Pharmaceutical compositions containing diacerein

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and represents a controlled-release preparative form of diacerein administered once a day for treating or autoimmune diseases or their complications. The preparative form contains a core, an active layer, a sustained-release film layer and a delayed-release film layer, wherein the active layer is followed by the sustained-release film, and the delayed-release film layer thereafter. The sustained-release film layer contains ethyl cellulose polymer, povidone, triethylacetate and talc; the delayed-release film layer contains Eudragit polymer, triethylacetate and talc.

EFFECT: reducing the negative side action of diacerein.

18 cl, 23 ex, 33 tbl

 

The level of technology

Diacerein (4,5-bis(atomic charges)-9,10-dioxo-2-anthracene carboxylic acid) is a antrahinonovye derived highly purified. It inhibits the activity of interleukin-1 and approved as symptomatic drug slow action in osteoarthritis (SYSADOA) in several countries.

Diacerein has a value of log P 2,42 and is practically insoluble in water. Diacerein is fully converted to a failure to comply before reaching the systemic circulation. The very failure to comply or be removed by renal (20%), or conjugated in the liver to Reina glucuronide (60%) and Reina sulfate (20%). These metabolites are removed through the kidneys.

There are two major negative side effects of diacerein: diarrhea or soft stool and yellow-brown discoloration of urine. The severity of the diarrhea is mild to moderate, and it occurs within the first two weeks of treatment. Discoloration of urine is caused by metabolites of diacerein present in the urine. Studies in vitro and in vivo showed that unabsorbed diacerein is metabolized to Reina in the colon. Failure to comply in the colon has a laxative effect through activation of chloride secretion by stimulating the submucosal neurons and release of endogenous acetylcholine and prostaglandins, but not through the release of histamine or serotonin.

Oral bioavailability of diacerein is about 35-56%. 3-year clinical study showed that up to 30% of cases of diarrhea or soft stools occur in patients who take diacerein twice a day with food (M. Dougados et al.,Arthritis & Rheumatism, 44(11), 2539-2547, 2001). Even if you intake of food increases the bioavailability of diacerein to 43-70%, incomplete absorption continues to cause local effects in the colon. The incidence of diarrhoea is proportional to the dose, as opposed to the nature of the other side effects that are not proportional to the dose (J. P. Pelletier et al.,Arthritis & Rheumatism, 43(10), 2339-2348, 2000). These data show that minimizing the exposure of diacerein for colon could improve the symptoms of diarrhea through improving absorption in the intestinal tract.

In addition to treating osteoarthritis, diacerein can be considered for use in the treatment of other inflammatory or autoimmune diseases, such as diabetes type I/II and its complications, such as nephropathy, retinopathy, neuropathy or foot ulcers and the like. There are clinical studies showing that diacerein and failure to comply slow the progression of the disease in diabetes and inhibit the hypermetabolism of renal function in diabetic Pets. Potential mechanics is the m steps of diacerein and its metabolite Reina, when slowing down the development of diabetes-type I/II and its complications, includes a reduction in the expression and activity of Pro-inflammatory cytokines, IL-1; down-regulation of expression of IL-6, TNF-α and TGF-β and inhibits the expression of iNOS; thereby expressiona and functioning of GLUT-1 and reducing the absorption of glucose.

The invention

The aim of the present invention to provide a formulation of diacerein controlled release for administration once daily for the treatment of inflammatory, autoimmune diseases or their complications, such as osteoarthritis, diabetes type I/II or diabetic nephropathy, with fewer negative side effects. More specifically, the preparative form of diacerein controlled release for administration once a day according to the present invention may be a membrane-controlled preparative form, matrix preparative form or preparative form with an osmotic pump. In a preferred embodiment, formulations of diacerein controlled release according to the present invention can, in addition, to increase bioavailability, compared to commercial preparative forms with quick release (IR). More specifically, this method reduces the negative is obecnie effects diarrhea caused by diacerein.

Another objective of the present invention is to obtain formulations of controlled release for administration once a day, containing diacerein and the second active ingredient, for the treatment of inflammatory, autoimmune diseases or their complications. More specifically, the second active ingredient may be an inhibitor of the angiotensin-converting enzyme or receptor blocker angiotensin II for the treatment of diabetic nephropathy, antihyperglycemic drug for diabetes type I/II or non-steroidal anti-inflammatory drug (NSAID) for the treatment of osteoarthritis.

Detailed description of the invention

The main negative side effects of diacerein is diarrhea and soft stool. Studies in vitro and in vivo showed that unabsorbed diacerein is metabolized to Reina in the colon. Failure to comply in the colon causes a laxative effect by activating the secretion of chloride by excitation submucosal neurons and release of endogenous acetylcholine and prostaglandins, but not through the release of histamine or serotonin.

The present invention provides a preparative form of diacerein controlled release for introduction once the su is key, which can minimize the release of diacerein in the colon to reduce these negative side effects. Perfect control of the release of diacerein is when the rate of release of drug and the absorption rate is close to identical, so that the negative side effects caused by the coming into contact of diacerein and mucosa of the colon, can be minimized. Control technology release of diacerein include, but are not limited to, membrane-controlled technology, the matrix-controlled technology and technology with an osmotic pump.

Diacerein or another active ingredient that is used in the present invention, can be obtained by micronisation or himself, or together with an auxiliary substance for grinding.

Diacerein used in the formulation of the present invention may be in crystalline or amorphous state.

Preparative form with delayed release may include conventional additives, in addition to the active ingredient and the polymer. For example, the coredelayed release may contain diluents such as microcrystalline cellulose, dextrose, starch, sucrose, lactose, sorbitol, mannitol or hospatility; loosening agent, such as talc, sodium carboxymethyl cellulose, L-hydroxypropylcellulose, crospovidone or corn starch; binders such as polyvinylpyrrolidone, starch, gelatin, tragakant, methylcellulose or hydroxypropylcellulose; and a solvent, such as water or a lower alcohol, such as ethanol or isopropanol; and a lubricating substance, such as light anhydrous silicic acid, talc, stearic acid and its zinc, magnesium or calcium salt or polyethylene glycol. In addition, preparative form with delayed release may also include loosening agent, such as sodium starch glycolate, starch, alginic acid or its sodium salt.

The pharmaceutical composition of the present invention can be prepared as various types of oral preparative forms containing the above composition. Preferably, the pharmaceutical composition of the present invention can be prepared in the form of tablets or balls.

Membrane-controlled technology

In one of the embodiments, the preparative form of the present invention can be surrounded by a film of controlled release, which can isolate the core with the drug from the environment of the GI (gastrointestinal tract) d is I to minimize direct contact of diacerein from the mucous membrane of the colon.

Film with controlled-release may contain water-insoluble polymer, which forms the membrane to eliminate direct contact of diacerein and mucosa of the colon. Water-insoluble polymer may include cellulose acetate, cellulose triacetate, agar acetate, amylose triacetate, beta glucan acetate, acetaldehyde dimethylacetal, acetate-methylcarbamate cellulose acetate-phthalate cellulose acetate-cellulose succinate, acetate-dimethylaminoacetyl cellulose, acetate-ethylcarbonate cellulose, acetachlor cellulose, acetate-ethylacetat cellulose acetate-propionate, cellulose, copolymers simple poly(vinylethylene esters), acetate-butyl sulfonate cellulose, acetate-octates cellulose acetate laurate cellulose, acetate-p-toluensulfonate cellulose, triacetate resin carob, gidroksilirovanii ethylene-vinyl acetate, acetate-butyrate cellulose, ethylcellulose and the like.

In addition, the film with controlled-release may contain a plasticizer or a pore-forming agent to obtain the corresponding properties of the film. Examples of appropriate plasticizers are dibutylsebacate, triethylcitrate and polyethylene glycol (PEG). Examples of appropriate pore-forming agents are hydroxymethylcellulose (HPMC), polyvinylpyrrolidone (PVP) and the guide is oxypropylation (HPC).

The rate of release of drugs of diacerein can be controlled by adjusting the increase inthe mass of the film controlled release. The corresponding increase in mass can be 3-50% of the core tablet or ball.

In one of the embodiments of the present invention, the preparative form controlled release contains the active layer, the film layer delayed release and the film layer delayed release.

In one of the embodiments of the present invention, the active layer contains in the range of about between 40,0% and about 50.0% mass. microcrystalline cellulose, in the range between about 20.0% and about 30.0 per cent of the mass. diacerein, in the range between approximately 2.0% and approximately 5.0% of the mass. of povidone, and in the range between about 20.0% and about 30.0 per cent of the mass. mannitol.

In another embodiment of the present invention, the active layer contains approximately 50.0% of the masses. microcrystalline cellulose, approximately 25.0% of the mass. diacerein, roughly 2.0% of the mass. of povidone and approximately 23.0 per cent of the mass. mannitol.

The film layer delayed release may include, but not limited to, polymers, ethyl cellulose, povidone, triethylcitrate and talc.

The film layer delayed release may include, but are not limited to, polymers Eudragit®, Tr is utiltity and talc.

Matrix technology

In another embodiment, the preparative form of the present invention may contain material controlled release, such as a hydrophilic polymer, a hydrophobic polymer or wax to form a matrix controlled release. Diacerein is captured in the matrix to eliminate the contact of diacerein and mucosa of the colon.

Examples of materials with controlled release include hypromellose with a molecular mass of between 1000 and 4000000, hydroxypropylcellulose with a molecular weight of from 2000 to 2000000, sodium alginate, carbomer (Carbopol®), sodium carboxymethylcellulose, xanthan resin, guar gum, resin carob, polyvinyl acetate, polyvinyl alcohol, carboxyvinyl polymers, polyvinyl alcohols, glucans, scleroglucan, mannans, xanthane, alginic acid and its derivatives, polyanhydride, polyaminoamide, carboxymethylcellulose, cross-linked sodium carboxymethylcellulose, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, carboxymethylated, the copolymer of potassium methacrylate/divinylbenzene, starches and their derivatives, β-cyclodextrin, derivatives dextrins with a linear or branched chain, ethylcellulose, methylcellulose and derivatives of cellulose.

In one the of the embodiments of the present invention, preparative form controlled release contains about 20.0% by mass. diacerein, in the range between about 20.0% and 40.0% of mass. hydroxyethylmethylcellulose, in the range between about 37,0% and about 57,0% of the mass. mannitol, roughly 2.0% of the mass. of povidone and about 1.0% of the mass. the stearate.

In a preferred embodiment of the present invention, the preparative form controlled release contains about 20.0% by mass. diacerein, about 20.0% by mass. hydroxyethylmethylcellulose about to 57.0% of the mass. mannitol, roughly 2.0% of the mass. of povidone and about 1.0% of the mass. the stearate.

In another preferred embodiment of the present invention, the preparative form controlled release contains about 20.0% by mass. diacerein, approximately 40.0% of mass. hydroxyethylmethylcellulose, approximately 37.0% of the mass. mannitol, roughly 2.0% of the mass. of povidone and about 1.0% of the mass. the stearate.

In another preferred embodiment of the present invention, the preparative form controlled release contains about 20.0% by mass. diacerein, approximately 33.0% of the mass. hydroxyethylmethylcellulose about 46,0% of the mass. mannitol and about 1.0% of the mass. the stearate.

System with osmotic pump

In another embodiment, the rate of release of diacerein can to trenirovatsya using system osmotic pump. The core containing the drug is covered by a semi-permeable membrane, which allows penetration of water only. When the external aqueous fluids are absorbed through the semipermeable membrane into the nucleus under the action of the gradient of osmotic pressure, the drug is released from the passageway in the membrane. The specified passage may be a recess, opening, passage, a cylindrical hole, a weakened area or erodynamic the item that is being eroded with the formation of a passage for the release of diacerein.

The materials used for the semi-permeable membrane in the present invention, are well known in the pharmaceutical industry. For example, in the present invention can be used commercially available unplasticized cellulose acetate, plasticized cellulose triacetate, agar acetate, acetate pentaglycine, dextran acetate, acetate methylurethane cellulose acetate phthalate cellulose acetate ethylurethane cellulose, acetate cellulose succinate, acetate dimethylglycine cellulose acetate estancarbon cellulose, acetate, methanesulfonate cellulose acetate butanesulfonate cellulose acetate propionate, cellulose, a polymer of the simple vinylmation ether acetate octanoate cellulose acetate laurate cellulose acetate p-toluensulfonate cellulo is s, ethylcellulose, triacetate resin carob, cellulose acetate with acetylcellulose, gidroksilirovanii the ethylene vinyl acetate membrane material made of epoxy polymer, alkylidene - simple alkylglycerol ether, polyurethane, polyglycolic acid and is well known politikarena-polyanionic membrane.

In one of the embodiments, the preparative form of diacerein controlled release, which is controlled with technology osmotic pump may be used preparative form containing layer medicines and buoyancy layer. Eject layer dosage with osmotic delivery contains osmopolitan. Osmopolitan swells when absorbed aqueous fluid. Examples of sopolimerov include poly(hydroxyethylmethacrylate) with a molecular mass of 30000-5000000, poly(vinyl pyrrolidone) with a molecular mass of 10000-36000, anionic and cationic hydrogels, polyelectrolyte complexes, poly(vinyl alcohol), polyethylene oxide, N-vinylacetate, acid carboxyimide Carbopol® with a molecular mass of 4000-4500000, polyacrylamides Cyanamer®, cross-linked swellable polymers in water inden-maleic anhydride, a copolymer of amylopectin, acrylate polymer Aqua-Keeps® and polysaccharides.

Ways to improve bioavailability

In another embodiment, the preparative form with controlled release of the present invention may additionally provide increased bioavailability of diacerein, compared to commercial preparative forms with quick release (from Arthrodar®, TRB Pharma's.a.). It is assumed that the increase in bioavailability would be useful to reduce the negative side effects. Methods of increasing the bioavailability include, but are not limited to, (a) adding a surface-active substances; (b) forming a solid dispersion; (c) use micronized or kanonizirovannogo of diacerein, (d) adding acidifying or buffer agents, and (e) the formation of complexes with cyclodextrins.

Adding the appropriate surface-active substances in the pharmaceutical compositions of diacerein can increase the dissolution rate in vitro and bioavailability in vivo. Appropriate surfactants include, but are not limited to, sodium laurylsulfate, polyethylenepolypropylene, glycerol-polyethylene-glycol-oxystearate, PEG-40 gidrirovannoe castor oil and stearoylethanolamine (polyoxygenated).

Solid dispersions are traditionally used to enhance the dissolution rate of the drug which means, from the point of view of improving bioavailability. The drug can be captured in the media in amorphous form, without recrystallization. A method of obtaining a solid dispersion is well known to specialists in this field.

Control of particle size of diacerein considered, would also be useful to improve its bioavailability. The preferred particle size of diacerein is a D50 of less than 20 μm, and more preferably D50 of less than 5 microns. In addition, the combination of micronized diacerein with hydrophilic excipients for grinding can promote the dissolution and bioavailability of drugs. Appropriate hydrophilic excipients for grinding include, but are not limited to, HPMC, sucrose, lactose, surfactants and superathletes. The method can be performed by use of a mill or micronizer, such as Aljet mill. Together micronized diacerein can then be mixed or granulomatosa together with other fillers.

The table below shows the solubility and stability of diacerein in buffer solutions with different pH values. At pH below 4,17 diacerein is stable, and its solubility is a Ki is relatively low. The degradation products, including failure to comply, increase in number at a pH above 5. Poor stability of diacerein in the environment of the intestine can lead to incomplete absorption and cause poor and variable bioavailability. In addition, one of the growing number of degradants in the environment of the intestine, failure to comply, as expected, is a major factor in stimulating the mucous membrane of the large intestine and causes diarrhea. Accordingly, methods of stabilization of diacerein during gastrointestinal absorption could improve its bioavailability and reduce side effects diarrhea. Methods of stabilization for use with diacerein can include adding acidifying or buffer agents or the formation of complexes with cyclodextrins.

Diacerein
Table 1
Profile of solubility and stability of diacerein at different pH at ambient temperature for 48 hours
System buffersThe final value of pHThe total solubility
(ág/ml)
The proportion of diacerein and its degradants (%)
Failure to complyMonoacetylated IMonoacetylated II
of 0.1 n HCl1,170,17100000
0.01 n HCl1,980,15100000
50 mm NaH2PO43,030,35100000
4,170,43100000
5,041,406027013
5,97152,777108 5
6,551105,245281413
6,703746,234361614
Water5,7944,090253

Table 2
The solubility and stability of diacerein at ambient temperature for one hour
The final value of pHThe total solubility
(ág/ml)
The proportion of diacerein and its degradants (%)
DiacereinFailure to complyMonoacetylated IMonoacetylated II
6,55*901,99044 2
6,70*4444,183476

Using preparative forms of the present invention

Pharmaceutical compositions of diacerein of the present invention can be used for the treatment of inflammatory or autoimmune diseases such as rheumatoid arthritis, osteoarthritis, osteoporosis, inflammatory bowel disease, including ulcerative colitis and Crohn's disease, ulcerative colitis, multiple sclerosis, periodontitis, gingivitis, reaction of graft rejection, psoriasis, scleroderma, atopic dermatitis, asthma, systemic lupus erythematosus (SLE), nephropathy and chronic obstructive pulmonary disease (COPD). Skin conditions that can be treated include those listed above, as well as psoriatic arthritis, bullous epidermis, atopic dermatitis, and vasculitis. Antiangiogenic activity may allow the treatment of conditions such as age-related macular degeneration and cancer. Preferably, the pharmaceutical compositions of the present invention are used for the treatment of osteoarthritis, diabetes type I/II or diabetic nephropathy, with fewer negative side effects.

The appropriate dose is diacerein for the treatment of the above diseases are in the range 5-200 mg/day, preferably 20-150 mg/day.

When administered to patients who have reached a stationary state of the plasma concentration, 50 mg of a commercial formulation of IR diacerein, administered twice a day, only support concentration Reina in the plasma above 2 mg/l for about 12 hours. However, in the preferred embodiment of the present invention:

50 mg preparative forms of diacerein of the present invention maintain the concentration of Reina in the plasma above a concentration of 1 mg/l for more than 12 hours in humans, when introduced orally to the patient-the person who has reached a stationary state;

100 mg preparative forms of diacerein of the present invention maintain the concentration of Reina in the plasma above a concentration of 2 mg/l for more than 12 hours in humans, when introduced orally to the patient-the person who has reached a stationary state;

150 mg preparative forms of diacerein of the present invention maintain the concentration of Reina in higher plasma concentrations of 3 mg/l for more than 12 hours in humans, when introduced orally to the patient-the person who has reached a stationary state;

and

200 mg formulation of diacerein of the present invention maintain the concentration of Reina in higher plasma concentrations of 4 mg/l over h is m 12 hours in humans, when introduced orally to the patient-the person who has reached a stationary state.

Combined preparative form

Preparative form with controlled release of the present invention may further comprise another active ingredient, such as blockers of the angiotensin II receptor (ARB), inhibitors of angiotensin-converting enzyme (ACEI), antihyperglycemics preparative form or NSAID. More specifically, the preparative form of diacerein in accordance with the present invention may further comprise an inhibitor of angiotensin-converting enzyme or receptor blockers angiotensin II for the treatment of diabetic nephropathy, antihyperglycemic drug for diabetes type I/II or non-steroidal anti-inflammatory drug (NSAID) for the treatment of osteoarthritis.

Examples include ACEI captopril, benazepril, enalapril, lisinopril, fosinopril, ramipril, perindopril, inapril, moexipril and trandolapril. Examples ARB include candesartan, eprosartan, irbesartan, telmisartan, valsartan and losartan. Examples antihyperglycemics funds include sulfonylureas, such as gliburid, glipizide and glimepiride; meglitinide, such as Repaglinide and nateglinide; biguanides such as Metformin; thiazolidinediones, such as the pioglitazone and rosiglitazone; inhibitor of alpha-glucosidase, such as acarbose. Examples of NSAIDs include salicylates such as aspirin; arylalkylamine acid, such as acetaminophen; 2-arylpropionic acids such as ibuprofen, Ketorolac, and naproxen; n-irelandlavalife acid, such as mefenamovaya acid, meclofenamic acid; oxicam, such as piroxicam, meloxicam; and COX-2 inhibitors such as celecoxib.

The second active ingredient may be in a dosage form with controlled release or dosed in the form of a quick release.

It should be noted that these options for implementation should be considered as illustrative and the present invention should not be limited to the details given in this document.

Examples

Example 1

Preparation of solid dispersion

Acceptable ranges for the components of a representative solid dispersions are shown in Table 3.

Table 3
IngredientsExamples%
APIDiacerein10-90
MediaHydrofil the s polymers (HPMC, HPC, HEC, MC, sodium CMC, and the like), hydrophobic polymers (EC, PVA, methyl methacrylate, and the like), surfactants (SLS and Tween 80, Gelucire, Cremophor, poloxamer, PEG, and the like), water-soluble excipients (lactose, sucrose, mannitol, glucose and the like), waxes (glyceryl begent, cetyl alcohol and the like) or combinations thereof10-90
Organic solventsAcetone, isopropyl alcohol or ethanolon demand

Method.

Diacerein can be dissolved using an appropriate organic solvent to form a solution of a medicinal product. Media, such as hydrophilic polymers, hydrophobic polymers, surfactants, water-soluble fillers or waxes, or a combination of the above media, and then dissolved or dispersed in a solution of a medicinal product. To obtain a solid dispersion can be used in the spray drying the above solution, or the solution may be applied to the appropriate fillers (water-soluble materials, which function as the second carrier) using a fluidized bed.

Example 2

The formation of complexes with cyclodextrins

The reception is established ranges for the components of representative complexes with cyclodextrins are shown in Table 4.

Table 4
Ingredients%
APIDiacerein10-90
Cyclodextrinsα-cyclodextrin, β-cyclodextrin, γ-cyclodextrin and their derivatives, such as 2-hydroxypropyl-β-cyclodextrin, and the like10-90

Method.

Can be prepared aqueous solutions of cyclodextrins with different percentage contents. Diacerein is added to the above solutions to produce saturated solutions. The solution is stirred for at least 72 hours, and then allow them to stand up until the entire nerastvorim material will not settle. The supernatant solution is filtered and dried by an oven, spray drying or freeze-drying or causing to appropriate fillers (which function as diluents) using a fluidized bed.

Example 3

Matrix system (pill)

Acceptable ranges for the components of a representative matrix systems of the tablets are shown in Table 5.

Table 5
Ingredients%
APIDiacerein, diacerein in solid dispersion or in the form of complexes with cyclodextrins10-90
Materials with controlled
release
Swelling in water of the polymers, hydrophilic polymers (HPMC, HPC, HEC, MC, sodium CMC, and the like), hydrophobic polymers (EC, PVA, methyl methacrylate, and the like), waxes (glyceryl begent, cetyl alcohol and the like)10-90

Method.

Part of the API is prepared as described in the above examples. Part of the API diacerein physically mixed or granularit together with materials with controlled-release, and then the mixture is pressed with the matrix tablets. Optional, preparative tablet form can include acidifying agent or a buffering agent.

Example 4

Matrix system (pill)

Two representative formulations of matrix tablets are shown in Table 6.

Table 6
The formula AFormula B
Ingredientsmg%mg%
Pellet 1Diacerein10020,010020,0
HPC10020,0--
HPMC--17935,8
Mannitol20440,8--
SLS102,0--
Cremophor --102,0
Pellet IIHPMC8016,0--
Mannitol--18036,0
PVP30,630,6
Tartaric acid255,0
GreaseStearate Mg30,6--
SiO2--30,6
Only500100,000 100,0

Method.

Solid dispersion Granules I prepared as described in Example 1, Granules II prepared using wet granulation. Granules I and II are mixed with lubricating substances, and then pressed to obtain a matrix tablets.

Example 5

Matrix system (pill)

Another representative preparative form of matrix tablets are shown in Table 7.

Table 7
IngredientsFormula C
mg%
PelletDiacerein10020,0
HPMC17535,0
Mannitol14729,4
Cremophor5010,0
Vinnakota 255,0
GreaseStearate Mg30,6
Only500100,0

Method.

Diacerein, HPMC, mannitol, cremophor and tartaric acid granularit using wet granulation. The granules are mixed with lubricating substances, and then pressed.

Example 6

Matrix system (balls)

Acceptable ranges for the components of a representative matrix systems beads are shown in Table 8.

Table 8
IngredientsPercentage
The core of the ball
APIDiacerein10-90% from the nucleus
MediaHydrophilic polymers (HPMC, HPC, HEC, MC, sodium CMC, and the like),
hydrophobic polymers (EC, PVA, methyl methacrylate, and the like), surfactants (SLS and Tween 80, Gelucire, Cremophor shelves is Amer, PEG and the like), water-soluble excipients (lactose, sucrose, mannitol, glucose and the like), waxes (glyceryl begent, cetyl alcohol and the like) or combinations thereof
10-90% from the nucleus
SeedThe scope of microcrystalline cellulose, powdered seed and the like10-90% from the nucleus

Method.

Diacerein is dissolved using an appropriate organic solvent, with the formation of a solution of a medicinal product. Media, such as hydrophilic polymers, hydrophobic polymers, surfactants, water-soluble fillers, wax or combination of the above media, and then dissolved or dispersed in the solution of a medicinal product. The solution is sprayed on the seed using a fluidized bed to obtain a matrix of balls. Then the balls are encapsulated in the capsule of appropriate size.

Example 7

Matrix system (balls)

Representative formulations of the matrix in the form of balls are shown in Table 9.

Table 9
The form is and D
Ingredientsmg%
The core ballsAPI10020,0
HPC10020,0
EC5010,0
scope MCC24048,0
Cremophor102,0
Only500,0100,0

Formula D prepared using the method described in Example 6.

Example 8

Membrane-controlled system (pill)

Acceptable ranges for components representative preparative forms membrane-controlled tablets are shown in Table 10.

Table 10
IngredientsPercentage
Tablet cores
APIDiacerein in solid dispersion or in the form of complexes with cyclodextrins10-90% from the nucleus
ThinnersLactose, MCC, mannitol and the like10-90% from the nucleus
LubricantsStearate Mg0.1 to 5% from the nucleus
Film coating
The composition of the membrane controlled releaseHydrophobic polymers (EC, PVA, methyl methacrylate, and the like), a pore-forming agent (HPMC, PVP, HPC, and the like), a plasticizer (dibutylsebacate, triethylcitrate, PEG, and the like)3-50% increase the weight of the tablet core

Part of the API is prepared as described in the above examples. Part of the API diacerein physically mixed or granularit together with the appropriate diluents and masiva the relevant substances, then pressed to obtain tablets kernel. Not necessarily, in the preparative form tablet cores may include acidifying agent or a buffering agent. Materials with controlled release of dissolved together with a pore-forming agent and a plasticizer in an organic solvent to obtain a coating solution for the above tablet cores. Then, on tablets is applied coating device for coating tablets.

Example 9

Membrane-controlled system (pill)

Three representative formulations of membrane-controlled tablets are shown in Table 11.

100,0
Table 11
Formula EFormula FFormula G
Ingredientsmg%mg%mg%
Tablet coresDiacerein100 22,710023,010023,0
Mannitol30469,1274,563,0289,566,5
SLS204,5--306,9
Cremophor--204,6--
PVP143,2143,2143,2
Tartaric acid--25the 5.7--
Stearate Mg20,520,520,5
Just for kernel440100435,5100435,5100
Tight coatingTablet cores44097,3435,597,3435,597,3
HPMC81,881,881,8
Talc40,940,940,9
Just for sealed cover452,0447,5100,0447,5100,0
SR FloorTablet with waterproof coating452,090,4447,5to 89.5447,5to 89.5
EC306,0255,0255,0
PVP153,0255,0255,0
TEC30,62,50,52,50,5
Only500,0100,0500,0 100,0500,0100,0

Method.

The tablet cores are made using the method of solid dispersion, as described in the above examples, or by wet granulation. Then the tablet cores cover the hermetic coating and coating with a slow release.

Example 10

Membrane-controlled system (balls)

Acceptable ranges for the components of representative systems with membrane-controlled balls are shown in Table 12.

Table 12
IngredientsPercentage
The ball core
APIDiacerein10-90% from the nucleus
MediaHydrophilic polymers (HPMC, HPC, HEC, MC, sodium CMC, and the like), hydrophobic polymers (EC, PVA, methyl methacrylate, and the like), surfactants (SLS and Tween 80, Gelucire, Cremophor, poloxamer, PEG, and the like), water-soluble excipients (lactose, sucrose, mannitol, glucose and the like), waxes (glyceryl begent, cetyl sleep is t, and the like) or combinations thereof 10-90% from the nucleus
StartersThe scope of microcrystalline cellulose, powdered seed and the like10-90% from the nucleus
Film coating
The composition of the membrane controlled releaseHydrophobic polymers (EC, PVA, methyl Methacrylate, and the like), a pore-forming agent (HPMC, PVP, HPC, and the like), a plasticizer (dibutylsebacate, triethylcitrate, PEG, and the like)3-50% increase in weight bulbs kernel

Method.

Diacerein is dissolved using an appropriate organic solvent to form a solution of a medicinal product. Media, such as hydrophilic polymers, hydrophobic polymers, surfactants, water-soluble fillers, wax or combination of the above media, and then dissolved or dispersed in the solution of a medicinal product. The solution is sprayed on the seed using a fluidized bed with obtaining balls kernel. Materials with controlled release of dissolved together with a pore-forming agent and a plasticizer in an organic solvent to obtain a coating solution for the balls poison the well. Then the balls are covered with a membrane controlled release. Then the balls slow release encapsulate in the capsule of appropriate size.

Example 11

Membrane-controlled system (balls)

Representative formulations of membrane-controlled system in the form of balls are shown in Table 13.

Table 13
Formula H
Ingredientsmg%
The ball coreAPI10022,8
HPC10022,8
sphere MCC228,552,1
SLS102,3
Only438,5100
Tight coatingØ the Rick kernel 438,598,0
HPMC61,3
Talc30,7
Only447,5100,0
Floor SRBall with a waterproof coating447,5to 89.5
EC255,0
PVP255,0
TEC2,50,5
Only500,0100,0

The formula H prepared using the method described in Example 10.

Example 12

System osmotic pump (push-pulling)

Acceptable ranges of components for the representative preparative forms with an osmotic pump (push-pulling) are shown in Table 14.

Table 14/td>
IngredientsExamplePercentage
Layer medicinesAPIDiacerein, diacerein in solid dispersion or in the form of complexes with cyclodextrins10-90% of the layer medicines
The osmotic agentNaCl, mannitol, fructose and the like10-90% of the layer medicines
Osmotic polymerThe polyethylene oxide (PEO)10-90% of the layer medicines
AntioxidantBHT0.01 to 0.5% of PEO
BinderHPMC, PVP, HPC, and the like0.5 to 30% of the layer medicines
GreaseStearate Mg, SiO20.1 to 5% of the layer medicines
Eject layerThe osmotic agent NaCl, mannitol, fructose and the like10-90% of the buoyancy layer
Osmotic polymerThe polyethylene oxide (PEO)10-90% of the buoyancy layer
AntioxidantBHT0.01 to 0.5% of PEO
BinderHPMC, PVP, HPC, and the like0.5 to 30% of the buoyancy layer
GreaseStearate Mg, SiO20.1 to 5% of the buoyancy layer
The composition of the semi-permeable membraneFilm-forming agentThe cellulose acetate3-50% increase in weight two-layer tablets
A pore-forming agent(HPMC, PVP, HPC, etc)
The plasticizerDibutylsebacate, triethylcitrate, PEG, and the like

Part of the API, as described in the above examples, prepared by physical mixing or granular the project for a part of the API diacerein together with PEO, osmotic agent, a binder and an antioxidant, and then mixing with the lubricant with the receiving layer of the medicinal product. Not necessarily, in the preparative form a layer of a medicinal product may include acidifying agent or a buffering agent. Eject the layer is also prepared by physical mixing or granulation. A semi-permeable membrane is introduced by dissolving cellulose acetate together with a pore-forming agent and a plasticizer in an organic solvent, and then the implementation of the method of applying a coating device for coating tablets. The passage is formed by laser or mechanical drilling on the film surface CA to layer medicines

Example 13

System with an osmotic pump (push-pulling)

Representative preparative form with osmotic pump for push-pull shown in Table 15.

Table 15
The formula I
Ingredientsmg%
Layer medicinesDiacerein100,0020,00
PEO (MW 200000)282,2556,45
NaCl100,0020,00
HPMC E515,003,00
BHT (bottled hydroxytoluene)0,250,05
Glyceril the monostearate2,500,50
Just for the layer medicines500,00100,00
Eject layerPEO (MW 7000000)194,0077,48
NaCl50,0019,97
HPMC E55,002,00
BHT0,1250,05
glycerylmonostearate 1,250,50
Just to eject layer250,38100
Palanimanickam membraneTwo-layer tablet750,3883,34
Cellulose acetate (CA-398)112,512,49
PEG 40007,50,83
HPC (Klucel EF)303,33
Acetone/water*On demandOn demand
Only900,38100,00
* Evaporates during processing

The formula I are prepared using the method described in Example 12.

Example 14

System with an osmotic pump (deepening in situ)

Acceptable ranges for components representative preparative forms with an osmotic pump (with the deepening of in-situ) are shown in Table 16.

Table 16
IngredientsExamplePercentage
Tablet coresAPIDiacerein, diacerein in solid dispersion or in the form of complexes with cyclodextrins10-90% of the tablet core
The osmotic agentNaCl, mannitol, fructose and the like10-90% of the tablet core
Osmotic polymerThe polyethylene oxide (PEO)10-90% of the tablet core
AntioxidantBHT0.01 to 0.5% of PEO
BinderHPMC, PVP, HPC, and the like0.5 to 30% of the tablet core
GreaseStearate Mg, glyceril the monostearate, SiO2and things0.1 to 5% of the tablet core
TrackHydrophilic HPMC, HPC, PVP, HEC and the like0.5 to 15% increase
sealed coverpolymer(NaCl, sugar and the like)mass of the tablet cores
The osmotic agent
Grease
(Talc, SiO2and the like)
Composition palanimanickam membraneFilm-forming agent
A pore-forming agent
The plasticizer
The cellulose acetate
(HPMC, PVP, HPC, sugar and the like)
Dibutylsebacate, triethylcitrate, PEG, and the like
1-20% weight gain from the pill with a waterproof coating

Way

Part of the API is prepared as described in the above examples. Part of the API diacerein physically mixed or granularit together with PEO, binder, osmotic agent and antioxidant. The mixture is stirred together with lubricating substances, and then pressed to obtain the tablet core. Not necessarily, in the preparative form tablet cores may include acidifying agent or a buffering agent. The solution hermetic coating is prepared by dissolving or dispel is the formation of hydrophilic polymer, the osmotic agent and lubricating substances in the water, then spraying the coating solution over the tablet cores in a device for coating. A semi-permeable coating is prepared by dissolving cellulose acetate together with a pore-forming agent and a plasticizer in an organic solvent and then spraying the coating solution on the tablet with a hermetic coating device for coating. During the dissolution of the dosage form is formed, at least one passage.

Example 15

System with an osmotic pump (deepening in situ)

Representative preparative form with an osmotic pump (deepening in situ) are shown in Table 17.

tr>
Table 17
Formula J
Ingredientsmg%
Layer medicinesDiacerein100,0019.93 per
PEO (MW 5000000)48,00to 9.57
PEO (MW 200000)192,0038,27
NaCl139,0027,70
Sodium lauryl15,002,99
BHT (bottled hydroxytoluene)0,250,05
SiO22,500,50
Glyceril the monostearate5,001,00
Just for the layer medicines501,75100,00
Tight coatingTablet cores501,7597,29
Opadry10,502,04
NaCl3,500,67
Water*On demandOn demand
Just for the Germa the ranks coating 515,75100,00
Palanimanickam membraneTablet with waterproof coating515,7597,06
Cellulose acetate (CA-398)of 9.301,750,1
PEG 4000,805
Triacetin0,800,15
Mannitol4,700,88
Acetone/water*on demandon demand
Only531,35100,00
* Evaporates during processing

The formula J prepared using the method described in Example 14.

Example 16

Preparative form with delayed release (matrix system)

Acceptable ranges for the components of a representative matrix preparative forms with delayed release shown in Alice 18.

Table 18
IngredientsPercentage
The core of delayed release
APIDiacerein, micronized diacerein or crushed together diacerein10-90% from the nucleus
The polymer with a slow releaseSwelling in water of the polymers, hydrophilic polymers (HPMC, HPC, HEC, MC, sodium CMC, and the like), hydrophobic polymers (EC, PVA, methyl methacrylate, and the like), waxes (glycerinated, cetyl alcohol and the like) or a combination of polymers10-50% from the nucleus
ThinnersMicrocrystalline cellulose, dextrose, starch, sucrose, lactose, sorbitol, mannitol and calcium phosphate10-50% from the nucleus
BinderPVP, HMPC, HPC1-20% of cores
Baking powder L-HPC, sodium glycolate, sodium, croscarmellose1-10% of cores
LubricantsStearate Mg0.1 to 5% from the nucleus

Method.

Preparative form with delayed release of the present invention can be prepared by direct compression, compaction-granulation, wet granulation or extrusion and spheronization.

In the case of direct extrusion or compaction-granulation, preparative form with delayed release can be obtained in such a way that diacerein, swelling polymer, diluent, loosening agent, binder and lubricating substance are mixed, followed by granulation using computeruser granulator (for example, roller computeruser device), sifting through a sieve of about 20 mesh and tableting.

In the case of wet granulation, preparative form with delayed release can be obtained in such a way that diacerein, swelling polymer, diluent, loosening agent, and the binder are mixed in wysokosciowe the granulator with the addition of water or solvent (e.g. ethanol or isopropyl alcohol). Then the granules are dried, crushed and mixed with the lubricant and tabletirujut.

In the case of extrusion and spheronization, preparative form with delayed release can be obtained in such a way that diacerein, swelling polymer, diluent, loosening agent, binder and lubricating substance is mixed in discodiva granulator or mixer with the addition of water or solvent (e.g. ethanol or isopropyl alcohol). The wet mass is added in a single screw or twin screw extruder, the extrudate spheronized device Marumerizer with getting balls with a slow release.

Example 17

Representative matrix preparative form of tablets with delayed release are shown in Table 17.

Table 19
Formula K
Ingredientsmg%
PelletDiacerein10020,0
HPMC17535,0
MCC 14729,4
SLS5010,0
L-HPC255,0
GreaseStearate Mg30,6
Only5000,100

The formula K prepared using the method described in Example 16.

Example 18

Membrane-controlled system

Acceptable ranges of components representative preparative forms membrane-controlled system with a slow release are shown in Table 20.

Table 20
IngredientsPercentage
The tablet core or ball
APIDiacerein, micronized diacerein or crushed together diacerein10-90% from the nucleus
ThinnersLactose, MCC, man is it sorbitol and the like10-90% from the nucleus
BinderPVP, HPC, HPMC, and the like1-10% of cores
LubricantsStearate Mg0.1 to 5% from the nucleus
Film coating
The composition of the membrane controlled releaseHydrophobic polymers (EC, PVA, methyl methacrylate, and the like), a pore-forming agent (HPMC, PVP, HPC, and the like), a plasticizer (dibutylsebacate, triethylcitrate, PEG, and the like)3-50% increase in weight from the pills kernel

Method.

The tablet cores are prepared by direct compression, use the compacting-granulation or wet granulation. The bead core is prepared by granulation in the fluidized bed.

When using direct pressing or compacting-granulation, tablet cores can be prepared in such a way that diacerein, a diluent, a binder and a lubricating substance are mixed, followed by granulation using computeruser granulator (n is an example, roller computeruser devices), by sieving through a sieve of about 20 mesh and pelletizing.

When using wet granulation, tablet cores can be prepared in such a way that diacerein, diluent and binder are mixed in wysokosciowe the granulator with the addition of water or solvent (e.g. ethanol or isopropyl alcohol). Granules optionally dried, crushed and mixed with the lubricant, and tabletirujut.

For the preparation of the core ball, the balls can be prepared in such a way that diacerein, diluent and binder granularity in the granulator, fluidized bed with the addition of water or solvent (e.g. ethanol or isopropyl alcohol). Pellet beads are then dried and sieved through an appropriate sieve.

Materials with controlled release of dissolved together with a pore-forming agent and a plasticizer in an organic solvent to obtain a coating solution for the above tablets or balls kernel. Then on tablets or pellets are coated or device for coating on the pill or device for coating fluidized bed.

Example 19

Preparative form into balls for membrane-controlled system

Representati the Naya preparative form into balls for membrane-controlled system is shown in Table 21.

Table 21
Formula L
Ingredientsmg%
The ball coreDiacerein10022,7
Lactoseof 302.668,8
SLS13,23
PVP225,0
Stearate Mg2,20,5
Just for kernel440100
Tight coatingThe ball core44097,3
HPMC81,8
Talc4 0,9
Just for sealed cover452,0100,0
Floor SRBalls with a waterproof coating452,090,4
EC306,0
PVP153,0
TEC30,6
Only500,0100,0

Example 20

Preparative form with a matrix of hydrogel

Representative formulations of the matrix of the hydrogel are shown in Table 22.

142,5
Table 22
DIAC-2001DIAC-2002DIAC-2005DIAC-2006DIAC-2017DIAC-2018
Ingredients mg/tab.% solid. productsmg/tab.% solid. productsmg/tab.% solid. productsmg/tab.% solid. productsmg/tab.% solid. productsmg/tab.% solid. products
Diacerein (Highsun))50,020,050 020,0
Diacerein (TRB)50,020,050 020,0
Diacerein (micronized) 50,020,050,020,0
HPMC K4MCR50,020,0100,040,0%25,010,0
HPMC K100LVCR25,010,050,020,075,030,0100,040,0
Mannitol142,557,092,537,0142,557,057,0115,046,090,036,0
HPMC E5LV7,53,07,53,0
Povidone K305,02,05,02,05,02,05,02,0
Stearate Mg2,51,02,51,02,51,02,51,02,51,02,51,0
Only250,0100,0250,0100,0250,0100,0250,0100,0250,0100,0250,0100,0

Diacerein (Highsun) refers to diacerein produced by Taizhou Highsun Pharmaceutical Co., Ltd.

Diacerein (TRB) refers to diacerein produced by TRB Chemedica.

"HPMC K4MCR," "HPMC K100LVCR, and HPMC E5LVCR" represent different products hypromellose METHOCEL™ manufactured by Dow Chemical Company.

Example 21

These dissolution for preparative forms the matrix of the hydrogel

The dissolution studies carried out on preparative forms of diacerein with the matrix of the hydrogel of Example 20. Studies of the dissolution is carried out in accordance with the so-called "baskets" and/or "way of the impeller and sinkers".

Way "baskets"

"The way baskets" uses the device 1 USP. It usually operates at 100 rpm (revolutions per minute) and is typically used for preparative forms in the form of balls. The FDA statement contain a description of the method "baskets".

"The way of the impeller and sinkers"

Way of the impeller and sinkers" uses us what the device 2 USP. It usually operates at 50 rpm "Sinker" can represent any wire wrapped around the capsules before the capsule is placed in the vessel for dissolution. Instructions FDA contain descriptions of the way "of the impeller and sinkers".

Both methods are usually used at 37°C±0.5°C. Samples are usually dissolved in 900 ml aqueous media.

Table 23 shows the results of dissolution studies carried out on preparative forms DIAC-2002, DIAC-2005, DIAC-2017 and DIAC-2018. All studies carried out using PBS buffer, pH of 6.0. Studies on formulation DIAC 2002 and DIAC-2005 carried out using the method of "baskets" at 100 rpm, and research on formulation DIAC-2017 and DIAC-2018 carried out using the method of the impeller and sinkers" at 100 rpm

Table 23
DIAC-2002DIAC-2005DIAC-2017DIAC-2018
Time (h)AVG. valueArticle off.AVG. valueArticle off.AVG. the value Article off.AVG. valueArticle off.
2264,6242,236the 13.4232,5
4517,6484,1648,9444,8
6666,8680,8856,1646,7
8785,2822,7931,9786,6
12881,796 950,7942,3
16891,0973,0950,7961,1
"Article. off." stands for "standard deviation"

Table 24 shows the results of dissolution studies carried out on preparative forms DIAC-2001, DIAC-2002, DIAC-2005 and DIAC-2006. All studies carried out using PBS buffer, pH 6,8, and how "baskets" at 100 rpm Research carried out three times, and the table shows the data for the average of these three measurements.

Table 24
DIAC-2001DIAC-2002DIAC-2005DIAC-2006
Time (h)AVG. valueArticle off.AVG. value Article off.AVG. valueArticle off.AVG. valueArticle off.
2230,2120,3329,0493,6
4440,1221,45414,9787,0
6580,7313,66916,893the 3.8
8681,2395,07713,9904,0
12791,4/td> 505,0854,386the 3.8
16871,1597,0860,583the 3.8

Example 22

Formulation with delayed release

Representative formulations of sustained-release are shown in Tables 25-29 as follows. Tables 25 and 26 show the composition of the active layer preparative forms DIAC-3002, DIAC-3004, DIAC-3006, DIAC-3007, DIAC-3008, DIAC-3010, DIAC-3011 and DIAC-3012; Tables 27 and 28 show the composition of the layers of film with a slow release (SR) these preparative forms and table 29 shows the composition of the layers of film with a delayed release (DR) preparative forms DIAC-3007, DIAC-3008, DIAC-3011 and DIAC-3012 (all other preparative forms do not contain layer film DR).

Table 25
The active layer
IngredientsDIAC-3002 DIAC-3004DIAC-3006DIAC-3007
mg/caps.% solid. productsmg/caps.% solid.
products
mg/caps.% solid.
products
mg/caps.% solid.
products
Cellets® 35010048,8%100,047,6%100,047,6%
Cellets® 700100,047,6%
Diacerein (Highsun)50,024,4%50,023,8%50,023,8% 50,023,8%
Diacerein (TRB)
Povidone K305,02,4%10,04,810,04,8%10,04,8%
Mannitol50,024,4%50,023,8%50,023,8%50,023,8%
Only205,0100,0%210,0100,0%210,0100,0%210,0100,0%

Cellets® 350 and Cellets® 750 are neutral source kernel for preparative forms with kontroliruemym release, produced Glatt Group.

Table 26
The active layer
IngredientsDIAC-3008DIAC-3010DIAC-3011DIAC-3012
mg/caps.% solid. productsmg/caps.% solid. productsmg/caps.% solid. productsmg/caps.% solid. products
Cellets® 350100,047,6%100,047,6%100,047,6%100,047,6%
Diacerein (Highsun)50,023,8%
Diacerein (TRB)50,023,8%50,023,8%50,023,8%
Povidone K3010,04,8%10,04,8%10,04,8%10,04,8%
Mannitol50,023,8%50,023,8%50,023,8%50,023,8%
Only210,0100,0%210,0100,0%210,0100,0%210,0100,0%

Table 27
The film layer SR
IngredientsDIAC-3002DIAC-3004DIAC-3006DIAC-3007
mg/caps.% solid. productsmg/caps.% solid. productsmg/caps.% solid. productsmg/caps.% solid. products
Ethocel 10 cps36,4%36,4%36,4%21,036,4%
Povidone K3036,4%36,4%36,4%21,036,4%
Triethylcitrate7,3%7,3% 7,3%4,27,3%
Talc20,0%20,0%20,0%11,520,0%
Only100,0%100,0%100,0%57,6100,0%

Table 28
Film SR
IngredientsDIAC-3008DIAC-3010DIAC-3011DIAC-3012
mg/caps.% solid. productsmg/caps.% solid. productsmg/caps.% solid. productsm is/caps. % solid. products
Ethocel 10 cps21,036,4%36,4%18,236,4%18,236,4%
Povidone K3021,036,4%36,4%18,236,4%18,236,4%
Triethylcitrate4,27,3%7,3%3,6to 7.2%3,6to 7.2%
Talc11,520,0%20,0%10,020,0%10,020,0%
Only57,6100,0%100,0 50,0100,0%50,0100,0%

Table 29
The film layer is DR
IngredientsDIAC-3007DIAC-3008DIAC-3011DIAC-3012
% solid. products% solid. products% solid. products% solid. products
Eudragit L30D-5566,9%
Eudragit S10066,9%66,9%
Eudragit L10066,9%
Triethylcitrate10,0%10,0%10,0% 10,0%
Talc23,1%23,1%23,1%23,1%
Just for the film layer100,0%100,0%100%100%

Example 23

These dissolution for preparative forms with delayed release

The dissolution studies carried out on preparative forms of diacerein delayed release of Example 22. Studies of the dissolution is carried out in accordance with the method of "baskets" and/or "way of the impeller and sinkers", as described in Example 21.

Table 30 shows the results of dissolution studies carried out on preparative forms DIAC-3002, DIAC-3004, DIAC-3006 and DIAC-3007. All studies carried out using PBS buffer, pH of 6.0, and using the method of "baskets" at 100 rpm

Table 30
Time (h)DIAC-3002DIAC-3004DIAC-3006DIAC-3007
/td> 6% SR*18% SR7% SR16% of SR6% SR18% SR19% DR
AVG. valueAVG. valueAVG. valueAVG. valueAVG. valueAVG. valueAVG. value
2261397291623
449251512512735
66935211672 3845
885462720884854
12996439281026772
161028051351058285
* % refers to the percentage of the polymer with a slow release (SR) or with the delayed release (DR) in each study preparative form

Table 31 shows the results of dissolution studies carried out on preparative forms DIAC-3010 and DIAC-3011. All studies carried out using PBS buffer, pH of 6.0, and using the method of "baskets" at 100 rpm

Table 31
Time (h)DIAC-3010DIAC-3011
16% of SR6% DR19% DR
AVG. valueAVG. valueAVG. value
2453
47108
6111413
8141917
12202625
16263433

Table 32 shows the results of dissolution studies carried out on preparative forms DIAC-3004, DIAC-3006 and DIAC-3007. All the surveys carried out using PBS buffer, pH of 6.8, and using the method of "baskets" at 100 rpm

Table 32
Time (h)DIAC-3004DIAC-3006DIAC-3007
7% SR16% of SR18% SR19% DR
AVG. valueAVG. valueAVG. valueAVG. value
246256792
4844893120
6986997119
8978695116
12 939591112
16929389110

Table 33 shows the results of dissolution studies carried out on preparative forms DIAC-3008, DIAC-3010, DIAC-3011 and DIAC-3012. All studies carried out using PBS buffer, pH 6,8, and using the method of "baskets" at 100 rpm

Table 33
Time (h)DIAC-3008DIAC-3010DIAC-3011DIAC-3012
5% DR13% DR7% SR16% of SR7% DR19% DR5% DR
AVG. valueAVG. valueAVG. valueAVG. valueAVG. value AVG. valueAVG. value
2155442228271
4589724254522
68715865975744
89527917491917
12936992909810316
169191929610132

1. Preparative form of diacerein controlled release for administration once daily for the treatment of inflammatory diseases, autoimmune diseases or their complications with reduced negative side effects, containing the core, the active layer, the film layer delayed release and the film layer delayed release, where the first active layer, then layer with a slow release and after the layer delayed release, where the specified layer of the film with a slow release includes the polymer ethyl cellulose, povidone, triethylcitrate and talc and where the film layer delayed release includes the polymer Eudragit®triethylcitrate and talc.

2. Preparative form controlled release under item 1, where the preparative form is a membrane-controlled preparative form, matrix preparative form or preparative form with an osmotic pump.

3. Preparative form controlled release under item 2, where the preparative form provides increased bioavailability compared with the preparative form with quick release.

3. PR is parachilna form controlled release under item 1, where preparative form contains a surface-active agent, acidifying agent or a buffering agent.

4. Preparative form controlled release under item 1, where the particle size of diacerein less than 2000 microns.

5. Preparative form controlled release under item 1, where diacerein is present as an amorphous state in a solid medium.

6. Preparative form controlled release under item 1, where diacerein is formed as a complex with cyclodextrin.

7. Preparative form controlled release under item 1, where diacerein is crystalline.

8. Preparative form controlled release under item 1, where the preparative form, containing 50 mg of diacerein supports concentration Reina in the plasma is higher than a concentration of 1 mg/l for more than 12 hours in humans, when administered orally to the patient-the person who has reached a stationary state.

9. Preparative form controlled release under item 1, where the preparative form containing 100 mg of diacerein supports concentration Reina in the plasma is higher than a concentration of 2 mg/l for more than 12 hours in humans, when administered orally to the patient-the person who has reached a stationary state.

10. Preparative form controlled release under item 1, where the preparative fo the mA containing 150 mg of diacerein supports concentration Reina in the plasma is higher than the concentration of 3 mg/l for more than 12 hours in humans, when administered orally to the patient-the person who has reached a stationary state.

11. Preparative form controlled release under item 1, where the preparative form containing 200 mg of diacerein supports concentration Reina in the plasma is higher than a concentration of 4 mg/l for more than 12 hours in humans, when administered orally to the patient-the person who has reached a stationary state.

12. A method of treating inflammatory diseases, autoimmune diseases or their complications, including introduction to the subject in need this, preparative forms of diacerein controlled release for administration once a day under item 1, where this method leads to fewer negative side effects than with the introduction of preparative forms of diacerein with quick release.

13. The method according to p. 12, in which the specified negative side effect is a diarrhea.

14. The method according to p. 12, in which the preparative form controlled release introduced for the treatment of diabetes type I/type II or osteoarthritis.

15. The method according to p. 12, in which the preparative form controlled release introduced for the treatment of Oslo is on the diabetes type I/type II.

16. The method according to p. 15, in which the complications of diabetes type I/type II oral introduction to the patient-the person represent nephropathy, retinopathy, neuropathy or foot ulcers.

17. Preparative form controlled release under item 1, in which the specified active layer contains between about 40.0 and about to 50.0 wt.% microcrystalline cellulose, between about 20,0 and about 30.0 wt.% diacerein, between about 2.0 and about 5.0 wt.% of povidone and between approximately 20,0 and about 30.0 wt.% mannitol.

18. Preparative form controlled release under item 1, where the specified active layer contains about to 50.0 wt.% microcrystalline cellulose, about to 25.0 wt.% diacerein, about 2.0 wt.% of povidone and about 23,0 wt.% mannitol.



 

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5 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of organic chemistry, namely to heterocyclic compound of general formula (I) or to its pharmaceutically acceptable salt, acid salt or stereoisomer, where Y: NRa and N+R1R2X-; Z: bond, -(CH2)p, -CHOH, -CH=CH-, -C≡C-, -CONH- and -CO-; Rb: C1-C8 alkyl, C2-C8 alkenyl, C6-C10 aryl, -NR5R6,: , and ; with each alkyl, alkenyl and aryl, representing Rb, possibly, contains 1-3 substituents, selected from C1-C4 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, C1-C4 alkoxy, C6-C10 aryl, 5-, 6- and 7-membered heterocyclyl, containing 1-3 heteroatoms, selected from nitrogen, oxygen and sulphur, halogen, -OH, -NH2, -CN and -NO2; Rc: halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkinyl, C3-C10 cycloalkyl, C3-C8 cycloalkenyl, C1-C4 alkoxy, C6-C10 aryl, 5-, 6-, 7- and 8-membered monocyclic heterocyclyl, containing 1-3 heteroatoms, selected from nitrogen, oxygen and sulphur, 9- and 10-membered bicyclic heterocyclyl, containing 1-3 heteroatoms, selected from nitrogen, oxygen and sulphur; with C1-C6 alkyl, C2-C6 alkenyl C2-C6 alkinyl, C3-C10 cycloalkyl, C3-C8 cycloalkenyl, C6-C10aryl, 5-, 6-, 7-, 8-membered monocyclic heterocyclyl and 9- and 10-membered bicyclic heterocyclyl, representing Rc, possibly contain 1-5 substituents, selected from the group, consisting of C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C6 cycloalkyl, C4-C8 cycloalkenyla, halogen, -OH, -NH2, C6-C10 (A)(A')(A")(A'")aryl, (A)(A')(A")(A'")heterocyclyl, containing 1-3 heteroatom, selected from nitrogen, oxygen and sulphur, NR14R15, (CH2)pNR14R15, -CN, -NO2, oxo, -COOR14, SOR14, SO2R14, SO2NR14R15, NR15SO2R16, COR14, CONR14R15 and NR15COR16; with each (A), (A'), (A") and (A'")independently absent or representing C1-C4 alkyl, and each heterocyclyl (A)(A')(A")(A'")heterocyclyl is independently selected from the group, consisting of 5-, 6-, 7- and 8-membered monocyclic heterocyclyl, containing 1-3 heteroatoms, selected from nitrogen, oxygen and sulphur, and 9- and 10-membered bicyclico heterocyclyl, containing 1-3 heteroatoms, selected from nitrogen, oxygen and sulphur; the remaining radicals have values given in i.1;and on condition that, if Rc represents heterocyclyl, said heterocyclyl is bound directly through carbon atom of heterocyclyl ring. Invention also relates to particular compounds and to pharmaceutical composition based on formula (I) compound.

EFFECT: obtained are novel imidazopyrazine and imidazodiazepine derivatives, useful for prevention or treatment of disease or condition, severity of which is reduced by receptors to cannabinoids.

21 cl, 5 dwg, 4 tbl, 71 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I) - oxytocin receptor agonists, to their pharmaceutical compositions containing them.

EFFECT: compounds can be used for preparing a drug for treating, among others, abdominal pain, irritable bowel syndrome (IBS), autism, erectile dysfunction, female sexual dysfunction, delivery stimulation and maintenance, lactation stimulation and maintenance, post-delivery syndrome, posttraumatic stress disorder (PTSD), pain, anxiety and other conditions.

19 cl, 1 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to isoxazoline FAAH inhibitors of formula (I) or their pharmaceutically acceptable forms, wherein each of G, Ra, Rb, Rc and Rd has a value described in the present application, to pharmaceutical compositions, and methods of treating a FAAH-mediated condition.

EFFECT: developing the method of treating the FAAH-mediated condition.

32 cl, 22 tbl, 351 ex

FIELD: chemistry.

SUBSTANCE: in claimed co-crystalline form molar ratio of 2-hydroxybenzamide and salicylic acid constitutes 1:1. Co-crystalline form is characterised by peaks at 2θ(°) 11.5, 14.8, 16.7, 18.8, 22.2, 23.5, 27.0 by the data of measurement of X-ray radiation diffraction on powder, and has endothermic peak from 116 to 124°C by the data of measurement by means of differential scanning calorimetry. Claimed co-crystalline form can be applied for manufacturing pharmaceuticals.

EFFECT: increased solubility of 2-hydroxybenzamide.

7 dwg, 2 ex

FIELD: food industry.

SUBSTANCE: biologically active food additive strengthening the organism adaptive power and body defences and having anti-inflammatory and antioxidant activity contains vegetal origin components represented by a complex extract of devil's-club root, Rhaponticum carthamoides root, Hedysarum neglectum Ledeb root, celery roots and leaves, rhodiola rosea root, Japanese angelica tree roots, boschniakia rossica roots, Hungarian sainfoin herb, magnolia-vine fruits; additionally the additive contains chitosan, trepang fermentative hydrolysate, ascorbic acid, taurine, glutathione, nicotinamide, vitamin B1, vitamin B2, vitamin B6, vitamin B12, folic acid, anhydrous calcium chloride, magnesium chloride, zinc chloride, bee honey at preset ingredients ratio.

EFFECT: biologically active food additive promotes effective strengthening of the organism adaptive power and body defences and human aging retardation.

4 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to medication, representing betulin bis-isonicotinoate .

EFFECT: low toxicity, expressed anti-ulcer, anti-inflammatory and hepatoprotective activity.

3 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: non-invasive treatment of Dupuytren's contracture of degree III-IV is ensured by injecting Collalysin dissolved in 2% Novocaine into a subcutaneous fold or nodes in a projection of fetlock, proximal digital joints and/or into a fold base; 24 hours later, the fold is separated from the skin subcutaneously; the skin is mobilised, and the involved finger (fingers) are redressed.

EFFECT: invention enables the non-invasion recovery of the complete motion function of the fingers.

4 dwg, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of biochemistry, in particular to single variable domain, aimed against IL-6R, to polypeptide and construction, directed against IL-6R, containing said single variable domain, as well as to methods of obtaining them. Disclosed are nucleic acids, coding said single variable domain, polypeptide and construction, as well as genetic constructions, containing said nucleic acids. Described are host cells and host organisms, containing said nucleic acids. Invention also deals with composition for blocking interaction of IL-6/IL-6R, containing effective quantity of described single variable domain, polypeptide, construction, nucleic acid or genetic construction. Also disclosed is method of prevention and/or treatment of at least one of diseases or disorders, associated with IL-6, IL-6R, complex IL-6/IL-6R and/or signal pathways, in which IL-6, IL-6R or complex IL-6/IL-6R is involved and/or biological functions and reactions, win which IL-6, IL-6R or complex IL-6/IL-6R takes part with application of described single variable domain, polypeptide, construction or composition.

EFFECT: invention makes it possible to block interaction of IL-6/IL-6R effectively with increased affinity and biological activity.

25 cl, 70 dwg, 56 tbl, 61 ex

FIELD: medicine.

SUBSTANCE: method for integrated treatment of hip diseases accompanying a total replacement involves a postoperative background therapy with using an infusion therapy, an antibiotic therapy, an anticoagulant therapy, therapeutic exercises and a physical therapy; aqueous herbal tea containing willow bark, common St.-John's wort herb, balm lemon herb, liquorice root, meadowsweet herb, mountain ash fruit, raspberry leaves taken in certain proportions 14 days before the operation and for three postoperative months in a dose of 0.5 glass 4 times a day half an hour before a meal.

EFFECT: method enables providing the higher effectiveness of the surgical management of hip diseases by improving patient's rehabilitation, promotes reducing trait and state anxieties, a rate of administration of analgesic preparations, improving the motor function of limbs and preventing postoperative complications.

1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to the pharmaceutical industry, particularly to a composition possessing anti-inflammatory properties. The composition with the anti-inflammatory properties comprising a herbal extract prepared by extracting rose hip shells or rose hip shells and kernels in water or a mixture of water and ethanol followed by purifying and drying together with collagen hydrolysate. A method for preparing the composition. The composition with the anti-inflammatory properties. Using the composition for preparing a therapeutic agent or a biologically active food supplement or a balanced diet for preventing or for relieving symptoms accompanying joint complaints. The therapeutic agent with the anti-inflammatory properties containing the composition. The biologically active food supplement with the anti-inflammatory properties containing the composition. The balanced dietary product with the anti-inflammatory properties containing the composition.

EFFECT: agents possess the evident anti-inflammatory properties.

10 cl, 13 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to traumatology and orthopaedics, and aims at conservative treatment of plantar fasciitis. That is ensured by administering platelet rich autoplasma in an amount of 2.0 ml for each injection into an attachment point of the plantar aponeurosis to the calcaneum (the heel sac), inner and outer side surfaces of a midfoot, as well as to a plantar surface of the midfoot. The autoplasma is prepared 1-2 hours before the procedure, and it contains from 1243 thousand/mcl to 3029 thousand/mcl platelets. The normal autoplasma contains from 162 thousand/mcl to 358 thousand/mcl platelets. The autoplasma is activated with 0.25% CaCl2 in a ratio of 2:1 with added 5% sodium hydrocarbonate in a ratio of 1:20 to the prepared platelet rich plasma.

EFFECT: above method enables providing pain management, recovering the extremity function, ensuring the stable clinical effect, and preventing complications.

2 ex

FIELD: medicine.

SUBSTANCE: group of inventions deals with medical prostheses for implantation into a human organism and methods of their manufacturing, in particular prosthesis of the jaw bone, which can be used in cosmetic surgery of the jaw bone or in the jaw bone reconstruction. Claimed is an implant of the jaw bone, manufactured in accordance with the method, including the following stages: selection of material of animal origin from an organism of cattle or pigs, with the material of animal origin being the jaw bone; shaping the material of animal origin to obtain a desirable shape of the jaw bone implant; removal of cells from the material of animal origin, crosslinking of the material of animal origin; removal of antigens from the material of animal origin; subjection of the material of animal origin to alkaline processing; introduction of active substances, improving adhesion on the implant of the growth factor and stem cells, produced by the human organism into the material of animal origin; packing the material of animal origin into a container with a sterilising solution. The jaw bone implant, manufactured by the said method, possesses high tissue compatibility.

EFFECT: group of inventions provides elimination of development or, at last, minimisation of phenomena of various types of discomfort under an impact of moving muscles in the period of the implant growing into tissues of the host organism, resorption and replacement with the new bone tissue with simultaneous provision of high tissue compatibility with elimination, or, at least, minimisation of phenomena of immunological rejection of a biological prosthesis of the jaw bone.

14 cl, 1 ex, 4 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) , where R1 and R2 have the following values: (i) R1 and R2 together form =O; (ii) R1 and R2 together with carbon atom, which they are bound with, form duoxacycloalkyl; R1 represents hydrogen or halogen; and R2 represents halogen; (iv) R1 represents C1-6alkyl, where alkyl is optionally substituted with cyano, -RxS(O)qRv or -RxNRyRz; and R2 represents hydrogen; (v) R1 represents -OR12 or -NR13R14; and R2 represents hydrogen, deutero or phenyl, which is optionally substituted with halogen; R3 represents hydrogen, halogen, C1-6alkyl, cyano, halogen C1-6alkyl, C3-10cycloalkyl or C1-6alkoxy; R4 and R5 represent hydrogen; R6 is independently selected from halogen, C1-6alkyl, halogenC1-6alkyl, -RxOR18 and -RxS(O)qRv; R7 independently represents halogen or -RxORw; R12 is selected from hydrogen and C1-6alkyl, R13 represents hydrogen; R14 is selected from hydrogen, C3-10cycloalkyl, -C(O)Rv and -C(O)ORw; R18 represents hydrogen, C1-6alkyl, or pyperidinyl, where R18 is optionally substituted with 1-3 Q1 groups, each Q1 is independenly selected from hydroxyl, C1-6alkoxy, C1-6alkoxycarbonyl, carboxyl and morpholinyl; Rx independently represents C1-6alkylene or simple bond; Rv and Rw represent hydrogen or C1-6alkyl; Ry and Rz represent hydrogen; n has value 0-4; p has value 0-5; and each q independently has value 0, 1 or 2. Invention also relates to compounds of formula (II) , where substituents have values, given in the invention formula, to pharmaceutical composition, possessing inhibiting activity with respect to JAK kinases, containing compounds of formula (I) or (II), methods of treating JAK-modulated disease, and application of compounds of formula (I) or (II).

EFFECT: compounds of formula (I) or (II) as inhibitors of JAK kinases.

32 cl, 6 dwg, 2 tbl, 84 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to treating arthropathies, such as arthrosis and inflammatory loss of cartilage, tendon disorders and/or degenerative spine diseases. What is presented is a pharmaceutical composition for the above application, containing a corticosteroid and a cytokine antagonist - a natural or recombinant protein of interleukin IL-1Ra antagonist, particularly orthokine or anakinra, and optionally a growth factor; the composition is injectable into an injured nerve root, or into an injured intervertebral disk, or into their local context, or for intraarticular injection. There are presented: a kit comprising the pharmaceutical composition with the above cytokine antagonist and optionally the growth factor, and the pharmaceutical composition with the corticosteroid; using the above cytokine antagonist and optionally the growth factor for preparing the pharmaceutical composition to be used in combination therapy together with the corticosteroid for the above application; using the corticosteroid for preparing the pharmaceutical composition to be used in combination therapy with the above cytokine antagonist and optionally the growth factor for treating the above arthropathies, tendon disorders and/or degenerative spine diseases.

EFFECT: clinical success of treatment manifested by apparent joint detumescence, pain reduction by 60-100%, functional improvement of the joint, with the effect persisting 8 months later and more after the treatment.

39 cl, 1 tbl

FIELD: medicine.

SUBSTANCE: composition for treating and preventing osteoarthritis and osteoarthrosis contains a powder or an extract of a dry plant specified in a group: burdock, dandelion, cowberry, birch, St.-John's wort, golden-rod, nettle, peppermint, licorice, cinquefoil, tormentil, brier, Greek valerian, valerian, corn, holy thistle, oat, agrimony, everlasting flower, ginseng, sage, starwort, squash, willow, wild strawberry, chicory, wheat-grass, Jerusalem artichoke, bilberry, marigold, horse radish, garlic, aspen, knotgrass, plantain, inula, Fagopyrum rubricaulis, chamomile flowers, balm lemon, blue poppy, cudweed, tripartite bur-marigold; a male larval bee lyophilisate and a quercetine or dihydroquercetine, or rutin powder in certain proportions.

EFFECT: composition is effective for treating and preventing osteoarthritis and osteoarthrosis, maintains the nutrition of the osteoarticular apparatus, growth and regeneration of connective tissue with no side effects, as well as enabled collagen synthesis for the recovery of connective and cartilage tissue, with preserving the anti-inflammatory and analgesic effect.

2 ex

FIELD: medicine.

SUBSTANCE: agent is prepared by boiling milled raw hard wheat grain in water, filtering, adding goat milk to the prepared brew, boiling, adding olive and sea buckthorn oil to prepare an oil mixture; further boiling milled herbal raw material in water, including chamomile blossom, elevated part of wormwood, elevated part of St. John's wort, rose hips, elevated part of mint, filtering, mixing the brew with the oil mixture to a homogenous state.

EFFECT: agent possesses high therapeutic activity in treating and preventing the locomotor diseases.

7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and represents a controlled-release aceclofenac preparation for oral administration once a day, exhibiting the fast analgesic and anti-inflammatory action, containing a fast-release layer containing aceclofenac, a solubiliser, a water-soluble additive, a disintegrating agent, a vehicle and a fast-acting additive, as well as a sustained-release layer containing aceclofenac, a solubiliser and a release control base consisting of mixture of hydroxypropyl methyl cellulose (HPMC) with a viscosity of 80,000 sP to 120,000 sP and carbomer taken in mass ratio 7:1 to 9:1.

EFFECT: invention provides a sequential and uniform dissolution rate and a controlled release of the active agent.

7 cl, 12 tbl, 11 dwg, 10 ex

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