Tablet of melatonin and method for preparing and using

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and pharmaceutical industry, and concerns a pharmaceutical composition for sublingual or buccal administration of the active ingredients of a low to poor water-solubility. As an active ingredient, the composition contains a solution of a hormone specified in a group consisting of melatonin, oestrogens, progesterone, testosterone and dihydrotestosterone in a pharmaceutically acceptable solvent, adsorbed or absorbed on particles of a pharmaceutically acceptable carrier. The invention also concerns methods for preparing and using the above pharmaceutical composition.

EFFECT: what is presented is the new composition for sublingual or buccal administration of the active ingredients of a low to poor water-solubility.

19 cl, 4 ex, 2 tbl, 2 dwg

 

Prior art

Hormones such as indole hormone melatonin, which is widely distributed in plant and animal sources. Melatonin can be found in human milk, bananas, beets, cucumbers and tomatoes. Chemical melatonin is a N-acetyl-5-methoxytryptamine, a derivative of serotonin, which, in turn, derived from tryptophan. Melatonin is a common natural neurotransmitter-like connection is formed mainly by the pineal gland and is involved in many aspects of biological and physiological regulation of body functions.

Cm. General discussion, for example, Malhotra, S., et al., Medscape General Medicine 2004; 6 (2), 46; and www.nlm.nih.gov/medlineplus/print/druginfo/natural/patient-melatonin.html.

Well-established role of endogenous melatonin in disorders of circadian rhythm and sleep disorders. Some studies have shown that melatonin may be effective in breast cancer, fibrocystic-breast and colon cancer. It was shown that melatonin modifies the immune system, stress response, and certain aspects of the aging process; some studies have demonstrated improvements in sleep disorders and evening exacerbation in patients with Alzheimer's disease. Antioxidant role of melatonin may sweaty the constraints to be used in the States, in which oxidative stress is involved in pathophysiological processes. The multiplicity of actions and diversity of the biological effects of melatonin suggest the possibility of a number of clinical applications and applications for improving health, especially considering that, as aging is a steady decrease in the formation of this key hormone. Indeed, a person aged 80 to 90 years produced a number of very slightly.

Through the release of melatonin, the pineal gland supports the management of the natural rhythms of the body functioning by means of the internal clock. This is a clear effect of melatonin on setting the clock led to the assumption that it is a substance-"chronobiotic"altering and possibly normalizing biological rhythms and adapting the temporal pattern of other critical processes and biomolecules (hormones, neurotransmitters, and the like), which, in turn, have many peripheral effects. Soporific effects of melatonin have advantages over conventional drugs means, because melatonin is not a sleeping drug. Melatonin is a natural state of drowsiness and has no unwanted side effects of conventional sleeping pills and RX is x pills.

Previously melatonin used in the pharmaceutical field, and it was made for oral administration (see, for example, WO 1995/003043). These drugs include melatonin, made with cyclodextrin (WO 1999/047175) and microemulsions (U.S. patent No. 5362745). However, as for most oral preparations, until the concentration of melatonin in plasma peak can be more than 30 minutes. Goldberg, MJ, Bergstrom, RFR, Smith, BP, Simcox, EA, Thomasson HR, Shipley, LA: Sleep Research 1997: 26:101. In part this may be due to the need of absorption in the gastrointestinal tract before melatonin will become available in the bloodstream. In addition, the bioavailability of melatonin at a dose insufficient and unpredictable. It was shown that the absolute bioavailability of melatonin at a dose of approximately 15% and peak plasma concentration can vary more than 20 times. DeMuro RL, Nafziger AN, Shine DE, Menhinick AM, Bertino JS: Journal of Clinical Pharmacology 2000: 40; 781; Di WL, Kadva A, Johnston A, Silman R: New England Journal of Medcine 1997: 336; vol.14, 1028. Thus, oral administration of melatonin in the currently available drugs do not provide a quick start steps, and its inadequate and unpredictable absorption in the gastrointestinal tract makes oral route of administration to be inappropriate.

Several soluble tablets and films for subli Gallego, transbukkalno, oral administration, contains melatonin, also available for sale. For example, compositions for administration through mucous membranes described in WO 1996/030013 and U.S. patent No. 5688520. However, these compositions contain melatonin in dissolved or solid form. For that to happen the absorption of any drug in the bloodstream, it must be dissolved, that is, to be in solution. Due to insufficient solubility of melatonin in the water most of the doses of currently available drug enters without being dissolved in the saliva, which leads to insufficient and unpredictable absorption in the gastrointestinal tract. Accordingly, expect the hormonal drugs, such as melatonin, having a solubility in water of low to insufficient will be poorly suited to transbukkalno or sublingual administration.

Were considered other routes of administration of melatonin, including nasal and oral sprays. U.S. patent No. 6007834. However, sprays are less desirable because of inherent problems with adherence, such as improper handling of device, the ingestion dose to dissolve the drug, and limitations for use when the patient is sinus congestion or runny nose. This again is riodic unpredictable and insufficient bioavailability of melatonin. Thus, the sprays are not the optimal way of introduction to conventional administration of melatonin.

Thus, in the medical and pharmaceutical areas, there is a need for oral dosage form, preferably sublingual, or transbukkalno introduction where considered dosage form can provide rapid and consistent delivery of the hormone with low or low solubility in water, such as melatonin. This meets the needs of this composition, and method of its manufacture and introduction. Consider the composition of melatonin can mainly be useful for the introduction of drugs to the patient in much less time and with more consistent and higher bioavailability than previously available dosage forms. Thus, in accordance this invention proposed a unique composition, delivery system and method of administration of melatonin and other hormones that have a solubility in water of low to inadequate.

Summary of the invention

According to the present invention proposed a pharmaceutical composition for sublingual or transbukkalno the introduction of hormones, such as melatonin, having a solubility in water or other water rastvorjajut relatively low to insufficient. The composition contains a hormone together with inactive carrier, where the hormone is preferably absorbed or adsorbed on the carrier and, thus, has the form of a solid dosage form such as tablet. The media used in the present composition, preferably is a pharmaceutically acceptable carrier in the form of beads, granules, particles or the like. The only way that the composition of this invention contains a pharmaceutically acceptable solvent in which is dissolved a hormone in which he saves solubilization at the final solid dosage form.

For the purposes of this invention, the term "melatonin" understand a certain hormone that has a solubility in water of low to insufficient. Preferably as an active ingredient in the compositions according to the invention using melatonin. It is also clear that the use of the term melatonin applies to other hormonal active ingredients having a solubility in water of low to insufficient, such as estrogen, progesterone, testosterone and dihydrotestosterone. Accordingly, embodiments of the present invention include compositions in which estrogen, progesterone, testosterone or dihydrotestosterone or their combinations are used instead of melatoni is a or jointly with him. Also it will be clear that these hormones can be in the form of their corresponding derivative. Thus, the reference to melatonin, estrogen, progesterone, testosterone and dihydrotestosterone includes any salt, prodrug, metabolite, isomer, or derivative, having a solubility in water or aqueous solutions of low to negligible.

In accordance with certain embodiments of the present invention the composition comprises a pharmaceutically acceptable carrier selected from silicon dioxide, microcrystalline cellulose, cellulose, silication microcrystalline cellulose, clay, talc, starch, pregelatinized starch, calcium carbonate, calcium silicate, calcium hydrogen phosphate, magnesium carbonate and mixtures thereof. These carriers are well known in the pharmaceutical field as suitable for the formation of particles, such as beads, pellets and granules, with conventional manufacturing methods. For the purposes of this invention, the term "particle" includes and refers to "media", "ball", "pellets", "pellet" or any other like form, and it is used interchangeably with "media", "ball", "pelleti", "pellet" or any other like form, as is well known and accepted in the pharmaceutical field. In the preferred embodiment pharmaceutically pickup is acceptable carrier is a silicon dioxide, also known as colloidal silicon dioxide. In certain preferred embodiments, the carrier has a particle size of from about 3 microns to about 30 microns.

In certain embodiments pharmaceutically acceptable solvent used for dissolving melatonin and education solution containing melatonin, for the Association of melatonin with particle carrier selected from polyethylene glycol, ethanol, ethyl acetate, isopropyl alcohol, triacetin, triethylcitrate, tributyltin, substituted glycols, propylene glycol, bisabolol, glycerin, mineral oil, oleic acid, olejowego alcohol, ethyloleate, esters of fatty acids, squalene, animal oils, vegetable oils, hydrogenated vegetable oils, isopropylmyristate, isopropylpalmitate, glycoluril, terpenes, essential oils, alcohols, water, polyols, silicone fluids and/or glycerides and mixtures thereof.

Preferred pharmaceutically acceptable solvent is a glycol and a mixture of polyethylene glycol and oleic acid. It is clear that the solution can be formed from aqueous or non-aqueous solvent, or a mixture thereof and can be formed from volatile or non-volatile solvent or mixtures thereof, provided that melatonin or another hormone that has a solubility of the water from low to insufficient is the solution when he covers the media either adsorbed or absorbed on a carrier. In the embodiment using a volatile solvent such volatile solvent is preferably removed, for example, by drying after coating, adsorption or absorption.

The concentration of the active ingredient, such as melatonin, the solvent is preferably from about 5% to about 30%, and more preferably from 10% to 20%. The preferred mass ratio of carrier: the solution is from about 1:0.5 to about 1:4 and more preferably from 1:1 to 1:2. In certain embodiments, the pharmaceutical composition contains from about 0.01 to about 3 mg of melatonin at the standard dose, and more preferably from 0.5 to 2 mg

The pharmaceutical composition according to this invention may additionally contain a diluent, baking powder, grease or other excipient, as will be made clear in the pharmaceutical field, for producing the desired final dosage form. For example, for the manufacture of solid dosage forms, such as molded tablet excipients known in the field of tablets, can be used in a manner that corresponds to such well-known techniques and methods tabletting education press the Noah dosage forms, such as molded tablet.

Preferably the pharmaceutical composition according to this invention are presented in the form of standard dosage forms, and more preferably in the form of a solid dosage form, such as a pressed tablet for transbukkalno or sublingual administration. The most preferred embodiment of the present invention includes a tablet that provides a quick introduction of the active pharmaceutical ingredient (API) with sublingual or transbukkalno the introduction of the composition.

The composition according to this invention mainly provides the active ingredient, for example a hormone, such as melatonin, which has a solubility in aqueous solvents from relatively low to the lack, in the dissolved form. Being in dissolved form melatonin can be absorbed directly into the bloodstream through the mucous membrane of the oral cavity without the need for dissolution of the water environment, represented by saliva in the oral cavity or gastrointestinal tract. An additional advantage of the delivery system for drugs in this invention include increased absorption of the active ingredient, represented in the composition, the mucous membrane of the mouth, because fewer drugs comes into nerest the non-indigenous medicines released from the dosage form. Accordingly, this system of delivery of drugs provides a rapid onset of drug action with a higher and more constant bioavailability.

According to the present invention is also a method of manufacturing a pharmaceutical composition, as described above, including the dissolution of the hormone, having a solubility in water of low to insufficient, such as melatonin, in a pharmaceutically acceptable non-aqueous solvent to form a solution of a medicinal product, mixing the solution with particles of a pharmaceutically acceptable carrier, to make possible the formation of the coating, the absorption or adsorption onto particles, and then, if desirable, mixing adsorbed or absorbed particles with other ingredients such as pharmaceutically acceptable excipients, with the formation of the final composition. In certain embodiments, the solution is mixed with the particles to obtain a free flowing powder which can be manufactured or presova with the formation of a solid dosage form or which can be combined with other or additional compression substances to facilitate extrusion of the composition in standard solid dosage form. The method may further include stage presso the project for a composition with the formation of the tablets.

According to the present invention is additionally a method of providing patient treatment melatonin, which includes stages of manufacture of the compositions of this invention, the introduction of the composition sublingual or transbukkalno by way of introduction to a patient in need of treatment with melatonin.

A brief description of graphic materials

Figure 1 shows the comparative transbukkalno thread using a 1 mg tablet of melatonin produced in accordance with Example 2 of the present invention, relative to commercially available tablets melatonin sublingual administration.

Figure 2 presents a block diagram that shows the stages that include the manufacture of tablets for sublingual administration, contains 1 mg of melatonin.

Detailed description of the invention

This invention relates to a pharmaceutical composition for sublingual or transbukkalno the introduction of the hormone, having a solubility in water of low to insufficient, such as melatonin. For the purposes of this invention, the description refers to the melatonin as an active pharmaceutical ingredient (API) or drug, but experts in the art it will be clear that it includes other hormones that have a solubility in water or aqueous biological fluids, that is them as saliva or fluid of the gastrointestinal tract, from low to insufficient. The invention also relates to a method for manufacturing dosage forms for sublingual or transbukkalno the introduction and use of the drug for sublingual or transbukkalno delivery melatonin and treatment of patients in need of treatment with melatonin.

This invention relates to a new system of drug delivery, such as melatonin, providing a unique mechanism for improving the delivery of drugs. This unique system is designed for delivery of melatonin via the buccal or sublingual mucosa and directly into the systemic circulation. It is different from any currently marketed products for sublingual or transbukkalno introduction, containing the hormone, such as melatonin, because these selling products made in solid form, such as emulsion or solid dispersion, so that a large portion of melatonin does not dissolve completely in limited buccal or sublingual delivery. These selling products dissolve in mouth or chew for the release of melatonin from the dosage form, resulting in receipt of undissolved melatonin inside and its absorption in the gastrointestinal tract, leading through the om to insufficient and unpredictable bioavailability of the released drug.

Melatonin is not sufficiently soluble in water or other aqueous biological fluids and at delivery in the undissolved state, as in currently available products containing melatonin drug remains dissolved in the saliva and, therefore, must come inside for suction in any substantial quantity. Thus, for these products the commencement of the action, absorption and presystemic metabolism does not differ from the ingestion of tablets or capsules for oral administration with immediate-release formulation containing undissolved melatonin. I guess these tablets provide an immediate release only due to the rapid disintegration of the dosage form. These tablets release melatonin in the undissolved state, and the absorption of drugs is limited by how quickly the drug is dissolved in a limited area of delivery.

Unlike other pills for sublinguales injection and orally disintegrating tablets where to suction melatonin must first be dissolved in saliva, according to this invention mainly proposed active drug, for example a hormone, such as melatonin, having a solubility in water or aqueous solutions of low to insufficient, it is in solution, as presented in the final dosage form. In this invention the hormone, such as melatonin, not presented in the form of an emulsion or a solid dispersion, and completely dissolved and is present in solution. Thus, this invention improves sublingual/transbukkalno delivery melatonin, because there is no need for the dissolution of melatonin in saliva before absorption. In addition, in the manufacture in the form of small fast-disintegrating tablets suction area is located around the disintegrating tablet. Solubilization state drug and its concentration in a limited area of delivery keeps the drug in solution, and thus provides a high thermodynamic activity, enhance absorption through the mucous membrane. Rapid onset of action of melatonin from the delivery system of this invention can provide rapid absorption of drugs, resulting in the pharmacokinetics of the drug in the plasma is largely similar to that of intravenous injection without the disadvantages associated with the introduction through the gastrointestinal (GI)tract, such as poor absorption, unpredictable absorption, presystemic metabolism, effect of food and food supplements on the oral bioavailability is doing.

Dosage form for sublingual/transbukkalno introduction, for example tablet, according to this invention can improve the delivery of drugs with poor solubility in water, such as melatonin, sublingual or transbukkalno the introduction by giving the drug in solution or dissolved in a solid dosage form developed for local delivery and absorption of the drug.

Sublingual tablets melatonin, included in this invention preferably have a total weight of tablets from 50 to 150 mg depending on the dose. In vitro study of the dissolution of drugs from compositions with quick release essentially takes no more than 15 minutes, and the tablet dissolves under the tongue, usually within a few minutes, preferably less than 5 minutes, more preferably from one to three minutes, and most preferably from 30 seconds to about two minutes. Thus, drowsiness appears after approximately 5-25 minutes and preferably within about 15 minutes after taking this tablet for sublingual administration, providing rapid increase in the levels of melatonin in plasma and achievement of therapeutic levels or maximum concentration of this dosage form in p is adalah these periods of time.

The tablet may alternatively be made for a slower release of drugs, such as adding coverage for slow release, the inclusion of a pore-forming substance in the coating or the core, enabling the matrix composition or the like, as is customary in the art, to simulate slow infusion using methods of making compositions with controlled release. Thus, since the dissolution rate of drugs is not a stage, limiting the delivery rate of the drug, the delivery and absorption of drugs from the patient in a predictable manner to regulate, by manipulating the disintegration of the dosage form.

Preferred pharmaceutical compositions of the present invention can be formulated to provide a single dose of the active ingredient, such as melatonin, from 0.01 mg to 3 mg, preferably from 0.2 to 2.0 mg When used in such low doses of the composition according to the invention are mainly to ensure a constant and relatively high peak concentrations of melatonin in plasma (Cmaxsoon after the introduction for effectiveness in treating human disease, in particular insomnia, or in the provision of drowsiness or sleep in humans. That is they way the present invention makes it possible to achieve consistently effective concentrations of melatonin in plasma even when using lower doses of melatonin than dose, administered at the currently available products.

In one embodiment of the invention melatonin dissolved in polyethylene glycol (PEG)such as PEG 400, PEG 200, PEG 300, PEG 600, or other suitable solvents, including brand PEG with other molecular weights, ethanol, ethyl acetate, isopropyl alcohol, triacetin, triethylcitrate, tributyltin, substituted glycols, propylene glycol, bisabolol, glycerin, mineral oil, etiloleat, oleic acid, alerby alcohol, fatty acid esters, squalane, animal oils, vegetable oils, hydrogenated vegetable oils, isopropylmyristate, isopropyl, glycoluril, terpenes, essential oils, alcohols, polyols, silicone fluids and/or glycerides, and combinations of such solvents.

For the conversion of the liquid solution melatonin bulk powder, suitable for use in pelletizing direct pressing, using media-adsorbent/absorbent material, such as silicon dioxide (ZEOPHARM 5170, AEROPERL 300, SYLOID 244FP, SYLOID 63FP, SYLOID 72FP, SIPERNAT 160PQ, SIPERNAT 50, SIPERNAT 50S, SIPERNAT 500LS, SIPERNAT 2200, SIDENT 8, SIDENT 9, SIDENT 10, SIDENT 22S). In certain embodiments, the media image is meniu may also be a microcrystalline cellulose, cellulose powder, silication microcrystalline cellulose (PROSOLV 50, PROSOLV 90HD), silica, clay, only, starches, pregelatinized starches, calcium carbonates, calcium silicates, cyclodextrins, hydrogen phosphates of calcium and magnesium carbonates, or combinations thereof.

For producing rapidly disintegrating directly compressible tablets for sublingual injection can be used other excipients. For example, the diluent may be a water-soluble excipient for tableting by direct pressing mannitol. Other water-soluble excipients according to the invention comprise one or more of the following: sugars, polyols, saccharides, polysaccharides, dextran, dextrin, dextrose, fructose (ADVANTOSE FS 95), lactate (FINLAC DC), lactose, eritria, maltose, maldita, maltodextrins, Polydextrose, trehalose, mannitol (PEARLITOL 300 DC, PEARLITOL 400 DC, PEARLITOL 500 DC, MANNOGEM 2080, MANNOGEM EZ, PARTEK M200, PARTEK M300), polyethylene glycols, isomalt, sorbitol, sucrose and xylitol (XYLITOL 200, XYLITOL 300). Can also be enabled baking powder to provide rapid disintegration of the tablet after administration. Typical baking powder is a sodium glycolate. Typical grease for tablets is a sodium fumarate.

In one embodiment of the composition according to the invention can be including the other trading excipients, selected to improve the processing characteristics, form, function, or aesthetic appeal of the composition. In this embodiment, another excipient according to the invention is a buffer agent (such as phosphate, carbonate, tartrate, borate, citrate, acetate and malaty buffers), dye, corrigent, solvent and co-solvent, the covering agent, a binder, a diluent, a carrier, a leavening agent, a sliding agent, a lubricating substance, cloud, humidifier, granulating agent, a gelling agent, polishing agent, suspendisse agent, sweetener, antiadhesive agent, preservative, emulsifier, antioxidant, grinding agent, plasticizer, surfactant, agent for creating a specific toychest, agent contributing to the regulation of viscosity, the enteric agent and the coating agent and the coating for controlled release, wax, wetting agent, thickener, a base for suppositories, agent, giving a stiffness, a stabilizing agent, solubilizers agent, complexing agent, bioadhesive substance, the wax-based, oil filler, film-forming agent, essential oil, emollient substance, power of dissolving, dispersing agent and/or cryoprotector or combinations thereof.

Example 1

TABLE I.
Composition 1 mg tablets melatonin sublingual/transbukkalno introduction
INGREDIENTQUANTITY (mg/tablet)
Melatonin1,00
The polyethylene glycol 4007,00
Silicon dioxide4,50
Mannitol84,00
The glycolate sodium 3,00
The sodium fumarate0,50
Total weight pills100,00

Example 2

In one embodiment according to the invention proposed 1 mg tablet melatonin sublingual/transbukkalno introduction, with the total weight of the tablet is approximately 68 mg. In this second typical embodiment of melatonin dissolved in a mixture of solvents, PEG 400 and oleic acid. To make the solution of melatonin in PEG 400/oleic acid in bulk powder, suitable for use in pelletizing direct pressing, media-adsorbent/absorbent in the form of particles, such as silicon dioxide, may be used as described above in Example 1. The diluent for tablets, such as mannitol, may be used for the manufacture of tablets manufactured by direct compression. The sodium glycolate was used as baking powder and sodium fumarate was used as the lubricant.

A typical composition that was produced for the embodiment of this invention, are presented in Table II below.

TABLE II.
The composition of 1 mg pills melatonin is and sublingual/transbukkalno introduction
INGREDIENTQUANTITY (mg/tablet)
Melatonin1,00
The polyethylene glycol 4005,00
Oleic acid1,30
Silicon dioxide5,00
Mannitol52,30
The glycolate sodium2,04
The sodium fumarate1,36
Total weight pills68,00

Example 3

Conducted research transbukkalno percutaneous migration in vitro comparison of the penetration of melatonin through tissue culture cheeks of the two 1 mg tablets melatonin sublingual administration, having the composition according to Example 2, against commercially available tablets for sublingual administration, not containing dissolved melatonin in the final dosage form. As shown in figure 1, the amount of melatonin released into the fabric of the tablets in question within 30 minutes, more than 3 times the appropriate amount of melatonin available from the sale of a 1 mg tablet of melatonin sublingual introduction GNC, as measured in terms of percent concentration of the label (% LC). This shows the improved rate of penetration through the tissue of the cheeks according to the invention compared to currently available on sale pill melatonin sublingual administration, indicating a more rapid onset of action and greater bioavailability in vivo tablets according to the invention. Thus, we can conclude that drowsiness will occur much faster when using the compositions of this invention, such as the composition shown in Example 2.

Example 4

In the method of manufacturing a tablet according to the embodiment of the present invention sublingual/transbukkalno injection may be used any suitable method known in this field, including, without limitation, adding MES melatonin to pre-manufactured tablets, cold pressing with inert fillers and binding agents, mixtures for direct compression of tablets, direct powder mixtures, wet or dry granulation, molding, lyophilization, microencapsulation, freeze drying, spray congealing, spray drying, joint fusion, spheronization, grinding to powder formulation, manufacture of pastilles, layering powder briquetting, encapsulation. Typical sposobstvovanie pills, manufactured by direct pressing, with the composition given in Example 1 described below and schematically shown in figure 2.

Embodiment 1

STAGE 1. Mix melatonin and PEG 400 with one another with formation of a solution.

STAGE 2. Stir the solution melatonin in PEG 400 with stage 1 with silicon dioxide to homogeneity with the formation of a mixture with silicon dioxide as a carrier.

STAGE 3. Add the mixture with silicon dioxide as the carrier from stage 2 to mannitol and sodium glycolate and mix to homogeneity with the formation of the other mixture.

STAGE 4. Add the sodium fumarate to another mixture from step 3 and mix until a full lubrication with the formation of a mixture with the lubricant.

STAGE 5. Compressing the mixture with the lubricant from the stage 4 in 100 mg tablets with the use of equipment with a diameter of 1/4 inch (6.35 mm).

The packaging method. Tablets for sublingual/transbukkalno introduction can be Packed in such a way as to help maintain stability. Packaging and packaging materials may include, without limitation, blister packaging laminates foil/foil foil/Acrylonitrile, foil/polychlorotrifluoroethylene for packaging in blisters or glass and plastic bottles.

The method of application. In one embodiment it is clear that the structure of the beginning of action of the composition in the form of tablets melatonin for transbukkalno/sublingual injection with constant bioavailability according to the invention is useful in the treatment of disorders of circadian rhythm and sleep disorders. Some studies have shown that melatonin may be effective in breast cancer, fibrocystic-breast and colon cancer. It was shown that melatonin modifies the immune system, stress response, and certain aspects of the aging process; some studies have demonstrated improvements in sleep disorders and evening exacerbation in patients with Alzheimer's disease. Antioxidant role of melatonin could potentially be applicable for conditions in which oxidative stress is involved in pathophysiological processes. Since the production of melatonin decreases with age, shows the use of melatonin as hormone replacement therapy or nutritional supplements. Accordingly, this invention is useful for all of the above therapies. A typical treatment regimen begins with the fact that you want to place a tablet of melatonin sublingual introduction under the tongue and not to shift it to dissolve, usually within 5 minutes. If necessary, this can be supplemented by additional pills. The dose range for this embodiment can vary from 0.01 to 3.0 mg depending on therapeutic need.

The invention has been described with reference to various specific and preferred embodiments and techniques. The man is e, it should be understood that many changes and modifications can be made within the essence and scope of the invention.

1. Solid dosage form for sublingual or transbukkalno the introduction of the hormone, having a solubility in water of low to insufficient containing the hormone selected from the group consisting of melatonin, estrogen, progesterone, testosterone and dihydroxytestosterone, in a dissolved state, and the specified dissolved hormone associated with a pharmaceutically acceptable carrier, where the specified hormone presented in a dissolved state in the final dosage form.

2. Dosage form according to claim 1, where the dissolved hormone covers specified media, the absorbed or adsorbed on it.

3. Dosage form according to claim 1, where the hormone is dissolved in a pharmaceutically acceptable solvent selected from polyethylene glycol, ethanol, ethyl acetate, isopropyl alcohol, triacetin, triethylcitrate, tributyltin, substituted glycols, propylene glycol, bisabolol, glycerin, mineral oil, ethyloleate, oleic acid, esters of fatty acids and olejowego alcohol, squalane, animal oils, vegetable oils, hydrogenated vegetable oils, isopropylmyristate, isopropylpalmitate, glycoluril, terpenes, essential oils, alcohols, water, floor the tins, silicone fluids, glycerides, or mixtures thereof.

4. Dosage form according to claim 3, where the pharmaceutically acceptable solvent is a glycol.

5. Dosage form according to claim 3, where the pharmaceutically acceptable solvent is a mixture of polyethylene glycol and oleic acid.

6. Dosage form according to claim 1 where the pharmaceutically acceptable carrier is selected from silicon dioxide, microcrystalline cellulose, cellulose, silication microcrystalline cellulose, clay, talc, starch, pregelatinized starch, calcium carbonate, calcium silicate, calcium hydrogen phosphate, magnesium carbonate and mixtures thereof.

7. The pharmaceutical composition according to claim 6, where the pharmaceutically acceptable carrier is a silicon dioxide.

8. The pharmaceutical composition according to claim 7, where the media, which are silicon dioxide, is a particle size which ranges from about 3 to about 30 microns.

9. The pharmaceutical composition according to claim 1, where the concentration of hormone in the solvent is from about 5% to about 30% wt./wt.

10. The pharmaceutical composition according to claim 1, where the mass ratio of carrier: the solution is from about 1:0.5 to about 1:4.

11. The pharmaceutical composition according to claim 1, Supplement is Ino containing the diluent.

12. The pharmaceutical composition according to claim 1, additionally containing baking powder.

13. The pharmaceutical composition according to claim 1, additionally containing a lubricating substance.

14. The pharmaceutical composition according to claim 1 containing from about 0.01 to about 3 mg of the hormone on the standard dose.

15. The pharmaceutical composition according to claim 1 in the form of tablets.

16. A method of manufacturing a pharmaceutical composition according to claim 1, which includes stages of dissolution specified hormone in a pharmaceutically acceptable solvent to form a solution of a medicinal product, mixing a solution of a medicinal product with particles of the pharmaceutically acceptable carrier to form a coating of the specified fluid at the carrier particles, adsorption or absorption of the specified solution on the particles of the medium.

17. The method according to clause 16, where the composition is in the form of loose powder.

18. The method according to item 16, further comprising compressing the composition with the formation of the tablets.

19. The way to ensure the patient's hormonal therapy, including the manufacture of the dosage form according to claim 1 and the introduction of the specified sublingual dosage form or transbukkalno way to a patient in need of this therapy.



 

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23 cl, 6 tbl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a pharmaceutical composition for treating and/or preventing depressions. The pharmaceutical composition contains an active substance presented by a selective serotonin reuptake inhibitor (SSRI) specified in a group of fluoxetine, paroxetine, citalopram, escitalopram, sertraline, fluvoxamine differing by the fact that as an active substance, it additionally contains N-acetyl-5-methoxytryptamine (melatonin) in the following proportions, mg: selective serotonin reuptake inhibitor (SSRI) - 10-30 mg, melatonin - 3-8 mg. The pharmaceutical composition may be presented by a solid dosage form - a tablet, a film-coated tablet, a capsule, by a soft dosage form - a rectal suppository.

EFFECT: pharmaceutical composition provides treating depressions and has a number of additional therapeutic properties: easing falling asleep and relieving sleeping disorders, recovering circadian rhythm and seasonal rhythm with reducing a risk of side effects of SSRI.

3 cl, 14 tbl, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a new (-)-stereoisomer of formula (I) wherein X is H, or its pharmaceutically acceptable salt which agonise GABA receptor, to a pharmaceutical composition on the basis of the presented compound, to a method for preparing the (-)-stereoisomer of formula (I) or its pharmaceutically acceptable salt, to a method for inducing or maintaining general anaesthesia, to a method for promoting pain management and to a method for promoting pain management and to a method for prototyping antiemetic activity with the use of the presented (-)-stereoisomer or its pharmaceutically acceptable salt, as well as to a new diastereoisomer (-)-2,6-di-fluoro-butylphenyl ester of carbamic acid of formula (II) wherein R1 represents a chiral amino group, and X is H, or to its pharmaceutically acceptable salt.

EFFECT: preparing the pharmaceutically acceptable salt which agonise GABA receptor.

14 cl, 15 ex, 8 tbl, 3 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a new (-)-stereoisomer of formula (I) wherein X is H, or its pharmaceutically acceptable salt which agonise GABA receptor, to a pharmaceutical composition on the basis of the presented compound, to a method for preparing the (-)-stereoisomer of formula (I) or its pharmaceutically acceptable salt, to a method for inducing or maintaining general anaesthesia, to a method for promoting pain management and to a method for promoting pain management and to a method for prototyping antiemetic activity with the use of the presented (-)-stereoisomer or its pharmaceutically acceptable salt, as well as to a new diastereoisomer (-)-2-fluoro-butyl-6-isopropylphenyl ester of carbamic acid of formula (II) wherein R1 represents a chiral amino group, and X is H.

EFFECT: preparing the pharmaceutically acceptable salt which agonise GABA receptor.

16 cl, 12 ex, 6 tbl, 4 dwg

FIELD: medicine.

SUBSTANCE: invention refers to a dietary and pharmaceutical composition containing ligustilide to be applied in a method of treating or preventing depression, generalised anxiety disorders, dysphoria, obsessive-compulsive behaviour, and affective disorders, as well as to a non-therapeutic application of the dietary composition containing ligustilide.

EFFECT: higher efficacy of the applied derivatives.

6 cl, 17 ex, 6 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: what is offered is a dosage form containing a drug substance for treating insomnia, containing a layer or a matrix-surrounding coating wherein a drug substance is dissolved or dispersed with said drug substance released after a time of delay (at least 1 hour after the introduction) which is not substantially accompanied by the drug substance release, and the coating material contains less than 5 % of substances which possess an ability to swell or gelate, and the matrix contains an release control agent.

EFFECT: invention provides exactly establishing and observing the time of delay before the active substance release that enables the patient to work before sleeping, being in the non-sleepy state.

20 cl, 3 dwg, 8 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: pyrazolo[1,5-a]-pyrimidine compounds according to the invention are specified in a group consisting of: N-{2-fluor-5-[3-nitro-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylacetamide, N-{2-fluor-5-[3-cyano-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylacetamide, N-{2-chlor-5-[3-nitro-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylacetamide, N-{2-chlor-5-[3-cyano-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylacetamide, N-{2-fluor-5-[3-nitro-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-ethylmethanesulphonamide; {2-fluor-5-[3-cyano-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylmethanesulphonamide, N-{2-chlor-5-[3-nitro-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylmethanesulphonamide, N-{2-chlor-5-[3-cyano-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylmethanesulphonamide, N-{2-fluor-5-[3-cyano-2-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylacetamide, N-{2-chlor-5-[3-cyano-2-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylacetamide, N-{2-fluor-5-[3-cyano-2-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-methanesulphonamide, N-{2-chlor-5-[3-cyano-2-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-methanesulphonamide, N-{2-methyl-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylacetamide, N-{2-methoxy-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylacetamide, N-{2,4-difluor-5-[3-(thiophene_2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylacetamide and N-{5-fluor-2-methoxy-3-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylacetamide.

EFFECT: preparing pyrazolo[1,5-a]pyrimidine compounds, their pharmaceutically acceptable salts and hydrates showing an ability to inhibit GABAA receptors, and applicable for treating and preventing anxiety, epilepsy and sleeping disorders, including insomnia, as well as for inducing a sedative-hypnotic, analgesic and sleeping effects and myorelaxation.

14 cl, 6 tbl, 4 dwg, 22 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: this invention relates to new compounds with formula (I) possessing the properties of mGLuR2 antagonists, to their obtainment methods, their application for production of medicines for prevention and treatment of disorders wherein mGLuR2 plays the activation role (in particular - central nervous system disorders). In formula (I) either any of X and Y represents N while the other represents CH or each of X and Y represents N; A represents aryl representing phenyl or 5- or 6-membered heteroaryl containing in the cycle 1-3 atoms selected from among nitrogen, oxygen or sulphur, the heteroaryl selected from among amidazolyl, [1,2,4] oxadiazolyl, pyrrolyl, 1H-pyrazolyl, pyridinyl, [1,2,4] triazolyl, tiazolyl and pyrimidinyl, each of them substitutable by C1-6-alkyl; B represents H, cyano or represents a possibly substituted aryl selected from among phenyl or possibly substituted by 5- or 6-membered heteroaryl containing in the cycle 1-3 atoms selected from among nitrogen, oxygen or sulphur where the substitutes are selected from the group consisting of nitro, C1-6-alkyl, possibly substituted hydroxy, NRaRb where Ra and Rb independently represent H, C1-6-alkyl etc. R1 represents H, a halogen atom, C1-6-alkyl, possibly substituted hydroxy, C1-6-alcoxy, C1-6-halogenoalkyl, C3-6-cycloalkyl represents H cyano, a halogen atom, C1-6-halogenoalkyl, C1-6-alcoxy, C1-6-halogenoalcoxi-, C1-6-alkyl or C3-6-cycloalkyl R3 represents a halogen atom, H, C1-6-alcoxy, C1-6-halogenoalkyl, C1-6-alkyl, C3-6-cycloalkyl, C1-6-halogenoalcoxy R4 reprsents H or halogeno.

EFFECT: creation of new compounds of formula (I) possessing mGLuR2 antagonist properties.

104 cl, 465 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to improved methods for preparing a hydrazide product of hydrazine and acid chlorides, particularly to a method for preparing 3-methyl-3-mercaptobutanoic acid hydrazide. The method involves the stages as follows: (a) preparing a stirred, substantially uniform suspension containing hydrazine and an inert solvent, and (b) continuously adding acid chloride to said suspension, wherein acid chloride has the structure: , wherein P represents a thiol-protective group; each of R1 and R2 are specified in a group consisting of C1-C5 alkyl; L represents an alkylene linker with continuously adding of the acid chloride solution adjusted so that a reaction temperature maintained within the range of -65°C to -75°C. The invention also refers to a method for preparing a hydrazine suspension involving the stages as follows: (a) cooling the inert solvent to a temperature within the range of -68°C to -75°C; and (b) adding hydrazine drop-by-drop to the specified cold inert solvent; and to a method for preparing an immunoconjugate of calicheamicin member and a monoclonal antibody as a carrier involving preparing monoacylated hydrazide.

EFFECT: method eliminates or limits the formation of the undesired bis-hydrazine side products.

31 cl, 15 ex, 9 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine, namely biopharmaceutics and may be used for preparing an immunogenic conjugate. That is ensured by: (a) a reaction of serotype 1 purified polysaccharide with an alkaline buffer to prepare serotype 1 partially des-O-acetylated polysaccharide; (b) a reaction of serotype 1 partially des-O-acetylated polysaccharide and a weak acid to produce serotype 1 neutralised partially des-O-acetylated polysaccharide; (c) a reaction of serotype 1 neutralised partially des-O-acetylated polysaccharide and an oxidising agent to prepare serotype 1 activated polysaccharide; (d) mixing of serotype 1 activated polysaccharide and a carrier protein; (d') combined lyophilisation of mixed serotype 1 activated polysaccharide and the carrier protein before a reaction with a reducing agent; (e) reaction of mixed serotype 1 activated polysaccharide and the carrier protein with the reducing agent to prepare a serotype 1 activated polysaccharide/carrier protein conjugate; and (f) capping of unreacted aldehydes in the serotype 1 activated polysaccharide/carrier protein conjugate. What is also presented is a method for preparing a multivalent immunogenic composition.

EFFECT: group of inventions enables preparing the composition presented in the form of vaccines that decreases a number of severe pneumococcal diseases.

27 cl, 17 ex

FIELD: chemistry.

SUBSTANCE: visualisation agent contains a conjugate of formula (I) of benzopyrylium dye through a linker group with a 3-100-dimensional synthetic peptide which provides directed delivery to the biological target. Also disclosed is a pharmaceutical composition which contains said conjugate of formula (I), a set for preparing said pharmaceutical composition and methods for visualisation of a mammal body in vivo.

EFFECT: invention provides efficient visualisation of a mammal body in vivo while monitoring diseased state thereof.

24 cl, 5 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine, namely biopharmaceutics, and may be used for making vaccines. For this purpose, the composition stabilising a polysaccharide-protein conjugate, contains: (1) buffer saline with said buffer having pKa approximately 3.5 to about 7.5, (2) polysorbate 80 in the final concentration of 0.001% to 0.05 wt/vol % of the composition, and (3) one or more polysaccharide-protein conjugates containing one or more pneumococcal polysaccharides. The group of inventions also relates to a syringe filled with the above composition.

EFFECT: use of this composition can improve the stability of the immunogenic compositions, and inhibit deposition thereof.

28 cl, 8 tbl, 7 dwg, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a magnetic system which has a structure containing magnetic nanosized particles of formula MIIMIII2O4, wherein MII=Fe, Co, Ni, Zn, Mn; MIII=Fe, Cr, or maghemite which are functionalized by bifunctional compounds of formula R1-(CH2)n-R2 where n = 2-20, R1 is specified in: CONHOH, CONHOR, PO(OH)2, PO(OH)(OR), COOH, COOR, SH, SR; R2 is an external group, and is specified in: OH, NH2, COOH, COOR; R is an alkyl group or an alkaline metal specified in C1-6-alkyl and K, Na or Li, respectively). The structure also includes a polymer optionally containing a pharmacologically active molecule, and an external pharmacologically active molecule may be specified in anticancer agents, antimicrobial agents, anti-inflammatory agents, immunomodulators, molecules acting on the central nervous system or able to mark cells so as to enable the identification thereof by means of the usual diagnostic detectors. The invention also refers to a method for preparing the nanosized particles of formula MIIMIII2O4 which consists in adding a metal salt to alcohol, heating to complete solubilisation of salts, adding water to facilitate salt hydrolysis and heating to temperature 150-180°C to prepare a suspension to be then functionalised. The invention also refers to a method for preparing the magnetic system, wherein the functionalised nanoparticles and the pharmacologically active molecules are integrated into the matrix of a water-insoluble polymer, and the prepared structure is continuously and one-stage coated with adequate surfactants.

EFFECT: invention aims at preparing the magnetic system suitable for hyperthermia procedures.

16 cl, 4 tbl, 1 dwg, 26 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry and represents a pharmaceutical composition for treating and preventing viral and bacterial infections, containing as active ingredients: lysocyme, peroxidase, poviargol, as anti-inflammatory ingredients: escin and glycyrrhizic acid or a salt thereof, as carriers - liposome based on high-active hydrogenated lecithins in a combination with cholesterol and pharmaceutically acceptable carriers and excipients, and the ingredients of the composition are taken in a certain ratio, wt %.

EFFECT: invention ensures maintaining prolonged activity of the enzymes being the ingredients of the composition, fast skin penetration and absorption.

4 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a controlled release compositions for preparing a prolonged release Udenafil containing preparation comprising (A) Udenafil or a pharmaceutically acceptable salt thereof, (B) a solubility modulator, (C) an adsorbent, and (D) a hydrophilic polymer. The controlled release composition for preparing the prolonged release Udenafil containing preparation releases a drug substance continuously, regardless of the gastrointestinal pH value, and thereby freely controls the drug substance release within 3-24 hours and reduces the variability of the individual effects of the drugs. In addition, this composition may be used in preparing the prolonged release of the drug which has an optimum condition for the manifested effect of the drug in treating the diseases including pulmonary arterial hypertension, portal hypertension, benign prostate hyperplasia, etc., which can be treated by Udenafil and require long-term administration of the drugs.

EFFECT: composition can control the drug release in accordance with the absorption length when the drug is administered into a living body, and thereby the use thereby may be of prime importance for the prevention and treatment of erectile dysfunction.

9 cl, 3 dwg, 7 tbl, 22 ex

FIELD: nanotechnology.

SUBSTANCE: invention relates to the use of nanoparticles for prevention and/or treatment of cancerous diseases, when the nanoparticles are injected with anti-cancer therapeutic agent, and the nanoparticles and anti-cancer agent are simultaneously present in the patient's body. The nanoparticles are free from binding with the anti-cancer medicinal product and have a coating which contains polycondensated aminosilanes.

EFFECT: simultaneous presence of nanoparticles and the anti-cancer therapeutic agent in the body of patients enables to increase the activity of the said anti-cancer agent with simultaneous reduction of the side effects.

12 cl, 1 tbl, 13 dwg, 196 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of veterinary microbiology and deals with method of obtaining specific immunomodulator. Claimed method includes the following stages: cultivation of vaccine strain of BCG, destruction of culture with ultrasound, separation of antigenic complex, mixing supernatant liquid with formalin and conjugation of reaction mixture on polyelectrolytes: polyvinylpyrrolidone (PVP) four parts and polyethyleneglycol (PEG) one part by weight, at ratio 1 mh/ml of protein - 480 mg PVP and 120 mg of PEG by weight on magnetic mixer at room temperature until homogenous liquid is obtained.

EFFECT: invention makes it possible to restore impaired immune reactivity, remove secondary immune deficits, obtain harmless for animals substances, which possess expressed protective properties.

6 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a contrast agent for magnetic-resonant tomography (MRT) based on a chemical exchange saturation transfer (CEST). The contrast agent contains polymersome provided by a paramagnetic substance, and a bilayer of an amphiphilic block copolymer or terpolymer comprising a cavity. In said cavity, there is a proton analyte pool containing water. The paramagnetic substance represents a paramagnetic chemical shift reagent containing a metal complex having a metal ion and a multidentate chelating ligand wherein the enclosure allows proton analyte diffusion. The invention also refers to a carrier of a drug preparation containing said contrast agent which is suitable for localised drug delivery. There is also declared a method for target MRT delivery of a bioactive substance into the patient which involves the stages of introducing the carrier of the drug preparation, performing MRT with using intensified CEST contrast, and enabling the carrier releasing the bioactive substance.

EFFECT: invention provides higher contrast, prolonged circulation and lesser tend to macrophage absorption.

9 cl, 7 dwg, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to tablet, which is decomposed in mouth, containing D-mannite, active ingredient, disintegrating preparation, selected from crospovidone and carmellose, lubricant, selected from sodium stearylfumarate and sucrose esters of fatty acids, binding agent and starch. D-mannite has average size of particles larger than 30 mcm and specific surface larger than 0.40 m2/g.

EFFECT: claimed tablet has time of decomposition in oral cavity within 30 seconds, excellent sensation in oral cavity and sufficient strength, as a result of which tablet is not decomposed in the process of distribution.

28 cl, 1 dwg, 12 tbl, 51 ex

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