Composition released in pulse mode at preset time

FIELD: medicine.

SUBSTANCE: composition contains: a. core composition including therapeutically active agent, swelling agent and capillary agent; b. coating composition including water-insoluble polymer and water-soluble polymer.

EFFECT: composition releases therapeutically active agent in pulse mode at preset time.

21 cl, 15 tbl, 7 ex

 

The technical FIELD of the INVENTION

The present invention relates to a structure allocated in a pulsed mode at a specified time in a pulse mode at approximately the specified time reliably distinguishes therapeutically active agent.

BACKGROUND of INVENTION

Many prototypes relate to pharmaceutical compositions, of which the drug is excreted in the delay. Some prototypes, ensuring the selection of medicines over a specified time described in U.S. patent No. 3247066; in the Irish application IE 902533; in U.S. patent No. 4871549; in U.S. patent No. 5229131; PCT publication WO 99/18938 and in PCT publication WO 00/74655. They all relate to systems consisting of a core, which after absorption of the surrounding liquid swells, and from the shell, which breaks under the pressure of the swollen core. In the prototypes discussed in U.S. patent No. 3247066, in European application 1123700, in U.S. patent No. 5260069 and in U.S. patent No. 4871549 considered a different system than the system of the present invention in that they refer to dosage forms with controlled selection. While the dose of the drug is divided into many units, and there is no guarantee that this unit will be interrupted at a specified time efficient manner. According to statistics of the different units are broken at different times and, therefore clicks the zoom, on average, over time provides a controlled release of active component. In accordance with the present invention in a single unit contains the total number of the active component, which is intended to highlight in a pulsed mode at a specified time. An important requirement for the use of such systems in relation to a large number of patients is that the system should deliver the drug in a pulsed mode approximately at a certain time in a secure manner to a large number of patients using this system. Thus, the shell should rupture reliably, the core must immediately be destroyed, then the drug should reliably be emitted in a pulsed mode. For example, if five to ten cases out of a hundred shells are not disclosed or not broken at a certain time, but the gap is much longer when tested by mixing in different modes of mixing and in different water compositions, there is no certainty that this gap will occur at the specified time. In addition, if the selection to the gap may influence the change in pH, the composition of the liquid and mixing modes, there is no assurance that the allocation will occur at the specified time. In addition, the EU and rupture of membranes, but therapeutically active drug is not allocated in pulsed mode with all or some units, there is no assurance that an allocation will occur in a pulse mode at a specified time. In the prototypes described, for example, in WO 99/18938, WO 00/74655 and IE 902533 not mentioned reliability gap or selection from a large number of tablets, or process optimization formulations to ensure reliable rupture or reliable selection with a large number of tablets. In U.S. patent No. 5229131 contains a large amount of data on the share of tablets are breaking up after 30 minutes and 60 minutes and by the share of tablets that produce their content after 60 minutes and 120 minutes (Table 12-18). Tablets do not provide a reliable gap, as provided by the composition of the present invention, with 36 of 36 tablets are broken within ±50% of the time of rupture of the membranes. Although there are many prototypes, however, there is no commercially successful systems in which was described the structure allocated in a pulsed mode at a specified time, containing:

(a) composition of the core, comprising a therapeutically active agent, a swelling agent and possibly a water-soluble composition (compositions) to initiate osmosis, and

b) the composition of the shell, including one film-forming polymer or a greater number of plank the forming polymers

characterized in that after the liquid is absorbed from the environment, the core swells and the shell is broken with the release of a reliable way in a pulsed mode therapeutically active means approximately at a specified time after oral administration of the compositions. In addition, previously not documented the ways in which would apply such compositions, providing a reliable destruction in the situation in vivo with the introduction of tablets to individuals. The composition of the present invention, emitted in a pulsed mode at a specified time, possesses these desirable characteristics so that the shell is broken and reliably produces therapeutically active means in a pulsed mode at approximately the specified time after oral administration of this composition.

The PURPOSE of the INVENTION

The aim of the present invention is a structure allocated in a pulsed mode at a specified time, including nabuhay core and a shell, after all liquid is absorbed from the environment, the core swells and the shell is broken with providing reliable output in pulse mode therapeutically active means approximately at the specified time.

Another objective of the present invention is a structure allocated in a pulsed mode at a specified time, which reliably operates in the patient's body. According to the governmental purpose of the present invention is a composition, secreted in a pulse mode at a specified time, after oral administration of this compound to the human shell is broken reliable way approximately the specified time after oral administration of this composition.

SUMMARY of the INVENTION

In the present invention proposes a structure allocated in a pulsed mode at a specified time, including:

(a) composition of the core, comprising a therapeutically active agent, a swelling agent and possibly a water-soluble composition (compositions) to initiate osmosis, and

b) the composition of the shell, including one film-forming polymer or more film-forming polymers,

characterized in that after the liquid is absorbed from the environment, the core swells and the shell is broken with the release of a reliable way in a pulsed mode therapeutically active means approximately at a specified time and under reliable gap means that after a specified period of 36 tablets torn 36, which is confirmed by tests of tablets on the solubility in aqueous medium by the method of U.S. Pharmacopeia at 37±0,5°in apparatus of the U.S. Pharmacopoeia type I or II at speeds from 50 to 100 rpm.

DETAILED description of the INVENTION

In the present invention proposes a structure allocated in a pulsed mode, the preset time, including:

(a) composition of the core, comprising a therapeutically active agent, a swelling agent and possibly a water-soluble composition (compositions) to initiate osmosis, and

b) the composition of the shell, including one film-forming polymer or more film-forming polymers,

characterized in that after the liquid is absorbed from the environment, the core swells and the shell is broken with the release of a reliable way in a pulsed mode therapeutically active means approximately at a specified time and under reliable gap means that after a specified period of 36 tablets torn 36, which is confirmed by tests of tablets on the solubility in aqueous medium by the method of U.S. Pharmacopeia at 37±0,5°in apparatus of the U.S. Pharmacopoeia type I or II at speeds from 50 to 100 revolutions per minute. In addition, if the specified time is in the range from 1 to 4 hours, 36 out of 36 tablets are broken within ±50% of the set time; and if the specified time is from 4 to 12 hours, 36 out of 36 tablets are broken within ±25% of the set time.

In accordance with the present invention the composition is emitted in a pulsed mode at a specified time, absorbs liquid from the environment that leads to swelling of the core. Then therapeutically active agent is released in a pulse of the second mode after the rupture of the membranes under the action of mechanical pressure, caused by swelling swelling funds in the core. The time of rupture of the membrane can be adjusted by changing (a) the degree and rate of swelling of the core; (b) structure allocated in a pulsed mode at a specified time, using various components and relationships between these components; and (C) the thickness of the shell.

Therapeutically active drug may be selected from a class of therapeutic agents, i.e. from alcohol alcohol drugs, drugs, drugs used in Alzheimer's disease, anaesthetics, medicines acromegaly, painkillers, anti-asthmatic medications, cancer drugs, anticoagulants, antithrombotic drugs, anticonvulsants, antidiabetic drugs, antiemetics, drugs for glaucoma, antihistamine drugs, antibacterial drugs, medicines for Parkinson's disease, medicines against platelets, Antirheumatic drugs, antispasmodics, anticholinergics drugs, antitussive funds the carbonic anhydrase inhibitors, cardiovascular drugs, cholinesterase inhibitors, Le is arctonyx means for the treatment of disorders of the Central nervous system, tools that excite the Central nervous system, drugs for the treatment of mucoviscidose, substances with affinity to the receptors of dopamine, a drug for the treatment of endometritis, therapy of erectile dysfunction drugs fertility drugs for gastrointestinal tract, immunomodulators, immunosuppressive funds, funds to improve memory, drugs for migraine headaches, muscle relaxants, nucleoside analogues, drugs for the treatment of osteoporosis, parasympathomimetics, prostaglandins, psihoterapevticheskii active drugs, sedatives, hypnotics, tranquilizers, drugs used in skin diseases, steroids and hormones.

It is generally accepted that the term "selection in pulsed mode" refers to the selection of traditional tablets and capsules, which are deprived of planned (scheduled) selection occurring slowly, prolonged, controlled. The term "selection in pulsed mode" should be understood as a characteristic selection of the drug, which provides a slow, prolonged, controlled or later allocation of therapeutically active drugs. For example, in accordance with one embodiments of the present invented the I, where desired time selection in pulsed mode is approximately 70 minutes, "the allocation of therapeutically active drugs in the pulse mode enables the selection of no more than 10% of the active component for 45 minutes and at least 70% of the active component in 2 hours when tested by the method of U.S. Pharmacopeia on solubility in the buffer with a pH of 6.8 at 37±0,5°in apparatus of the U.S. Pharmacopoeia type II a rotation speed of 75 rpm.

The swelling agent used in the composition of the emitted pulse mode at a specified time, includes one or more nabukenya gidrofilnyh polymers. The number or the relative content of the polymer change. But at the core there is enough material in the absorption of water provides the pressure caused by swelling greater than the adhesive strength of the membrane surrounding the tablet or the core. Preferably, the polymers used in the dry state or in such a form that provides sufficient capacity to absorb water. Examples nabukenya gidrofilnyh polymers of the present invention, which can be used in the composition of the emitted pulse mode at a specified time as swelling of the funds may be polymers of class vinylpyrrolidone type povidone is, or cross-linked polyvinylpyrrolidone type of crosspovidone; cellulose and derivatives of cellulose type microcrystalline cellulose, methyl cellulose, ethyl cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, karboksimetsiltsellyulozy or stitched carboxymethylcellulose and their alkali metal salts; glycolate sodium starch-based, starch and derivatives of starch, ion-exchange resins and mixtures of them. It is desirable that as the swelling of the means used such swelling tool that greatly swollen, but not formed under this strong gel, and you can choose from a group of funds, which includes crosslinked carboxymethylcellulose sodium, crosslinked polyvinylpyrrolidone, glycolate sodium starch-based.

Salt of an alkali metal stitched karboksimetsiltsellyulozy, that is, crosslinked carboxymethylcellulose sodium, also known as croscarmellose sodium or Ac-Di-Sol, is commercially available under the name Nymcel® ZSX, Pharmacel® XL, Primellose® or Solutab®. The amount of swelling agent that can be used depends on the desired time of rupture, torn in a pulsed mode at a specified time, the nature or quantity of the other components of the core, as well as on the composition and thickness of the membrane. In General, croscarmellose sodium can use the I as polymer swelling agent, mass fraction is in the range from approximately 0.5% to 50% of the core, it is desirable that its mass fraction was approximately in the range from 2% to 40% of the core, even better that its mass fraction was approximately in the range from 5% to 20% of the core. In accordance with a separate preferred variants of the present invention, the mass fraction of croscarmellose sodium is in the range from approximately 6% to 10% of the core, even better that its mass fraction was approximately in the range of 7% to 9% of core.

The polymers of vinylpyrrolidone or polyvinylpyrrolidone (PVP), also known as Povidone, is a synthetic polymer consisting essentially of linear groups 1-vinyl-2-pyrrolidinone, during polymerization which produces polymers of different molecular weight range which varies from 2500 to 3000000 daltons. PVP is commercially available under the name Kollidon® (BASF), Plasdone® and Peristone® (General Aniline). Depending on the viscosity in an aqueous solution of PVP is divided into different grades, for example, PVP K-12, PVP K-15, PVP K-17, PVP K-25, PVP K-30, PVP K-60, PVP K-90 and PVP K-120. The value of K corresponds to the design value of the viscosity of PVP in aqueous solution relative to water. Crosspovidone or cross-PVP-synthetic cross-linked homopolymer of N-vinyl-2-pyrrolidinone can also apply as for the crashing hydrophilic polymer. Commercially it is known under the name Kollidon CL and Polyplasdone XL, and its molecular weight exceeds 1000000 daltons. In accordance with the present invention, the mass content of crosspovidone is in the range from approximately 2% to 5% of the core. In accordance with a preferred variant of the present invention as swelling hydrophilizing of polymineralic used PVP K-30, a molecular weight which is approximately 50,000 daltons. Its mass fraction can be in an approximate range from 0.5% to 5% of the core, it is desirable that its mass fraction was approximately in the range from 1% to 2% of the core.

Glycolate sodium starch-based, sodium salt of carboxymethylated starch, can also be used as polymer swelling funds. Its molecular weight is from 500,000 to 1,000,000 daltons, and in the commercial network, it is known as Explotab and Primojel. In accordance with the present invention the mass fraction of glycolate sodium starch-based can be in an approximate range from 0.5% to 40% of the core, it is desirable that its mass fraction was approximately in the range from 2% to 40% of the core, even better that its mass fraction was approximately in the range from 2% to 10% of the core.

It is desirable that the composition n of the present invention, secreted in a pulse mode at a specified time, contained the capillary tool. In this context, the term "capillary tool" should be understood more widely than conventional capillary tool and it refers to any pharmaceutical excipient, which provides the flow of water into the core using any suitable mechanism, preferably using capillaries, which is typical for conventional capillary means. Materials suitable for use as a capillary means comprising secreted in a pulse mode at a specified time, include colloidal silicon dioxide, kaolin, titanium dioxide, highly dispersed silicon dioxide, alumina, sulphate lauryl sodium, microcrystalline cellulose, low molecular weight polyvinylpyrrolidone, bentonite, magnesium aluminum silicate and the like, the Composition of the present invention, emitted in a pulsed mode at a specified time, can be optimized to ensure reliable gap without using capillary means. However, it was found that when using capillary means the optimization of the reliability gap is solved easier.

In accordance with a preferred variant of the present invention, the capillary tool is used microcrystalline cellulose (MCC). Its circuit is in listello of 250 molecules of glucose and has the appearance of microcrystals, consisting primarily of crystalline clusters obtained by removal of the amorphous regions of pure cellulose by hydrolytic degradation using an inorganic acid. The average molecular weight MCC is approximately 36,000 daltons and there are several varieties of MCC, which differ bulk density, particle size and moisture content. In the commercial network MCC known Vivapur®, Avicel®, Vivacel®, Emcocel®, Fibrocel® and Tabulose®. In accordance with a preferred variant of the present invention, the particles Avicel® PH 102, the size of which is around 100 μm (that is 8% or less of particles retained on sieve No. 60 (in accordance with the definition of the American society for testing and materials) and 45% of particles or more retained on sieve No. 200 (in accordance with the definition of the American society for testing and materials) with humidity ≤5%) are used as a structure allocated in a pulsed mode at a specified time, with a mass fraction comprising from about 2% up to 5% of the core, it is desirable that this value was approximately in the range from 2% to 3% of the core.

When the drug does not create sufficient osmotic pressure to ensure the absorption of fluid from the environment in the core composition, you is semoga in a pulsed mode at a specified time, use water-soluble compositions, suitable to cause osmosis, i.e. osmotic means. Osmotic means, which may be present in the core composition emitted in pulsed mode at a specified time, include all pharmaceutically acceptable and pharmacologically inert water-soluble compounds mentioned in the Pharmacopoeia type Pharmacopoeia of the United States, as well as in Remington: the Science and Practice of Pharmacy, edition of 20, the authors of Lippincott, the William and Wilkins (Lippincott Williams and Wilkins), PCs Philadelphia, USA, 2000 in General, the preferred pharmaceutically acceptable water-soluble salts of inorganic or organic acids, or nonionic organic compounds having high water-solubility, for example, carbohydrates such as sugar, or the amino acids. Examples of tools used to cause osmosis, include inorganic salts type of magnesium chloride or magnesium sulfate, lithium chloride, sodium or potassium hydrogen phosphate lithium, sodium or potassium, secondary acid phosphate lithium, sodium or potassium, salts of organic acids of the type of sodium acetate or potassium, magnesium succinate, sodium benzoate, sodium citrate or sodium ascorbate; carbohydrates-type mannitol, sorbitol, arabinose, ribose, xylose, glucose, fructose, mannose, galactose, sucrose, maltose, lactose, raffinose; water-soluble and is inability type glycine, leucine, alanine or methionine; urea and the like, and mixtures of them. Mass fraction of osmotic tools that can be used depends on the specific osmotic media and may be in an approximate range from 1% to 60% of the core.

In addition to the above ingredients, the core of the structure allocated in a pulsed mode at a specified time, may contain pharmaceutically acceptable inert fillers of the type of binder, means disintegration of dosage forms, lubricants, etc. are Examples of commonly used binders include starch, gelatin, sugar-type sucrose, glucose, dextrose, molasses, and lactose; acacia, sodium alginate, cellulose derivatives type of methyl cellulose, ethyl cellulose, carboxymethyl cellulose and the like; polymers of type polyvinylpyrrolidone, Veegum, polyethylene glycol, waxes, etc.

Examples of lubricants that can be used in the chemical compound secreted in a pulse mode at a specified time, can serve as talc, magnesium stearate, calcium stearate, aluminum stearate, stearic acid, hydrogenated vegetable oil, colloidal silicon dioxide, polyethylene glycol, cellulose derivatives type karboksimetsiltsellyulozy and its alkali metal salts, or mixtures of them. Hydrophobic or water-insoluble lubricating the mother of the crystals can degrade the properties of the core by water absorption, whereas the hydrophilic or water-soluble lubricants don't do that and they also get preference. Colloidal silicon dioxide is the preferred option of the lubricant. A mixture of colloidal silicon dioxide and magnesium stearate can be used as the preferred lubricant. In accordance with a more preferred option as capillary means is a combination of microcrystalline cellulose and colloidal silicon dioxide, and as a lubricating material is silicon dioxide. In the commercial network of the colloidal silicon dioxide is known under the name Aerosil® companies Degussa-Huls (Degussa-Huls), Nippon (Nippon) and Fischer (Fischer GmbH). As the preferred option applies a lubricant on the basis of colloidal silica is Aerosil® 200, the specific area of the outer surface of which is approximately 200 m2/g Mass fraction of colloidal silica can be in an approximate range from 0.5% to 5% of the core.

In accordance with a preferred variant of the present invention the core structure allocated in a pulsed mode at a specified time, is obtained by mixing therapeutically active drug with a swelling agent and binder in a rapidly rotating mix the e-granulator and by granulating the mixture. In accordance with a preferred variant of the present invention only a portion swelling tools are included in the composition, and the remainder is mixed at the stage of lubricating the dried granules. The granules obtained using a suitable granulating solvent, sieved in the wet state through a sieve and then dried in a fluidized bed dryer at 40-50°to a moisture content of 2-3%. Then the dried granules are sifted through a sieve with a mesh size of 2 mm and mixed with one lubricant or more lubricants, and capillary means. As described above, in accordance with a preferred variant of the present invention at this stage mixed with the remainder of swelling means. Granules with a lubricant can be introduced into hard gelatin capsules or can be pressed to obtain a CT or hearts.

Therapeutically active drug, including extruded core/capsule covered by a shell composition comprising one film-forming polymer or a larger amount with the purpose of obtaining a structure allocated in a pulsed mode at a specified time. Film-forming polymers that can be used for the formation of this structure allocated in a pulsed mode the e at the specified time, selected from the group which consists of water-insoluble polymers, pH-dependent polymers, and a mixture of water-soluble and water-insoluble polymers, or mixtures thereof. As examples of suitable film-forming polymers can be applied to complex derivatives of cellulose ether type methyl cellulose, ethyl cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, cellulose acetate, azettftalat cellulose, pH-independent copolymers of methacrylic acid and esters of methacrylic acid, which are available commercially under the name Eudragit®or mixtures thereof. Time allocation therapeutically active drug first composition can be changed by selection of components of membranes, and/or by changing the ratio of these components. By selecting appropriate components and the corresponding ratios can provide elapses after oral administration of the drug. In accordance with a preferred variant of the present invention to obtain a shell with delayed allocation uses a mixture of water-insoluble polymer with a water-soluble polymer. In accordance with a preferred variant of the present invention as a water-insoluble polymer is used ethylcellulose, and is as a water-soluble polymer is hypromellose. Preferably, this mixture was used with a mass ratio of ethyl cellulose to the hypromellose from 0:20 to 20:0, it is desirable that this ratio was in the range from 6:3 to 9:3.

Covering means dispersed in the solvent or solvent system and thus obtained solution or dispersion is used for coating a core containing a therapeutically active agent to obtain a composition emitted in pulsed mode at a specified time. To obtain a solution or dispersion on the basis of the covering means can be used in various solvents and solvent mixtures. Some of the preferred solvents include water, halogenated hydrocarbons type of trichloroethylene, methylene chloride (dichloromethane), carbon tetrachloride and chloroform; alcohols type anhydrous alcohol, isopropyl alcohol and methanol; low molecular weight esters of the type of ethyl acetate and amylacetate; and ketones of the type of acetone, 2-butanone, etc. In accordance with a preferred variant of the present invention uses a mixture of dichloromethane and methanol, preferably in the ratio of dichloromethane to methanol is 1:10 to 10:1, even better in a ratio of about 3:1 to 6:1.

On extruded core/capsule containing a therapeutically active drug, nanosats the solution, create the wrapper, which consists of film-forming polymers that are included in a suitable solvent system, with this solution is applied to obtain a certain increase of the weight, shell thickness depending on the specific time allocation active drugs. The sheath material may be applied using any technologies that support the creation of a continuous film of essentially equal thickness. One way to get the shell includes a rotation layer uncovered cores in the usual Chan for applying a coating on the tablets and applying the solution or dispersion of the covering means in a suitable solvent by pouring or spraying the solution on the heart in motion. Can also be used and other technologies shell type shell in the fluidized bed, vertical spray, etc. Coated cores are dried by heat, dry air and can be cured under the influence of dry air, annealing or forced dehumidification. In accordance with one variant of the present invention molded core is covered with a solution of ethyl cellulose and hydroxypropylmethylcellulose to obtain the mass component of from about 2% to 20% of the mass of the molded core. For applied what I shell to the core is used automated perforated Chan, then there is the drying and curing of the core with the shell in longline dryer for 24 hours at 40-50°C.

The following examples do not limit the ability of the present invention and are presented as an illustration.

Example 1

The composition of the present invention, emitted in a pulsed mode at a specified time has been prepared in accordance with the data presented in Table 1.

Table 1
IngredientsThe quantity mgMass fraction, %
Hydrochloride Metformin500,083,33
Croscarmellose sodium (Ac-Di-Sol)50,08,33
Simple corn starch (in the form of a 10% starch paste)of 17.02,83
Microcrystalline cellulose (MCC)13,52,25
Colloidal silicon dioxide13,52,25
Magnesium stearate6,01,0
Only600,0100,0
The shell
Ethylcellulose40,7The shell is applied to obtain the mass oblock is, component of 9.5% by weight of the core
Hydroxyprop illiterate16,3

The method of preparation of the core with the release of the drug in a pulsed mode at a specified time included sifting hydrochloride Metformin and croscarmellose sodium through the appropriate sieve with further mixing of powders in the mixer-granulator. Then dry the powder mixture was granulated with 10% starch paste, followed by grinding in a wet condition in the crusher Fitz. Thus obtained pellets were dried to a moisture content of 3-4%. Then dry granules are crushed in the crusher Fitz and passed through a sieve with a mesh size of 1.5 mm, after which they were passed through sieve No. 16 (in accordance with the requirements of the American society for testing and materials). Then the granules of Metformin hydrochloride was mixed with MCC, colloidal silicon dioxide and magnesium stearate, and the resulting mixture with lubrication have merged on a rotating machine using oblong shaped stamps. Then on tablets in the usual Chan coating was applied to the membrane using a solution of ethyl cellulose and hydroxypropylmethylcellulose in a mixture with methanol and dichloromethane.

Tablets were tested for dissolution in the buffer with a pH of 6.8 at 37±0,5°the apparatus of the U.S. Pharmacopoeia type II (a rotation speed of 75 rpm). Table 2 shows the profile selection for Metformin. The time of rupture of membranes deposited on the core-based biguanide emitting in a pulsed mode at a specified time, was observed for 30 tablets, which were tested for dissolution. It was found that the tablet securely opened approximately in the range of from 1 hour to 1.3 hours after the start of the test solubility.

Table 2
Time minThe proportion of excreted Metformin, % (± allowable deviation)
451±0,5
10591±6,89
12098±4.26 deaths

It was found that tablets were allocated Metformin in pulsed mode after rupture of the membranes at a specified time.

The tablets were tested in different environments with different pH levels, and using different devices, erection time was recorded. Table 3 shows test data.

Table 3
№ p/pWednesdayConditionsThe erection time of 6 tablets (hour, min)
1.pH 6.8the apparatus of the United States Pharmacopeia, type I, the frequency of rotation 100 of oratov min 1,08; 1,25; 1,13; 1,16; 1,02; 1,12
2.pH 6.8the apparatus of the United States Pharmacopeia, type I, the rotational speed of 100 revolutions per min1,04; 1,14; 1,18; 1,09; 1,09; 1,25
3pH 6.8the apparatus of the United States Pharmacopeia, type I, the rotational speed of 100 revolutions per min1,23; 1,05; 0,59; 1,12; 0,58; 1,25
4.pH 6.8the apparatus of the United States Pharmacopeia, type I, the rotational speed of 100 revolutions per min1,18; 1,26; 1,24; 1,01; 1,12; 1,06
5.pH 6.8the apparatus of the United States Pharmacopeia, type II, speed of 75 revolutions per min1,28; 1,30; 1,21; 1,17; 1,09; 1,03
6.0,1N HClthe apparatus of the United States Pharmacopeia, type II, speed of 75 revolutions per minute1,07; 1,18; 1,21; 1,10; 1,03; 1,30
7.pH 6.8the apparatus of the United States Pharmacopeia, type II, the rotational speed of 50 revolutions per min1,02; 1,39; 1,28; 1,21; 1,03; 1,26
8.0,1N HClthe apparatus of the United States Pharmacopeia, type II, the rotational speed of 50 revolutions per min1,24; 1,10; 1,05; 1,12; 1,29; 0,50

It was found that 48 of the tested tablets of 48 shell exploded within ±50% of the set time at 70 minutes So the shell was broken reliable way.

Example 2

The composition according to astasia the invention, secreted in a pulse mode at a specified time, obtained in accordance with the data given in Table 4.

Table 4
IngredientsThe quantity mgMass fraction, %
Hydrochloride Metformin500,083,33
Croscarmellose sodium (Ac-Di-Sol)50,08,33

Simple corn starch(in the form of a 10% starch paste)of 17.02,83
Microcrystalline cellulose(MCC)13,52,25
Colloidal silicon dioxide13,52,25
Magnesium stearate6,01,0
Only600,0100,0
The shell
Ethylcellulose42,0The shell is applied to obtain the mass of the shell component of 9.8% of the mass of the core
The hypromellose16,8

Tablets with the release of the drug in a pulsed mode at a specified time prepared the way, as the m in Example 1. Tablets with the release of the drug in the pulse mode was studied by the method of U.S. Pharmacopeia on solubility in the buffer with a pH of 6.8 at 37±0,5°in apparatus of the U.S. Pharmacopoeia type II a rotation speed of 75 rpm. Table 5 shows the release profile of Metformin.

Table 5
Time minThe proportion of excreted Metformin, % (± allowable deviation)
451
12091±5,33

It was found that tablets were allocated Metformin in pulsed mode after rupture of the membranes at a given time. The tablets were tested in different environments with different pH levels, and using different devices, erection time was recorded. Table 6 shows test data.

Table 6
№ p/pWednesdayConditionsThe erection time of 6 tablets (hour, min)
1pH 6.8the apparatus of the United States Pharmacopeia, type I, the rotational speed of 100 revolutions per min1,15; 1,04; 1,16; 1,13; 1,21; 1,16
7pH 6.8the apparatus of the United States Pharmacopeia, type I, the frequency of rotation is 100 revolutions per min 1,37; 1,18; 1,20; 1,12; 1,00; 1,15
3pH 6.8the apparatus of the United States Pharmacopeia, type I, the rotational speed of 100 revolutions per min1,02; 1,15; 1,07; 1,10; 1,15; 0,53
4.0,1N HClthe apparatus of the United States Pharmacopeia, type II, speed of 75 revolutions per min1,11; 1,10; 0,50; 0,58; 0,59; 0,45
5.pH 6.8the apparatus of the United States Pharmacopeia, type II, the rotational speed of 50 revolutions per min1,00; 1,09; 0,55; 1,09; 1,09; 1,22
6.0,1N HClthe apparatus of the United States Pharmacopeia, type I, the rotational speed of 100 revolutions per min1,02; 1,00; 1,23; 1,23; 1,26; 1,01

Example 3

To determine the time of rupture of the membranes in vivo composition of the present invention, emitted in a pulsed mode at a specified time, were subjected to radiological examination. In radiological studies performed with the compositions of Example 2 with the addition of the core 25 mg of barium sulfate. Core tablets with Metformin delayed allocation containing barium sulfate were prepared according to the method described in Example 1, at the same time to ensure uniform distribution of the core barium sulfate mixed with starch paste.

In six healthy male volunteers were tested the effect of a single dose. Before the introduction of the carstvo subjects fasted overnight and within 4 hours after drug administration. 2 hours before the dose and within 2 hours after its introduction it was forbidden to drink. Each test, along with 240 ml of drinking water was administered one core tablets with Metformin delayed allocation containing barium sulfate. 4 hours after drug administration was given ordinary food. X-rays were performed in 30, 45, 60, 75 and 90 minutes after administration of the dose. Table 7 shows the result of radiological studies.

Table 7
Volunteer № p/pThe position of the tablet, min
3045607590
1The proximal part of the small intestine (tablet a)The proximal part of the small intestine (tablet a)It is unclear (tablet a)Podnebesnaya region of the colon on the left side (tablet a)The tablet has completely disappeared
2The tablet is not visibleThe tablet is not visibleThe tablet is not visibleThe tablet is not visibleThe tablet is not visible
3The small intestine (tablet a)The small intestine (tablet a)Misunderstood what about the The small intestine (tablet a)The tablet has completely disappeared
4The fundus of the stomach (tablet a)Pyloric part of stomach (tablet a)Pyloric part of stomach (tablet a)Pyloric part of stomach (tablet a)Proximal todecision loop (disintegration of tablets)
5The distal section todecision loop (tablet a)The proximal section podsosnoe loop (tablet a)Podvzdoshnaja loop (disintegration of tablets)Podvzdoshnaja loop (disintegration of tablets)The tablet has completely disappeared
6Pyloric part of stomach (tablet a)Pyloric part of stomach (tablet a)The bend between the duodenum and the jejunum (tablet a)The distal section of the duodenum (the disintegration of the tablets)The tablet has completely disappeared

As can be seen from Table 7, the tablet was not observed in volunteer # 2, which could happen due to insufficient content of barium sulfate in the core. Four of the five remaining volunteers tablet was completely dissolved after 90 minutes, and the volunteer No. 4 through 90 minutes marked began the disintegration of the tablets. Thus, by oral administration of the composition of the emitted pulse mode at a specified time, the shell securely exploded at approximately the specified time after oral administration of the composition.

Example 4

The composition of the present invention, emitted in a pulsed mode at a specified time, was prepared in accordance with the data presented in Table 8.

Table 8
IngredientsThe quantity mgMass fraction, %
Inside the granules
Oxybutin ingnored3,33,66
Microcrystalline cellulose (Avicel pH 101)50,055,56
The lactose monohydrate18,220,22
Croscarmellose sodium (Ac-Di-Sol)9,010,0
Starch maize5,05,56
Outside granules
Microcrystalline cellulose (Avicel pH 102)2,02,22
Colloidal silicon dioxide (Aerosil 200)2,02,22
Magnesium stearate0,50,56
Only100,0

Tablets of the hearts were prepared in accordance with the description in Example 1. At the core was deposited covering the composition shown in Table 9.

Table 9
IngredientsThe quantity mg

Ethylcellulose (Standard 20)3,75
The hypromellose (receiver array 50)1,25
Dichloromethane76
Methanol19

The time of rupture equal to 4 h, can be obtained if the coating weight is 13-14% by weight of the tablet; and the time of rupture equal to 8 h, can be obtained if the coating weight is 20% by weight of the tablet.

Example 5

The composition of the present invention, emitted in a pulsed mode at a specified time, was prepared in accordance with the data presented in Table 10.

Table 10
IngredientsThe quantity mgMass fraction of the core, %
Inside the granules
Carvedilol5,007,14
Lactose34,0048,57
Microcrystalline cellulose12,0017,14
Starch10,0014,29
Croscarmellose sodium1,502,14
Red iron oxide0,50,71
Polyvinylpyrrolidone (PVP K-30)2,002,86
Outside granules
Croscarmellose sodium2,002,86
Talc2,503,57
Magnesium stearate1,001,43
Colloidal silicon dioxide0,500,71

Tablets of the hearts were prepared in accordance with the description in Example 1. At the core was deposited covering the composition shown in Table 11.

Table 11
IngredientsMass fraction of the core, %
Ethylcellulose (M7)7,86
The hypromellose 2910 (receiver array E5)2,0
Triethylcitrate0,71
Talc0,43

The time of rupture equal to 4 h, can be obtained if the coating weight is 11% by weight of the tablet; and the time of rupture equal to 7 h, can be obtained if the coating weight is 13% of the mass of the tablets.

Comparative example 1

This example illustrates the optimization process of composition in order to secure the rupture of the membranes at a certain time.

The core tablets were prepared according to the composition shown in Table 12. The time of rupture of membranes was set to 1 hour.

Table 12
IngredientsThe quantity mg
Hydrochloride Metformin500,0
Croscarmellose sodium (Ac-Di-Sol)34,5
PVP K-90F10,0
Magnesium stearate5,0
Only550,0

The above core was covered with the composition of ethyl cellulose and hydroxypropylmethylcellulose dissolved in the solvent system consisting of methylene chloride and methanol in the ratio of 4:1. The ratio of ethyl cellulose to the hypromellose varied to assess its impact at the time of rupture of membranes. When the ratio was 9:2 and the weight after nanesenia shell increased by 4% of the total mass is ardavin, the time of rupture of membranes was approximately 2 hours. The time of rupture of the membranes can be reduced by reducing the mass of the coating composition of the shell. However, when the ratio of ethyl cellulose to the hypromellose is 9:2, the time of rupture of membranes was sensitive to this factor and this could lead to the change of the time of rupture of the membranes in the mass change caused depending on the party. It was found that the smallest change in weight as a result of applying the membrane from 4% to 3%, the time of rupture of membranes was reduced to 45-60 minutes. With the increase in the relative content of hydroxypropylmethylcellulose time of rupture of the membranes decreased. Estimated ratio of ethyl cellulose to the hypromellose in the range of 8:3 to 7:3, and suddenly came to the conclusion that when these ratios, the time of rupture of membranes was approximately 1 hour, and the time of rupture of the membranes did not depend on the mass of the applied coating. However, shell did not explode in a secure manner, which is clear from the results of the estimated time of rupture of the membranes when testing for solubility are shown in Table 13. The test was carried out in the apparatus of the U.S. Pharmacopoeia type II when the pH of the buffer is equal to 6.8, and when the rotational speed of 50 rpm.

Table 13
Relative weight gain (%) when applying the shell of ethyl cellulose and hydroxypropylmethylcellulose with a ratio of 7.5:3The number of test tabletsThe erection time, min
9%1860, 53, 60,>135, 60, 58, 48, 50,>135, 50, 75, 55, 65, 64, 55, 55, 55, 48
11%1890, 71, 78, 80,>150, 79, 60, 66, 73, 60, 91, 70, 76, 85,did not deploy, 76, 76,did not deploy
14,6%666, 65, 78,180, 86, 60

It is seen that the average time of rupture of the shell meets the specified time gap, which is approximately 1 hour, however, the reliability of rupture is low, therefore some tablets rupture of membranes excessively long. To ensure reliability in the rupture of allocation and drugs the composition of the shell remained unchanged, while the composition of the core was optimized, for example, the compounds described in Examples 1 and 2.

Comparative example 2

The following example is taken from Example 1 of European patent 408496, which is equivalent to IE 902533. Tablets were manufactured in accordance with the composition shown in Table 14.

Table 14
Ing eventy Quantity (mg/tablet
Core
Diclofenac sodium50 mg
Polyvinylpyrrolidone (stitched)100 mg
Sodium chloride50 mg
The silica aerogel (Aerosil® 200)7 mg
Magnesium stearate3 mg
The shell
Cellulose acetate (containing 32% acetyl)31 mg
Cellulose acetate (containing 32,9% acetyl)32,33 mg
The hypromelloseof 3.33 mg

Components of the core are mixed in a drum mixer and were compacted in the press for tablets using 8 mm concave stamp. Components of the shell was dissolved in a mixture of methylene chloride and methanol. This solution was used for applying the coating on the core in the fluidized bed. By applying the shell to the core were obtained from three different batches with increasing mass (relative to the weight of the core) by 4% and 9.8%. Within 48 hours the tablets were dried.

The tablets obtained in accordance with this part and have been tested in 900 ml water at 37°C. Table 15 shows the time of disclosure.

Table 15
The weight of the shell relative to the weight of the core, %ObservationsThe set time of the disclosure in accordance with table 1 of Example 1 of the patent IE 902533
4% (before drying)One tablet was revealed in approximately 45 minutes. Other tablets have not revealed up to 3 h 20 min65 minutes
4% (after drying for 48 h at 40°)One tablet was revealed in approximately 30 minutes, and the other appeared in approximately 50 minutes. Other tablets have not revealed until 2 hours and 15 minutes65 minutes
9,8%No pill is not revealed until 2 hours 56 minutes120 minutes

The above observations indicate that the tablets obtained in accordance with the composition described in patent IE 902533 do not meet the specified timing of the disclosure and do not provide reliable disclosure, as described in the claims of a given patent.

Variants of the invention, in which description reference was made, is provided only to illustrate and not limit the scope of the invention.

1. The composition of the emitted pulse mode at a predetermined time, containing

a. composition is ardavin, includes a therapeutically active agent, a swelling agent and dye penetrant agent; b. the shell composition comprising water-insoluble polymer and a water-soluble polymer, where the swelling agent, which is present in the core, is a hydrophilic polymer selected from the group consisting of vinylpyrrolidone polymers, crosslinked polyvinylpyrrolidone, cellulose and cellulose derivatives, sodium starch glycolate, starch and starch derivatives, ion exchange resins, and mixtures thereof, and where the swelling agent is present in the core in a quantity sufficient to heart swelled after all liquid is absorbed from the environment or after the introduction of what is causing the rupture of the membranes and the allocation of therapeutically active agent in a pulsed mode at a predetermined time a reliable way, where under the safe gap means that after a predetermined time from 36 tablets torn 36, which is confirmed by tests of tablets on the solubility in aqueous medium by the method of U.S. Pharmacopeia at 37±0,5°in apparatus of the U.S. Pharmacopoeia type I or II at speeds from 50 to 100 rpm.

2. The composition of the emitted pulse mode at a predetermined time according to claim 1, where after oral administration of this composition to a person shell reliably breaks at a predetermined time th the oral administration of this composition.

3. The composition of the emitted pulse mode at a predetermined time according to claim 1, where the predetermined time is in the range from approximately 1 to 4 hours, and 36 of 36 tablets are broken within about ±50% in advance a specified time.

4. The composition of the emitted pulse mode at a predetermined time according to claim 1, where the predetermined time is in the range from >4 h to about 12 h, and 36 of 36 tablets are broken within about ±25% pre-specified time.

5. The composition of the emitted pulse mode at a predetermined time according to claim 1, where the swelling polymer is polyvinylpyrrolidone (PVP) K-30.

6. The composition of the emitted pulse mode at a predetermined time according to claim 5, where PVP K-30 is present in an amount of from 0.5 to 5% by weight of the core.

7. The composition of the emitted pulse mode at a predetermined time according to claim 1, where the sodium starch glycolate is present in an amount of from 0.5 to 40% by weight of the core.

8. The composition of the emitted pulse mode at a predetermined time according to claim 1, where the sodium starch glycolate is present in an amount of from 2 to 40% by weight of the core.

9. The composition of the emitted pulse mode at a predetermined time according to claim 1, where the sodium starch glycolate is present in an amount of from 2 to 10% by weight of the core.

10. The composition of the emitted pulse is egime in a predetermined time according to claim 1, where the core further comprises a water-soluble substance for inducing osmosis.

11. The composition of the emitted pulse mode at a predetermined time of claim 10, where the water-soluble substance for inducing osmosis selected from the group consisting of pharmaceutically acceptable salts of an inorganic acid, pharmaceutically acceptable salts of organic acids, non-ionic organic substances with high solubility in water, carbohydrate, sugars or amino acids.

12. The composition of the emitted pulse mode at a predetermined time according to claim 10 or 11, where the water-soluble substance for inducing osmosis is present in an amount of from 1 to 60% by weight of the core.

13. The composition of the emitted pulse mode at a predetermined time according to claim 1, where the swelling agent is selected from the group consisting of croscarmellose sodium, cross-linked polyvinylpyrrolidone and sodium starch glycolate.

14. The composition of the emitted pulse mode at a predetermined time indicated in paragraph 13, where croscarmelose present in the core in an amount of from 0.5 to 50% by weight of the core.

15. The composition of the emitted pulse mode at a predetermined time indicated in paragraph 13, where croscarmelose present in the core in an amount of 5 to 20% by weight of the core.

16. The composition of the emitted pulse mode at a predetermined time indicated in paragraph 13, where the AOC is caramelise present in the core in an amount of from 6 to 10% by weight of the core.

17. The composition of the emitted pulse mode at a predetermined time indicated in paragraph 13, where the crosslinked polyvinylpyrrolidone is present in the core in an amount of from 2 to 5% by weight of the core.

18. The composition of the emitted pulse mode at a predetermined time according to claim 1, where the capillary agent selected from the group consisting of microcrystalline cellulose and colloidal silicon dioxide.

19. The composition of the emitted pulse mode at a predetermined time according to claim 1, where the core further comprises starch.

20. The composition of the emitted pulse mode at a predetermined time according to claim 1 where the water-insoluble polymer is ethylcellulose, and a water-soluble polymer is hypromellose (receiver array).

21. The composition of the emitted pulse mode at a predetermined time according to claim 20, where the mass ratio of ethyl cellulose to the hypromellose is within approximately 6:3 and 9:3.



 

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