-based nanosystems can significantly increase the rate of dissolution and provides uniform release of the active substance under conditions modeling oral administration.

1. Phospholipid emulsion comprising liposomes (nanosomes) with an average diameter of liposomes (sediment) from 20 to 500 nm, containing ethanol and water, characterized in that it further comprises a lecithin content of phosphatidylcholine not less than 60% and diclofenac sodium in the following ratio of components of liposomes and active ingredients, wt.% (100 wt.%):

2. Phospholipid emulsion according to claim 1, containing at least one acceptable accessory component as a diluent.

3. Phospholipid emulsion according to claim 1, characterized in that the emulsion is used to dose f is mikologicheskie active component in effective quantities and limit their upper limit.

4. Phospholipid emulsion according to claim 1, characterized in that it contains at least one of the excipients chosen from the group of preservatives, aromatic compositions.

5. Phospholipid emulsion according to any one of claims 1 to 4, which further comprises at least one vitamin and/or vitamin-like substance.

6. Phospholipid emulsion according to any one of claims 1 to 4, which further comprises at least one extract.

7. Phospholipid emulsion according to any one of claims 1 to 4, which further comprises at least one micro - or macro element.

8. Phospholipid emulsion according to any one of claims 1 to 4, which further comprises at least one compound from the group of carotenoids.

9. Phospholipid emulsion according to any one of FG1-4, which additionally contains at least one compound from the group of organic acids.

10. Phospholipid emulsion according to any one of claims 1 to 4, which further comprises at least one compound from the group of enzymes.

11. Phospholipid emulsion according to any one of claims 1 to 4, which further comprises at least one compound from the group of flavonoids.

12. Phospholipid emulsion according to any one of claims 1 to 4, which further comprises at least one compound from the group of chondroprotective.

13. Phospholipid emulsion according to any one of claims 1 to 4, which is more the tion contains resveratrol.