Amplifiers absorption for pharmaceutical compositions for local application

 

(57) Abstract:

Method of enhancing the penetration of pharmacologically active products includes local application to the skin or mucosa of the pharmacologically active funds and connections to enhance its penetration. Penetration enhancers are biodegradable substances and represent a new group of esters of long chain aliphatic acids with N,N-disubstituted-aminoalcohols. The preferred penetration enhancers are dodecanoate 1-(N,N-dimethylamino)-2-propanol, monistat 1-(N,N-dimethylamino)-2-propanol and oleate 1-(N,N-dimethylamino)-2-propanol. New penetration enhancers increase the permeability of the separation membranes and increase the absorption of the pharmacologically active compounds of the skin and mucous membranes. 4 C. and 18 h.p. f-crystals, 10 ill., 7 table.

The invention is a partial continuation of application for U.S. patent N 08/133454, filed October 7, 1993.

The invention relates to the development of safe and effective tools that increase the speed of delivery of physiologically active agents through the skin or mucous membrane of the mouth. In particular, the present invention relates to improvements in the ski active agents in the body of a mammal.

Cutaneous drug formulations are examples of the oldest medicinal forms in the history of mankind. It is highly likely that the ancient people used resins and animal fats for the treatment of skin damage caused by wounds and burns. The use of such skin compositions for local application largely remained unchanged until the middle of our century. The concept of prescribing through the skin to achieve local or systemic effects for the first time seriously put forward in the early 1970 H. Since in this area of intensive research is being conducted.

Percutaneous path of drug delivery offers several advantages over the traditional ways of drug delivery. For example, the drug can be delivered to the desired tissue within the surrounding area of the skin. Percutaneous path of drug delivery also allows you to perform slow controlled secretion of drugs into the systemic circulation. Because many drugs are poorly absorbed or difficult delivery traditional ways of assigning a percutaneous path is an effective way to achieve the best bioavailability of these drugs. Percutaneous path of becoming, if therapy may cause unwanted side effects.

Despite the above advantages, the number of percutaneous compositions is limited. They cannot be used with most polar medicines, because they are too slow to penetrate the skin. This property is crucial, because most medicines are polar compounds. In addition, many drugs cause a reaction and/or irritation on the skin at the site of their application.

There are two ways of increasing the rate of penetration of polar drugs through the skin. The first is the preparation of an improved composition containing the drug, with the aim of increasing thermodynamic activity. thermodynamic activity of the drug in the skin of a composition depends on the concentration of the medicinal product and media selection. The second method involves the use of physical methods, in particular medicinal electrophoresis, or the use of chemical compounds, in particular amplifiers penetration of reagents, with the aim of increasing the permeability of the separating membrane. The last method in the General case is more in practice the number of connections from the point of view of their efficiency to increase the speed of penetration of drugs through the skin. Classic examples of recognized active amplifiers are protonotaria solvents, in particular dimethyl sulfoxide (DMSO) and dimethylacetamide (DMEM). Recently as an effective amplifiers described 2-pyrrolidone, N, N-diethyl-m-toluamide (DETA), 1-dodecylsulfate-2-he (Azone registered trademark of "Nelson Research), N,N-dimethylformamide, N-methyl-2-pyrrolidone and thioglycollate calcium.

In the previous work of one of the applicants of the present invention, namely U.S. patent 4980378, issued on 25 December 1990, and in U.S. patent 5082866, issued on January 21, 1992, is a group of biodegradable amplifiers absorption, which are N,N-disubstituted aminoacetate.

Biodegradable amplifiers absorption described in the above patents, to solve several problems that arose with many previously known from the technical field amplifiers penetration through the skin. One of these problems is the inability to use the well-known amplifiers with most polar drugs, since they are too slow to penetrate the skin. In addition, many of the previously known from the field of technology penetration enhancers cause skin reactions and/and is a peaceful purposes, help to solve some problems.

We have found that compounds which are N,N-disubstituted derivatives of esters of aminoalcohols with some aliphatic acids, unexpectedly good amplifiers penetration of reagents. For example, a single representative of this class of compounds is derived and alanovoy acid and aminoalcohol, dodecanoate 1-(N,N-dimethylamino)-2-propanol, which can be obtained by the interaction of aminoalcohol with laurolactam in the presence of triethylamine. These compounds are easily obtained in large quantities.

Thus, one of the purposes of the present invention are more biodegradable amplifiers absorption, which significantly increase thermodynamic activity of the pharmacologically active agents and increase the permeability of the separation membrane, such as skin and mucous membranes.

Another objective of the present invention is to improve percutaneous drug delivery with additional new compounds that enhance the absorption of active compounds the skin and mucous membranes such as the gums. These drugs is s, previously used for this purpose.

The way to achieve these and other objectives of the present invention will become apparent from the detailed description of the invention, which is described later.

Designed and synthesized a new group of esters of long chain aliphatic acids with N,N-disubstituted-aminoalcohols. Fragment of a long-chain acid may be a residue or a saturated carboxylic acid or the unsaturated carboloy acid with a long chain, such as oleic or linoleic acid. These compounds as saturated (I) and unsaturated (II) are a class of biodegradable (or "soft") amplifiers penetration of reagents, which due to its structure have less harmful or toxic effects and yet are excellent amplifiers absorption through the skin or mucous membranes of the mouth (especially through the gums).

The present invention claims a method of administration of physiologically active agents through a body surface such as skin and mucous membranes, as well as compositions for use in the specified way. In particular, the invention relates to a method for amplification of proniknovenie the active funds in the amount sufficient to achieve the desired local or systemic effect, in combination with the above-described biodegradable (or "soft") amplifier penetration of the reagent in an amount sufficient to enhance penetration of physiologically active funds. In the claimed invention is also a pharmaceutical composition comprising one or more of these compounds together with a pharmaceutically acceptable carrier.

Brief description of drawings

In Fig. 1 shows a graph of the profile of the penetration of drugs (the dependence of the total number of drugs detected in foster diffusion cell device with vertical cells, from time to time) for solutions containing clonidine in the presence of the amplifier of the present invention, dodecanoate 1-(N, N-dimethylamino)-2-propanol [DAIPD )], known from the technical field amplifier Azone ( ), and control solutions that do not contain power ( ).

In Fig. 2 shows a graph of the profile of the penetration of drugs for solutions containing hydrocortisone in the presence DAIPD ( ), Azone ( ), and control solutions ( ).

In Fig. 3 shows a graph of the profile of the penetration of drugs for solutions containing indomethacin in the presence of DAIPD ( ), Azone ( ), and kadirgama clonidine in the presence of another amplifier of the present invention, myristate 1-(N,N-dimethylamino)-2-propanol (DAIPM ( ), Azone ( ), and control solutions ( ), mean +/- standard deviation, n = 3-5.

In Fig. 5 shows a graph of the profile of the penetration of drugs for solutions containing hydrocortisone in the presence DAIPM ( ), Azone ( ), and control solutions ( ), mean +/- standard deviation, n = 3-5.

In Fig. 6 shows a graph of the profile of the penetration of drugs for solutions containing indomethacin in the presence of DAIPM ( ), Azone ( ), and control solutions ( ), mean +/- standard deviation, n = 3-5.

In Fig. 7 shows a graph of the profile of the penetration of drugs for solutions containing prostaglandin E in the presence of DAIPM ( ), Azone ( ), and control solutions ( ), mean +/- standard deviation, n = 3-5.

In Fig. 8 shows a graph of the profile of the penetration of drugs for a 45-percentage ethanol solutions containing prazosin after pre-treatment DAIPM ( ), Azone ( ), and control solutions ( ).

In Fig. 9 shows the Biodegradability DAIPD in presets tvii porcine esterase in the 32oC and pH 7.0.

In Fig. 10 is a graph of the profile of the penetration of drugs for solutions containing clonidine in the presence of unsaturated E. ntalnyh solutions ( ).

As mentioned previously, the compounds of the present invention are esters of long chain acids can be saturated (formula I), or unsaturated (formula II), with aminoalcohols. In that case, if the long-chain fragment is saturated, the compounds have the formula:

< / BR>
where n = 5-18 integer; y = 0-5, integer; R1- R7the same or different are members of the group comprising hydrogen and (C1-C8)alkyl, a R8is a member of the group comprising hydrogen, hydroxyl and (C1-C8)alkyl.

Examples of suitable compounds of formula (I) according to the present invention are shown in table. 1.

R1and R2preferably chosen from the group comprising hydrogen, methyl and ethyl, and more preferably R1and R2denote methyl. If the compounds of formula (I) is a saturated long-chain fragment, the preferred amplifier is dodecanoate 1-(N, N-dimethylamino)-2-propanol [DAIPD, PL. 1 (5)] . Other preferred amplifier of the formula (I) is monistat 1-(N,N-dimethyl amino)-2-propanol [DAIPM, PL. 1 (12)].

Although the alkyl radicals can be straight or branched chain, in castnet what adically with a straight chain, because, apparently, provide a larger gain.

If connection is made from untreated long-chain acids, they have the formula:

< / BR>
where t, v and z each represent an integer of 0 to 1 inclusive, s, u, w, and x each represent an integer from 0 to 12 inclusive, with (s+ u + w + x) is an integer from 4 to 18, inclusive, y = 0-5 integer, a R9-R22can be the same or different from each other and are members of the group comprising hydrogen (C1- C8)alkyl.

For compounds of formula (II) R9and R10preferably are members of the group comprising hydrogen, methyl ethyl, and more preferably R9and R10denote methyl. The most preferred compound of formula (II) oleate is 1-(N,N-dimethylamino)-2-propanol (DAIPO), i.e. a compound of formula (I), in which S and x = 7, t = 1, u, v, w, y, and z = zero, a R9, R10, R19and R20is methyl.

The compounds of formula (I) or formula (II) can easily get in one stage by reacting the corresponding aminoalcohol with alkanoyl or alkanolammonium, mainly chloride, in the presence of triethylamine usually in a suitable solvent, such as chloroform. Rea is is mandatory.

The number of amplifier penetration of formula (I), which can be used according to the present invention, is a non-toxic amount effective to enhance absorption through the skin and mucous membranes. Generally this amount is from about 0.4% to about 95% of the total amount of the composition. It is preferable to use from about 0.5 to about 40% of the total amount of the composition.

In the present description, the compounds are useful for improving quasiparallel absorption or absorption through the mucous membranes of physiologically active agents. The term "shostokovich" in the context of the present invention denotes percutaneous or respecrively, it means the penetration of substances through intact skin. Although the term "absorption through the mucous membranes" in General refers to any mucous membranes of the body, of particular interest is the absorption through the mucous membranes of the oral cavity. Thus, in the present invention mainly seen buccal, sublingual, gingival and palatal absorption. In a preferred embodiment of the present invention, the data amplifiers penetration of reagents isney the structure of go, i.e. through the gums and palate. The term "physiologically active agent" is used in this description to refer to a broad class of useful chemical and therapeutic agents, including physiologically active steroids, antibiotics, fungicide, antibacterial agents, antineoplastic agents, pain relievers and combination analgesics, means of reducing appetite, sedative, anti-arthritis means antasticheskie tools, anti-convulsants, antidepressants, protivodiabeticheskie tools, anti-diarrhea, antihistamines, anti-inflammatories, funds from migraines tools to enhance motor function, anti-emetics, drugs against Parkinson's disease, antipruritic tools, antipsychotics, antipyretics, antispasmodic, including gastrointestinal and urinary, anticholinergics, sympathomimetic tools, xanthine derivatives, cardiovascular preparations including calcium channel blockers, betablockers, anti-arrhythmia, tools, lowers blood pressure, macegan the batteries of the Central nervous system, the medicines of cough and cold, anti-inflammatory remedies, hormones, sleep AIDS, immunosuppressive drugs, muscle relaxants, parasimpaticescoe funds parasympathomimetics tools, psychostimulants, sedatives, tranquilizers, allergens, antihistamines, anti-inflammatory means, physiologically active peptides and proteins, protection from UV rays, perfumes and preparations for repelling insects, means for dyeing hair, etc., the Term "physiologically active", which is used for the characteristics considered in the present description means, has a wide meaning and includes not only tools that have a direct pharmacological effect on the recipient, but funds that have an indirect or observed effects and is useful in medicine, in particular dyes or pigments to the fabric used for diagnostic purposes, protection of tissues from ultraviolet rays, etc.

For example, a typical fungicide means, and means inhibiting the growth of fungi, are thiabendazol, chloroxine, amphotericin, candicidin, fungisil, nystatin, Loganton, clotrimazole, atonal nition and sodium salt of pyrithione.

Steroids include cortisone, ortodoxo, floratone, fludrocortisone, diverse diacetate, flurandrenolide acetonide, Madison, antenatal, aminated, betamethasone and its esters, chloroprednisone, clocortolone, destinaion, desonide, dexamethasone, dichloride, difluprednate, fluchloralin, flumetazon, flunisolide, fluocinonide, flowerdale, formation, flaperon, fluprednisolone, meprednisone, methylprednisone, paramethasone, prednisolone and prednisone.

Antibacterial agents include sulfonamides, penicillins, cephalosporins, penicillinase, eritromicina, lincomycine, vancomycin, tetracycline, chloramphenicol, streptomycin, etc., Specific examples of antibiotics are erythromycin, ethylcarbonate erythromycin, erythromycin estolate, erythromycin puzenat, erythromycin ethylsuccinate, erythromycin lactobionate, lincomycin, clindamycin, tetracycline, chlortetracycline, demeclocycline, doxycycline, metatsiklina, oxytetracycline, minocycline, etc.

Peptides and proteins include, in particular, peptides from small to medium in size, in particular insulin, vasopressin, oxytocin and human growth hormone.

Other tools include iododeoxyuridine, pedofilia acid, aminopropionitrile and penicillamine.

The above list is by no means exhaustive, and in the method according to the present invention may be any physiologically active agent.

An important advantage of the present invention is that it improves the absorption and polar and non-polar drugs. Polar bioactive tools include various therapeutic agents, such as xantina, triamterene and theophylline, anti-cancer drugs, 5-forumdiscussionid, 6-mercaptoundecanoic, vidarabine, narcotic analgesics, hydromorphone, ciklin, pentazocine, bupenorphine, compounds with organic anions, heparin, prostaglandins and prostaglandine compounds, sodium salt Klavina, carbenoxolone, polyhydroxylated compounds, dopamine, dobutamine, L-DOPA and hydrochlorothiazide methyldopa, polypeptides, antagonists of angiotensin, bradykinin, insulin, adrenocorticotropic hormone, enkephalins, endorphins, somatostatin, secretin, and various connections, such as tetracyclines, parlodel, lidocain, cimetidine or related compounds. The number of these polar biologically active agents required to prepare ldelim to obtain a therapeutically effective dosage forms.

Tools that are typically used in the form of eye drops, drops in ears or nose drops, or in the form of drugs for administration via the oral cavity, more effective if they are applied together with amplifiers penetration of the reagents of the present invention.

As noted above, the tools that are used in the diagnosis, can be more effective if they are dissolved in one of the carriers of the present invention. Test spots for the diagnosis of allergies you can quickly run without scratching go out and covering the surface, which is subjected to the action of the allergen, if the allergens used in conjunction with amplifiers of the present invention.

The present invention is also useful in the local application of cosmetic and aesthetic resources. For example, such compounds as melanocytestimulating hormone or dihydroxyacetone, etc. more effective when applied to go to the stimulation of the sun, if they are used in conjunction with amplifiers of the present invention. The tool is applied to the skin faster and in larger quantity, if it is used in accordance with the present invention. Dyes for hair also penetrate better and more effective if dissolved Eski active agents along with amplifier penetration of reagents, power penetration can, if necessary, be applied before or after application of physiologically active funds.

Assume that the physiologically active funds are used in accordance with the present invention, used for systemic and local application.

Dosage forms for topical use on the skin or mucous membranes of humans and animals include creams, lotions, gels, ointments, suppositories, sprayable substances, for example sprayed substance nose aerosols, Transbaikalia and sublingual tablets, gingival and buccal plaque or one of a variety of percutaneous medical devices for use in long-term purpose of systemically active drugs by absorption through the skin, mucous membranes of the mouth or other membranes. See, for example, one or more of U.S. patent numbers 3598122, 3598123, 3731683, 3742951, 3814097, 3921636, 3971376, 3993072, 3993073, 3996934, 4031894, 4060084, 4069307, 4201211, 4230105, 4292299, 4292303 and 4077407. In these patents are diverse and specific systemically active funds, which can also be useful for percutaneous delivery of drugs, and descriptions of these patents are cited here for reference.

In these com is about being conventional pharmaceutical compound tools, diluents or carriers. The number and type of diluent or carrier must, of course, be determined based on compatibility with the compound of the present invention. For example, to maintain the desired concentration of the reagent in solution suspension may require a co-solvent or surfactant.

For trains sprayed through the nose and other mucous membranes diluent is preferably physiological saline solution, In these dosage forms may, in various concentrations, for example, from about 2% to about 75 wt%. or more to attend the amplifier according to the present invention.

Lotions and gels, ointments or creams may contain the usual ingredients that make up the basis of the composition, for example cetyl alcohol or emulsifier, such as dodecyl sulfate, and water. Another type of basics get by mixing equal amounts of stearic acid, cetyl alcohol, triethanolamine monostearate and glycerol with water. In other types of bases can be used glycols having different viscosity depending on the desired consistency.

Suppositories can be prepared from polyethylene glycol 4000 with high viscosity, Vosa in the above dosage forms, are conventional forming a composition of a substance, such as, for example, acetone, ISO-propyl alcohol, halogenated hydrocarbons (freons), ethyl alcohol, polyvinylpyrrolidone, propylene glycol, fragrances, gel-forming compounds, such as the "Carbopol", mineral oil, stearyl alcohol, stearic acid, spermaceti, monooleate sorbitol, "Polysorbates","Tweens", sorbitol, methylcellulose, etc. of the Composition of the present invention is mixed with any non-toxic pharmaceutically acceptable inert carriers. Such carriers are well known to experts in the field of preparation of pharmaceutical compositions. Specialists refer to the Handbook, "Remington''s Pharmaceutical Sciences, 18 th Edition, 1990 (Ed. Alfonso R. Jenaro), Mack Publiscing Company, Easton, Pa.

Any type of system for percutaneous delivery of drugs suitable for implementing the present invention, for example a system such as percutaneous patch, transbukkalno tablet, etc., Various systems for percutaneous drug delivery are described in U.S. patent 4624655, which is reproduced here for reference.

The number of the composition and, thus, the number contained therein appointed physiologically active tool is an effective amount which is practitioner based on their own experience. Thanks achieved increased activity dosage physiologically active funds can often be reduced in comparison with the commonly used dosage. In accordance with the usual practice for composing the beginning establish a dose that is close to the lower limit of the useful dose range of specific tools, and then to increase the dosage depending on the observed response, and it is a common procedure used by doctors.

The concentration of the physiologically active products in various dosage forms, of course, corresponds to the commonly used concentration for specific tools in conventional compositions for obtaining the expected result for this method of drug administration. The desired result has an impact on the quantity of physiologically active funds and the number of amplifier penetration of the drug. If you want to achieve a more localized impact as, for example, in the treatment of superficial infections with antibiotics, you can use smaller amounts of physiologically active agents and a lower concentration of the amplifier penetration of the drug with the, the La ensure proper penetration may be desirable to apply a high concentration of the amplifier. If the local application is required overall systemic concentration of the reagent, it usually requires even greater concentration of the amplifier, and a number of medications, such as steroid included in the composition, may be sufficient to provide the desired level of maintenance funds in the blood.

Description of embodiments of the invention

For further explanation of the present invention and its advantages, the following specific examples, it should be understood that these examples are intended only for illustration and in no case do not limit the present invention.

Example 1

The ability of dodecanoate 1-(N, N-dimethylamino)-2 propanol (DAIPD) to enhance the penetration of drugs

The ability DAIPD to enhance the penetration of drugs compared with the same ability Azone, which are taken as typical of the amplifier, to increase the penetration of drugs, at the same time as model membranes using discarded snake skin (wypasek snakes). Profiles PR is SUP>oC shown in Fig. 1 - Fig. 3 and table. 2 - table. 4. Penetrating substances are selected in such a way as to obtain examples of medicines basic type (clonidine), drug neutral type (hydrocortisone) and acidic drugs (indomethacin).

To 20.6 g (0.2 M),1-(N,N-dimethylamino)-2-propanol in 250 ml of chloroform in the presence of triethylamine (30 ml), add portions of 43.2 g (0.2 M) laureillard and stirred at room temperature for 24 hours, the Residue is filtered off, the reaction mixture was washed with water three times (each time with 250 ml) and the organic phase is dried over anhydrous magnesium sulfate. The solvent is evaporated in vacuum and the oily residue is dissolved in ethylacetate and purified column chromatography using the same solvent. Over the course of the reaction is monitored by thin layer chromatography. As a solvent for thin-layer chromatography using ethylacetat. The visualization is carried out using iodine vapours. The yield is 95%. Values of Rfamount of 0.21 (ethyl acetate) and 0.74 (chloroform; methanol, 1:1). Record the IR spectrum, NMR spectrum and mass spectrum (electron ionization) IR-spectrum): 2920, 2840 (C-H), 1730 (C= O), 1040 (C-O-C) cm-1.1H NMR (chloroform-d): to 0.88 (3H, triplet, CH3), 1,21-1,23 (32-N), 2,46-2,52 (2H, multiplet, CH2-CO), 5,02-5,08 (1H, multiplet, -CH3), part per million, the mass spectrum (E1): m/z (RA%) 285(10), 158(45), 145(70), 102(28), 58(100), C17Y35NO2(285,47), you need 285.

Lipophilicity, expressed by the value of Rmdetermine in accordance with the method described in the publication J. K. Seydel and K. J. Schaper, "Chemische Struktur und biologische Aktivitaet von Wirkstoffen", Verlag Chemie, Weinheim, New York, 1979, pp. 257-259. Plates impregnated with a 5% solution of paraffin in diethyl ether. As a developer, a mixture of acetone and phosphate buffer (0.01 M, pH 7.0) (4:1). The value of Rmcalculated by the following equation Rm=log[(1/Rf)-1].

Apparent pKa value is determined by titration with 0.25 mm solution of the amplifier using the water of 0.1 N hydrochloric acid in 50 ml of a mixture of acetonitrile and water (1: 1). Be calculated in accordance with the methodology published by A. Albert and E. P. Sergeant, "The Determination of Ionization Constants", Chapman and Hall, London, 1971, pp. 39-40.

Wypasek snake prepared as described previously (publication S. Buyuktimkin, N. Buyuktimkin and J. H. Rytting. "Synthesis and enhancing effect of dodecyl 2-(N, N-dimethylamino) propionate on the transepidermal delivery of indomethacin, clonidine and hydrocortisone", Pharm. Res., 10 1632-1637, 1993, and U.S. patent N 4980378 and N 5082866, which are cited as references. Wypasek snakes stored at temperately least 12 h before use. In order to reduce the scatter of the results obtained for each series of experiments using pieces cut from a single piece of snake skin.

Indomethacin, clonidine and hydrocortisone analyzed by liquid chromatography high pressure, as described previously (see earlier Buyuktimkin et al., 1993).

Pieces of wyporska snake (approximately 3 x 3 cm) pre-two hours prior to the experiment treated with 15 μl of the amplifier is divided into three portions 5 µl). After placing the skin in the upper part of the receiving cell Franz filled with phosphate buffer solution with pH 7.0 (0,1 on top of the receiving cell is placed to feed the cell. In the input cell is placed the sample in the amount of 0.5 ml suspension hydrocortisone indomethacin received by suspendirovanie, respectively, 50 mg or 25 mg of the drug in 25 ml of the same buffer, and mixing, 32oC for 24 h, or clonidine solution (2%) in the same buffer. The solution in the receiving Department is stirred with a magnetic stirrer. After a certain period of time from reception of a cell taking samples and analyzing them by liquid chromatography high pressure. The surface area of the snake skin is 1.8 cm2, the TV compared to Azone observed for clonidine and hydrocortisone and roughly corresponds to the improvement of permeability twice. Compared with the control samples, the largest increase was observed for DAIPD in the case of hydrocortisone. In the system n-octanol/buffer pH 7.0 coefficients of medicine, expressed as log P, 0.4, 0.8 and 1.2 for clonidine, hydrocortisone and indomethacin, respectively. Indomethacin, which is the most lipophilic of the three considered drugs, amplification, approximately equal to the amplification, which has Azone. It was expected that for indometacin, as more lipophilic compounds, the effect of penetration through the skin is more pronounced. However, the expected order is not observed in the present study. These observations suggest that in addition to solid can play a role, other factors, such as interactions medicine/amplifier and medicine/skin.

The penetration profile is studied in the present invention penetrating drugs shows the time delay with subsequent linear continuous flow. The delay times calculated by known methods, the values obtained are given in table. 5.

The study only one time delay allows you to find the reason for the relatively low gain for indomethaci the et up to 45 min, while for indometacin it is approximately 24 minutes Pre-treatment with Azone also shows a similar trend, confirming the fact that in addition to lipophilicity on the flow of these drugs affected by other mechanisms.

Analysis of the data presented in Fig. 1 - Fig. 3 and table. 2-5 shows that the compounds of the present invention are effective penetration enhancers local action and they are useful to enhance percutaneous drug delivery, thus they are more efficient than conventional amplifiers, known from the technical field.

Example 2

The ability of myristate 1-(N,N-dimethylamino)-2-propanol (DAIPM) to enhance the penetration of drugs.

The ability of myristate 1-(N,N-dimethylamino)-2-propanol (DAIPM) to enhance the penetration of drugs will explore, through a series of experiments similar to those described in example 1. The results are presented in Fig. 4 - Fig. 8 and table. 7.

As DAIPD, DAIPM approximately doubles the flow, compared to Azone, clonidine (Fig. 4, compare table. 2 and table. 7) and hydrocortisone (Fig. 5, compare table. 3 and table. 7). However DAIPM shows the best properties in comparison with DAIPD, and . and table. 7).

DAIPM leads to greater improvement compared with Azone in experiments with two other drugs. DAIPM increases the penetration of prostaglandin E1(Fig. 7) almost four times compared with Azone (PL. 7). Almost 20-fold improvement was achieved in experiments with prazozin (Fig. 8, PL. 7).

Example 3

The Biodegradability of dodecanoate 1-(N,N-metilamino)-2-propanol (DAIPD).

An aliquot of 0.1 ml esterase pigs (235 units per mg of protein) were diluted to a volume of 100 ml with phosphate buffer pH 7.0. The amplifier solution is prepared by dissolving approximately 12 mg (approximately 0.045 mmol) of the amplifier 10 ml of acetonitrile. An aliquot of 100 ál of the resulting solution is transferred into a 10 ml flask for titration. Added to 9.8 ml of buffer solution with pH 7.0 and 100 µl of the diluted solution esterase. The mixture was stirred at 32oC in a water bath. The disappearance of the peak amplifier is controlled by liquid chromatography high pressure. Disappears absorption band at the wavelength of 204 nm. The solvent system is a mixture of acetonitrile and 0.02 M aqueous solution hexanesulfonate sodium (7: 4) with a feed rate of solution of 0.9 ml/min retention Time DAIPD is 3.95 min Kinetic studies what is (B. T. Nghien and T. Higuchi, "Esterase activity in snake skin", Int. J. Pharm. 44: 125-130, 1988) esterase activity was detected in vypolzti snakes. In order to confirm the Biodegradability DAIPD study fragmentation in the presence of esterase pigs. Dependence of the logarithm of the peak height from the time shows that the kinetics of degradation corresponds to pseudoprime order, with KOBS.= 0,0087 min-1t1/2= 79,5 min (Fig. 9). Thus confirmed catalyzed by esterase biorelease amplifier. Hirvoven et al. (see below) showed that percutaneous delivery propanolol after pre-treatment dodecyl-N,N-diethylaminoacetate (DDAA), a biodegradable amplifier, which is described in U.S. patent N 4980378 and N 5082866 no longer increases after four days, while strengthening under the action of A. O. E. still there after a week. (J. Hirvonen, P. Paronen and A. Urtti, "Reversible enhancement of the transdermal propanolol by dodecyl N,N-dimethylamino acetate", 18 th International Symposium on Coontrolled Release of Bioactive Materials, July 8-11, 1991, Amsterdam, p. 31. ). Thus, if they exist, toxic and irritating effects of biodegradable compounds can be significantly reduced, and the period of activity may be limited.

Thus, the results show that DAIPD is bioreclamation several different classes of medications.

Example 4

Synthesis of oleate 1-(N,N-dimethylamino)-2-propanol (DAIPO)

The oleate-(N, N-dimethylamino)-2-propanol (DAIPO) is an example of the compounds of formula (II).

To 10.3 g (0.1 mol 1-(N,N - dimethylamino)-2-propanol in 250 ml of chloroform containing triethylamine (15 ml), portions add 50 g (0.1 mol) of Reinhold (60%) and stirred at room temperature for 24 h

The residue is filtered off, the reaction mixture was washed with water three times (each time with 250 ml) and the organic phase is dried over anhydrous magnesium sulfate. The solvent is evaporated in vacuum and the oily residue is dissolved in ethyl acetate and purified column chromatography on silicagel using the same solvent. The procedure is carried out in the dark, and the connection is kept under nitrogen. Over the course of the reaction is monitored by thin layer chromatography. As a solvent for thin-layer chromatography using ethyl acetate. The visualization is carried out using iodine vapours. The yield is 60%. Values of Rfamount of 0.24 (ethyl acetate). IR (spectrum) (CHCl3) 2925, 2845 (C-H),1730 (C= O), 1090 (C-O-C) cm-1,1H NMR (chloroform-d): to 0.88 (3H, triplet, CH3), 1,21-of 1.23 (3H, doublet, CH), 1,32 (broadened singlet, 22H, (CH2)11), 1,98-of 2.08 (4H, multiplet, 2( -CH=)), of 2.25 (6H, the B>3), 5,32 is 5.38 (2H, doublet, CH=CH). M. D., mass spectrum (E1): m/z (RA%) 367(38.), 158(15), 145(20), 102(10), 58(100), C23H45NO2(367,61), it is necessary 367.

In Fig. 10 shows the amplification profiles for penetration clonidine with unsaturated ether of the formula (II), DAIPO, in comparison with oleic acid, DDAA and with a control sample obtained for the tests of penetration through the skin in the model considered in example 1. These data show that these compounds in General are potentially more powerful amplifiers absorption. molecules with the basic properties than the compounds described in U.S. patent N 4980378 and N 5082866, and they are effective in enhancing the penetration of neutral and acidic reagents.

Thus, the invention achieved all previously set goal.

The above description and examples are given to illustrate and not limit the present invention. Other variants are possible, corresponding to the nature and scope of the claims of the present invention, and they are quite obvious to a person skilled in the art.

1. Method of enhancing the penetration of pharmacologically active products through the skin or mucous membrane of the body of a mammal, comprising or systemic physiological effects, pharmacologically active funds and connections to enhance the penetration of active products, having the formula I

< / BR>
where n = 5 to 12, an integer;

y = 0 to 5, an integer; R1- R7the same or different, selected from the group comprising hydrogen and (C1- C8) alkyl;

R8selected from the group comprising hydrogen, hydroxyl and (C1- C8)alkyl.

2. The method according to p. 1, where R1and R2selected from the group comprising hydrogen, methyl and ethyl.

3. The method according to p. 2, where R1and R2is methyl.

4. The method according to p. 1, where the amplifier penetration of formula I is dodecanoate 1-(N,N-dimethylamino)-2-propanol.

5. The method according to p. 1, where the amplifier penetration of formula I is monistat 1-(N,N-dimethylamino)-2-propanol.

6. Method of enhancing the penetration of pharmacologically active products through the skin or mucous membrane of the body of a mammal, comprising the local application to the skin or mucous membrane in a quantity sufficient to achieve a desired local or systemic physiological effects, pharmacologically active funds and connections to enhance the penetration of active products, having the formula II
y = 0 to 5, an integer;

R9- R22the same or different, selected from the group comprising hydrogen and (C1- C8)alkyl.

7. The method according to p. 6, where R9and R10selected from the group comprising hydrogen, methyl and ethyl.

8. The method according to p. 6, where R9and R10is methyl.

9. The method according to p. 6, where the amplifier penetration of formula II is the oleate 1-(N,N-dimethylamino)-2-propanol.

10. The method according to p. 6, where s and x = 7, t = 1, u, v, w, y, and z = 0, and R9, R10, R19and R20is methyl.

11. Pharmaceutical composition for topical application of pharmacologically active local medicines containing: (a) a pharmacologically active local drug in a quantity sufficient to achieve the desired physiological effect, and (b) connection to enhance penetration through the skin active products having the formula I

< / BR>
where n = 5 - 18, integer y = 0 to 5, an integer;

R1- R7the same or different, selected from the group comprising hydrogen and (C1- C8)alkyl;

R8selected from the group comprising hydrogen, hydroxyl and (C1- C8)alkyl.

12. The composition according to p. 11, where R1What SUP>2is methyl.

14. The composition according to p. 11, where the amplifier penetration of formula I is dodecanoate 1-(N,N-dimethylamino)-2-propanol.

15. The composition according to p. 11, where the amplifier penetration of formula I is monistat 1-(N,N-dimethylamino)-2-propanol.

16. Pharmaceutical composition for topical application of pharmacologically active local medicines containing: (a) a pharmacologically active local drug in a quantity sufficient to achieve the desired physiological effect, and (b) connection to enhance penetration through the skin active products having the formula II

< / BR>
where, t, v and z each are 0 or 1;

s, u, w and x each represents an integer from 0 to 12 inclusive, with (s + u + w + x) is an integer from 4 to 18 inclusive;

y = 0 to 5, an integer;

R9- R22the same or different, selected from the group comprising hydrogen and (C1- C8)alkyl.

17. The composition according to p. 16, where R9and R10selected from the group comprising hydrogen, methyl and ethyl.

18. The composition according to p. 16, where R9and R10is methyl.

19. The composition according to p. 16, where the amplifier penetration formula II9, R10, R19and R20is methyl.

21. The composition according to p. 11, made in the form of cream, lotion, gel, ointment, suppository, means for spraying, aerosol, transbukkalno tablets, sublingual tablets or alkaline, sublingual, gingival or palatal patch.

22. The composition according to p. 16, made in the form of cream, lotion, gel, ointment, suppository, means for spraying, aerosol, transbukkalno tablets, sublingual tablets, or buccal, sublingual, gingival or palatal patch.

 

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FIELD: medicine.

SUBSTANCE: method involves carrying out patient premedication with Phenozepam tablets at a dose of 0.0005-0.001 g, Sibazon intramuscularly introduced at a dose of 10 mg 30 min before operation on the eve and in the morning at operation day and Dimedrol at a dose of 10 mg. Then the patient is placed on operational table on mattress heated to temperature of 37-39°C and connected to monitor. The central vein is punctured and catheterized and preoperative patient infusion preparation is started by intravenously dropping 500 ml of crystalloid solutions heated to temperature of 37-42°C like Ringer solution or Acesol, or Trisol, or Lactasol, and the same quantity of colloid solutions HES 6% or HES 10%. Then epidural space is punctured at Th7-L1 level with subsequent catheterization following so that with catheter top being arranged at Th5-Th11 level. 4 ml of 0.5% Bupivacaine hydrochloride solution test-dose is epidurally introduced in bolus mode into the epidural space with its action being estimated. Then anesthetic is fractionally introduced in 4-5 ml large portions under arterial blood pressure and pulse control with the total amount reaching 15-20 ml with earlier entered test-dose quantity being taken in account. Oxygen inhalation is carried out through narcosis apparatus mask at a rate of 5-8 l/min on the background of independent patient breathing. Then intravenous bolus 0.1% atropine injection is introduced at a dose of 0.005 mg/kg. Anesthesia induction of 2% sodium thiopental solution is carried out at a dose of 4-5 mg/kg, and also 0.005% Phentanyl solution at a dose of 0.0025-0.0035 mg/kg as intravenous bolus injection into the central vein. Trachea intubation is carried out on the precurarization background by introducing Arduan at a dose of 1-2 mg or Esmeran at a dose of 10-20 mg. The patient is transferred to artificial lung ventilation on the background of a muscular relaxation by introducing 2% Ditiline solution at a dose of 1.5-2 mg/kg, and body temperature control gauge is arranged in the middle one-third of patient esophagus. Anesthesia is supported at all stages of operation under artificial lung ventilation conditions by carrying out inhalation with nitrous oxide and oxygen mixture with their proportion being from 2:1 up to 3:1 using flow-reversing respiratory contour having respiratory ventilation volume of 7-8 ml/kg and minute ventilation of 100-120 ml/kg. 0.5% Bupivacaine hydrochloride solution is also introduced into the epidural space every 120-150 min at a dose of 3-5 ml, Arduan is intravenously introduced every 40-60 min at a dose of 2-4 mg or Esmeron every 25-35 min at a dose of 10-20 mg. Intravenous dropping infusion of crystalloid solutions heated to temperature of 37-42°C is carried out at a rate of 10-20 ml/kg/h at neoplasm removal stage. 500 ml of colloid solutions heated to temperature of 37-42°C or 400 ml of 20% albumin solution heated to temperature of 36-37°C is intravenously introduced 25-35 min prior to the beginning of chemotherapy. Transfusion of 400-450 ml of fresh frozen blood heated to temperature of 36-37°C is carried out. The warming up mattress is switched off at chemotherapy preparation stage. Patient head occipital part and main cervical blood vessel passage area is compulsorily cooled with ice packages at the beginning of chemotherapy stage, with intravenous heated crystalloid and colloid solutions, albumin and blood plasma introduction being simultaneously terminated and crystalloid solutions introduction at room temperature being continued with patient body temperature controlled not to be above 38.5°C according to esophageal gauge indications. Sodium bicarbonate and electrolytes are intravenously introduced in planned amount after having finished the chemotherapy treatment. Anesthesia is stopped at operation finish stage by stopping introducing the preparations into the epidural space and intravenously introducing relaxants, continuing artificial lung ventilation using oxygen and air mixture with FiO2 equal 0.4-0.6.

EFFECT: maximum nociceptive pulsation blockade from surgical intervention zone; patient body temperature supported at the level of 36-37°C; prevented brain hyperthermia.

4 cl

FIELD: medicine.

SUBSTANCE: invention refers to medicine specifically to anaesthesiology and blood-saving techniques in anaesthesiology and resuscitation science, and can be used as anaesthetic management within adrenalectomy caused by epinephros pheochromocytoma. For this purpose operation is preceded with complex patient examination. Preanesthetic medication applied one day before and in the morning prior to operation implies introduction of tableted phenozepam dosed 0.0005-0.001 g, and 30 min before operation sybazone is injected intramuscularly in dosage 10 mg combined with Dimedrol in dose 10 mg. In operating theatre monitoring, puncture and catheterisation of central vein are performed. Then epidural cavity is punctured at height Th7-L1, catheterised so that catheter cap is being placed at height Th5-Th11 to provide following postoperative anaesthesia. Unassisted breathing is accompanied with oxygen inhalation through anaesthesia apparatus mask at rate 5-8 l/minute. Preanaesthetic medication is completed with intravenous bolus dosing of 0.1% atropine solution dosed 0.005-0.007 mg/kg. 5-10 minutes prior to surgical intervention patient blood is exfused in volume 1.0 litres in case arterial pressure is reduced lower than 140/90 mm m.c., and in volume 1.5 litres in case arterial pressure is reduced higher than 140/90 mm m.c. followed by drop-by-drop intravenous introduction of warmed to 37-42°C crystalloid solution either acesol, or trisol, or lactasol or Ringer's solution. Afterwards anaesthesia is added with intravenous bolus dosing to central vein of 2% thiopental sodium solution in dosage 4-5 mg/kg, 0.005% fentanyl solution dosed 0.0025-0.0035 mg/kg followed by intubation of trachea accompanied with precurarisation by introduction of either pipecuronium bromide (arduan) in dosage 1-2 mg or rocuronium bromide (esmerone) in dosage 10-20 mg and against muscular relaxation introduction of 2% suxamethonium iodide solution (dithylinum) in dosage 1.5-2 mg/kg, then patient is transferred to artificial pulmonary ventilation. Within epinephros central vein clipping and crossing for separation of pathologically modified epinephros complete or partial autoblood is reinfused until patient arterial pressure is completely stabilised at level 100-110/60-70 with following infusion crystalloids warmed up to 37-42°C. In case of partial autoblood reinfusion, repeated reinfusion of the rest autoblood volume is performed within the first days of early postoperative period. Anaesthesia management within all stages of surgical intervention is carried under artificial pulmonary ventilation by inhalation of mixed nitrogen monoxide and oxygen at ratio 2:1 to 3:1 using reversive breathing circuit of ventilation respiratory capacity 7-8 ml/kg at minute ventilation 100-120 ml/kg, intravenous introduction of fentanyl dosed 5-6 mkg/kg/h, as well as introduction of arduan in dosage 2-4 mg every 40-60 minutes of operation procedure or introduction of esmerone in dosage 10-20 mg every 25-35 minutes of operation procedure. Anaesthesia is completed at stage of operation termination by termination of intravenous introduction of fentanyl and relaxing agents against continuation of artificial pulmonary ventilation by oxygen-air mix with FiO2 equal to 0.4-0.6. Method provides stabilisation of haemodynamics and cardiac activity during adrenalectomy without vasopressor application.

EFFECT: provided possibility of stabilisation of hemodynamics and cardiac activity during adrenalectomy without vasopressor application.

3 ex, 4 cl

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to dermatology and cosmetology and can be used for treatment of such skin disease as rosacea. For this purpose Doppler examination of face skin microcirculation is carried out, during which background volume rate of tissue blood flow on affected and unaffected sections of face skin is determined with further comparison of obtained parameters with each other. In case compared parameters have deviation value not less than 10%, base care of face skin is prescribed: use of purifying and moisturising preparations for sensitive skin, microcurrent therapy in lymphodrainage mode for 20 minutes 2-3 tines a week with course of 8-10 sessions, and introduction of Sulodexide 250 LSU after meal with 4-8 week course. In case compared parameters of background volume rate of blood flow have deviation value from 10 to 20% in case of papula-pustular stage of rosacea, course of microcurrent therapy in lymphodrainage mode is carried out 3 times a week with course consisting of 10 sessions, and Sulodexide is introduced with course of 4 weeks. In case compared parameters of background volume rate of blood flow have deviation value from 20% and greater, rosacea stage being hypertrophic, Sulodexide is introduced with course of 8 weeks, and microcurrent therapy in lymphodrainage mode is carried out from 4th week 3 times a week with course consisting of 10 sessions in combination with basic care of face skin.

EFFECT: method allows ensuring stable therapeutic effect including treatment of severe forms of rosacea due to complex influence.

3 cl, 2 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly to experimental cardiopharmacology and can be used for correction of endothelial dysfunction in experiment ensured by modelling endothelial dysfunction in laboratory animals during 7 days through daily intraperitoneal introduction of L-nitro-arginine-methyl ester dosed 25 mg/kg and followed with endogastric introduction of macrolide Midecamycin in single dose 10 and 30 mg/kg a day.

EFFECT: method ensures effective correction of endothelial dysfunction due to anti-oxidant action of Midecamycin.

1 ex, 1 tbl

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