Method of preparing analgesics

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a product of oxymorphone hydrochloride exhibiting an analgesic activity and containing less than 10 parts/million of alpha, beta unsaturated ketones by HPLC, also the invention refers to a pharmaceutical formulation containing said product of oxymorphone hydrochloride and to a method of oxymorphone hydrochloride purification involving reduction of a basic substance of oxymorphone hydrochloride in highly acid aqueous and alcohol reaction medium with hydrogen gas at temperature within 60 to 70°C.

EFFECT: there is produced and described improved analgesic oxymorphone hydrochloride containing less than 10 parts/million of alpha, beta unsaturated ketones.

22 cl, 3 ex, 1 dwg

 

The technical field to which the invention relates.

This invention relates to an improved method of preparation of analgesics, in particular making the opiate of Oxymorphone in the form of its hydrochloride.

The level of technology

Oxymorphone, which is usually used in the form of its cleaners containing hydrochloride salt, is a powerful semi-synthetic opioid analgesic to relieve moderate and severe pain, approved for applications in 1959, It can be applied in the form of solution for injection, suppository, tablet or tablets slow release. It is necessary to develop highly purified forms of Oxymorphone and the method of their synthesis.

There are several known methods of synthesis of Oxymorphone of compounds isolated from the opium poppy or compounds derived from it, for example, from morphine, thebaine or oxycodone. However, there remains a need for methods that allow to form Oxymorphone with low contamination alpha, beta unsaturated ketones. The present invention provides an improved product Oxymorphone and method of manufacturing such Oxymorphone.

Patent US 7129248 describes the production process of oxycodone hydrochloride with less than 25 hours/million 14-hydroxycotinine by hydrogenation of oxycodone containing more than 100 hours/million 14-hydroxycotinine. The way of synthesis of oxycodone, about widely in patent US'248, begins with the rich and gives 14 hydroxytoluene as an intermediate product and 8,14-dihydroxy-7,8-digitoxigenin as a by-product resulting from excessive oxidation of thebaine. During the conversion of the free base of oxycodone in cleaners containing hydrochloride salt by-product may be subjected to acid-catalyzed dehydration and turn into a 14-hydroxycotinine. Thus, the final cleaners containing hydrochloride salt of oxycodone contains unreacted 14 hydroxycotinine and 14 hydroxycodone obtained from by-products of 8,14-dihydroxy-7,8-dihydrocodeinone. Phase hydrogenation stated as reducing the content of 14-hydroxycotinine from at least 100 hours/million to less than 25 hours/million

Disclosure of inventions

The present invention provides a product Oxymorphone hydrochloride containing less than 10 hours/million alpha, beta unsaturated ketones.

The invention also provides a method of purification of Oxymorphone hydrochloride with a yield of Oxymorphone hydrochloride, containing less than 10 hours/million alpha, beta unsaturated ketones, including restoration of the original material Oxymorphone hydrochloride in strongly acidic aqueous or alcoholic solvent, using gaseous hydrogen at a temperature in the range from 60 to 70°C. the Recovery can be performed within, by Raina least 20 hours, but in another embodiment the recovery is carried out from 1 to 20 hours.

Preferably the solvent is ethanol/water, although there may be other miscible with water, alcohols, such as isopropanol and n-propanol. The reaction medium is strongly acidic, preferably by the inclusion of at least two equivalents of hydrochloric acid. The desired pH is less than 1.

The reaction temperature is most preferable support about 65°C. Hydrogen is simply fed into the vessel for the reaction under pressure 2,41 bar.

The method of the invention can purify the source material - Oxymorphone hydrochloride - with a very high content (about 0.3 to 0.5%, or 3000-5000 hours/million) alpha, beta unsaturated ketones to less than 10 hours/million, and in many cases to non-detectable levels (according to HPLC).

The source material Oxymorphone hydrochloride can be selected or unselected material. It is advisable to get it in the formation cleaners containing hydrochloride salt by heating the free base Oxymorphone in the presence of hydrochloric acid and spirit/water reaction medium. A suitable temperature is 60-70°C. one Can see that the reaction medium is ideal for the recovery method of the invention, so that in General no need to allocate Oxymorphone hydrochloride. However, the source material Oxymorphone hydro is lorida can be isolated from the reaction medium, or can be obtained from another source.

The free base Oxymorphone itself is preferably prepared by restoring the 14-hydroxymorphinone. It can be in the form of one - and two-step process. Recovery is preferably carried out in acetic acid with the use of gaseous hydrogen and a catalyst of palladium on coal. The preferred temperature is about 30°C. the Base is precipitated by adding aqueous ammonia (NH4OH).

This recovery can be carried out in the presence of a reaction medium in which add dichloromethane in methanol, Florasil (Florisil) and n-propanol.

14 Hydroxymorphinan as such, most preferably prepared by hydroxylation oripavine, with the use of hydrogen peroxide in the presence of formic acid.

Oripavine is a known compound, which is extracted from poppy straw. The line developed in Tasmania with the aim of obtaining varieties with high yield of thebaine, also produces levels oripavine higher than normal.

The process of the invention is very flexible, allowing many stages of the reaction without isolation of intermediate products, while maintaining high (about 50%) of the total output of oripavine, as well as providing a remarkable high purity. Under favorable conditions presets is of alpha, beta unsaturated ketones were not detected by conventional means, such as HPLC, but expert in this field of technology can easily achieve contamination less than 10 hours/million Process according to the invention is successfully performed in kilogram scale.

Oxymorphone hydrochloride with alpha, beta unsaturated ketones less than 10 hours/million can be included in pharmaceutical dosage forms, for example, by mixing Oxymorphone hydrochloride with alpha, beta unsaturated ketones less than 10 hours/million with conventional excipients, i.e. pharmaceutically suitable organic or inorganic substances media. For oral formulations, the dosage form can provide a delayed release of the active ingredient. Suitable pharmaceutically suitable carriers include, without limitation alcohols, gum Arabic, vegetable oils, benzyl alcohols, polyethylene glycols, gelatinous substances, carbohydrates such as lactose, amylose or starch, magnesium stearate, talc, silicic acid, viscous paraffin, aromatic oil, monoglycerides and diglycerides of fatty acids, pentaerythritol fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidone, etc. Pharmaceutical preparations can be sterilized and, if necessary, mixed with auxiliary agents, e.g., lubrican the AMI, disintegrants, preservatives, stabilizers, wetting agents, emulsifiers, salts, buffers, influencing the osmotic pressure, coloring agents, flavoring and/or aromatic substances and the like. Compositions intended for oral use may be prepared according to any method known in the art, and such compositions may contain one or more agents selected from the group consisting of inert, nontoxic, pharmaceutically suitable excipients suitable for the manufacture of tablets. Such fillers include, for example, an inert diluent, such as lactose; granulating and dezintegriruetsja agents such as corn starch; binders such as starch; lubricants such as magnesium stearate. Tablets may not have a shell or be coated by known techniques to improve appearance or for slow release of the active ingredients. Formulations for oral use may also be presented as hard gelatin capsules where the active ingredient is mixed with an inert diluent. Oral dosage forms of the present invention can be in the form of tablets (sustained release or immediate release), pastilles, lipase is, powders or granules, hard or soft capsules, microparticles (e.g., microcapsules, microspheres and the like), buccal tablets, solutions, suspensions, etc.

In specific embodiments the present invention provides a method of treating pain by applying a human patient dosage forms described herein.

Oral dosage form of the present invention contains from about 1 mg to about 40 mg Oxymorphone hydrochloride, containing less than 10 hours/million alpha, beta unsaturated ketones. An especially preferred dosage is about 5 mg, about 10 mg, about 20 mg or about 40 mg, however, can also be applied to other dosage. Oxymorphone hydrochloride, containing less than 10 hours/million alpha, beta unsaturated ketones can also be prepared in a formulation with suitable pharmaceutically suitable excipients to provide medication slow release, containing less than 10 hours/million alpha, beta unsaturated ketones. Such formulations can be prepared in accordance with US 2003/129230 A1, US 2003/129234 A1 and US 2003/157167 A1.

Oxymorphone hydrochloride, containing less than 10 hours/million alpha, beta unsaturated ketones can be prepared in the form of oral formulations of slow-release in any suitable tablet, coated tablet or formulation of multicystic known special is Stam in the art. Dosage form for sustained release can include slow release material embedded in the matrix together with the salt of Oxymorphone.

Dosage form for sustained release may also include particles containing Oxymorphone hydrochloride, containing less than 10 hours/million alpha, beta unsaturated ketones. In specific embodiments, the particles have a diameter from about 0.1 mm to about 2.5 mm, preferably from about 0.5 mm to about 2 mm, Preferably particles coated with a material that enables the release of the active substance with delayed velocity in the aquatic environment. Covering the shell is selected to achieve in combination with other established properties required properties of the release. Recipes, coated for slow release of the present invention, preferably should be capable of creating a strong, continuous film that is smooth and has a good appearance, is able to carry the pigments and other additives for coatings, non-toxic, inert and does not contain glue.

Coated globules.

In specific embodiments of the present invention is applied hydrophobic material for coating an inert pharmaceutical grains, such as grains nonpareil 18/20, and thus many of the obtained solid is s particle grain sustained release can be placed in a gelatin capsule in an amount sufficient to provide an effective dose of slow-release if swallowed and in contact with the surrounding fluid, such as gastric juice or solvent environment.

Recipe grain sustained release of the present invention slowly release the active component of the present invention, for example, when ingested and exposed to gastric juice, and then intestinal juice. Profile of sustained release formulations of the invention can be changed, for example, by varying the number of membranes with hydrophobic material changes in the manner of addition of plasticizer to hydrophobic material, by varying the amount of plasticizer relative to hydrophobic material, by the inclusion of additional ingredients or excipients, by altering the method of manufacture etc. of the dissolution Profile of the final product can also be modified, for example, by increasing or reducing the thickness of the retarding coating.

Spheroids or grains covered by the agent(s) of the present invention is prepared, for example, by dissolving agent(s) in water, followed by spraying the solution on the substrate, for example on the grist nonpareil 18/20, using the Wurster insert. If necessary, add additional ingredients before coating on the grains to free the th binding of the active ingredient with nibs, and/or to color the solution, etc. for Example, the product comprising hypromellose, etc., with dye or without it (for example, Opadry™, commercially supplied use, Inc.), can be added to the solution and the solution mixed (e.g., one hour) before it is applied to the grains. The obtained coated substrate, in this example, the grains can then be coated over the barrier agent to separate the active component(s) from hydrophobic coating sustained release. An example of a suitable barrier agent is one that includes hypromellose. However, it can also be used any foaming agent known in the art. Preferably, the barrier agent did not affect the dissolution rate of the final product.

The grains can then be coated on top of the aqueous dispersion of hydrophobic material. The aqueous dispersion of hydrophobic material preferably include an effective amount of plasticizer, such as triethylcitrate. Can be applied pre-formed aqueous dispersion of ethyl cellulose, such as Aquacoat™ or Surelease™. If you use Surelease™, not necessary to separately add a plasticizer. Alternatively, you can apply a pre-formed aqueous dispersion of acrylic polymers, is aka as Eudragit™.

Solutions for the coatings of the present invention preferably contain, in addition to the foaming agent, plasticizer and solvent (i.e. water), the dye to provide a beautiful appearance and recognition of the product. The dye can be added to the solution of therapeutically active agent instead of or in addition to the aqueous dispersion of hydrophobic material. For example, the dye can be added to Aquacoat™ through the use of dye dispersions on the basis of alcohol or propylene glycol, powdered aluminum pigments and cloud emulsions, such as titanium dioxide by adding dye with mixing to the solution of water-soluble polymer and then using low shear to the plasticized Aquacoat™. An alternative may be any suitable way to ensure color formulations of the present invention. Suitable ingredients to ensure color recipes when using water dispersion of acrylic polymer include titanium dioxide and pigments such as iron oxide pigments. The incorporation of pigments, however, can increase the slowing effect of the shell.

Plasticized hydrophobic material can be applied onto the substrate comprising the agent(s), by spraying using any spray equipment known in the field t is the transport. In the preferred method the system with Wurster coating in a fluidized bed in which the air jet, injected from underneath, washes the material of the nucleus and promotes drying, when it is sprayed acrylic polymer coating. You can apply the amount of hydrophobic material sufficient to obtain a predefined release agent(s), when the coated substrate is exposed to aqueous solutions, e.g. gastric juice. After covering a hydrophobic material on the grit if necessary, put an additional film-forming coating, such as Opadry™. This additional coating provide, if available, to significantly reduce the agglomeration of grains.

The release agent(s) from the formulation of sustained release can be optionally changed, i.e. summed to the desired speed, by adding one or more modifying release agents or by providing one or more passages through the shell. The ratio of hydrophobic material to water-soluble material is determined, among other factors, the rate of release and solubility characteristics of the selected materials.

Agents that modify the release of functioning as a pore-formers can be organic or neorg the technical and include materials, which can be dissolved, extracted or washed from the membrane into the environment. The pore-formers can include one or more of hydrophilic materials, such as hypromellose.

Membrane for sustained release of the present invention can also include enabling the erosion agents such as starch and gums.

Membrane for sustained release of the present invention may also include materials suitable for making microporous plate used in the environment, such as polycarbonates comprising linear polyesters of carbonic acid in which carbonate groups meet again in the polymer chain.

Agents that modify the release may also include semi-permeable polymer.

In specific preferred embodiments the agent that modifies the release, selected from hydroxypropylmethylcellulose, lactose, metal stearates, and mixtures of any of the above substances.

Membrane for sustained release of the present invention may also include means output, including at least one passageway, orifice, or the like. The passage may be formed through methods such as those described in US 3845770, US 3916899, US 4063064 and US 4088864.

The formulation of the matrix.

In other embodiments of the present invention Rotz the tour delayed release is achieved by matrix, additionally, having a membrane for sustained release, as outlined here. Materials suitable for inclusion in a slow-release matrix may depend on the method used for formation of the matrix.

For example, the matrix in addition to Oxymorphone hydrochloride, containing less than 10 hours/million alpha, beta-unsaturated ketones may include hydrophilic or hydrophobic materials, such as gums, cellulose ethers, acrylic resins, materials obtained from proteins. This list is not considered exhaustive, and may be any pharmaceutically suitable hydrophobic material or hydrophilic material capable of slow release agent(s) and raspravlyalsya (or razmyagchayuschiesya to the degree necessary for extrusion in accordance with the present invention.

Preferred digestible, long chain (C8-C50especially C12-C40), substituted or unsubstituted carbohydrates, such as fatty acids, fatty alcohols, glycerol esters of fatty acids, mineral and vegetable oils and waxes, and stearyl alcohol; and polyalkylene glycols. Of these polymers, preferred are acrylic polymers, especially Eudragit™, cellulose ethers, especially hydroxyethylcellulose and karboksimetsiltsellyulozy. Oral drug Fort is s may contain between 1% and 80% (by weight), at least one hydrophilic or hydrophobic material.

When the hydrophobic material is a hydrocarbon, the hydrocarbon preferably has a melting point between 25°C and 90°C. Of the hydrocarbon materials with long chain preferred are fatty (aliphatic) alcohols. Oral dosage form may contain up to 60% (by weight)of at least one digestible hydrocarbon long chain.

Preferably the oral dosage form contains up to 60% (by weight), at least one polyalkyleneglycol.

The hydrophobic material preferably selected from the group consisting of alkylsilanes, polymers and copolymers of acrylic and methacrylic acid, shellac, Zein, hydrogenated castor oil, hydrogenated vegetable oil, or a mixture thereof. In specific preferred embodiments of this invention, the hydrophobic material is a pharmaceutically suitable acrylic polymer, including, without limitation, copolymers of acrylic acid and methacrylic acid, methyl methacrylate, copolymers of methyl methacrylate, ethoxyethylacetate, cyanoethylation, a copolymer of aminoalkylsilane, copolymer of polyacrylic acid, polymethacrylic acid, copolymer of methacrylic acid and alkylamine, copolymers of polymethyl methacrylate, an is igrid polymethacrylic acid, polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride) and glycidylmethacrylate. In other embodiments the hydrophobic material is selected from materials such as hydroxyethylcellulose, such as hypromellose, and mixtures of the aforementioned substances.

Preferred hydrophobic materials are insoluble in water, with more or less pronounced hydrophilic and/or hydrophobic branches. Preferably the hydrophobic materials useful in the invention have a melting point from about 25°to about 200°C., preferably from about 45°to about 90°C. In particular, the hydrophobic material may include natural or synthetic waxes, fatty alcohols (such as lauric, ministerului, stearyl, cetyl or preferably cetosteatil alcohol), fatty acids, including, without limitation, esters of fatty acids, glycerides of fatty acids (mono-, di - and triglycerides), hydrogenated fats, hydrocarbons, normal waxes, stearic acid, stearyl alcohol and hydrophobic and hydrophilic materials having hydrocarbon skeletons. Suitable waxes include, for example, beeswax, glycophos, castor wax and Carnauba wax. For the purposes of this invention, a wax-like substance is defined as any material that is normally solid at room temperature and having the second melting point from about 25°to about 100°C.

Suitable hydrophobic materials that can be used in accordance with the present invention include digestible, long chain (C8-C50especially C12-C40), substituted or unsubstituted hydrocarbons, such as fatty acids, fatty alcohols, glyceriae esters of fatty acids, mineral and vegetable oils and natural and synthetic waxes. Preferred are hydrocarbons having a melting point between 25°C and 90°C. Of the hydrocarbon materials with long-chain specific embodiments are preferred fatty (aliphatic) alcohols. Oral dosage form may contain up to 60% (by weight)of at least one digestible hydrocarbon long chain.

Preferably a combination of two or more hydrophobic materials include in the matrix formulation. If you include additional hydrophobic material, it is preferably selected from natural and synthetic waxes, fatty acids, fatty alcohols and mixtures thereof. Examples include beeswax, Carnauba wax, stearic acid and stearyl alcohol. This list is not exclusive.

One particular acceptable matrix includes at least one water-soluble hydroxyethylcellulose at least one12-C36, preferably the C 14-C22, aliphatic alcohol and, optionally, at least one polyalkyleneglycol. At least one hydroxyethylcellulose preferably is hydroxy (C1-C6) alkylsilane, such as hydroxypropylcellulose, hypromellose and especially hydroxyethylcellulose. The amount of at least one hydroxyethylcellulose in the present oral dosage form is determined, among other things, an exact rate of release of Oxymorphone hydrochloride. At least one aliphatic alcohol may be, for example, lauric alcohol, ministerului alcohol or stearyl alcohol. However, in private preferred embodiments presented oral dosage form of at least one aliphatic alcohol is etilovym alcohol or cetostearyl alcohol. The amount of at least one aliphatic alcohol in the present oral dosage form is determined, inter alia, an exact rate of release of the opioid Oxymorphone. It also depends on whether present or absent, at least one polyalkyleneglycol in oral dosage form. In the absence of at least one polyalkyleneglycol oral dosage form preferably contains between 20 and 50% (by weight), the least one aliphatic alcohol. When at least one polyalkyleneglycol present in the oral dosage form, then the combined weight of at least one aliphatic alcohol and at least one polyalkyleneglycol is preferably between 20 and 50% (by weight) of the total dose.

In one embodiment is determined by the ratio, for example, at least one hydroxyethylcellulose or acrylic resin to the at least one aliphatic alcohol/polyalkyleneglycol as (m/m), preferred is a ratio of at least one hydroxyethylcellulose to at least one aliphatic alcohol/polyalkyleneglycol between 1:2 and 1:4, with a particularly preferred ratio of between 1:3 and 1:4.

At least one polyalkyleneglycol may be, for example, polypropylenglycol or preferably polyethylene glycol. The average molecular weight of at least one polyalkyleneglycol is preferably between 1000 and 15000, particularly between 1500 and 12000.

Other suitable matrix sustained release includes alkylsalicylate (especially ethylcellulose)12-C36aliphatic alcohol, and optionally polyalkyleneglycol.

In another preferred embodiment, the matrix includes pharmaceutically suitable combination, at the ore, two hydrophobic materials.

In addition to the above ingredients a slow-release matrix may also contain suitable quantities of other materials, e.g. diluents, lubricants, binding agents, means of granulation, coloring agents, flavoring substances and glidants customary in the pharmaceutical field.

The matrix particles.

To facilitate the preparation of a solid, sustained-release, oral dosage forms in accordance with this invention, can be used with any method of cooking recipes matrix, known to specialists in this field of technology. Embedding in the matrix may be, for example, by (a) forming granules comprising at least one water-soluble hydroxyethylcellulose and Oxymorphone hydrochloride, containing less than 10 hours/million alpha, beta unsaturated ketones; (b) mixing the granules containing hydroxyethylcellulose, with at least one12-C36aliphatic alcohol; and (C) optionally, compressing and shaping the granules. Preferably the granules form a wet granulation granules hydroxyethylcellulose with water.

In other alternative embodiments spheronizers agent together with the active component may be spheronization prior to the formation of spheroids. Microcrystalline C is llulose is preferred spheronizers agent. A suitable microcrystalline cellulose is, for example, the material sold as Avicel PH 101 (trademark of FMC Corporation). In such embodiments, in addition to the active ingredient and spheronizers agent, the spheroids may also contain a binding agent. Suitable binding agents, such as low-viscosity water-soluble polymers, well known to experts in the pharmaceutical field. However, preferred is a water-soluble hydrocellulose with a lower alkyl group, such as hydroxypropylcellulose. Additionally (or alternatively), the spheroids may also contain water-insoluble polymer, especially an acrylic polymer such as a copolymer of methacrylic acid - acrylate, or ethylcellulose. In such embodiments, the shell for slow release as a whole includes a hydrophobic material, such as (a) a wax, either alone or in a mixture with a fatty alcohol, or (b) shellac or Zein.

Matrix processed from the melt.

The slow release matrices can also be prepared by techniques from the melt granulation or extrusion from the melt. In General, methods of granulation of the melt include melting at the rate of solid hydrophobic material such as wax, and embedding it in a powdered medication. To obtain the dosage form with the replacement of the slow release may be necessary to incorporate additional hydrophobic substance, for example, ethylcellulose or water-insoluble acrylic polymer, in a molten waxy hydrophobic material. Examples of slow release formulations prepared using the techniques of granulation of the melt, are in US 4861598.

Additional hydrophobic material may include one or more water-insoluble wax-like thermoplastic substances, possibly mixed with one or more wax-like thermoplastic substance, less hydrophobic than the specified one or more water-insoluble wax-like substances. In order to achieve a constant release of individual wax-like compounds in the formulations should be essentially non-volatile and insoluble in gastric and intestinal juices during the phase of initial release. Suitable water-insoluble wax-like substances may be those whose solubility in water below about 1:5000 (m/m).

In addition to the above ingredients a slow-release matrix may also contain suitable quantities of other materials, e.g. diluents, lubricants, binding agents, granulating agents, colorants, flavors and glidants, conventional in the pharmaceutical art. The number of these additional materials should be sufficient to ensure that it is possible to effect the necessary recipes.

In addition to the above ingredients a slow-release matrix comprising microparticles processed from the melt may also contain suitable quantities of other materials, e.g. diluents, lubricants, binding agents, granulating agents, colorants, flavors and glidants customary in pharmaceutical technology, in amounts up to 50% by weight of the particles, if necessary.

Specific examples of pharmaceutically suitable carriers and excipients that may be used for forming the oral dosage forms are described in Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (1986).

Multicystic, processed from the melt.

Preparation of a suitable matrix processed from the melt, in accordance with the present invention may, for example, include the steps of mixing Oxymorphone hydrochloride containing less than 10 hours/million alpha, beta unsaturated ketones, together with at least one hydrophobic material and preferably additional hydrophobic material to obtain a homogeneous mixture. The homogeneous mixture is then heated to a temperature sufficient at least to soften the mixture, sufficient to extrusion. The obtained homogeneous mixture was then ekstragiruyut to the formation of the threads. The extrudate preferably a cooling gap is try and cut on multicystic by means known in the art. The filaments are cooled and cut on multicystic. Multicystic then divided into unit dosage. The extrudate preferably has a diameter from about 0.1 mm to about 5 mm and provides a slow release of therapeutically active agent over a period of time from about 8 hours to about 24 hours.

Additional preparation process of extrusion from the melt of the present invention includes a direct measurement in an extruder a hydrophobic material, Oxymorphone hydrochloride, containing less than 10 hours/million alpha, beta unsaturated ketones, and additional bonding agent; heating the homogenous mixture; extruding the homogeneous mixture with the formation of strands; cooling the strands containing the homogeneous mixture; cutting the strands into particles with a size from about 0.1 mm to about 12 mm, and the separation of these particles per unit dosage. This aspect of the invention is implemented relatively continuous production procedure.

The diameter of the hole or port of exit of the extruder can also be adjusted to vary the thickness of the extrudable threads. Further, the producing part of the extruder does not necessarily have to be circular; it may be oblong, rectangular, etc. Outgoing filament can be reduced to particles using a string-cut the forming machine with the heated wire, and guillotine shears, etc.

The system is extruded from a melt multicystic may be, for example, in the form of granules, spheroids or balls, depending on the discharge outlet of the extruder. For the purposes of the present invention the term "extrudable from a melt multicasting(s)" and "processed from the melt system(s) multicystic and processed from the melt particles" refer to multiple units, preferably within the range of similar size and/or shape that contains one or more active agents and one or more excipients, preferably including a hydrophobic material, as described herein. In this respect extrudable from a melt multicystic must be in the range from about 0.1 mm to about 12 mm in length and have a diameter from about 0.1 mm to about 5 mm, In addition, you need to understand that from the melt extrudable multicystic can be any geometrical shape within a given range of sizes. Alternative extrudate can be simply cut to length and divided into unit doses of a therapeutically active agent without the need of phase spheronization.

In one preferred embodiment of the oral dosage form is prepared to include an effective amount of extrudable from a melt multicystic in the capsule. For example, the centre is in the extrudable from a melt multicystic can be placed in a gelatin capsule in an amount sufficient to provide an effective dose of slow-release if swallowed and in contact with gastric juice.

In another preferred embodiment of a suitable number of die multicystic pressed into an oral tablet using conventional tabletiruemogo equipment using standard techniques. Specialists in the art there are known various methods and compositions for making tablets (compressed and molded), capsules (hard and soft gelatin) and pills.

In another preferred embodiment, the extrudate can be shaped into tablets as described in US 4957681.

If necessary, processed from the melt system multicystic or slow release tablets can be coated, or gelatin capsule, containing multicystic, may be additionally coated slow release, such as shell slow release described above. Such membranes preferably comprise a quantity of hydrophobic material, sufficient to obtain the level of added weight from about 2% to about 30%, although the outer covering, among other things, may largely depend on the required speed of release.

Processed from the melt dosage forms of the present invention may further is entrusted to include combinations of extrudable from the melt particles before encapsulation. Further, the unit dosage forms can also include the number of agent quick release for faster release. Agent quick release can be embedded, for example, in the form of separate globules within gelatin capsules, or it may be deposited on the surface of multicystic after preparation of dosage forms (e.g., shells, slow release, or on the basis of the matrix). Unit dosage forms of this invention may also contain a combination of semolina slow release and multicystic matrix to achieve the desired effect.

The slow release formulations of the present invention preferably slow release agent(s), e.g., when ingested and exposed to gastric juice, and then intestinal juice. Profile of sustained release formulations processed from the melt, can be changed, for example, by variation of the amount of retardant, i.e. hydrophobic material, by variation of the amount of plasticizer relative to hydrophobic material, by the inclusion of additional ingredients or excipients, by altering the method of manufacture, etc.

In other embodiments of the invention material, processed from the melt, prepared without the inclusion of Oxymorphone hydrochloride, containing less than 10 hours/million alpha, beta is easymenu ketones, which can be added to the extrudate later. Such formulations usually contain agents that are mixed together with the extruded matrix material, and then the mixture tabletirujut to ensure the formulation of slow release.

Shell.

Dosage forms of the present invention may optionally be coated with one or more material suitable for the regulation of the release or protection formulations. In one embodiment of the shell are provided to maintain or pH-dependent or pH-independent release. the pH-dependent membrane serves to release the active substance in the necessary areas of the gastro-intestinal (GI) tract, such as stomach or small intestine, which is the absorption profile, capable of providing at least eight hours, preferably from about twelve hours to about twenty-four hours of analgesia to the patient. When the desired pH-independent shell, shell design for optimal release regardless of changes in pH in the surrounding liquid, for example, the digestive tract. It is also possible to form compositions which release of the doses in one region of the gastrointestinal tract, for example in the stomach, releasing the remainder of the dose in another area of the gastrointestinal tract, for example in the small intestine.

Prescription what s in accordance with the invention, using pH-dependent membrane to obtain formulations, can also give the effect of repeated actions, when unprotected medicine is applied on top of enteric membranes and is released in the stomach, while the remainder, being protected enteric shell, subsequently released in the gastrointestinal tract. Shell, which is pH-dependent, which are assessed in accordance with the present invention include shellac, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, and methacrylic acid esters, Zein, and the like.

In certain preferred embodiments, the substrate (e.g., grist for the core tablets, the particle matrix)containing Oxymorphone hydrochloride with less than 10 hours/million alpha, beta unsaturated ketones, cover with a hydrophobic material selected from (i) alkylaryl; (ii) an acrylic polymer; or (iii) mixtures thereof. The shell can be applied in the form of organic or aqueous solution or dispersion. The shell can be applied to obtain a gain in weight from about 2% to about 25% of the substrate to obtain the desired slow release profile. Membranes obtained from aqueous dispersions, described in detail in US 5273760, US 5286493, US 5324351, US 5356467 and US 5472712.

The polymers alkylsalicylate.

Cellulosic material and a polymer, including alkylaryl provide hydrophobic materials, well suited for coating the shell crumbles in accordance with the invention. Just as an example, one preferred polymer alkylsalicylate is ethylcellulose, although manufacturers recognize that other polymers cellulose and/or alkylaryl can easily be used individually or in combination, as all or part of the hydrophobic membrane in accordance with the invention.

Acrylic polymers.

In other preferred embodiments of the present invention, the hydrophobic material comprising the shell of a slow-release, is pharmaceutically suitable acrylic polymer, including, without limitation, copolymers of acrylic acid and methacrylic acid, copolymers of methyl methacrylate, a copolymer of ethoxyethylacetate, cyanoacrylate, polyacrylic acid, polymethacrylic acid, methacrylic acid alkylamide, a copolymer of polymethyl methacrylate, polymethacrylate, polymethylmethacrylate, a copolymer of polyacrylamide, aminoalkylsilane, copolymers polyamidization acid and glycidylmethacrylate.

In specific preferred embodiments of the acrylic polymer includes one or more copolymers of ammoniojarosite. Copolymers of ammoniojarosite well known in this on the region of the equipment and described as fully polymerized copolymers of acrylic esters and methacrylic acid with a low content of Quaternary ammonium groups.

In order to obtain the desired dissolution profile, it may be necessary to incorporate two or more ammoniumnitrate copolymer having differing physical properties, such as different molar ratio of Quaternary ammonium groups to the neutral (meth)acrylic esters.

Certain polymers of the type of esters of methacrylic acid are suitable for the preparation of pH-dependent membrane, which can be used in accordance with the present invention. For example, there is a family of copolymers synthesized from diethylaminoethylmethacrylate and other neutral methacrylic esters, also known as methacrylic acid or polymeric methacrylates, commercially available as Eudragit™ from Rohm Tech, Inc. There are several different types of Eudragit™, for example Eudragit™ E is an example of a methacrylic acid copolymer, swelling and dissolving in the acidic environment. Eudragit™ L is a copolymer of methacrylic acid, not swelling around at pH<5.7 and is soluble at about pH>6. Eudragit™ S does not swell at about pH < 6.5 and is soluble at about pH>7. Eudragit™ RL and Eudragit™ RS are swellable in water, and the amount of water absorbed by these polymers is pH-dependent, however, dosage forms coated with Eudragit™ RL and RS, are pH-independent.

In certain preferred embodiment the s acrylic shell includes a mixture of two varnishes of acrylic resin, commercially available from Rohm Pharma under the trade names Eudragit™ RL30D and Eudragit™ RS30D, respectively. Eudragit™ RL30D and Eudragit™ RS30D are copolymers of acrylic and methacrylic esters with a low content of Quaternary ammonium groups, the molar ratio of ammonium groups to the remaining neutral (meth)acrylic esters is 1:20 in Eudragit™ RL30D and 1:40 in Eudragit™ RS30D. The average molecular weight is about 150,000. Code RL (high permeability) and RS (low permeability) refer to the properties of permeability data agents. A mixture of Eudragit™ RL/RS are insoluble in water and in digestive fluids. However, the shell formed from them, are swellable and permeable in aqueous solutions and digestive fluids.

Dispersion Eudragit™ RL/RS of the present invention can be mixed together in any desired ratio for the final receipt of slow release formulations with the desired dissolution profile. The required slow release formulations may be obtained, for example, of the protective sheath, derived from 100% Eudragit™ RL, 50% Eudragit™ RL and 50% Eudragit™ RS, and 10% Eudragit™ RL and 90% Eudragit™ RS. Of course, the specialist in the art will understand that can be applied to other acrylic polymers such as Eudragit™ L.

Plasticizers.

In embodiments of the present and the gain, in which the shell consists of an aqueous dispersion of hydrophobic material, the inclusion of an effective amount of plasticizer in the aqueous dispersion of hydrophobic material further improves the physical properties of membranes delayed release. For example, because ethylcellulose has a relatively high glass transition temperature and does not form flexible films under normal coating, it is preferable to incorporate a plasticizer in the membrane of a slow-release, containing ethylcellulose floor, before it is used as a sheath material. In General, the amount of plasticizer included in the covering solution, based on the concentration of the foaming agent, for example, most often from about 1 wt.% to about 50 wt.% the foaming agent. The concentration of the plasticizer, however, can be properly determined only after careful experimentation with concrete covering solution and method of application.

Examples of suitable plasticizers for ethyl cellulose include water insoluble plasticizers such as dibutylsebacate, diethylphthalate, triethylcitrate, tributyltin and triacetin, although it is possible that can be applied to other water-insoluble plasticizers (such as acetylated monoglycerides, Calatafimi, castor oil is so). Triethylcitrate is particularly preferred plasticizer for aqueous dispersions of ethyl cellulose of the present invention.

Examples of suitable plasticizers for the acrylic polymers of the present invention include without limitation, esters of citric acid such as triethylcitrate, tributyltin, dibutyl phthalate, and possibly 1,2-propylene glycol. It is proved that other plasticizers are suitable for enhancing the elasticity of the films formed from acrylic films such as solutions varnishes Eudragit™ RL/RS, including glycols, propylene glycol, diethylphthalate, castor oil, and triacetin. Triethylcitrate is particularly preferred plasticizer for aqueous dispersions of ethyl cellulose of the present invention.

The addition of small amounts of talc can also help to reduce the tendency to stick together water dispersion during processing, and talc can act as a polishing agent.

Osmotic dosage form is a delayed release.

Dosage form is a delayed release in accordance with the present invention can also be prepared in the form of osmotic drug formulations. Osmotic dosage forms preferably include a two-layer core comprising a layer of drug-containing Oxymorphone hydrochloride with less than 10 hours/ml is. alpha, beta unsaturated ketones) and deliver or push layer in which a two-layer core surrounded by a semipermeable wall and optionally has at least one passage located therein.

The expression "passageway"as used for purposes of the present invention, includes aperture, orifice, channel, pore, porous element through which Oxymorphone hydrochloride, containing less than 10 hours/million alpha, beta unsaturated ketones, can be delivered, to diffuse or migrate through the fiber, capillary tube, porous overlay, porous insert, microporous member or porous composition. The passage may also include a connection that erodes the wall or washed out from the wall in a liquid environment, for use in obtaining at least one passage. Exemplary compounds for the formation of passage include undergoing erosion polyglycolic acid or polylactic acid in the wall; a gelatinous filament, remove water polyvinyl alcohol; discharge connection, such as a disposable liquid pore-forming polysaccharides, acid, salts or oxides. The passage can be formed by leaching from the wall compounds, such as sorbitol, sucrose, lactose, maltose or fructose, to the formation of the spatial time - pass slow release. Dosed the Orme can be made with one or more passages, located separately in relation to one or more surfaces of the dosage form. Aisles and equipment for education pass disclosed in US 3845770, US 3916899, US 4063064 and US 4088864. Passages, including sizes for slow release, made in size, shaped and adapted as releasing pores formed by aqueous leaching to ensure cleans pores with a slow release, are disclosed in US 4200098 and US 4285987.

In specific embodiments, the layer medicines may also include at least one polymer hydrogel. Polymer hydrogel can have an average molecular weight between about 500 and about 6000000. Examples of polymeric hydrogels include, without limitation maltodextrin polymer comprising the formula (C6H12O5)nH2Oh, in which n is from 3 to 7500, and maltodextrin polymer comprises an average molecular weight of from 500 to 1250000; polyalkylene oxide represented, for example, polyethylene oxide and polypropylene oxide having an average molecular weight of from 50,000 to 750,000 people, and more specifically represented by poly(ethylene oxide) with an average molecular weight of at least 100000, 200000, 300000, or 400000; alkaline karboksimetilcelljulozojj, in which the alkali is sodium or potassium alkyl is stands, ethyl, propylene or b is tilam with an average molecular weight from 10,000 to 175000; and copolymer ethylenically acid, including methacrylic and ethacrylate acid with an average molecular weight from 10,000 to 500,000.

In specific embodiments of the present invention deliver or push layer includes osmopolitan. Examples of osmopolitan include, without limitation element selected from the group consisting of polyalkyleneglycol and karboksimetsiltsellyulozy. Polyalkylene oxide has an average molecular weight of from 1000000 to 10000000. Polyalkylene oxide may be an element selected from the group consisting of polyethylenoxide, polyethylene oxide, polypropyleneoxide, polyethylene oxide having an average molecular weight of 1000000, polyethylene oxide having an average molecular weight of 5000000, polyethylene oxide having an average molecular weight of 7000000, cross-linked polyethylenoxide having an average molecular weight of 1000000, and polypropyleneoxide having an average molecular weight 1200000. Typical cosmopolitan karboksimetilcelljuloza includes an element selected from the group consisting of alkaline karboksimetsiltsellyulozy, sodium carboxymethylcellulose, potassium carboxymethylcellulose, sodium karboksimetilcelljulozy, lithium carboxymethylcellulose, sodium karboksimetilcelljulozy, carboxylmethylcellulose, karboksimetiltselljulozy, karboksimetsiltsellyulozy karboksimetiltselljulozy. Osmopolitan used for the replacement layer, create an osmotic pressure gradient across semipermeable wall. Osmopolitan absorb the liquid in the dosage form, thus swelling and expanding as osmotic hydrogel (also known as smogeli), while pushing Oxymorphone hydrochloride, containing less than 10 hours/million alpha, beta unsaturated ketones of the osmotic dosage form.

Eject layer may also include one or more effective compounds, also known as emagency and as osmotically effective solute. They absorb the surrounding liquid, for example, from the gastrointestinal tract in the medical form and contribute to the kinetics of delivery of transporting layer. Examples of osmotically active compounds include an element selected from the group consisting of salts and osmotic osmotic carbohydrates. Examples of specific asmagenta include without limitation sodium chloride, potassium chloride, magnesium sulfate, lithium phosphate, lithium chloride, sodium phosphate, potassium sulfate, sodium sulfate, potassium phosphate, glucose, fructose and maltose.

Eject layer may optionally include hydroxypropylmethylcellulose having an average molecular weight of from 9,000 to 450000. Hydroxypropylmethylcellulose represented by element selected from the group, with Toyama from hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose and hydroxypropylmethylcellulose.

Eject the additional layer may include a non-toxic pigment or dye. Examples of pigments or dyes include, without limitation dyes for use in the food and drugs (FD&C), such as FD&C No. 1 blue dye, FD&C No. 4 red dye, red iron oxide, yellow iron oxide, titanium dioxide, carbon black and Indigo.

Eject layer may also include an antioxidant to inhibit oxidation of the ingredients. Some examples of antioxidants include, without limitation element selected from the group consisting of ascorbic acid, ascorbyl palmitate, butylated of hydroxyanisole, a mixture of 2 - and 3-tert-butyl-4-hydroxyanisole, bottled hydroxytoluene, sodium isoascorbate, dihydroguaiaretic acid, potassium sorbate, sodium bisulfate, sodium metabisulfate, sorbic acid, potassium ascorbate, vitamin E, 4-chloro-2,6-di-tert-butylphenol, alpha-tocopherol and propylgallate.

In a particular alternative embodiment of the dosage form includes a homogeneous core, including Oxymorphone hydrochloride, containing less than 10 4,/million alpha, beta unsaturated ketones, pharmaceutical is suitable polymer (e.g., polyethylene oxide), advanced disintegrant (e.g., polyvinylpyrrolidone), advanced power absorption (e.g., fatty acid, surfactant, chelating agent, a bile salt, and so on). Homogeneous core surrounded by a semipermeable wall having a passage (as defined above) to release Oxymorphone hydrochloride containing less than 10 hours/million alpha, beta unsaturated ketones.

In specific embodiments of the semipermeable wall comprises an element selected from the group consisting of a polymer of ester of cellulose, a polymer of the cellulose ether and the polymer of ester - ether of cellulose. Exemplary polymers walls include an element selected from the group consisting of cellulose of Atzilut, pulp of diallate, pulp of triacetate, cellulose acetate, cellulose diacetate, cellulose triacetate, mono-, di - and tritelluride altenrative, and mono-, di - and tritelluride alkylates. Poly(cellulose)used in the present invention, includes average molecular weight of from 20,000 to 7500000.

Additional semipermeable polymers for the purpose of the present invention include acetylcholinesterase acetate, ethylcarbamate cellulose acetate, methylcarbamate cellulose acetate, propellernet cellulose diacetate, diethylaminoacetate cellulose acetate; semipermeable polyamide; semipermeable polyurethanes; of polypr nicely from sulphonated polystyrene; semipermeable cross-linked polymer formed by simultaneous deposition of polyanion and polycation, a semi-permeable cross-stitched polystyrene, semipermeable cross-linked poly(sodium steren sulfonate), semipermeable cross-linked poly(wikiversitymainpage chloride) and semipermeable polymers having moisture permeability from 2.5×10-8up to 2.5×10-2(cm2/h·ATM)expressed per atmosphere of the difference of hydrostatic or osmotic pressure across the semipermeable wall. Other polymers suitable in the present invention, are known in the art, including as described in Handbook of Common Polymers, Scott, J.R. and W.J.Roff, 1971, CRC Press, Cleveland, Ohio.

In specific embodiments of the semi-permeable wall is preferably non-toxic, inert and maintains its physical and chemical integrity during the time of release of the drug. In specific embodiments of the dosage form comprises a binding agent. An example of a coupling agent includes, without limitation therapeutically suitable vinyl polymer having an average viscosity molecular weight of from 5,000 to 350,000, represented by element selected from the group consisting of copolymers of poly-n-vinylamide, poly-n-vinylacetate, poly(vinylpyrrolidone), also known as poly-n-vinylpyrrole icon, poly-n-vinylcaprolactam, poly-n-vinyl-5-methyl-2-pyrrolidone, and poly-n-vinyl-pyrrolidone with an element selected from the group consisting of vinyl acetate, vinyl alcohol, vinyl chloride, winifrida, vinylboronate, vanillaware and ministereth. Other binding agents include, for example, gum Arabic, starch, gelatin and hydroxypropylmethylcellulose with an average molecular weight from 9200 to 250,000.

In specific embodiments of the dosage form includes a lubricant that can be used in the manufacture of the dosage form to prevent sticking to the wall of the matrix or the surface of the stamp. Examples of lubricants include, without limitation, magnesium stearate, sodium stearate, stearic acid, calcium stearate, magnesium oleate, oleic acid, potassium oleate, Caprylic acid, sodium stearyl fumarate and magnesium palmitate.

In specific preferred embodiments of the present invention includes a therapeutic composition comprising an amount of Oxymorphone hydrochloride, containing less than 10 hours/million alpha, beta unsaturated ketones, equivalent to 10-40 mg Oxymorphone hydrochloride, 25 mg to 500 mg of poly(accelerated)having an average molecular weight of 150,000 to 500,000, 1 mg-50 mg of polyvinylpyrrolidone having an average molecular weight of 40,000, and from 0 mg to about 7.5 mg of a lubricant.

Suppositories.

Rotz the tours sustained release of the present invention can be formed in the form of a pharmaceutical suppository for rectal application, including a suitable suppository base and Oxymorphone hydrochloride, containing less than 10 hours/million alpha, beta unsaturated ketones. Preparation of formulations of sustained-release suppositories are described, for example, in US 5215758.

Before the absorption of the drug must be in solution. In the case of suppositories solution must be preceded by the dissolution basis of suppository or melting of the substrate and subsequent separation of the drug from the base of the suppository in the rectal fluid. Absorption of drugs in the body can be changed by the base of the suppository. Thus, the specific basis of the suppository for use in connection with a particular drug should be chosen with consideration of the physical properties of drugs. For example, soluble in lipids drugs do not separate quickly in rectal fluid, but drugs are only slightly soluble in lipid basis, quickly separated in the rectal fluid.

Among the various factors influencing the time of dissolution (or the rate of release) drugs are the surface area of the drug substance, presented in a solvent medium, the pH of the solution, the solubility of the substance in the specific environment of the solvent, and the driving force saturating concentrations of dissolved materials in the solvent environment. In General, the factors affecting the absorption of drugs from the suppository is, used rectally include solvent suppository, the pH at the site of absorption, the pKa of the drug, the degree of ionization and solubility in lipids.

The selected basis of the suppository should be compatible with the active substance of the present invention. Further, the base of the suppository is preferably non-toxic and does not irritate the mucous membranes, melt or dissolve in the rectal fluids and stable during storage.

In specific preferred embodiments of the present invention for water-soluble and water-insoluble drugs, the basis of the suppository comprises a wax, a fatty acid selected from the group consisting of mono-, di - and triglycerides of saturated natural fatty acids with a chain length of C12-C18.

In the preparation of suppositories of the present invention can be applied to other fillers. For example, the wax can be applied to create the proper form for use rectal way. This system can also be used without wax, but with the addition of a diluent, filled in a gelatin capsule for rectal and oral administration.

Examples of suitable commercially available mono-, di - and triglycerides include saturated natural fatty acids with a chain of 12 to 18 carbon atoms, supplied under the trade name Novata™ (types AB, AB, is, BC, BD, AF, E, BCF, C, D and 299), produced by Henkel, and Witepsol™ (type H5, H12. N, n, H1 85, n, N, N, N, N, W25, W31, W35, W45, S55, S58, E75, E and E85), produced by Dynamit Nobel.

Other pharmaceutically suitable bases for suppositories can be substituted in whole or in part the above-mentioned mono-, di - and triglycerides. The number of bases in suppositories is determined by the size (i.e. the actual weight of the dosage form, the amount of base (e.g., alginate) and applied medicine. In General, the amount of the suppository ranges from about 20% to about 90% by weight of the total weight of the suppository. Preferably the amount of suppository in suppositories is from about 65% to about 80% by weight of the total weight of the suppository.

Additional embodiments.

Oxymorphone hydrochloride, containing less than 10 hours/million alpha, beta unsaturated ketones, can be used as a substitute Oxymorphone hydrochloride in any existing commercial product, such as Orapa™, Orapa ER™ and Numorphan™. Such formulations are listed in the FDA Orange Book.

The invention is further illustrated by the following examples showing the synthesis of high-purity Oxymorphone from oripavine, and the accompanying drawing, which is a sample of x-ray powder diffraction collected for the hydrogenated product Oxymorphone guy is rochloride, manufactured in accordance with example 3.2D.

Example 1.1A

Hydroxylation oripavine to 14-hydroxymorphinone

1 kg oripavine was added under stirring vessel for the reaction containing 2.76 kg of formic acid and 0.53 kg of water, and continue stirring until complete dissolution oripavine, and the temperature was maintained in the range of 20-30°C. was Then added to 0.36 kg 35 wt.% the hydrogen peroxide solution and stirred the reaction mixture for three hours or more, keeping the temperature in the range of 20-35°C. the Vessel for the reaction was cooled to 10°C and slowly added 7,12 liters of dilute ammonium hydroxide, maintaining the temperature of the reaction mixture below 40°C. If necessary, the pH of the reaction mixture was brought to between 8-10 appropriate a more dilute solution of ammonium hydroxide or hydrochloric acid and continued the stirring for 3-5 hours.

The precipitate product 14-hydroxymorphinan was separated by filtration. The precipitate was washed with water until a colorless state, and then dried to a damp condition and collected for the next step.

Example V

The education Foundation of Oxymorphone

In the vessel for hydrogenation was placed 1 liter of water and 0.73 kg of acetic acid before adding 1 kg 14-hydroxymorphinone, prepared as in example 1.1A, and stirred the mixture to a transparent state. 40 is wet 10% Pd catalyst on coal was added under a stream of nitrogen and were served with hydrogen at 35-40 F./psig (2,41 was 2.76 bar). The temperature was maintained at 30±5°C until cessation of hydrogen, then the vessel supported 35-40 F./psig (2,41 was 2.76 bar) and 30±5°C for 3-4 hours. The vessel for the reaction was cooled to temperature below 25°C and the sample was subjected to analysis by HPLC to check for 14 hydroxymorphinan. If the area 14 of hydroxymorphinone detected by HPLC, was >0.1%, the hydrogenation was repeated.

Once it was established that the reaction is complete, the catalyst was separated by filtration, the pH of the filtrate is brought to pH 9 with ammonium hydroxide solution, the product was besieged, was separated by filtration and dried under vacuum. The product was dissolved in dichloromethane/methanol (9:1/o/o) and suspended in Florisil, filtered, and the filtrate was subjected to distillation to be exchanged for n-propanol. A mixture of n-propanol was cooled, and the product was besieged and was collected by filtration with a 66% yield. A sample of the product was analyzed by HPLC on an alpha, beta unsaturated ketones, and found that it contains 0,51% in the measurement space.

Example S

The formation of high-purity Oxymorphone hydrochloride

In the vessel for the reaction was placed 1 kg of base Oxymorphone, prepared as in example 1.1, with 2,05 kg absolute alcohol and 0,66 kg of water. The mixture was heated to 60±2°C and stirred until the formation of the suspension. To the suspension base Oxymorphone obavljale solution of hydrochloric acid, made from 0,66 kg of concentrated hydrochloric acid, 0.24 kg of water and 0.31 kg of absolute alcohol, and check the pH to ensure that it is <1.0 in. 40 g water-wetted paste 10% Pd catalyst on coal was added in a stream of nitrogen into the reaction mixture and the mixture was first made at 35±5 f./psig (2,41 bar) for 20 hours, maintaining a temperature of 65±3°C. the Reaction mixture was filtered while hot through celite and 0.2 µm glossy filter. The filtrate was cooled to 0-5°C for 2-3 hours and stirred for another 2 hours before the sediment of Oxymorphone hydrochloride. The precipitate was washed with absolute alcohol and dried. The yield was 80%.

A sample of the product was analyzed by HPLC on an alpha, beta unsaturated ketones, and found that it contains a 6.2 hours/million

Example 1.2A

Hydroxylation oripavine to 14-hydroxymorphinone

40 g oripavine was added under stirring vessel for the reaction containing 30 g of water and 85 g of formic acid, and continued stirring until complete dissolution oripavine. The temperature remained in the range of 20-30°C. was Further added 17,72 g of 30 wt.% the hydrogen peroxide solution, and stirred the reaction mixture for three hours and more, maintaining a temperature in the range of 20-35°C. the Reaction mixture was cooled to <20°C and slowly added 335 ml of dilute ammonium hydroxide, TF is Riva the temperature of the reaction mixture below 32°C. If necessary, brought the pH of the reaction mixture to 9.0 by adding more dilute solution of ammonium hydroxide or hydrochloric acid are added and continued stirring for 2 hours at 20°C and 2 hours at 4-5°C.

Sediment 14-hydroxymorphinone formed and was separated by filtration. The precipitate was washed with water, dried to a damp condition and collected for the next step.

Example 1.2V

The education Foundation of Oxymorphone

In the vessel for hydrogenation contributed 148 g of water, of 90.6 g of acetic acid and 250 g wet 14-hydroxymorphinone (water content 48%), prepared as in example 1.2A. The mixture was stirred until a transparent state, and then added to 1.34 g of 10% Pd catalyst on coal (dry weight) in the form of pasta under a stream of nitrogen. Vessel for hydrogenation was purged with nitrogen and hydrogen, respectively, and then was first made of the reaction mixture at 30°C and 35 f./psig (2,41 bar) for 5 hours. Analysis in the process of getting through HPLC showed the area of the 14-hydroxymorphinone of 0.07%.

Once it was established that the reaction is complete, the catalyst was separated by filtration over a substrate Celica and a layer of celite washed with 25 ml water. The filtrate was cooled 0-5°C and brought the pH up to 9.5±0.5 s 1:1 mixture (o/o) of concentrated ammonium hydroxide and water. The precipitate was stirred at 0-5°C for one hour and was separated by filtration. The crude product Visu ivali in a vacuum oven at 50°C to obtain 113 g (86,9% yield) of a light beige solid. A sample of the product was analyzed by HPLC on an alpha, beta unsaturated ketones, and found that it contains a 0.27% area measurement.

113 g of the crude base Oxymorphone contributed 1.13 l of dichloromethane/methanol (9:1, o/o). To the solution was added 113 g of Florisil and the mixture was stirred for 12 hours. The mixture was filtered through a layer of 113 g of Florisil and a layer of Florisil washed with 120 ml of dichloromethane/methanol. The solvent was removed by distillation, and then was replaced with n-propanol. The mixture was cooled to 0-5°C. and was stirred for 1 hour to precipitate the base of Oxymorphone, which was separated by filtration, washed with cold n-propanol and dried in a vacuum oven to obtain and 67.2 g (59,47%) of a white solid.

A sample of the product was analyzed by HPLC on an alpha, beta unsaturated ketones, it was found that he 0,027% according to the results of the measurement space.

Example S

The formation of high-purity Oxymorphone hydrochloride

In the vessel to the reaction was added to 50.1 g base Oxymorphone, prepared as in example 1.2, together with 120 g of absolute alcohol. The mixture was heated to 60±2°C and stirred until the formation of the suspension. The hydrochloric acid solution prepared from the 32.7 g of concentrated hydrochloric acid and 33.6 g of water, was added to the suspension base Oxymorphone, checked the pH to make sure what it is <1.0 in. To the reaction mixture were added 2.0 g water-wetted paste 10% Pd catalyst on the corner under a stream of nitrogen and the reaction mixture was first made at 35 F./psig (2,41 bar) for 20 hours, maintaining a temperature of 65°C. the Reaction mixture was filtered while hot through celite. The filtrate was cooled to 0-5°C for 2-3 hours and stirred for another 2 hours before the sediment of Oxymorphone hydrochloride. The precipitate was separated by filtration, washed with absolute alcohol, and then dried to obtain white crystals with 77% yield.

A sample of the product was analyzed by HPLC on an alpha, beta unsaturated ketones, it was found that it contains 1.1 hours/million

The above method can be modified by the person skilled in the technical field with excellent purity product Oxymorphone hydrochloride, and examples of such variations are shown below.

Example 2.1V

The recovery of 14-hydroxymorphinone to the base of Oxymorphone

In the vessel for hydrogenation contributed 2.5 kg of water, 0,73 kg of acetic acid and 1 kg 14-hydroxymorphinone. The reaction mixture was stirred to obtain a clear solution, was then added 40 g of wet 10% Pd catalyst on the corner under a stream of nitrogen. Hydrogen was applied under pressure 35-40 F./psig (2,41 was 2.76 bar). The temperature was maintained at 30±5°C until cessation of hydrogen, then SOS is d maintained at 35-40 F./psig (2,41 was 2.76 bar) and 30±5°C for 3-4 hours. The vessel for the reaction was cooled to temperature below 25°C, and the sample was subjected to HPLC analysis on 14 hydroxymorphinan. If the area 14 of hydroxymorphinone identified by HPLC, was >0.1%, the hydrogenation was repeated.

Once it was established that the reaction is complete, the catalyst was removed by filtration, to the filtrate was added a dichloromethane/methanol (9:1 o/o) and brought the pH of the mixture to 9-10 by adding ammonium hydroxide solution. Phase dichloromethane/methanol was separated, suspended with Florisil, filtered, and the filtrate was subjected to distillation to be replaced by n-propanol. A mixture of n-propanol was cooled, and the product was besieged and was collected by filtration with 73% yield. A sample of the product was analyzed by HPLC on an alpha, beta unsaturated ketones, and found that it contains 0,32% by area.

Example V

The recovery of 14-hydroxymorphinone to the base of Oxymorphone

In the vessel for hydrogenation contributed 35 g of water, 17 g of acetic acid and 38,08 g 14-hydroxymorphinone, prepared as in example 1.2A. The reaction mixture was stirred until a clear solution, and then added 1.8 g of wet 5% Pd catalyst on the corner under a stream of nitrogen. Hydrogen was applied under pressure 35-40 F./psig (2,41 was 2.76 bar). Maintained a temperature of 30±5°C until cessation of hydrogen, and then the vessel was maintained at 35-40 F./psig (2,41 was 2.76 bar) and 3±5°C for 4 hours. The vessel for the reaction was cooled to temperature below 25°C and analyzed the sample by HPLC to check for 14 hydroxymorphinan. Area 14-hydroxymorphinone identified by HPLC was 0.26%.

Once it was established that the reaction is complete, the catalyst was separated by filtration and the layer washed with 15 ml of water. To the filtrate was added 180 ml of dichloromethane/methanol (9:1, o/o), and the pH of the mixture was brought to pH 9-10 by the addition of concentrated ammonium hydroxide. Layer dichloromethane/methanol was separated and purified by creating a slurry with about 20 g of Florisil. The suspension was filtered, and the filtrate was subjected to distillation to be replaced by n-propanol, cooled the mixture to 0-5°C. and was stirred for 1-2 hours prior to the deposition of the base Oxymorphone, which was separated by filtration. The basis of Oxymorphone then suspended from n-propanol, receiving product from 74% yield. A sample of the product was analyzed by HPLC on an alpha, beta unsaturated ketones, it was found that it contains 0,32% by area.

Example S

The formation of high-purity Oxymorphone hydrochloride

In the vessel to the reaction was added 2.5 g of base Oxymorphone, prepared as in example 2.2, together with 7.5 ml of absolute alcohol, 2.5 g of water and 1.66 g of concentrated hydrochloric acid. The mixture was heated to 50-60°C and received the solution. Checked pH, th is would be sure what it is <1.0 in. In the reaction mixture was added 0,111 g water-wetted paste 10% Pd catalyst on the corner under a stream of nitrogen, and the mixture was first made at 35±5 f./psig (2,41 bar) for 21 hours, maintaining a temperature of 65±3°C. the Reaction mixture was filtered while hot through a 0.45 µm filter. The filtrate was cooled to 0-5°C for 2-3 hours and stirred for another 2 hours before the sediment of Oxymorphone hydrochloride. The precipitate was separated by filtration, washed with cold absolute alcohol, and dried under vacuum to obtain white crystals with 77% yield.

A sample of the product was analyzed by HPLC for the presence of alpha, beta unsaturated ketones, it was found that it contains a 2.8 hours/million

Example V

The recovery of 14-hydroxymorphinone to Oxymorphone hydrochloride

The procedure of formation of the free base of Oxymorphone was, as shown above, but instead allocate the free base from a solution of dichloromethane/methanol was added to 0.35 volumetric equivalents of 3 N. hydrochloric acid (against volume of a solution of dichloromethane/methanol), the reaction mixture was stirred, stood and the aqueous layer (containing the product) was separated from the organic layer. The aqueous layer was subjected to distillation under vacuum to remove about 35% of the volume, and then the remaining solution was cooled for 2 hours to 20-25°C.,was stirred for 1-2 hours, was cooled to 0-5°C and stirred for 2-3 hours. White solid formed during the mixing process was separated by filtration and washed with cold isopropanol. The yield was 64%, and the product contained 0,34% alpha, beta unsaturated ketones.

Example S

Cleaning Oxymorphone hydrochloride

Using a process analogous to example 1.1, but starting from the product from example 3.1, got purified Oxymorphone hydrochloride with a yield of 92%, with no detectable alpha, beta unsaturated ketones.

Example 3.2S

Preparation of high-purity Oxymorphone hydrochloride

In the vessel to the reaction was added of 5.05 g of Oxymorphone hydrochloride prepared in example 3.1, together with 13.5 ml of absolute ethanol, and 4.5 ml of water and 1.51 g of concentrated hydrochloric acid. The mixture was heated to 50-60°C and received the solution. Checked the pH to ensure it is below 1.0. In the reaction mixture was added 0.21 g water-wetted paste 10% Pd catalyst on the corner under a stream of nitrogen and the reaction mixture was first made at 35±5 f./psig (2,41 bar) for 20 hours, maintaining a temperature of 65±3°C. the Reaction mixture was filtered while hot through a 0.45 µm filter. The filtrate was cooled to 0-5°C for 2-3 hours and stirred for another 2 hours before the sediment. The precipitate was collected by filtration, washed with cold absolute ethanol, then dried. In the course amounted to 92%.

A sample of the product was analyzed by HPLC, and found that it has not defined the content of alpha, beta unsaturated ketones.

Without changing the basic stages of the process, but with a slight variation of the process to raw materials, such as allocation or no allocation of such source materials, and using the basic recovery requirements of the invention for the final stage for purified Oxymorphone hydrochloride were obtained other products with levels of alpha, beta unsaturated ketones of 3.8 hours/million, a 1.7 hours/million, or 6.2 hours/million and 6.9 hours/million, or 2.8 hours/million, a 3.1 hours/million, and 0.9 hours/million, 6,0 hours/million and other non-detectable or zero levels.

Example 3.2D

Hydrogenation of Oxymorphone hydrochloride

In the cuvette for drying was added Oxymorphone hydrochloride, prepared as in example C, S, S, S or 3.2S, containing approximately 5-13 wt.% of ethanol. The sample was placed in a vacuum furnace with a cuvette containing 100 ml of water. Filed vacuum 24-29 mm Hg and an oven maintained at 20-40°C for 24 hours. Received the product free of ethanol or with low ethanol content (around 0.04 wt.%), containing approximately 10-13 wt.% water. The water absorbed by the sample can be removed in a vacuum oven at 50-55°C. the drying Process was stopped when the water content of the product by the method of Karl the Fisher was 6-8 wt.%. The final hydrogenated to Oxymorphone hydrochloride was homogeneous polymorph with the regular nature of x-ray diffraction.

1. Product Oxymorphone hydrochloride having analgesic activity, containing less than 10 hours/million alpha, beta unsaturated ketones according to the HPLC data.

2. The product according to claim 1, in which the alpha, beta unsaturated ketones less than 5 hours/million

3. The product according to claim 1 or 2, in which the ketones include 14 hydroxymorphinan.

4. The product according to claim 1 for use as an analgesic.

5. Pharmaceutical formulation comprising at least one pharmaceutically suitable excipient and product Oxymorphone hydrochloride according to any one of claims 1 to 3.

6. The purification method of Oxymorphone hydrochloride to obtain a product according to claims 1, 2 or 3, including the restoration of the original material Oxymorphone hydrochloride in strongly acidic aqueous or alcoholic reaction medium, with the use of gaseous hydrogen at a temperature in the range from 60 to 70°C.

7. The method according to claim 6, in which the recovery can be performed during a period of at least 20 hours

8. The method according to claim 6 or 7, in which the recovery is carried out in the period from 1 to 20 hours

9. The method according to claim 6, in which the reaction medium has a pH less than 1.

10. The method according to claim 6, in which the acid is hydrochloric acid.

11. The method according to claim 6, in which the tempo is the atur is about 65°C.

12. The method according to claim 6, in which the source material Oxymorphone hydrochloride is not isolated from the reaction mixture in which it was founded.

13. The method according to item 12, in which the source material Oxymorphone hydrochloride is obtained by heating the free base Oxymorphone in the presence of hydrochloric acid and in spirit/water reaction medium.

14. The method according to claim 6, in which the source material Oxymorphone hydrochloride is prepared with the help of the recovery process 14-hydroxymorphinone.

15. The method according to 14, in which the source material 14 hydroxymorphinan prepared using the process of hydroxylation oripavine.

16. The method according to item 15, in which the source material oripavine is obtained from the concentrated poppy straw.

17. The method according to clause 16, in which a concentrated poppy straw produced from poppy varieties with a high content of thebaine.

18. A method of obtaining a hydrogenated product Oxymorphone hydrochloride, including cleaning Oxymorphone hydrochloride to obtain a product according to claims 1-3 and the stage of removal of the molecules of the residual alcohol from the crystal structure of Oxymorphone hydrochloride by drying Oxymorphone hydrochloride in the presence of water vapor, so that the residual molecules of alcohol are replaced by water molecules.

19. The method according to p, in which the residual molecules of the alcohol is removed by vacuum hydrogenation of oxymor what she hydrochloride, in which the residual molecules of alcohol are replaced by water molecules.

20. The method according to p or 19, comprising the additional step of removing some of the water molecules from the crystal structure of Oxymorphone hydrochloride by heating Oxymorphone hydrochloride in vacuum to a temperature in the range from 50 to 55°C.

21. Hydrogenated product Oxymorphone hydrochloride produced by the method according to PP, 19 or 20, containing less than 10 hours/million, according to HPLC, the alpha, beta unsaturated ketones, and water according to Karl Fischer method 6-8 wt.%.

22. Hydrogenated product Oxymorphone hydrochloride produced by the method according to PP, 19 or 20, containing less than 10 hours/million, according to HPLC, the alpha, beta unsaturated ketones, and having peaks within the next 20 ranges in the analysis of powder x-ray diffraction: 8.5-9.5, 11.0-12.0, 11.5-12.5, 12.4-13.4, 15.2-16.2, 17.6-18.6, 19.3-20.3, 19.9-20.9, 24.6-25.6, 24.9-25.9, 29.0-30.0 and 31.0-32.0.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compound of general formula (I): , where R1 and R2, each independently, represent hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted cycloalkyl, optionally substituted aryl, etc., R3 represents hydrogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkinyl, optionally substituted lower alkoxy, etc, R4 represents hydrogen or lower alkyl, R5 represents hydrogen, lower alkyl, cycloalkyl-lower alkyl or lower alkenyl, or its pharmaceutically acceptable salt or solvate.

EFFECT: obtaining pharmaceutical composition for treatment and/or prevention of nausea, vomiting and/or constipation.

13 cl, 68 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of purifying plant extracts which mainly consist of noroxymorphone compounds and contain α,β-unsaturated noroxymorphone compounds as impurities, through (a) conversion of a plant extract or product of the next step in synthesis of the selected noroxymorphone compound as a result of conversion of hydroxyl groups present in the mixture to groups of formula -OR2 which can be split, in which R2 is an introduced radical of the said group which can be split, (b) said groups, if necessary, can be removed once more, after which (c) the obtained mixture is subjected to selective hydrogenation so that a saturated bond forms in the α,β-position of unsaturated noroxymorphone compounds and all the remaining groups which can be split are converted to a hydroxyl group, after which (d) a pure noroxymorphone compound is extracted; processing the purified noroxymorphone to naltrexone or naloxone or a salt of these compounds or a quaternary derivative of these compounds, which are known pharmaceutically active compounds particularly used for reducing psychological dependency and during drug abuse.

EFFECT: improved purification of compounds.

21 cl, 8 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furyl)acrylamido]morphinan hydrochloride having sustained quality of production and high purity. Crystalline forms of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furyl)acrylamido]morphinan hydrochloride are proposed, including A-forms, B-forms or C-forms, and method of producing said forms.

EFFECT: obtaining compounds which have analgesic, diuretic and antipruritic effect.

10 cl, 8 dwg, 2 tbl, 8 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new 6-amino-morphinane derivatives of formula I wherein meanings of R1-R4 and X are as defined in specification; composition based on the same having analgesic action, and uses thereof as high active analgesics.

EFFECT: new high active analgesics.

9 cl, 4 tbl, 5 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to compounds, namely, to derivative of 14-hydrxoynormorphinone of the formula (IV) , derivative of morphinone of the formula (III) , derivative of morphine of the formula (II) wherein R1 represents (C1-C7)-alkyl; R2 represents benzyl or benzyl substituted with one or some (C1-C6)-alkoxy-groups, or benzyl substituted with one or some halogen atom. Also, invention relates to a method for synthesis of derivative of 14-hydroxynormorphinone of the formula (IV) involving interaction of compound of the formula (III) with cobalt (II) as oxidant in the presence of a weak base and air or oxygen as co-oxidant. Also, invention relates to a method for synthesis of derivative of morphinone of the formula (III) involving interaction of derivative of morphine of the formula (II) with oxidizing agent that is effective in oxidation of allyl hydroxy-groups. Mainly, invention relates to a method for synthesis of noroxymorphone. The process involves oxidation of derivative of morphinone of the formula (III) to derivative of 14-hydroxynormorphinone of the formula (IV), removal of protection from 3-position and reduction of double bond at 7,8-position in derivative of 14-hydroxynormorphinone of the formula (IV) to yield derivative of 3,14-hydroxynormorphinone of the formula (V) and hydrolysis of derivative of 3,14-hydroxynormorphinone of the formula (V) to yield noroxymorphone of the formula (VI) wherein formulae (V) and (VI) are given in the invention description. Invention provides synthesis of noroxymorphone using novel intermediate compounds.

EFFECT: improved method of synthesis.

25 cl, 1 sch, 1 ex

FIELD: medicine.

SUBSTANCE: there are described compound of formula, its pharmaceutically acceptable salt or their mixture, enentiomerically pure 4-{(R)-(3-aminophenyl)[4-(4-fluorobenzyl)pyperazin-1-yl]-N,N-diethylbenzamide or its pharmaceutically acceptable salt. Also described are method of anxiety therapy, method of pain therapy and method of depression therapy in animal.

EFFECT: compounds are of use in therapy, in particular for elimination of pain, depression and anxiety.

5 cl, 1 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to chemical-pharmaceutical industry and deals with sublingual coated tablet, method of its manufacturing. Tablet contains nucleus, which does not contain pharmaceutically active substance, and coating, containing at least one active substance, tablet disintegrate within 15 minutes, providing fast supply of opioid analgetic into blood stream.

EFFECT: claimed tablet has high efficiency in treatment of beyond-threshold cancer pains.

25 cl, 3 ex, 7 tbl, 1 dwg

FIELD: medicine.

SUBSTANCE: invention relates to protected against unadministered application peroral medication form with controlled release from it of opioid for single intake per day which is different in that it contains opioid (A), which potentially is a subject of its non-medicinal applicatuion, synthetic or natural polymer (C), which forms retarding opioid release matrix material or retarding opioid release coating, optionally physiologically compatible auxiliary substances (B), optionally wax (D), component (C), respectively component (D) possess resistance to destruction 500 H and component (C) and possibly applied component (D) are present in amounts at which resistance of medication form to destruction constitutes 500 H.

EFFECT: invention also relates to methods of obtaining protected against unadministered application coompositions, which include stages of component mixing, formation by force applicatuion and/or thermal influence and, if necessary, providing retarding opioid release coating.

36 cl, 1 dwg, 1 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: benzamide derivatives are presented by the formula [1] or its salt, where Z is -O-, -NR5-, -S-, -SO-; 1 is 0 or 1; m is 0 or 1; R1 is hydrogen atom, C1-6-alkyl group, R2 is hydrogen atom, hydroxylic group, C1-6- alkyl group, carboxyl group, C1-6-alkoxycarbonyl group or -CONR10R11, or R2 and R1 together form =O; R3 is hydrogen atom or C1-6-alkyl group; R4 is hydrogen atom or halogen atom; V is direct bond or -(CR21R22)n-; P1 and P2 rings are the same or different, and each is aromatic or saturated carbocyclic group, or 5-10-member saturated or unsaturated heterocyclic group containing 1-3 heteroatoms selected out of N, O, S.

EFFECT: obtainment of compound with excellent inhibition effect on vanilloid receptor type 1 activity, efficiency in treatment of diseases involving vanilloid receptor type 1 activity.

17 cl, 56 tbl, 8 ex

FIELD: medicine.

SUBSTANCE: present invention concerns medicine, specifically a percutaneously absorbed adhesive preparation containing fentanyl made of economic source materials, has more simple structure, than that of existing preparations, has sufficient skin permeability and allows regulating skin permeability by changing the mixing ratio of two types of polyisobutylene of different molecular weights, improving adhesiveness of the agent and organic fluid.

EFFECT: percutaneously absorbed adhesive preparation contains a substrate and an adhesive layer laminated on one side thereof where said adhesive layer contains fentanyl, two types of polyisobutylene of different molecular weights that improves adhesiveness of the agent and organic fluid compatible with specified two types of polyisobutylene and specified adhesiveness improving agent.

10 cl, 8 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: described are new derivatives of imidazo-pyridine with general formula I in racemic, enantiomeric form or in combination of these forms, and their pharmaceutically used salts. Radicals R1-R4 are described in the description.

EFFECT: these compounds have affinity to melanocortin receptor; possibility of using them in making medicinal agents for treating disorders, related to body weight, mental disorders, pain, sexual activity disorders.

21 cl, 5 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention relates to medication from combination of flupirtine or its pharmaceutically acceptable salts with tolperisone or its analogue eperisone or silperisone, or their therapeutically acceptable salts for treatment of pain conditions associated with higher muscle tone.

EFFECT: synergic effect with respect to pain killing and muscle relaxation.

8 cl, 3 ex, 6 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to new spirocyclic cyclohexane derivatives of general formula I , where: R1-R3, R5-R10, W, X are disclosed in the claim 1 of formula.

EFFECT: compounds exhibit analgesic activity to be applied for making a medical product for pain therapy.

20 cl, 1 tbl, 54 ex

FIELD: medicine.

SUBSTANCE: invention concerns the solid medicinal composition, including flupirtin or its physiologically comprehensible salts as biologically active substance. At least, one part of flupirtin exists as preparative ready form with the slowed down liberation of the active component. The preparative ready form contains the pressed forms flupirtin, which are preferably in regular intervals covered by a prolonging component. Form pressing of flupirtin is characterised by the size of particles of 160-800 mcm, in bulk volume less than 5 ml/g and preferably are spherical or close to spherical. The prolonging component provides diffused-controllable flupirtin release and preferably includes polymer or a copolymer from acrylic acid, derivatives of acrylic acid, methyl-acrylic acid and-or derivatives of the methyl-acrylic acid, or their admixtures.

EFFECT: new flupirtin composition provides uniform and long release of active substance during long time, frequency of reception to two times day, more rare implication of side effects and a risk exception of a "dose dumping".

16 cl, 3 dwg, 3 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine. Described is method and single-unit subsaturated plaster with unregulated rate for introduction of fentanyl and its analogues to subject through skin.

EFFECT: anesthesia during long period of time.

5 cl, 8 dwg, 4 tbl, 11 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers drugs, and concerns an anticancer composition containing: a) a therapeutically effective amount of 13-deoxyantracycline of formula specified below and b) a therapeutically effective amount of taxane. Also, there are disclosed pharmaceutical formulation and cancer therapy involving the introduction of the therapeutically effective amount of 13-deoxyantracycline and the therapeutically effective amount of taxane.

EFFECT: compositions under the invention synergetically inhibit cancer cell growth and provide considerable side effect reduction where each of R1, R2, R3, R4, R5 and R6 have the values specified in formula.

9 cl, 4 dwg, 6 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed is application of biologically active substance for production of medication for treatment of syndrome of resistance to insulin, diabetes, including type I diabetes and type II diabetes, syndrome of ovary polycystosis, treatment or reduction of probability of atheroslerosis development, arterioslerosis, obesity, hypertension, hyperlipidemia, fatty infiltration of liver, nephropathy, neuropathy or retinopathy, feet ulceration or cataracts associated with diabetes, where medication represents compound of formula , as well as corresponding treatment method, pharmaceutical composition and biologically active substance of the same purpose.

EFFECT: increase of compound activity: 75% reduction of glucose level with loading in contrast to 10% reduction for analogues known before, as well as reduction of level of triglycerides in blood serum.

17 cl, 1 dwg, 2 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine and pharmaceutical industry, namely to a composition containing acetocyclopropyl-taxotere and Trastuzumab used for treating breast cancer, for treating taxoid resistant cancer types.

EFFECT: preparation of the pharmaceutical composition for treating breast cancer.

2 cl, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a method of obtaining 10-deacetylbaccatine III with purity of over 99%, which does not contain 10-deacetyl-2-debenzoyl-2-pentenoylbaccatine III. The disclosed method includes: a) treating crude 10-deacetylbaccatine III with an activated derivative of trichloroacetic acid; b) carrying out chromatography on silica gel and elution of 7,10-bis-trichloroacetyl-10-deacetylbaccatine III with dichloromethane or a dichloromethane/ethylacetate mixture; and c) treatment of 10-deacetyl-7,10-bis-trichloroacetylbaccatine III with an alkali followed by crystallisation. The invention also relates to production of paclitaxel, which involves production of 10-deacetylbaccatine III using the disclosed method and its subsequent conversion to N-debenzoylpaclitaxel with its subsequent benzoylation.

EFFECT: convenient semi-synthesis of anti-tumour agents with a taxane backbone, which enables to avoid laborious methods of removing corresponding 2-debenzoyl-2-pentenoyl analogues.

7 cl, 1 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relates to medicine, namely to oncology, and may be used for cancer treatment. Methods and applications according to invention includes administration of (2R,Z)-2-amino-2-cyclohexyl-N-(5-(1-methyl-1H-pirazole-4-yl)-1-oxo-2,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indole-8-yl)acetamide (compound 1) for treatment of cancer, such as colon cancer, prostate cancer and breast cancer in combination with therapeutically efficient amount of anticancer agent selected from gemcitabine, irinotecan and mitomycin C.

EFFECT: application of inventions makes it possible to increase efficiency of colon cancer, prostate cancer and breast cancer treatment by increasing cytotoxicity of hemcitabine, irinotecan, doxorubicin and mitomycin C under action of compound 1.

33 cl, 5 tbl, 42 ex

Up!