Application of solid peroral dosing composition of prolonged action for preparing medications

FIELD: medicine.

SUBSTANCE: claimed is application of solid peroral dosing composition of prolonged action, which includes (a) core, containing effective amount of pseudoephedrine or its salt, (b) first envelope, covering core and including swelling in water film-forming neutral or cationogenic copolymer ester, film modifier and lubricating substance, and (c) second envelope, covering first envelope and including effective amount of desloratadine, amount of pseudoephedrine or its salt is sufficient for ensuring maximaum of average geometrical values of pseudoephedrine concentration in plasma, from 345 to 365 ng/ml, for the time from 7.60 to 8.40 h, and amount of desloratadine is sufficient for ensuring maximum of its average geometrical values of concentration in plasma, from 2.10 to 2.45 ng/ml, for period from 4.0 to 4.5 h after intake of single dose of said composition, for preparation of medication for treatment of allergic and/or inflammatory states of upper and lower respiratory ways and skin, or urticaria and nasal and non-nasal symptoms of year-round and seasonal allergic rhinitis.

EFFECT: composition ensures necessary profile of active agents release and is efficient in treatment of allergic bronchospasm, couphing, seasonal allergic rhinites.

3 cl, 4 tbl, 4 ex

 

Prior art

The present invention relates to oral dosage composition of prolonged action with film-coated, containing nasal a decongestant, such as pseudoephedrine, the kernel variable selection and film outer casing containing nnegative antihistaminic agent, desloratadin. Oral dosage composition corresponding to the present invention, applicable to the treatment of patients with signs and symptoms related to allergic and/or inflammatory conditions such as colds, as well as signs and symptoms related to allergic and/or inflammatory conditions of the skin and the respiratory tract, such as dermatitis, allergic rhinitis, seasonal allergic rhinitis and swelling in the nose.

Desloratadin, also called descarboethoxyloratadine described in U.S. patent No. 4659716 as nnegative antihistaminic agent, applicable as an anti-allergic drug. In U.S. patent No. 6100274 disclosed are compositions containing desloratadin. In U.S. patent No. 5595997 disclosed methods and compositions for the treatment of symptoms of seasonal allergic rhinitis using desloratadine. The oral absorption of desloratadin hydroxylases in position 3 with the formation of the metabolite, 3-hydroxydesloratadine is.

In U.S. patent No. 4990535 and 5100675 described tablet prolonged action with shell designed to receive two times a day, and the shell tablet contains descarboethoxyloratadine, and a hydrophilic polymer, and polyethylene glycol, and the core tablets contains acetaminophen, pseudoephedrine or its salt, a swellable hydrophilic polymer and acceptable from a pharmaceutical point of view fillers.

In U.S. patent No. 5314697 described tablet prolonged action with a matrix core containing pseudoephedrine sulfate, and the shell containing loratadine.

In the prior art has not disclosed which is intended to receive once daily, coated film-coated oral dosage composition, corresponding to this invention.

The successful development of a compounding product, desloratadine-pseudoephedrine destined for reception once a day, would be desirable, but this requires velocity profile selection pseudoephedrine component for an extended period of time, equal to about twelve hours, and preferably not less than 16 hours, while ensuring the delivery of effective daily dose of desloratadine.

For patient's adherence to an enhanced mode of treatment, it is desirable to obtain a product of desloratadine-pseudoephedrine prolonged action is imposed which when taken once a day would be effective and safe when used for the treatment and/or relief of the signs and symptoms that accompany colds, and allergic and/or inflammatory conditions of the skin and upper and lower respiratory tract, such as seasonal allergic rhinitis and swelling in the nose.

Summary of the invention

We found the product desloratadine-pseudoephedrine, designed to receive once daily, which provides the velocity profile selection pseudoephedrine for an extended period of time in excess of twelve hours, and preferably at least 16 hours, while ensuring the delivery of effective daily dose of desloratadine.

Thus, the present invention provides a solid oral dosage composition of prolonged action with a film cover, comprising (a) a core containing an effective amount of pseudoephedrine or its acceptable from a pharmaceutical standpoint, salt, and (b) film shell, uniformly covering the core and containing an effective amount of desloratadine, and the amount of pseudoephedrine or its acceptable from a pharmaceutical point of view of salt is sufficient to provide maximum geometric average concentrations of pseudoephedrine in the plasma, is what about from about 345 to about 365 ng/ml, from about 7,60 to about 8,40 h, and the number of desloratadine is sufficient to ensure maximum geometric average concentrations of desloratadine in the plasma is from about 2.10 to about 2.45 ng/ml, from about 4.0 to about 4.5 hours after administration of a single dose of the indicated composition.

Preferred options perorating dosing compositions prolonged action with a film cover, corresponding to the present invention, also provide the maximum geometric average concentrations of 3-hydroxydesloratadine in the plasma is equal to from about 0.75 to about of 1.15 ng/ml, from about 5.50 to about 6.25 hours after administration of a single dose of the indicated composition.

Preferred variants of the oral dosage composition of prolonged action with a film cover, corresponding to the present invention, also provide the maximum geometric average concentrations of desloratadine in the plasma is from about 2.10 to about 2.45 ng/ml, from about 4.0 to about 4.5 hours and the maximum geometric average concentrations of 3-hydroxydesloratadine in the plasma is equal to from about 0.75 to about of 1.15 ng/ml, from about 5.50 to about 6.25 hours after administration of a single dose of the indicated composition.

Thus the m in a preferred embodiment, the present invention provides a pharmaceutical composition comprising an effective therapeutic point of view, the amount of pseudoephedrine sulfate in the core and an effective amount of desloratadine in a membranous sheath that supports the desired pharmacokinetic parameters of desloratadine, 3-hydroxydesloratadine and pseudoephedrine above in the present invention, and containing less than about 2% decomposition products of desloratadine, such as N-formyl-desloratadin, preferably less than from about 1.4 to about 1.6% of the products of decomposition of desloratadine, such as N-formelbasierten, as in the initial state, and the storage of such compositions at 25°C and a relative humidity of about 60% during the periods of time that is at least about 24 months.

We also found that the placement of the first shell between film-coated, containing desloratadin, and a core containing a decongestant nasal, for example salt of pseudoephedrine, preferably sulfate pseudoephedrine, provides a selection of desloratadine from the second film membranes and prolonged isolation of nasal decongestants funds sulfate pseudoephedrine from the nucleus, preferably a matrix kernel, during the period of time in excess of twelve is the substance of hours, while maintaining the necessary pharmacokinetic parameters of desloratadine, 3-hydroxydesloratadine and pseudoephedrine mentioned above in the present invention, and the flow decomposition of desloratadine with the formation of N-formelbasierten less than 2%.

Thus, in a preferred implementation of the present invention provides a solid oral dosage composition of prolonged action with a film cover, including:

(a) a matrix core, which contains:

1. providing a prolonged action quantity is acceptable from a pharmaceutical point of view decongestants funds;

2. polymer matrix;

3. water-insoluble salt of calcium, magnesium or aluminum;

4. binder;

5. lubricating substance; and optional

6. the substance, which imparts lubricity;

(b) the first film shell, evenly covering the matrix core, which contains:

(1) swelling in water, film-forming neutral or cationogenic ester copolymer;

(2) grease;

(3) the modifier film; and

(4) optional protivovspenivayushchie substance;

(c) a second film shell, evenly covering the first shell, which contains:

(1) providing direct effect of the number of desloratadine;

(2) nabuhay what s in the water film-forming neutral or cationogenic copolymer ester;

(3) grease;

(4) swelling in water modifier film; and an optional

(5) protivovspenivayushchie substance.

This preferred solid oral dosage composition of prolonged action with a film cover, corresponding to the present invention, when examined by the method of blade mixer USP (United States Pharmacopeia) with a speed of 100 revolutions/min in 0.1 N. HCl solution at 37°C allocates not less than about 80% of desloratadine about 45 minutes, and about 64% of the pseudoephedrine sulfate for 6 hours, and 88% of the pseudoephedrine sulfate for 12 hours, and this solid oral dosage composition of prolonged action with a film cover contains less than about 2% decomposition products of desloratadine, such as N-formelbasierten.

In another preferred embodiment, the present invention provides a solid oral dosage composition of prolonged action with a film cover, including:

(a) a matrix core, which contains:

about 160-480
Componentmg in the nucleus
Sulfate pseudoephedrineapproximately 240
The hypromellose 2208 with a viscosity of 100000 SP
Ethylcelluloseapproximately 40-120
Dehydrate disubstituted calcium phosphateabout 54-162
Povidone (polyvinylpyrrolidone)approximately 20-60
Silicon dioxideapproximately 6-12
Magnesium stearateapproximately 2-6
The approximate mass range of the matrix kernel:about 518-1082 mg

and

(b) the first film shell, evenly covering the matrix core, which contains:

(1) a neutral copolymer of ethyl acrylate with methyl acrylate;

(2) lubricating substance selected from the group comprising talc, silicon dioxide and magnesium stearate;

(3) a glycol selected from the range of peg 200 to peg 8000, or mixtures thereof;

(4) optional acceptable from a pharmaceutical point of view, the mixture of homologous liquid methylsiloxane polymers with silica gel; and

(c) a second film shell, evenly covering the first shell, which contains:

(1) the number of desloratadine sufficient to ensure Maxim is mA geometric average concentrations of desloratadine plasma, equal to from about 2.10 to about 2.45 ng/ml, from about 4.0 to about 4.5 hours after administration of a single dose of the indicated composition;

(2) a neutral copolymer of ethyl acrylate with methyl acrylate;

(3) a lubricating substance selected from the group comprising talc, silicon dioxide and magnesium stearate;

(4) a glycol selected from the range of peg 200 to peg 8000; optional

(5) acceptable from a pharmaceutical point of view, the mixture of homologous liquid methylsiloxane polymers with silica gel.

The above preferred solid oral dosage composition of prolonged action with a film cover may further include a third film shell, evenly covering the second film membrane, and in the third film shell contains:

(1) a neutral copolymer of ethyl acrylate with methyl acrylate;

(2) lubricating substance selected from the group comprising talc, silicon dioxide and magnesium stearate;

(3) an effective amount of at least one water-soluble modifier film selected from the group comprising hydroxypropylcellulose low viscosity, methylhydroxyethylcellulose and sodium salt of carboxymethyl cellulose and polyethylene glycol selected from the range of the polyethylene glycol is polyethylene glycol 200 to 800, or mixtures thereof;

(4) acceptable from a pharmaceutical point of view, the dye; and

(5) optional acceptable from a pharmaceutical point of view, the mixture of homologous liquid methylsiloxane polymers with silica gel.

In a more preferred embodiment, the present invention provides a solid oral dosage composition of prolonged action with a film cover, including:

(a) a matrix core, which contains:

Componentmg in the nucleus
Sulfate pseudoephedrineapproximately 240
The hypromellose 2208 with a viscosity of 100000 SPabout 160-480
Ethylcelluloseapproximately 40-120
Dehydrate disubstituted calcium phosphateabout 54-162
Povidoneapproximately 20-60
Silicon dioxideapproximately 6-12
Magnesium stearateapproximately 2-6
Approximate dia is the azone mass matrix kernel: about 518-1082 mg

(b) the first film shell, evenly covering the matrix core, which contains:

Componentmg in the first shell
(1) a neutral copolymer of ethyl acrylate withabout 1.36 - about 4,08
methyl acrylate, with an average
molecular weight equal to 8000000;
(2) lubricating substance selected from the groupabout 1.36 - about 4,08
includes talc, silicon dioxide and magnesium stearate
magnesium;
(3) a glycol selected from the rangeabout 0,136 - about 0,408
from polyethylene glycol 6000 to peg
8000 and
(4) optional acceptableabout 0,11 - prima is but 0,33
pharmaceutical point of view, the mixture
homologous liquid methylsiloxane
polymers with silica gel
Just for the first film coating:about 2,96-8,89 mg

and

(C) a second film shell, evenly covering the first shell, which contains:

Componentmg in the second film the shell
(1) 24-hour number of desloratadine;about 5.0 to about 6,0
(2) a neutral copolymer of ethyl acrylate withapproximately 3.04 from - about 9,12
methyl acrylate, with an average
molecular weight equal to 8000000;
(3) a lubricating substance selected from the groupabout 3.5 - about of 10.05
includes talc, silicon dioxide and magnesium stearate
magnesium;
(4) a glycol selected from the rangeabout 0,915 - about 2,75
from polyethylene glycol 6000 to peg
8000 and
(5) optional acceptableabout 0.14 to about 0,42
pharmaceutical point of view, the mixture
homologous liquid methylsiloxane
polymers with silica gel
Just for a second coverage:about 12,60 - about 38,79 mg

In a preferred embodiment, the present invention provides a solid oral dosage composition of prolonged action with a film cover, including:

(a) a matrix core, which contains:

Componentmg in the nucleus
Sulfate pseudoeph the Rina approximately 240
The hypromellose 2208 with a viscosity of 100000 SPabout 160-480
Ethylcelluloseapproximately 40-120
Dehydrate disubstituted calcium phosphateabout 54-162
Povidoneapproximately 20-60
Silicon dioxideapproximately 6-12
Magnesium stearateapproximately 2-6
The approximate mass range of the matrix kernel:about 518-1082 mg

(b) the first film shell, evenly covering the matrix core, which contains:

(1) a neutral copolymer of ethyl acrylate with methyl acrylate having an average molecular weight equal to 8000000;

(2) lubricating substance selected from the group comprising talc, silicon dioxide and magnesium stearate;

(3) a glycol selected from the range of the polyethylene glycol is polyethylene glycol 6000 to 8000; and

(4) optional acceptable from a pharmaceutical point of view, the mixture of homologous liquid methylsiloxane polymers with silica gel; and

(c) W is the ROI of the film shell, evenly covering the first shell,

which contains:

(1) the number of desloratadine sufficient to ensure maximum geometric average concentrations of desloratadine in the plasma is from about 2.10 to about 2.45 ng/ml, from about 4.0 to about 4.5 hours after administration of a single dose of the indicated composition;

(2) a neutral copolymer of ethyl acrylate with methyl acrylate having an average molecular weight equal to 8000000;

(3) a lubricating substance selected from the group comprising talc, silicon dioxide and magnesium stearate;

(4) a glycol selected from the range of peg 200 to peg 8000; and

(5) optional acceptable from a pharmaceutical point of view, the mixture of homologous liquid methylsiloxane polymers with silica gel.

A more preferred composition, corresponding to this invention, to the following:

1. Matrix kernel

Componentmg in the nucleus
The pseudoephedrine sulfate USP240
The hypromellose 2208 USP*, viscosity 100000 SP320
Ethylcellulose NF type 7 80
Dehydrate disubstituted calcium phosphate USP108
Povidone USP40
Silicon dioxide NF8
Magnesium stearate NF4
Approximate weight of the matrix core800 mg
* NF - national formulary (USA)
USP - USP

1. Shell matrix kernel

1. The first film sheath

Componentmg tablet
Simethicone0,22
Polyethylene glycol 80000,27
Talc NF2,72
Neutral copolymer of an acrylate/methyl acrylate (30%2,72
dispersion in water)
Just for the first shell to 5.93 mg

2. The second film sheath (direct action)

Componentmg tablet
Desloratadine6,0
Simethicone0,28
Polyethylene glycol 80001,83
Talc NF5,88
Neutral copolymer of an acrylate/methyl acrylate6,09
For the second shell20,08 mg

3. The third film sheath

Componentmg tablet
The hypromellose 2910 USP, viscosity 6 SP2,09
Talc NF5,79
Neutral copolymer of an acrylate/methyl acrylate4,18
Polyethylene glycol 8000 NF0,42
SimethiconeThe dye Spectra Spray Med Bluethe 3.65
Just for the third shell16,24
An approximate total weight of the three membranes42,37 mg
Approximate weight of tablets (matrix core and three shell)842,97 mg

Another preferred composition, corresponding to this invention, to the following:

1. Matrix kernel

Componentmg in the nucleus
The pseudoephedrine sulfate USP240
The hypromellose 2208 USP, viscosity 100000 SP320
Ethylcellulose NF type 780
Dehydrate disubstituted calcium phosphate USP108
Povidone USP40
Silicon dioxide NF8
Magnesium stearate NF4
Approximate weight of the matrix core800 mg

2. Shell matrix kernel

1. The first film sheath

Componentmg tablet
Simethicone0,22
Polyethylene glycol 80000,27
Talc NF2,72
Neutral copolymer of an acrylate/methyl acrylate (30%2,72
dispersion in water)
Just for the first shellto 5.93 mg

2. The second film sheath (direct action)

Componentmg tablet
Desloratadine5,0
Simethicone0,28
Polyethylene glycol 80000,61
Talc NF5,17
athelny copolymer of an acrylate/methyl acrylate 6,09
The hypromellose 2910 USP, viscosity 6 SP3,05
For the second shell20,20 mg

3. The third film sheath

Componentmg tablet
The hypromellose 2910 USP, viscosity 6 SP2,09
Talc NF5,79
Neutral copolymer of an acrylate/methyl acrylate4,18
Polyethylene glycol 8000 NF0,42
Simethicone0,11
The dye Spectra Spray Med Bluethe 3.65
Just for the third shell16,24
An approximate total weight of the three membranes42,37 mg
Approximate weight of tablets (matrix core and three shells842,97 mg

Similar results followed on IDate, when instead of pseudoephedrine sulfate used the effective number of other acceptable from a pharmaceutical point of view salts pseudoephedrine, such as hydrochloride pseudoephedrine.

Compositions corresponding to the present invention is applicable for treatment of allergic and/or inflammatory skin conditions (e.g., urticaria) and upper and lower respiratory tract, including nasal and nenasilny the symptoms of seasonal allergic rhinitis, including swelling in the nose, patients in need of such treatment.

Detailed description of the invention

During the development of the composition corresponding to the present invention discovered that desloratadin is unstable and discolored during storage in a mixture with various fillers, such as disclosed in U.S. patent No. 5314697 and are part of the matrix core containing pseudoephedrine sulfate. For fillers, leading to discoloration and instability of desloratadine are acidic fillers having in water a pH value equal to less than 7, such as organic acids, such as stearic acid, povidone, crosspovidone and carbonyl-containing substances, such as lactose, and ethylcellulose and hypromellose. Binders such as povidone, and polymers, such as hypromellose, applicable as polimernoi matrix for prolonged excretion of pseudoephedrine sulfate from the internal polymer matrix kernel.

We found that after the internal matrix core containing nasal a decongestant, such as pseudoephedrine sulfate and hypromellose, ethylcellulose and povidone, uniformly applied first film sheath containing a swelling in water of the film-forming neutral or cationogenic copolymer ester, modifier film and a lubricating substance, the first shell can reliably apply desloratadin. Discovered that desloratadine has a reasonable profile of direct discharge from the second shell (0.1 N. HCl solution at 37°C in less than 45 minutes is allocated 80%) and even after storage for at least 24 months, preferably up to 36 months at 25°C and relative humidity (RH) of about 60% contains less than about 2% N-formelbasierten, preferably from 1.4 to 1.6% N-formelbasierten.

If the second shell to cause the third film membrane containing swelling in water, film-forming neutral or cationogenic copolymer ester and polyethylene glycol as a modifier of the film, the dissolution rate of desloratadine located in the first shell, and pseudoephedrine, found in the nucleus, is reduced to an unacceptably low level.

Unexpectedly discovered that the addition of the third shell hydroxypropyl what ethylcellulose, with low viscosity, as a modifier of the film leads to the restoration of the dissolution rate of both active components (sulfate pseudoephedrine and desloratadine) to levels approximately the same as observed in the case of a uniform coating on the matrix core of the two film surfaces.

The phrase "allergic and inflammatory condition of the skin and respiratory tract" means those allergic and inflammatory conditions and symptoms that are found on the skin and in the upper and lower respiratory tract from the nose to the lungs. Typical allergic and inflammatory condition of the skin and upper and lower respiratory tract include seasonal and perennial allergic rhinitis, non-allergic rhinitis, asthma, including allergic and non-allergic asthma, sinusitis, colds, dermatitis, especially allergic and atopic dermatitis, and urticaria and symptomatic dermographism, as well as retinopathy and disease of small vessels associated with diabetes.

The number of desloratadine, effective for treating or preventing allergic and inflammatory conditions of the skin and upper and lower respiratory tract will depend on age, sex, body weight and severity of allergic and inflammatory condition of the patient. Usually the number of desloratadine, effective for the treatment and prevention of such allergic and inflammatory conditions, is in the range from about 2.5 to about 60 mg/day, preferably from about 2.5 to about 20 mg/day, or from about 4.0 to about 15 mg/day, or from about 5.0 to about 10 mg/day, more preferably from about 5.0 to about 10.0 mg/day and most preferably from about 5.0 to about 6.0 mg/day as a single dose.

Desloratadin is non-sedating antagonist of histamine prolonged action with high selective antagonistic activity against peripheral H1-receptor. After oral administration loratadine rapidly undergoes metabolism with the formation of descarboethoxyloratadine, or desloratadine, which is the pharmacologically active metabolite. To evaluate various pharmacodynamic effects of desloratadine and loratidine conducted pharmacological tests on animals in vivo and in vitro. When evaluating antihistaminas activity in mice (comparison of values of ED50) discovered that desloratadin basically does not change the behavior of functions of the Central and peripheral nervous system. The ability of desloratadine and loratidine to block the H1 receptors in the brain was evaluated in Guinea pigs after intraperitoneal administration, and the results indicate the difficulty of access desloratadine and loratidine to histamine is the first receptors of the Central nervous system.

According to numerous tests in vitro and in vivo, along with antihistaminas activity of desloratadin found anti-allergic and anti-inflammatory activity. These tests are conducted in vitro (mainly on human cells), showed that desloratadine can inhibit many of the events in the sequence allergic inflammation. These anti-inflammatory effects of desloratadine not depend on the antagonistic activity of desloratadine in relation to the H1-receptor and include:

Selection mastocytoma inflammatory mediators - histamine, tryptase, leukotriene and prostaglandin D2;

The secretion of inflammatory cytokines, including IL-4, IL-6, IL-8 and IL-13;

The secretion of inflammatory chemokines, such as RANTES (regulated upon activation, expressed by Mature T-cells and predominantly secreted);

Production naproxeno anion polymorphonuclear neutrophils;

The expression of endothelial cell factors, cell adhesion factors such as intracellular adhesion (SAM-1) and P-selectin;

The migration and adhesion of eosinophils.

Tests conducted in vivo also showed that we can expect the overwhelming impact of desloratadine allergic bronchospasm and cough.

Clinical efficacy and safety of desloratadine documented on the of tveretina in 4 clinical trials, conducted a double-blind random sample involving more than 3,200 patients suffering from seasonal allergic rhinitis. The results of these clinical trials have demonstrated the effectiveness of desloratadine in the treatment of adults and adolescents with seasonal allergic rhinitis.

Nasal anti-inflammatory agents used in the present invention include phenylpropanolamine, phenylephrine and pseudoephedrine. Pseudoephedrine, and it is acceptable from a pharmaceutical point of view of molecular salts with acids, for example Hcl or H2SO4, are sympathomimetic drugs that are known to specialists in this field of technology are safe therapeutic agents effective in the treatment of edema in the nose and is usually prescribed orally and in conjunction with antigistaminnami drugs for the treatment of edema in the nose associated with allergic Renita. As a remedy against the swelling in his nose in the present invention preferably use pseudoephedrine; more preferably the use of pseudoephedrine sulfate.

During the development of oral dosage composition corresponding to the present invention discovered that in order to ensure the period of excretion of pseudoephedrine sulfate average of n is less than 12 hours, preferably from 12 to 16 hours, and more preferably of not less than 16 hours, it is critical that the selection of polymers for the matrix kernel. In particular, the use of hydroxypropylmethylcellulose having a viscosity of 4000 to 15000 SP as a polymer matrix for the kernel does not provide such a preferred period of prolonged action dosage of pseudoephedrine sulfate of not less than 16 hours. We have found that the desired profile selection pseudoephedrine is provided only in the case when for inclusion in the matrix core select three specific polymer with a specific mass relations. The preferred profile of prolonged excretion of pseudoephedrine sulfate matrix kernel, consisting of not less than 16 hours can only be achieved by mixing (1) four parts by weight of hydroxypropylmethylcellulose 2208 USP with a viscosity of 100,000 CPS with (2) one parts by weight of ethyl cellulose and (3) 1/2 parts by weight of povidone (as a secondary binder. Matrix kernel also contains the specified amount of silica as a substance, which imparts lubricity, and magnesium stearate as the lubricant. The higher the content of the lubricant (6 mg/tablet) does not greatly affect the hardness of the tablets is 22±6% hardness Cobb (ETK), but preferably with the holding of the lubricant was 1/10 parts by weight of lubricants per parts by weight of povidone used as a secondary binder.

The term "grease" in the present invention refers to a substance that is added in a dosage form to a dosage form such as tablet, after pressing was separated from the mold or stamp.

Suitable lubricants include talc, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable fats, etc. it is Preferable to use magnesium stearate or talc.

The term "substance giving slipperiness" in the present invention refers to a substance, such as a substance that prevents caking and clumping, which improves the characteristics of flowability of the powder mixture.

Suitable substances which impart lubricity include silicon dioxide and talc. It is preferable to use silicon dioxide.

The term "binder" in the present invention means any material that is added to the pharmaceutical compositions to facilitate the holding of such compositions in solid form and the selection of medicinal drug.

Suitable binders are selected in the group comprising sodium salt of croscarmelose, cross-linked polymer sodium salt of carboxymethyl cellulose, povidone, crosspovidone, starches, cellulose, alginates and Kameda is; see also USP XXII page 1858 (1990). It is preferable to use povidone.

Typical suitable protivovspenivayushchie substances comprise a mixture of homologous liquid methylsiloxane polymers with silica gel, sold under the trade name Simethicone.

The term "swellable in water film-forming neutral or cationogenic ester copolymer in the present invention means a neutral or cationogenic copolymers of acrylate and substituted or unsubstituted methyl or amylmetacresol.

Typical suitable swelling in water forming a neutral copolymer esters include neutral copolymers of ethyl acrylate and methyl methacrylate, such as production Pharma Polymers, the company Hüls Group with the trade name EUDRAGIT®, EUDRAGIT NE30D and Kollicoat production BASF Mt Olive, New Jersey. The preferred aqueous dispersion containing 30 wt.% neutral copolymers based on ethyl acrylate and methyl methacrylate (average molecular weight of about 800000).

Typical suitable swelling in water forming cationogenic copolymer esters include cationogenic copolymers based dimethylaminoethylmethacrylate and neutral methacrylic ester, such as copolymers EUDRAGIT E production Pharma Polymers, supplied in the form of a solution concentration of 12.5% (EUDRAGIT E 12,5) or in the form of solid washes the VA (EUDRAGIT E 100) and copolymers of Quaternary ammonium compounds, described in the USP/NF as "Amononio methacrylate copolymer, Type "A" and Type "B". Such copolymers are produced in the form of aqueous suspensions of copolymers of acrylic and methacrylic esters of methacrylic acid with a low content (substitution) of Quaternary ammonium groups present in the form of salts (e.g. chlorides Quaternary ammonium compounds). Type a and type b are produced in the form of aqueous suspensions concentration of 30% under the trade names EUDRAGIT RL 30D and EUDRAGIT RS 30D, respectively. Preferably the use of swelling in water forming a neutral copolymer of esters based on ethyl acrylate and methyl methacrylate.

The term "water-soluble modifier film" in the present invention means a film-forming substance which modifies the characteristics of swelling in water of the film-forming neutral or cationogenic copolymer of esters used in the compositions of the present invention. Typical suitable water-soluble modifier films is the cellulose low viscosity (≤20 SP), such as low viscosity hypromellose, hydroxyethylmethylcellulose low viscosity sodium carboxymethyl cellulose low viscosity and a glycol selected from the range of peg 200 and peg 8000.

For use in quality is TBE modifier film in the first and second shell preferred glycol, selected from the range of the polyethylene glycol is polyethylene glycol 6000 to 8000; for use in each shell, the most preferred is polyethylene glycol 8000.

For use in the third shell is preferred glycol together with hydroxypropylcellulose low viscosity. For use in the third or the outer film wrapper more preferred is a mixture of polyethylene glycol 8000 and hydroxypropylmethylcellulose 2910 with a viscosity of 6 CP.

The term "water-insoluble basic salts of calcium, magnesium and aluminium in the present invention means acceptable from a pharmaceutical standpoint, carbonates, phosphates, silicates and sulfates of calcium, magnesium and aluminum, or a mixture thereof. Usually suitable acceptable from a pharmaceutical point of view of basic salts include anhydrous calcium sulfate, hydrates of calcium sulfate, hydrates of magnesium sulfate, disubstituted calcium phosphate, disubstituted calcium silicate, magnesium trisilicate, magnesium phosphate, aluminum silicate and the hydrates of magnesium phosphate, aluminum phosphate; and more preferred is calcium phosphate. Most preferably the use dihydrate disubstituted phosphate of calcium.

In a film sheath hypromellose 2910 act as film-forming substances, and polietilenglikol and acts as a modifier of the film. Other suitable film-forming polymers that can be used include hydroxypropylcellulose low viscosity (720 SP), methylhydroxyethylcellulose and sodium carboxymethyl cellulose.

Oral dosage composition corresponding to the present invention also provides a shelf life when stored for more than 24 months to 36 and 48 months, if the tablets are stored in standard packaging at a temperature between 2 and 30°C and relative humidity of the environment, equal to 60%.

In the manufacture of the core tablet povidone dissolved in a mixture of alcohol and water. The pseudoephedrine sulfate, hypromellose 2208 USP viscosity 100000 SP, ethylcellulose and disubstituted calcium phosphate are mixed and granularit using an aqueous solution of alcohol containing povidone. Granules are milled and dried to a residual moisture content of from 0.5 to 2.0%.

The dried granules are milled and mixed with required quantities of silicon dioxide and magnesium stearate. The mixture is pressed to obtain the composition of the internal polymer matrix kernel.

The shell on the inner polymer matrix core is usually applied as follows.

The kernel is loaded into a suitable tank for drawing the shell. As the first shell on the matrix kernel is applied aqueous dispersion of talc, simeticone, polietilen ikola 8000 and EUDRAGIT NE30D. Then these matrix kernel shell cause the variance of desloratadine, simeticone, EUDRAGIT NE30D, polyethylene glycol 8000 NF and dispersion of talc. After that put in a third envelope containing the variance of the FD&C blue No. 2 aluminum lacquer containing EDTA as a chelating reagent, talc, simethicone, EUDRAGIT NE30D, containing hypromellose 2910 with a viscosity of 6 JV and polyethylene glycol 8000 NF. The tablet shell is marked (using black ink) and are packaged in plastic vials and blister packs designed to be stored at a temperature between 2 and 30°C in ambient conditions.

During the development of the formulations of the present invention, we have found that the dissolution studies in vitro indicate that with increasing pH, especially at pH>7.5, and the allocation rate of desloratadine, and the concentration of desloratadine reduced compared with values for tablets containing 5 mg of desloratadine. In vivo studies showed that TM is more than 4 hours and that the process of absorption of desloratadine largely takes place in the small intestine, the environment in which is alkaline (pH>7,0).

We have found that can enhance the allocation of desloratadine, increasing the content of hydroxypropylmethylcellulose and decreasing in the second film envelope, including esloratadine, the content of plasticizing agents, such as polyethylene glycol 8000, and lubricants, for example talc. Cm. Example 4.

In another preferred embodiment, to ensure an acceptable pharmacokinetic profile of an effective amount of desloratadine in the second film of the shell was increased to 6.0 mg, and the amount of talc was reduced (approximately 1.12 mg). Cm. Example 3 and table 3.

For solid oral dosage compositions of the present invention, the maximum geometric average concentrations of pseudoephedrine (PES) in the plasma is equal to from about 345 to about 365 ng/ml over time (TM) from about 7,60 to about 8,40 h; maximum geometric average concentrations of desloratadine (DL) in plasma is equal to from about 2.10 to about 2.45, preferably from 2.15 to about 2,35 ng/ml over time (TM) from about 4.0 to about 4.5 hours, and the maximum geometric average concentrations of 3-hydroxydesloratadine (3-HE-DL) in plasma is equal to from about 0.75 to about of 1.15 ng/ml, preferably from about 0.85 to about 1.05 ng/ml, and more preferably from approximately 0.88 to about of 1.02 ng/ml, time (TM) from about 5.50 to about 6.25 hours after administration of a single dose of the indicated compositions healthy people.

Pharmacokinet the practical test # 1

Pharmacokinetic objective of this test was to determine the bioavailability and biological equivalence of desloratadine (DL), 3-HE-DL and pseudoephedrine (PES)derived from the composition of Example 2 (5 mg DL/240 mg PES) of this application in comparison with containing 5 mg of the composition of Example 11 of U.S. patent No. 6100274 (PSS '274) and the core of the prolonged action containing pseudoephedrine, which was the control. This trial was a Phase I open three-parameter cross-over study with a random sample using single doses and seven-day preparatory periods, providing the excretion of previous drugs, observed among all treatments. Thirty-six healthy men and women were all of the following treatments in the order determined by random numbers, computer generated:

Treatment A:One tablet of Example 2: 5 mg DL/240 mg PES.
Treatment:One tablet of Example 11 from PSS '274: 5 mg / DL.
Course of treatment:One dose of 240 mg of pseudoephedrine sulfate (oval nucleus
prolonged action with pseudoephedrine sulfate
Claritin® D-24 shell of placebo Claritin® D-24).

Took pills with 180 ml (6 fluid ounces) of non-carbonated water at room temperature. Tablets are swallowed whole, without chewing or grinding. After administration conducted an investigation of the oral cavity, to make sure that the subject swallowed the pill. The subjects didn't eat until the completion of a four-hour examination. During this fasting period allowed for drinking water, except for two hours after the dose. The subjects were awake and sat upright in the clinic for four hours after taking the dose. All subjects remained in the research centre before the end held within 120 hours of sampling blood, studying important symptoms and laboratory tests.

Serial blood samples (10 ml) was collected in tubes containing heparin as an anticoagulant, at the following times: 0 (pre-dose), through 0,5, 1, 1,5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 20, 24, 36, 48, 60, 72, 96 and 120 hours after the dose. Within four hours after the dose were not allowed to eat. Within one hour before dosing and hours after admission were not allowed to drink water, excluding 120 m is, assigned together with the drug. The concentration of pseudoephedrine in plasma were determined using certified by liquid chromatography with tandem mass spectrometry (LC/MS/MS) with a lower limit of detection (NGOs), equal to 10.0 ng/ml, and the range of linearity from 10.0 to 400 ng/ml Corresponding mean values of pharmacokinetic parameters are shown in table 1.

Mean values of Cmax for DL after taking the tablet DL, corresponding to Example 2 of the present invention, and tablets containing 5 mg of desloratadine corresponding to Example 11 of U.S. patent 6100274 amounted to 1.79 and of 2.23 ng/ml, respectively, and was established after the average values TM, equal to 6.78, and 5,10 hours, respectively.

The mean Cmax values for 3-HE-DL after taking the tablet 5 mg DL/240 mg PES, corresponding to Example 2 of the present invention, and tablets containing 5 mg of desloratadine corresponding to Example 11 of U.S. patent 6100274 amounted 0,695 and 0,832 ng/ml, respectively, and was established after the average values of Tmax equal 6,09 and 4,96 hours, respectively. Peak concentration of 3-OH-DL slightly decreased in accordance with an elimination half-life equal to 29.6 hours after taking the tablet 5 mg DL/240 mg PES, corresponding to Example 2 of the present invention, and 29.5 after administration of tablets containing 5 mg of desloratadine, with the corresponding Example 11 of U.S. patent 6100274.

Statistical comparison of values of Cmax and AUC (tf) (CPD - area under the curve, tf - time biological half-life) after taking the tablet, corresponding to Example 2 of the present invention, and tablets containing 5 mg of desloratadine corresponding to Example 11 of U.S. patent 6100274, was performed on the data for concentrations of DL and 3-OH-DL of plasma.

The results showed that the 90% confidence intervals for DL and 3-OH-DL is not recommended for Cmax and AUC (tf) values of biological equivalence, equal 80-125%. For subjects for whom it was impossible to define ACC (I), confidence intervals DL for CPD (I) did not meet the recommended values of biological equivalence, equal 80-125%. However, the condence intervals of 3 HE-DL for AUC (tf) met the recommended values of biological equivalence, equal 80-125%.

The mean values of pharmacokinetic parameters for pseudoephedrine are shown in table 2.

Table 2
Average (% CVavalues of pharmacokinetic parameters of pseudoephedrine for healthy subjects after administration of a single oral dose of pills DL D-24 and 240 mg pseudoephedrine sulfate (oval nucleus prolonged action with pseudoephedrine from Claritin® D-24 oblock the th of placebo Claritin® D-24) (n=36)
Pseudoephedrine
Example 2 of this application of 5 mg/240 mgSulfate pseudoephedrine (oval nucleus prolonged action with pseudoephedrine from Claritin® D-24)
Average% CVAverage% CV
Cmax (ng/ml)3282534918,1
Tmax (h)8,4234of 7.3636,3
AUC (tf) (ng-6438 has been426225a 38.5
h/ml)
tf (4)44,03740,025,8
CPD (1) (ng-678040645237,3
h/ml)
t 1/2 (4)10,31487,2521,6
a: the % CV is the coefficient of variation, expressed as a percentage, which is a relative measure of variability. Cm. Steele and Torrie, "Principles and Procedures of Statistics", (1980) 2ndEdition, McGraw-Hill, NY, at page 27.

Mean values of Cmax for pseudoephedrine after taking the tablet (5 mg / DL/240 mg PES), corresponding to Example 2, or kernel prolonged action, containing 240 mg of pseudoephedrine sulfate, was $ 328 and 349 ng/ml, respectively. The statistical comparison of the value of Cmax and AUC (tf) for DL D-24 (5 mg/240 mg) and 240 mg pseudoephedrine sulfate (core prolonged action). The ability to detect constituting 20% of the difference in the effects of drugs with α-criteria equal to 0.05 (two-sided), presented in logarithmic scale Cmax and AUC (tf) was equal to 100 and 93%, respectively.

90% confidence intervals for pseudoephedrine matched with the are recommended for Cmax and AUC (tf) values of biological equivalence, equal 80-125%. For the subjects for which you can define ACC (I), confidence intervals DL for CPD (I) is also consistent with the recommended value of 80-125%.

Pharmacokinetic test # 2

The subjects were at the centre of research for at least 12 hours prior to the conduct of all courses of treatment (day 1). In the morning on day 1 after fasting at night for ten hours every subject underwent one of the following courses of treatment in accordance with his/her number and test period:

Treatment A:One tablet (5 mg / DL/240 mg PES) of Example 2 of the present
application.
Treatment:One tablet (6 mg DL/240 mg PES) of Example 3 of the present
application.
Course of treatment:One tablet containing 5 mg / DL, Example 11 of PSS '274
plus one tablet containing 240 mg PES (oval nucleus
prolonged action with pseudoephedrine).

Used the test method, the timing of blood collection and analytical methods described in Test No. 1.

The mean values of pharmacokinetic parameters are shown in table 3. The ability to detect constituting 20% of the difference in the impact of DL α-criteria equal to 0.05 (two-sided), presented in logarithmic scale AUC (tf), ACC (I) and Cmax was $ 89, 90 and 88%, respectively.

Table 3 Average (% CV1values of pharmacokinetic parameters DL, 3-HE-DL and pseudoephedrine for healthy adult subjects (n=42) after administration of a single oral dose of pills DL, corresponding to Example 2 (5 mg DL/240 mg PES), Example 3 (6 mg DL/240 mg PES), or tablets containing 5 mg / DL, corresponding PSS '274, plus one of the tablets containing 240 mg TEC
The treatmentDL
Cmax (ng/ml)/CVTmax (h)/CV
And21,91444,8952
In32,3543 4,3350
With42,2840a 3.8767
The treatment3-HE-DL
Cmax (ng/ml)/CVTmax (h)/CV
And20,7728to 6.6752
In31,00396,1248
With40,9331of 5.6858
The treatmentPseudoephedrine
Cmax (ng/ml)/CVTmax (h)/CV
And2353307,7145
In362 288,1446
With4349228,3147

1. %CV is the coefficient of variation, expressed as a percentage, which is a relative measure of variability. Cm. Steele and Torrie, "Principles and Procedures of Statistics", (1980) 2ndEdition, McGraw-Hill, NY, at page 27.

2. Treatment A = One tablet of Example 2 (5 mg/240 mg).

3. Treatment = One tablet of Example 3 (6 mg/240 mg).

4. Treatment With = One tablet of Example 11 of U.S. patent 6100274 containing 5 mg / DL, plus one tablet containing 240 mg of pseudoephedrine.

These results show that data on the concentrations of 3-OH-DL plasma tablet (5 mg/240 mg), corresponding to Example 2, is not equivalent to the tablet containing 5 mg / DL, corresponding to Example 11 PSS '274, and that tablet 6 mg DL/240 mg PES, corresponding to Example 3, and a tablet containing 5 mg / DL, corresponding to Example 11 PSS '274 are biologically equivalent.

These results indicate that the biological equivalence of pseudoephedrine in the compositions corresponding to Examples 2 and 3, improved compared with the control product.

Pharmacokinetic test # 3

In this open three-parameter cross the coherent test with random sampling using single doses participated forty healthy volunteers. After fasting the night for ten hours subjects using a random sample was distributed in the following courses of treatment:

Treatment A:6 mg DL/240 mg PES of Example 4 of this application.
Treatment:5 mg / DL of Example 11 from PSS '274 plus 240 mg sulfate
pseudoephedrine.

When carrying out the above treatment regimens used the procedure described in Test No. 1.

The mean values of pharmacokinetic parameters for DL, 3-HE-DL and pseudoephedrine are shown in table 4.

Table 4. Average (% CV1values of pharmacokinetic parameters DL, 3-HE-DL and pseudoephedrine for healthy adult subjects (n=40) after administration of a single oral dose of one tablet D-24 containing 5 mg, corresponding to Example 4, or one tablet containing 5 mg / DL, corresponding PSS '274, plus one of the tablets containing 240 mg TEC
The treatmentDL
Cmax (ng/ml)/SU TM (h)/SU
And22,15414,1366
In32,3044a 4.8362
The treatment3-HE-DL
Cmax (ng/ml)/SUTM (h)/CV
And20,8948the ceiling of 5.6042
In31,07356,1037
The treatmentPseudoephedrine
Cmax (ng/ml)/SUTM (h)/SU
And2382347,8329
In3399 328,4336
1. %CV is the coefficient of variation, expressed as a percentage, which is a relative measure of variability. Cm. Steele and Torrie, "Principles and Procedures of Statistics", (1980) 2ndEdition, McGraw-Hill, NY, at page 27.
2. Treatment A = One tablet of Example 4 of this application (5 mg / DL/240 mg PES).
3. Treatment = One tablet of Example 11 of U.S. patent 6100274 containing 5 mg / DL, plus one tablet containing 240 mg of pseudoephedrine.

Example 1

This example illustrates the preparation of a preferred oral dosage composition corresponding to the present invention. Components and their necessary quantity specified below.

1. Matrix kernel

A. a Method of manufacturing:

1. Povidone is dissolved in a mixture of 3 hours of alcohol and 1 tsp of purified water.

2. In a suitable tank for mixing put the pseudoephedrine sulfate, hypromellose 2208, ethylcellulose and disubstituted calcium phosphate and stirred in a nitrogen atmosphere.

3. The mixture obtained in Stage 2, granularit using the solution obtained in Stage 1, and in order to break down large pieces of wet granules are treated on suitable equipment for grinding.

4. The wet granules are dried at a temperature of about 70°C. in a suitable facility for treatment is in the fluidized bed to a residual moisture content of from 0.5 to 2.0%, which is determined using the balance scale, graduated in percent moisture, or equivalent.

5. The dried granules are treated with the appropriate equipment for grinding.

6. To the dried and milled granules add the necessary amount of silicon dioxide and magnesium stearate and mix.

7. The mixture is pressed at a suitable tabletirujut press.

On the matrix kernel is applied to the shell as follows:

A. Preparation of dispersions and solutions for the application of shells:

1. The solution for the deposition of the first film shell

(1) In a portion of purified water is dispersed simethicone and polyethylene glycol 800 and stirred until complete dissolution.

(2) the product obtained in Stage 1, add the remaining purified water and talc; the thus obtained suspension is stirred at room temperature until a homogeneous state.

(3) a Homogeneous suspension thus obtained in Stage 2, while stirring slowly added to the dispersion of EUDRAGIT NE30D and the resulting mixture is stirred until a homogeneous dispersion. The dispersion is passed through a sieve.

(4) the Dispersion dispersed in the matrix core, which is placed in a rotating tank and the temperature maintained at 40±5°C.

(5) Chilled matrix kernel is dried in a rotary BA is E.

2. Dispersion for coating the second film shell

(1) In a portion of purified water is dispersed simethicone and polyethylene glycol 800. Add additional amounts of water and at room temperature stirred dispersion to dissolve.

(2) To the dispersion obtained in Stage 1, slowly add desloratadin and stirred until a homogeneous dispersion. To the thus obtained homogeneous dispersion add talc and continue mixing until a homogeneous dispersion.

(3) the Dispersion obtained in Stage 2, is added to the dispersion of EUDRAGIT NE30D and stirred until a homogeneous dispersion. The dispersion is passed through a sieve.

(4) the Required amount of dispersion obtained in Stage 3, dispersed in the matrix kernel with the first shell, placed in a rotating tank and having a temperature of 25-27°C.

(5) the Matrix kernel is dried in a rotating tank.

3. The solution for applying the third film shell

(1) To hot (75°C.) purified water add a hypromellose 2910 and stirred to form a solution. Thus obtained solution is cooled to room temperature.

(2) In a separate container for purified water add simethicone and polyethylene glycol 8000 and continue to mix until the formation of the solution.

(3) To the solution, the floor is built in Stage 2, add talc and continue to mix until a homogeneous dispersion.

(4) To the dispersion obtained in Stage 3, add the solution obtained in Stage 1, and continue mixing until a homogeneous dispersion.

(5) To the purified water in the third tank, added FD&C blue No. 2 aluminum lacquer containing EDTA (ethylenediaminetetraacetic acid) as a chelating reagent, and stirred to form a solution.

(6) To the dispersion obtained in Stage 4, was added a solution of blue varnish obtained in Stage 5, and stirred to form a homogeneous mixture.

(7) the dispersion of EUDRAGIT NE30D slowly added to the mixture obtained in Stage 6, and continue mixing until a homogeneous mixture.

(8) the Dispersion obtained in Stage 6, pass through a sieve of 60 mesh.

(9) the Required amount of dispersion obtained in Stage 8, dispersed in the matrix kernel with two shells, placed in a rotating tank and having a temperature of 35-45°C. with tablets kernel matrix with three membranes are dried in a rotating tank.

(10) thus Obtained tablets are removed from the tank and additionally dried for 16 hours at 40°C.

Example 2

The following preferred composition corresponding to the present invention, prepared according the procedure, described above in Example 1.

1. Matrix kernel

ComponentMg in the nucleus
The pseudoephedrine sulfate USP240
The hypromellose 2208 USP, viscosity 100000 SP320
Ethylcellulose NF type 780
Dehydrate disubstituted calcium phosphate USP108
Povidone USP40
Silicon dioxide NF8
Magnesium stearate NF4
Approximate weight of the matrix core800 mg

3. Shell matrix kernel

1. The first film sheath

Componentmg tablet
Simethicone0,22
Polyethylene glycol 80000,27
Talc NF2,2
Neutral copolymer of an acrylate/methyl acrylate (30%2,72
dispersion in water)
Just for the first shellto 5.93 mg

2. The second film sheath (direct action)

Componentmg tablet
Desloratadine5,0
Simethicone0,28
Polyethylene glycol 80001,83
Talc NF7,00
Neutral copolymer of an acrylate/methyl acrylate6,09
For the second shell20,20 mg

3. The third film sheath

Componentmg tablet
The hypromellose 2910 USP, viscosity 6 SP2,09
Talc NF 5,79
Neutral copolymer of an acrylate/methyl acrylate4,18
Polyethylene glycol 8000 NF0,42
Simethicone0,11
The dye Spectra Spray Med Bluethe 3.65
Just for the third shell16,24
An approximate total weight of the three membranes42,37 mg
Approximate weight of tablets (matrix core and three shell)842,97 mg

The dissolution profile of the tablets of Example 1 in vitro was investigated under stirring in 0.1 N. HCl solution at 37°C (1 hour), and then with stirring in phosphate buffer solution at pH 7.5 at 37°C. 80% of desloratadine in the shell was dissolved within the first 30 minutes, and a full dose of pseudoephedrine sulfate, located in the matrix core, slowly stood on the mechanisms of destruction and dissolution in the period, equal to not less than 16 hours.

Example 3

The following preferred composition corresponding to the present invention, prepared in accordance with the procedure described above in Example 1.

1. Mat the ranks nucleus

ComponentMg in the nucleus
The pseudoephedrine sulfate USP240
The hypromellose 2208 USP, viscosity 100000 SP320
Ethylcellulose NF type 780
Dehydrate disubstituted calcium phosphate USP108
Povidone USP40
Silicon dioxide NF8
Magnesium stearate NF4
Approximate weight of the matrix core800 mg

4. Shell matrix kernel

1. The first film sheath

Componentmg tablet
Simethicone0,22
Polyethylene glycol 80000,27
Talc NF2,72
Neutral with is OLIMAR the acrylate/methyl acrylate (30% 2,72
dispersion in water)
Just for the first shellto 5.93 mg

2. The second film sheath (direct action)

Componentmg tablet
Desloratadine6,0
Simethicone0,28
Polyethylene glycol 80001,83
Talc NF5,88
Neutral copolymer of an acrylate/methyl acrylate6,09
For the second shell20,08 mg

3. The third film sheath

Componentmg tablet
The hypromellose 2910 USP, viscosity 6 SP2,09
Talc NF5,79
A neutral copolymer of ethyl is relat/MMA 4,18
Polyethylene glycol 8000 NF0,42
Simethicone0,11
The dye Spectra Spray Med Bluethe 3.65
Just for the third shell16,24
An approximate total weight of the three membranes42,37 mg
Approximate weight of tablets (matrix core and three shell)842,97 mg

Example 4

The following preferred composition corresponding to the present invention, prepared in accordance with the procedure described above in Example 1.

1. Matrix kernel

tr>
ComponentMg in the nucleus
The pseudoephedrine sulfate USP240
The hypromellose 2208 USP, viscosity 100000 SP320
Ethylcellulose NF type 780
Dehydrate disubstituted calcium phosphate USP108
Povidone USP40
Silicon dioxide NF8
Magnesium stearate NF4
Approximate weight of the matrix core800 mg

5. Shell matrix kernel

1. The first film sheath

Componentmg tablet
Simethicone0,22
Polyethylene glycol 80000,27
Talc NF2,72
Neutral copolymer of an acrylate/methyl acrylate (30%2,72
dispersion in water)
Just for the first shellto 5.93 mg

2. The second film sheath (direct action)

Componentmg tablet
Desloratadine5,0
Simethicone0,28
Polyethylene glycol 80000,61
Talc NF5,17
Neutral copolymer of an acrylate/methyl acrylate6,09
The hypromellose 2910 USP, viscosity 6 SP3,05
For the second shell20,20 mg

3. The third film sheath

Componentmg tablet
The hypromellose 2910 USP, viscosity 6 SP2,09
Talc NF5,79
Neutral copolymer of an acrylate/methyl acrylate4,18
Polyethylene glycol 8000 NF0,42
Simethicone0,11
The dye Spectra Spray Med Bluethe 3.65
Just for the third shell16,24
An approximate total weight of the three membranes42,37 mg
Approximate weight of tablets (matrix core and three shell)842,97 mg

Similar results were to be expected, when, instead of pseudoephedrine sulfate used providing anti-edematous effect of the number of other acceptable from a pharmaceutical point of view salts pseudoephedrine, such as hydrochloride pseudoephedrine.

Compositions corresponding to the present invention is applicable for treatment of allergic and/or inflammatory skin conditions (e.g., urticaria) and upper and lower respiratory tract, including nasal and nenasilny the symptoms of seasonal allergic rhinitis, including swelling in the nose, in a patient in need of such treatment. The exact dosage and mode of administration of a drug can vary by the attending physician in accordance with the present invention directions depending on the needs of the patient, such as age, sex of the patient and severity subjected to the treatment of allergic and/or inflammatory condition. Determining the correct dosage and mode of administration of a drug for a particular patient rests with the treating physician.

Although above we use the example is presented in a number of preferred implementations of the present invention, it is clear that the scope of the present invention should be defined by the attached claims.

1. The use of solid oral dosage composition of prolonged action, including (a) a core containing an effective amount of pseudoephedrine or pharmaceutically acceptable salts, (b) a first shell covering the core and comprising a swelling in water of the film-forming neutral or cationogenic copolymer ester, modifier film and a lubricating substance, and (C) a second membrane covering the first shell and including an effective amount of desloratadine, and the amount of pseudoephedrine or its acceptable from a pharmaceutical point of view of salt is sufficient to provide maximum geometric average concentrations of pseudoephedrine in the plasma is equal to from about 345 to about 365 ng/ml for a time from about 7,60 to about 8,40 h, and the number of desloratadine is sufficient to ensure maximum geometric average concentrations of desloratadine in the plasma is from about 2.10 to about 2.45 ng/ml, from about 4.0 to about 4.5 hours after administration of a single dose of the indicated composition, for the preparation of drugs for the treatment of allergic and/or inflammatory conditions of the upper and lower respiratory tract and skin.

<> 2. The use of solid oral dosage composition of prolonged action, including (a) a core containing an effective amount of pseudoephedrine or pharmaceutically acceptable salts, (b) a first shell covering the core and comprising a swelling in water of the film-forming neutral or cationogenic copolymer ester, modifier film and a lubricating substance, and (C) a second membrane covering the first shell and including an effective amount of desloratadine, and the amount of pseudoephedrine or its acceptable from a pharmaceutical point of view of salt is sufficient to provide maximum geometric average concentrations of pseudoephedrine in the plasma is equal to from about 345 to about 365 ng/ml for a time from about 7,60 to about 8,40 h, and the number of desloratadine is sufficient to ensure maximum geometric average concentrations of desloratadine in the plasma is from about 2.10 to about 2.45 ng/ml, from about 4.0 to about 4.5 hours after administration of a single dose of the indicated composition, for the preparation of drugs for the treatment of urticaria.

3. The use of solid oral dosage composition of prolonged action, including (a) a core containing an effective amount of pseudoephedrine or its farmaci is almost acceptable salt, (b) a first shell covering the core and comprising a swelling in water of the film-forming neutral or cationogenic copolymer ester, modifier film and a lubricating substance, and (C) a second membrane covering the first shell and including an effective amount of desloratadine, and the amount of pseudoephedrine or its acceptable from a pharmaceutical point of view of salt is sufficient to provide maximum geometric average concentrations of pseudoephedrine in the plasma is equal to from about 345 to about 365 ng/ml, from about 7,60 to about 8,40 h, and the number of desloratadine is sufficient to ensure maximum geometric average concentrations of desloratadine in the plasma is from about 2.10 to about 2.45 ng/ml, from about 4.0 to about 4.5 hours after administration of a single dose of the indicated composition, for the preparation of drugs for the treatment of nasal and nenasala symptoms year-round and seasonal allergic rhinitis.



 

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39 cl, 1 tbl, 99 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to application in an effective amount and to new nicotine receptor agonists described by general formula (i) or (ii) for treating inflammatory diseases chosen from a group including asthma, chronic obstructive pulmonary disease (COPD), interstitial pulmonary tissue fibrosis (IPF), sarcoidosis, hypersensitivity pneumonitis (HP), chronic hypersensitivity pneumonitis and bronchiolitis obliterans organising pneumonia (BOOP). The compounds (i) and compounds (ii) relate to formulae (i) (ii) where in formula (i) R1 and R2 independently mean alkyl with 1-10 carbon atoms; Xa means CH or N; Ya means one or more substitutes chosen from hydrogen, halogen, cyano, hydroxyl, alkyl with 1-10 carbon atoms optionally substituted with one or more halogen atoms, and alkoxy with 1-10 carbon atoms; n means an integer 0 or 2; J means a counterion representing a compound for maintaining electric neutrality, e.g., halogen, sulphate, sulphonate; in formula (ii) R3 is chosen from or Xb means N or N+-R10; R4 means one or more substitutes chosen from hydrogen, halogen; each R10, R11 and R12 independently means alkyl with 1-10 carbon atoms; provided the presence of the counterion when Xb means N+-R10.

EFFECT: use of nicotine receptor agonists in the effective amount for treating inflammatory diseases.

26 cl, 40 dwg, 3 tbl, 38 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine and concerns cat allergen fused proteins and application thereof. Substance of the invention involves a compositions containing a virus-like particle (VLP) or a viral particle and at least, one antigen, first of all at least, one cat antigen, and more specifically at least one cat antigen which is human allergen. In specific versions of the invention, said antigen represents cat antigen Fel d1 or its fragment covalently bound with the VLP.

EFFECT: invention can be applied for preparing vaccines first of all aimed at treatment and/or prevention of cat dander allergy and other cat antigens and allergens responses.

25 cl, 20 ex, 5 tbl, 4 dwg

FIELD: medicine.

SUBSTANCE: daily in morning hours nasal passages are washed with physiological solution, 10% oil solution of vitamin E in dose 3 drops into each passage is dropped into both nasal passages. After 2 hours transcutaneous impact with constant magnetic field and low-intensity laser irradiation with power 30-80 mW, wavelength 0.85-0.89 mcm, pulse repetition rate 50-80 Hz is carried out on region of projection of thymus, maxillary sinuses, submandibular lymph nodes, spinous process of the third cervical vertebra, mastoid process. Time of impact is 60 seconds per each region. Ozonised olive oil is dropped into each nasal passage in dose 3 drops. After that, by means of light-conducting nozzle performed is impact on anterior parts of inferior nasal conchas with pulse red irradiation with wavelength 0.63-0.65 mcm, pulse power of irradiation at outlet not less than 5 W, pulse repetition rate 50-80 Hz, frequency of light diode modulation - 4-8 Hz. Impact time is 60-120 seconds. Total treatment course is 7 days with 4 month interval, 3 times per year. During the first interval between courses bacterial immunomodulator IRS-19 is introduced in age dose in therapeutic regimen. During the second interval antihomotoxic therapy with drugs Luffel and Lymphomyosot is administered.

EFFECT: method makes it possible to increase treatment efficiency, reduce frequency of disease recurrences, reduce medication load in case of allergic rhinites, which usually require long treatment.

2 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention refers to producing versions of group I Poaceae (holy grass) allergen, also can be used either for specific immunotherapy (hyposensitisation) of patients with grass pollen allergy, or for preventive immunotherapy of grass pollen allergies. The produced versions are characterised by Cys41 Ser, Cys57Ser, Cys69Ser, Cys72Ser, Cys77Ser, Cys83Ser and Cysl39Ser substitutes in a Phi p1 mature protein sequence. Also, a structure of the allergen versions can be presented with no fragments relevant to amino acid residues 1-6, 1-30, 92-104, 115-119, 175-185 and 213-220 or 1-6, 115-119 and 213-220 as a part of a primary sequence of Phi p1 mature protein.

EFFECT: invention allows producing a version of group I Poaceae allergen characterised lower IgE responsiveness as compared with common wild allergen and substantially maintained responsiveness to T-lymphocytes.

8 cl, 9 dwg, 2 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to application of N-acyl derivatives of amino acids of general formula

, where n equals 2 or 3 and their pharmaceutically acceptable salts as anti-allergic, anti-inflammatory and anti-anaphylactic medications.

EFFECT: obtaining pharmaceutical composition for treatment of allergic and inflammatory diseases, for instance such as bronchial asthma, allergic rhinitis, pollinosis, psoriasis.

11 cl, 12 tbl, 19 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (III): , in which D is a benzene ring, 2-pyridone ring, pyridine ring, benzoxalone ring, benzoxadinone ring or benzimidazole ring; R1 denotes carboxy or hydroxy; R2 independently denotes a halogen atom; alkyl optionally substituted with a halogen atom, aryl or alkylamine; alkynyl, optionally substituted alkoxy; hydroxy; carboxy; alkoxy optionally substituted with phenyl, aromatic heterocyclic ring which denotes a 5-6-member aromatic monocyclic carbocyclic ring containing one or two heteroatoms, independently selected from oxygen and nitrogen atoms; alkylsulphonyl; aryloxy; amino optionally substituted with alkyl; acyl optionally substituted with alkyl or alkyloxy; alkyloxycarbonyl; alkanesulphonyl; arylsulphonyl or alkylcarbamoyl; carbamoyl optionally substituted with alkyl, phenyl, cycloalkyl, acetyl, alkanesulphonyl, heteroarylalkyl, cycloalkylalkyl, heteroaryl which denotes a 5-6-member aromatic monocyclic ring containing one or three heteroatoms independently selected from oxygen and nitrogen atoms, and which is optionally substituted with alkyl or cycloalkyl; acylcyano; nitro, aryl; heteroaryl which denotes a 5-6-member aromatic ring containing one or more heteroatoms independently selected from oxygen, sulphur and nitrogen atoms, and which is optionally substituted with alkyl; alkylsulphonyl; morpholinylsulphonyl; non-aromatic heterocyclic group which denotes a 5-6-member non-aromatic heterocyclic ring containing one or more nitrogen atoms and optionally an oxygen and/or sulphur atom; R3 denotes C1-C6alkyloxy, C1-C6alkylthio; R4 denotes a halogen atom or alkyloxy; R5 denotes alkyl; M denotes sulphonyl; L3 independently denotes alkylene optionally containing one oxygen or nitrogen atom, alkenylene, or -N(R7)-; R7 independently denotes a hydrogen atom, alkyl; Y denotes a single bond or CO; Z denotes CH or N; n equals 0 or 1; p equals 0, 1, or 2; q equals 0 or 1; provided that R1 does not denote carboxy when ring D is a benzene ring, -L3- denotes -(O-alkylene)- and the substitution position of L3 and Y is an ortho-position in ring D; to pharmaceutically acceptable salts thereof. The invention also relates to compounds of formula (IV), a pharmaceutical composition, a method of treating diseases associated with the DP receptor, use of compounds in any of the claims 1-17, as well as compounds of general formula (V).

EFFECT: obtaining novel biologically active compounds having DP receptor antagonist activity.

30 cl, 8 ex, 62 tbl

Infant food // 2404785

FIELD: food industry.

SUBSTANCE: invention relates to food and pharmaceutical industry. Infant food composition, containing protein, fats, carbohydrates, nucleotides, nucleosides and nonprotein negatively charged polygalacturonic acid taken at in certain amounts. Application of composition for production of composition for infant feeding. Application of nutrient composition to produce composition for treatment and/or prophylactics of inflammatory disease, diarrhea, eczema and/or atopic dermatitis of a baby.

EFFECT: nutrient composition efficiently imitates protective action of human milk, in particular, against allergies and infections.

9 cl, 4 ex

FIELD: medicine.

SUBSTANCE: daily in morning hours nasal passages are washed with physiological solution, 10% oil solution of vitamin E in dose 3 drops into each passage is dropped into both nasal passages. After 2 hours transcutaneous impact with constant magnetic field and low-intensity laser irradiation with power 30-80 mW, wavelength 0.85-0.89 mcm, pulse repetition rate 50-80 Hz is carried out on region of projection of thymus, maxillary sinuses, submandibular lymph nodes, spinous process of the third cervical vertebra, mastoid process. Time of impact is 60 seconds per each region. Ozonised olive oil is dropped into each nasal passage in dose 3 drops. After that, by means of light-conducting nozzle performed is impact on anterior parts of inferior nasal conchas with pulse red irradiation with wavelength 0.63-0.65 mcm, pulse power of irradiation at outlet not less than 5 W, pulse repetition rate 50-80 Hz, frequency of light diode modulation - 4-8 Hz. Impact time is 60-120 seconds. Total treatment course is 7 days with 4 month interval, 3 times per year. During the first interval between courses bacterial immunomodulator IRS-19 is introduced in age dose in therapeutic regimen. During the second interval antihomotoxic therapy with drugs Luffel and Lymphomyosot is administered.

EFFECT: method makes it possible to increase treatment efficiency, reduce frequency of disease recurrences, reduce medication load in case of allergic rhinites, which usually require long treatment.

2 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly - to otorhinolaryngology and paediatrics. The method involves the integrated effect of inhalations and magnetotherapy. Dry sodium chloride aerosol is inhaled with using the individual halo inhaler 'Haloneb'. The inhalations are daily. The inhalation procedure lasts for 10-15 minutes in the 2nd halo aerosol generation mode. The therapeutic course is 8-10 inhalations. 5-10 minutes later, the inhalation is followed with low-frequency magnetic field exposure of sinusoidal current shape, frequency 50 Hz, in a continuous mode. Induction is 10-15 mT. The session duration is 10-15 minutes. The procedures are daily. The therapeutic course is 8-10 procedures.

EFFECT: method improves clinical effectiveness ensured by better nasal air passage, reduced oedema and inflammation of the upper-airway mucosa and improved drainage, provided local immunopotentiating and mucolytic action on the nasal and paranasal sinus mucosa.

2 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to otolaryngology, and deals with treatment of chronic recurring inflammatory diseases of nasal mucosa and paranasal sinuses. Method includes preliminarily obtaining of autologic lymphocytes from venous blood of patient, cultivation of obtained lymphocytes together with immunomodulator, preferably immunofan. After that from 0.1 to 3.0 ml of lymphocyte suspension, which contains 106-107 cells/ml, is introduced into paranasal sinuses with intervals between introductions from 2 to 7 days.

EFFECT: method is efficient, including cases of recurring polyps rhynosinutisis, allows to reduce treatment terms, increase remission terms, reduce frequency of appearance of symptoms of main and accompanying disease with reduction of need in other therapy.

4 cl, 3 ex, 6 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to otorhinolaryngology and can be used for treating sinusitis. That is ensured by the integrated treatment that includes ceftriaxone, 1 g of dry substance dissolved in 5 ml of 1% novocaine. Ceftriaxone solution is introduced in a single dosage of 0.5 ml on each side into a skin fold of wing of nose from the vestibule with an insulin needle of external diametre 0.25-0.35 mm.

EFFECT: invention provides higher clinical effectiveness and reduced treatment length due to a certain mode of the lymphotropic introduction of ceftriaxone that allows creating its depot in the immediate proximity from an involved organ with prolonged release into the paranasal sinuses in the therapeutic concentration.

2 ex

FIELD: medicine.

SUBSTANCE: rehabilitation of children with remitted chronic rhinosinusitis is ensured by the administration of Sinupret as a cytoprotector. The preparation is introduced by 25 drops 3 times a day, daily for 24-30 days. Rehabilitation is conditioned by ensured competence of nasal mucosa cells due to newly ascertained reparative ability of Sinupret, with local destructive processes of pavement and columnar epithelium cells and neutrophils be decreased.

EFFECT: higher rehabilitation effectiveness.

5 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention relates to stable pharmaceutical composition, which contains as active ingredient phenylephrine in pharmaceutically effective amount and silicified microcrystalline cellulose in amount, effective for reduction of phenylephrine destruction, caused by exposure to oxygen.

EFFECT: phenylephrine tablets by invention demonstrate acceptable physical characteristics, such as form, colour, strength, and satisfactory stability profile.

9 cl, 2 tbl, 6 ex

FIELD: medicine.

SUBSTANCE: present invention concerns medical products, particularly a nasal pharmaceutical composition for treating or relieving the rhinitis symptoms, containing aqueous suspension of solid particles of fluticasone with the following particle size distribution profile: approximately 10% of particles are smaller than 0.90 microns; approximately 25% of particles are smaller than 1.6 microns; approximately 50% of particles are smaller than 3.2 microns; approximately 75% of particles are smaller than 6.2 microns; approximately 90% of particles are smaller than 10.0 micron; where the composition is available for intranasal introduction in nasal mucosa. Besides the invention relates to the methods of treating said diseases.

EFFECT: composition provides improved therapeutic efficiency at a small dose of fluticasone.

58 cl, 4 dwg, 3 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: carboxylic acid compounds are presented by formula (I) where R1 represents (1) hydrogen atom, (2) C1-4alkyl; E represents -CO-; R2 represents (1) halogen atom, (2) C1-6 alkyl, (3) trihalogen methyl; R3 represents (1) halogen atom, (2) C1-6alkyl; R4 represents (1) hydrogen atom; R5 represents (1) C1-6alkyl; represents phenyl; G represents (1) C1-6alkylene; represents 9-12-merous bicyclic heterocycle containing heteroatoms, chosen of 1-4 nitrogen atoms, one or two oxygen atoms; m represents 0 or an integer 1 to 4, n represents 0 or an integer 1 to 4, and i represents 0 or an integer 1 to 11 where R2 can be identical or different provided m is equal to 2 or more, R3 can be identical or different provided n is equal to 2 or more, and R5 can be identical or different provided i is equal to 2 or more; both R12 and R13, independently represent (1) C1-4alkyl, (2) halogen atom, (3) hydroxyl or (4) hydrogen atom, or R12 and R13 together represent (1) oxo or (2) C2-5alkylene and where provided R12 and R13 simultaneously represent hydrogen atom, carboxylic acid compound presented by formula (I), represents a compound chosen from the group including the compounds (1) - (32), listed in cl.1 of the patent claim. Besides the invention concerns a pharmaceutical composition based in the compound of formula I and to application of the compound of formula I for making the pharmaceutical composition.

EFFECT: there are produced new carboxylic acid derivatives with antagonistic activity with respect to DP receptor.

14 cl, 74 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to otorhinolaryngology and physiotherapy. The method involves endonasal introduction of bromide ipratropium by positive-pole endonasal electrophoresis of the solution 1 ml containing bromide ipratropium 0.25 mg/ml. Electrophoresis is performed at current strength not exceeding 2 mA during 10 - 20 minutes. Therapeutic course is 5 daily procedures.

EFFECT: higher clinical effectiveness with decreased number of daily procedures, excludes intillate ingress into gastrointestinal tract.

3 ex, 6 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to new derivatives of imidazo[1,2-c]pyrimidinyl acetic acid of formula (I) or to its salts: , where R1 is ,, in which n is an integer ranging from 0 to 6; Y is aryl, where the said aryl is optionally substituted at a substitutable position with one or more substitutes selected from a group which consists of halogen or C1-6alkyl, optionally substituted with mono-, di- or trihalogen; R2 is hydrogen; R3 is hydrogen or halogen; and R4 is hydrogen. The invention also relates to derivatives of imidazo[1,2-c]pyrimidinyl acetic acid of formula (I-i) or to its salts, to a drug, to use of compounds in paragraph 1, as well as to a drug in form of a standard single dosage.

EFFECT: obtaining new biologically active compounds, which are active towards CRTH2.

23 cl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to chemical-pharmaceutical industry and relates to hard, suitable for oral intake pharmaceutical forms of application with modified release, which contain 5-chlor-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morphoilinyl)-phenyl]-1,3-oxazolidin-5-yl} -methyl)-2-thiophencarboxamide, as well as to method of their obtaining, their application as medication, their application for prevention, secondary prevention and/or treatment of diseases, mediated by blood coagulation factor Xa.

EFFECT: permanent concentration of active substance of the blood.

19 cl, 10 ex

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