Method of medicinal agent bioavailability increase

FIELD: medicine; pharmacology.

SUBSTANCE: medicinal agent is mixed with preaerated and irradiated with accelerated electron current or pulse UV-laser radiation 5.0-50.0% polyethylene oxide solution of molecular weight 0.4-20 kilodaltons in presence of 0.01-0.1 M phosphate buffer, pH 6.0-8.0 and containing 0.05-0.3 M sodium chloride. Offered method is easy and multipurpose, and can be applied to increase enteral bioavailability of medicinal agents introduced mainly or solely parenterally due to low resorption by intestine walls.

EFFECT: increased enteral bioavailability of medicinal agents.

4 cl, 3 tbl, 10 ex, 1 dwg

 

The present invention relates to pharmacology and medicine and can be used to produce oral dosage forms and pharmaceutical compositions containing as active ingredients of a medicinal product, which have low oral bioavailability and consequently are introduced mainly parenteral.

In pharmacology, there are three main routes of administration of drugs with obscherezorbtivnymi action and manifesting their therapeutic effect after entering the blood system: enteric (per os or the administration of drugs through the gastroduodenal probe), parenteral (intravenous, subcutaneous or intramuscular injection of drugs) and external (application of a drug to the skin or mucous: intranasal or inhalation administration). Route of administration of a drug depends on clinical indications, and from the physico-chemical properties of the drug. In modern pharmacology there are very few examples where the drug can be used in any way the introduction of glucocorticoid hormones and local anaesthetics). As a rule, because of the nature of solubility in aqueous and nonaqueous media, permeability through cell membranes medications administered one liduma ways. There are medications that are administered only by parenteral (cyclosporine) or enterline (fluoroquinolones). For medical applications the most convenient and safe oral forms of drugs, as the number of complications of parenteral drugs (abscesses, phlegmon), as well as inhalation and intranasal (allergic rhinitis and bronchial asthma) is large enough. In addition, only oral administration of a medicinal product in the form of capsules, tablets or liquid dosage forms acceptable for long-term treatment of chronic diseases.

In current clinical practice, there is a large group of drugs that are administered only parenterally because they are either not absorbed from the gastrointestinal tract, or dissolved in it. These medications include: peptide hormones (insulin, ACTH, Cortexin, oxytocin, growth hormone), antibiotics (aminoglycoside and cephalosporin), heparin, etc. All these drugs are used long-term, which creates some inconvenience for patients, but also helps emergence of infectious-inflammatory complications typical for injection route of administration of drugs. In the modern scientific literature contains only e is inicie information about how to obtain oral dosage forms of these drugs.

Known methods of increasing the bioavailability of injectable drugs and receiving on the basis of oral dosage forms are not universal, but on the contrary, individual for each specific drug. For example, when receiving oral form of insulin the main objective of the modification of this peptide is to reduce the damaging effect of this peptide hydrochloric acid of gastric juice and digestive proteolytic enzymes. To obtain the oral forms of heparin this way is unacceptable, since heparin resistant to proteolytic enzymes and hydrochloric acid, however, its absorption in the intestine practically does not occur due to the physico-chemical characteristics. Similar properties have antibiotics from the group of aminoglycosides and cephalosporins. Another example of a drug that is administered only parenterally due to the low ability to penetrate through the intestinal wall, is DNA. Its low bioavailability when administered orally due to its high molecular weight, from 10 to several thousand kDa. At the same time unique therapeutic effects of parenteral introduction of DNA make it a very promising pharmaceutical drug. In clinical practice, drugs based on DNA extracted from sturgeon ROE is o fish (drug, "Derinat"), used as activators of cellular and humoral immunity to stimulate haematopoiesis and leucopoiesis. Lack of preparation "Derinat" is that it is only applied topically and parenterally. Oral application "Derinat" inefficient, because of high molecular weight deoxyribonucleic acid its absorption from the gastrointestinal tract is not sufficient for the manifestation of therapeutic action.

In the modern scientific literature there are no data about receiving oral forms of heparin and its analogs.

A method of obtaining drug insulin for oral administration by immobilization of insulin in the amount of crosslinked polymer modified inhibitor of proteolytic enzymes (R.Z.Creenley, et.all Polymer Matrices for orol delivery, Polymer Preprits 1990, v.31, № 2, p.182-183). As a cross-linked polymer used acrylic or methacrylic acid, crosslinked, triethyleneglycol(meth)acrylate, and as an inhibitor of proteolytic enzymes used Aprotinin - pancreatic trypsin inhibitor.

The disadvantage of this method is the low stability of the synthesized polymer hydrogels to the action of digestive enzymes, resulting in a low activity in penetrating the blood insulin.

Closest to the claimed method of the prototype is the fast way to increase the bioavailability of insulin by immobilization of the last in the volume of cross-linked polymer, modified inhibitor of proteolytic enzymes, which use ovomucoid in amount of 0.2-25 mg/g (swollen hydrogel in water). Immobilization is carried out by immersing stitched modified polymer in an aqueous solution of insulin with a concentration of 0.01-5 mg/ml for 1-2 hours until complete swelling of the polymer. The modified polymer is used in an amount of 0.01 to 1.0 g per 1 ml solution of insulin (RF Patent No. 2066551, CL AC 38/28, publ. 20.09.96).

The disadvantages of this method are the technological complexity of the allocation ovomucoid and obtain a cross-linked polymer, modified them, the high cost and low therapeutic efficacy of the final product. In addition, the disadvantages of this method are the lack of universality and its inefficiency to increase the bioavailability of other drugs, administered parenterally, in particular drugs based on DNA and heparins.

The technical object of the present invention is to develop a simple and universal method of increasing the bioavailability of drugs, administered primarily or exclusively parenteral due to the low absorption through the intestinal wall.

The technical problem is achieved by the proposed method lies in the following.

A drug with a low enteral the second bioavailability, taken at standard therapeutic doses determined for each drug individually dissolved in 5.0 to 50.0% of an aerated solution of polyethylene oxide with a molecular weight of from 400 to 20000 Da in the presence of 0.01-0.1 M phosphate buffer with a pH of 6.0-8.0, containing 0.05-0.3 M sodium chloride, pre-activated by ionizing radiation (flow accelerated electrons or gamma rays) in doses from 0.5 to 5.0 Mrad or pulsed UV-laser radiation with a wavelength 193-308 nm with pulse energy of 100-500 MJ, pulse duration of 15 to 25 NS and the pulse repetition rate 50 Hz. The result is a complex that contains a pharmacologically active ingredient and activated by irradiation of a water-soluble polymer, while the pharmacologically active substance is modified irradiated polymer. The resulting complex has the ability to penetrate through the intestinal wall and, thus, pharmacologically-active substance is delivered into the systemic circulation and exerts its therapeutic effect.

Enhancing enteral bioavailability of the drug is achieved due to the properties of the irradiated polyethylene oxide quickly penetrate through any biological barriers and its ability to chemically modify the drug. The ability of irradiated is of poliatilenaksida contact with drugs is based on the process of radiation-chemical activation of polymers. High-energy ionizing radiation, which is generated by linear electron accelerators type ILU, ELV, or UV laser radiation influences the dissolved polymers via free radical chain reactions. Oxidative free radicals cause in the structure of polymers with reactive groups capable of binding a variety of pharmacologically active compounds. Processes in irradiated solutions of polymers, mainly associated with radiation-chemical or photochemical oxidation and degradation-With-C - and-C-O - bonds in the polymer formed chemically active groups: carbonyl and peroxide. They can form a large number of labile (e.g., hydrogen bonds) and relatively chemically stable relationships (for example, azomethine, peroxide and acetaline communication) with various drug substances. This forms a temporary complex drug substances and irradiated water-soluble polymer that is not an independent chemical compound, all physico-chemical characteristics of the drug substance remains, but at the expense of such temporary complexing the pharmacologically-active substance appears high enteral bioavailability. The use of 0.01-0.1 M phosphate buffer with a pH of 6.0-8.0 poses which enables you to optimize the process of oxidative radiation chemical and photochemical activation of polyethylene oxide. When the concentration of the buffer is less than 0.01 M in the process of irradiation due to accumulation of radiolysis products of water is offset pH below 6.0 and this leads to a decrease in the yield of activated polyethylene oxide. The increase in the concentration of the buffer 0.1 M reduces the solubility of the pharmacologically active compounds in irradiated solution of polyethylene oxide. The choice of phosphate buffer is dictated by the fact that phosphate ions, unlike other inorganic anions used in the range of doses of ionizing radiation and settings UV laser radiation, chemically inactive and do not undergo radiolysis and photolysis. The choice of pH buffer solution due to the fact that at pH below 6.0 and above 8.0 outputs radiation-activated polyethylene oxide is significantly reduced. Introduction in the irradiated solution of polyethylene oxide of sodium chloride in the claimed range of 0.05-0.3 M allows to increase the number of oxidative radicals produced by the radiolysis of water, which in turn increases the yield of activated polyethylene oxide. The concentration of sodium chloride is less than 0.05 M does not significantly affect the increase in the yield of activated polyethylene oxide, and the concentration of more than 0.3 M create excessive salt stress on the kidneys and bowels when using drugs. To increase the yield of radiation-activated polyethylenes is Yes its solution before irradiation is subjected to additional aeration by bubbling air or oxygen for 30 minutes at 4-8° C.

Determining significant difference between the proposed method from the prototype is that as a transport agent to deliver pharmacologically active agent through the intestinal wall, use pre-activated by ionizing radiation, the polymer is polyethylene oxide with a molecular weight of from 400 to 20000 Da in the form of 5,0-50,0% aqueous solution, with which it forms a labile complex, releasing the active pharmacologically active substance after passing through the intestinal wall into the systemic circulation.

The claimed method is confirmed by the following examples of specific performance.

Example 1

10% aqueous solution of polyethylene oxide, pre-aerated by bubbling air, with a molecular weight of 400 Da in 0.01 M phosphate buffer with pH 8.0, containing 0.3 M sodium chloride, is irradiated with a stream of accelerated electrons at a dose of 0.5 Mrad. In the irradiated solution make DNA from salmon ROE fish to a final concentration of 25 mg in 1 ml (ratio of the polyethylene oxide:DNA equal to 4:1). The mixture is stirred for 15 minutes and get the DNA preparation in the form of a slightly opalescense viscous solution. The yield is 99%.

Example 2

50% aqueous solution of polyethylene oxide, pre-aerated by bubbling oxygen with molecular weight of 4000 Da in 0.1 M phosphate buffer with pH 7.0, containing 0,0 M sodium chloride, irradiated by a stream of accelerated electrons at a dose of 5 Mrad. In the irradiated solution make DNA from salmon ROE fish to a final concentration of 50 mg in 1 ml (ratio of the polyethylene oxide:DNA is 10:1). The mixture is stirred for 15 minutes and get the DNA preparation in the form of a slightly opalescense viscous solution. The yield is 98%.

Example 3

25% aqueous solution of polyethylene oxide, pre-aerated by bubbling air with a molecular mass of 1500 Yes in 0.05 M phosphate buffer with pH 6.0, containing 0.1 M sodium chloride, is irradiated with a stream of accelerated electrons at a dose of 2.5 Mrad. In the irradiated solution make insulin to a final concentration of 5 mg in 1 ml (ratio of the polyethylene oxide:insulin is 50:1). The mixture is stirred for 15 minutes and get insulin product in the form of a slightly opalescense solution. The yield is 99%.

Example 4

5% aqueous solution of polyethylene oxide, pre-aerated by bubbling air, with a molecular weight of 20,000 Da in 0.1 M phosphate buffer with pH 7.0, containing 0.2 M sodium chloride, is irradiated with a stream of accelerated electrons at a dose of 5 Mrad. In the irradiated solution make insulin to a final concentration of 50 mg in 1 ml (ratio of the polyethylene oxide:insulin is 1:1). The mixture is stirred for 15 minutes and get insulin product in the form of a slightly opalescense solution. The output of finished products is KTA is 99%.

Example 5

20% aqueous solution of polyethylene oxide, pre-aerated by bubbling air, with a molecular weight of 400 Da in 0.05 M phosphate buffer with pH 8.0, containing 0.2 M sodium chloride, is irradiated with a stream of accelerated electrons at a dose of 1.5 Mrad. In the irradiated solution contribute heparin to a final concentration 19,25 mg (2500 UNITS) in 1 ml (ratio of the polyethylene oxide:heparin is 10:1). The mixture is stirred for 15 minutes and get the drug heparin in the form of a transparent solution. The yield is 97%.

Example 6

10% aqueous solution of polyethylene oxide, pre-aerated by bubbling oxygen with molecular weight of 4000 Da in 0.01 M phosphate buffer with pH 7.0, containing 0.1 M sodium chloride, is irradiated with a stream of accelerated electrons at a dose of 3.5 Mrad. In the irradiated solution contribute heparin to a final concentration of 38,50 mg (5000 IU) in 1 ml (ratio of the polyethylene oxide:heparin equal to 2.5:1). The mixture is stirred for 15 minutes and get the drug heparin in the form of a transparent solution. The yield is 98%.

Example 7

5% aqueous solution of polyethylene oxide, pre-aerated by bubbling oxygen with a molecular weight of 20,000 Da in 0.01 M phosphate buffer with pH 8.0, containing 0.01 M sodium chloride, is irradiated with a stream of accelerated electrons at a dose of 5 Mrad. In the irradiated solution make a protease of Bacillus subtilis to the end to the concentrations of 5 mg (5000 IU) in 1 ml (ratio of the polyethylene oxide:protease is 10:1). The mixture is stirred for 15 minutes and get the product of the modified protease in the form of a transparent solution. The yield is 98%.

Example 8

10% aqueous solution of polyethylene oxide, pre-aerated by bubbling oxygen with a molecular mass of 1500 Yes in 0.01 M phosphate buffer with pH 7.4, containing 0.1 M sodium chloride, is irradiated with a stream of accelerated electrons at a dose of 1 Mrad. In the irradiated solution make a protease of Bacillus subtilis to a final concentration of 5 mg in 1 ml (ratio of the polyethylene oxide:protease equal to 20:1). The mixture is stirred for 15 minutes and get the product of the modified protease in the form of a transparent solution. The yield is 98%.

Example 9

10% aqueous solution of polyethylene oxide, pre-aerated by bubbling oxygen with a molecular mass of 1500 Yes in 0.01 M phosphate buffer with pH 7.4, containing 0.1 M sodium chloride, is irradiated with UV laser light, the wavelength of 193 nm, pulse energy of 500 MJ with the duration of 15 NS and a frequency of 50 Hz. In the irradiated solution make a protease of Bacillus subtilis to a final concentration of 5 mg in 1 ml (ratio of the polyethylene oxide:protease equal to 20:1). The mixture is stirred for 15 minutes and get the product of the modified protease in the form of a transparent solution. The yield is 99%.

Example 10

5% aqueous solution of polyethylene oxide, pre is varicella aerated by bubbling oxygen, with a molecular weight of 4000 Da in 0.01 M phosphate buffer with pH 7.4, containing 0.1 M NaCl and protease of Bacillus subtilis at a concentration of 5 mg in 1 ml (ratio of the polyethylene oxide:protease is 10:1), is irradiated with UV laser light, the wavelength 308 nm, pulse energy of 100 MJ with a duration of 25 NS and a frequency of 50 Hz. The result is the preparation of the modified protease in the form of a transparent solution. The yield is 99%.

The drawing presents data on increased enteral bioavailability of protease of Bacillus subtilis, modified by the claimed method. Enteral bioavailability was investigated by the dynamics of changes in proteolytic activity (hydrolysis of azocasein) serum of Wistar rats for 8 hours after a single intragastric administration at equivalent doses of unmodified protease and protease modified by the claimed method. As is seen in the drawing results, unmodified protease after intragastric administration practically does not possess enteral bioavailability and appropriately throughout the measurement time does not lead to a statistically significant increase in the proteolytic activity of blood serum. The modified protease of Bacillus subtilis, on the contrary, after intragastric administration have high enteral bio what otoplasty, that is reflected in the significant increase in the proteolytic activity of blood serum, namely more than 10-fold when comparing the maximum values of the activity of proteases in the serum of rats.

Table 1 presents data on enteral bioavailability of heparin and heparin, modified by the claimed method, after a single intragastric administration to mice. Enteral bioavailability was investigated by changing the APTT (activated partial thromboplastin time) of the blood serum of experimental animals after 3 hours after intragastric administration in equivalent doses (1250 IU in 0.5 ml of isotonic solution of sodium chloride) of unmodified and modified heparin. As seen in the table 1 results, unmodified heparin intragastric (W/W) introduction practically does not possess enteral bioavailability and accordingly the value of the APTT serum 3 hours after it in/W introduction practically does not differ from the APTT blood serum of mice in the control group, which was/W entered isotonic solution of sodium chloride in equivalent amount. When added to the serum of the mice of the control group selective sorbent heparin - jasonb value of the APTT remains within the original values that svidetelstvo is about the absence of serum heparin in doses beyond its physiological level of serum no heparin, rezorbirovanny from the gastrointestinal tract. Modified heparin, on the contrary, when the/W introduction has high oral bioavailability, which is reflected in a significant increase (more than 3 times) the APTT blood serum in the experimental group of mice. When added to the serum of the mice of the experimental group HEPSERA value of the APTT is reduced, which suggests that serum is present heparin in doses greatly exceeding the physiological level, i.e. in the blood is heparin, rezorbirovanny from the gastrointestinal tract.

Table 2 presents data on the study of enteral bioavailability human insulin modified by the claimed method, and unmodified insulin. Enteral bioavailability was assessed by the hypoglycemic action of insulin on the model of alloxan diabetes in rats. In the experimental group experimental animal/W once introduced 1 ml of modified insulin activity 50 IU/ml (ratio of the polyethylene oxide: insulin is 70:1). In the control group animals introduced 1 ml of unmodified human insulin with an activity of 50 IU/ml

As can be seen from table 2, the modified insulin the possession the t pronounced hypoglycemic activity when the/W rats with alloxan model of diabetes, indicating that it has high oral bioavailability in comparison with the unmodified insulin.

Table 3 shows data on comparative study of clinical efficacy in the treatment of chronic venous insufficiency of the lower extremities unmodified DNA in combination with standard treatment (control group) and monotherapy drug containing DNA, modified by the claimed method (experimental group). The analyzed DNA preparations were used in both groups per os. The clinical efficacy of therapy was evaluated by the standard parameters of electroradiographic. As can be seen from the presented results, the electrophysiological parameters of the venous system of the lower extremities in the experimental group indicate significantly more expressed therapeutic effect when taking DNA modified by the claimed method, which indicates its high oral bioavailability.

The inventive method is universal and can be used to improve enteral bioavailability of a wide range of drugs, including insulin, proteases, heparin and nucleic acids (DNA and RNA).

The method of increasing the bioavailability of drugs

Table 3
Investigated parametersThe control groupThe main group
Before the treatmentAfter the treatmentBefore the treatmentAfter the treatment
The rate of lymph outflow, Ω/s0,17±0,020,2±0,020,18±0,020,25±0,02
The volume of lymphatic drainage, MD0,26±0,020,28±0,030,25±0,020,32±0,03
Resistance lymphatic drainage, with/Ω2,97±0,172,69±0,153,12±0,212,54±0,15
The rate of venous outflow, Ω/s0,25±0,020,28±0,020,22±0,020,31±0,02
The volume of venous outflow, MD0,31±0,030,37±0,030,33±0,030,42±0,42
Resistance to venous outflow, with/Ω3,35±0,242,96±0,183,19±0,222,73±0,16

1. The way polystyerene bioavailability of drugs includes mixing the latter with a water-soluble polymer, wherein the drug is mixed with 5,0-50,0% pre-aerated and exposed to a stream of accelerated electrons or pulsed UV-laser radiation with a solution of polyethylene oxide with a molecular mass of 0.4-20 kDa in the presence of 0.01-0.1 M phosphate buffer, pH 6.0 to 8.0 and containing 0.05-0.3 M sodium chloride.

2. The method according to claim 1, characterized in that the solution of polyethylene oxide aeronaut by bubbling air or oxygen for 30 min at 4-8°C.

3. The method according to claim 1, characterized in that the solution of polyethylene oxide is irradiated with a stream of accelerated electrons or gamma radiation at doses of 0.5 to 5.0 Mrad.

4. The method according to claim 1, characterized in that the solution of polyethylene oxide is irradiated with a pulsed UV-laser radiation with a wavelength of 193-308 nm with pulse energy of 100-500 MJ, pulse duration of 15 to 25 NS and the pulse repetition frequency of 50 Hz.



 

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14 cl, 3 tbl, 13 dwg

FIELD: medicine, oncology, pharmacy.

SUBSTANCE: invention relates to pharmaceutical compositions used for inhibition of metastasis or prophylaxis of malignant tumor relapse after the topical therapy. As an active component, compositions contain derivative of polysaccharide comprising polysaccharide with carboxyl group bound with an active substance possessing anti-tumor activity through amino acid or peptide consisting of from 2 to 8 amino acids that are similar or different, or its salt wherein this active anti-tumor substance is represented by derivative of camptothecin of the formula (I) by claim 1 or compound of the formula (II) by claim 1 given in the invention description. The topical therapy involves surgery, radiation therapy, thermotherapy, cryotherapy or laser-burning therapy. Proposed compositions allow providing the high concentration of active substance in tumor metastasis region and prophylaxis of relapses of malignant tumor after carrying out the topical therapy.

EFFECT: valuable medicinal properties of pharmaceutical compositions, improved method of treatment.

9 cl, 1 dwg, 4 tbl, 6 ex

FIELD: medicine.

SUBSTANCE: invention relates to conjugates consisting of molecule transporting through biological membranes. Molecule represents biopolymer, peptide-nucleic acid or polyamide and aryl residue used in treatment of diseases caused by super-production of definite genes, a method for preparing conjugates, a method for transport of molecule through biological membrane, a medicinal agent, a method for preparing medicinal agent, diagnostic agent and test-set based on indicated conjugate.

EFFECT: improved preparing method.

21 cl, 9 dwg, 6 tbl, 18 ex

FIELD: pharmaceutical industry.

SUBSTANCE: invention provides immobilized form of cephasoline wherein cephasoline is included into polymer matrix made of sodium-carboxymethylcellulose.

EFFECT: reduced (by three days) treatment time.

1 dwg, 5 tbl

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