Pharmaceutical composition for combining piperidinemethanol with antitumor agent

 

Proposed: dosage form for ease congestion in the nose, which consists of two discrete areas: the first is the composition based sympathomimetic and ensures its continuous selection, the second - antihistamine composition for immediate allocation of its active ingredient. The invention expands the Arsenal of tools specified destination, while ensuring acceptable bioavailability of each of the active ingredients, stability during storage and acceptable physical strength. 2 C. and 15 C.p. f-crystals, 11 PL.

Background of the invention it Was found that various compounds piperidinemethanol useful as antihistamines, antiallergic agents and bronchodilators, as disclosed in U.S. patent 3878217, 4254129 and 4285957. Here are some examples of compositions containing such various connections piperidinemethanol.

J. Domet and D. Shah in U.S. patent 4929605 disclose a pharmaceutical composition in solid standard dosage form comprising a therapeutically effective amount of a compound piperidinemethanol or its pharmaceutically acceptable salt, pharmaceutically acceptable non-ionic who Cesky acceptable carbonate in an amount of from about 2 to about 50% by weight of the composition.

N. Webb and G. Hammer in U.S. patent 4996061 disclose a pharmaceutical composition in the form of a multi-layer compressed tablet comprising a discrete area, consisting of a composition that provides a rollover allocation therapeutically effective decongestant amount of sympathomimetic drugs and dicterow zone comprising a different composition, which provides an immediate allocation of a therapeutically effective antihistaminic amount piperidinemethanol, and, optionally, a therapeutically effective decongestant amount of sympathomimetic drugs.

N. Schock with TCS. in U.S. patent 4999226 discloses a multi-layer tablet containing layer of ibuprofen, a layer antihistamine piperidinemethanol and the layer or layers containing conventional pharmaceutical excipients, which are located between the layers of ibuprofen and piperidinemethanol and serve to physically divided. N. Schock with TCS. specifies that attempts to create a two-layer tablet failed as a result of chemical decomposition piperidinemethanol in the presence of ibuprofen. In addition, attempts to slow the rate of decomposition through the use of antioxidants, taket pharmaceutical composition in the form of a solid standard dosage forms, including a connection piperidinemethanol and at least one inert ingredient.

Currently available a number of products for the treatment of symptoms associated with such ailments as the common cold, seasonal rhinitis, headache associated with sinusitis, sinusitis, etc. that contain a variety of therapeutic agents. Many of these products contain antihistamine in combination with a sympathomimetic decongestant agent. These combined products convenient for the patient, as they allow the patient to alleviate a number of symptoms, not taking multiple medications.

Attempts were made to fabricate multilayer extruded tablets containing sympathomimetic medication, pseudoephedrine hydrochloride, in the form of slow release in combination with piperidinemethanol, hydrochloride 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl] -1-hydroxybutyl] -,-dimethylbenzoxazole acid, in the form of immediate selection using a composition similar to the composition described N. Webb and G. Hammer in U.S. patent 4996061. But failed to get such a composition due to unexpected and unacceptable cracking and n attempts to obtain a separate compressed tablet, in which balls with continuous selection hydrochloride pseudoephedrine and form with immediate allocation hydrochloride 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl] -,-dimethylbenzoxazole acid were combined in a single layer tablet. However, this composition also did not work, because some of the samples collected during pressing of tablets and tested in relation to the homogeneity of their content did not meet the requirements of United States Pharmacopeia (USP).

The aim of the present invention is to provide a pharmaceutical composition in dosage form for oral administration in the form of a two-layer tablet, which provides an immediate allocation of the connection piperidinemethanol and the prolongation selection sympathomimetic drugs, which demonstrates acceptable bioavailability of each of the compounds. An additional objective of the present invention is to provide a pharmaceutical composition in the form of a two-layer tablet of sufficient strength immediately containing the secreted form of connection piperidinemethanol and shape with an extended selection of sympathomimetic drugs, and the tablet does not need narodnosti content which would meet the requirements of USP. Another objective of the present invention is to provide a two-layer tablet, which demonstrates the characteristic solubility piperidinemethanol, which is similar to the characteristic solubility ALLEGRA60 mg capsules, and this characteristic solubility sympathomimetic drugs, which slowly characteristics solubility SUDAFED120 mg tablets.

The authors have created a new pharmaceutical composition in the form of a two-layer tablet, which provides effective and immediate absorption and bioavailability piperidinemethanol, such as hydrochloride 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl] -,-dimethylbenzoxazole acid, and an effective prolonged isolation and bioavailability sympathomimetic drugs, such as hydrochloride pseudoephedrine after its oral administration. In addition, the new two - layer tablet of the present invention demonstrates the homogeneity of the content, which meets the requirements of USP, resistant to cracking during storage and has acceptable is Ristiku the solubility of the hydrochloride of 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl] -,-dimethylbenzoxazole acid, which is similar to the characteristic solubility ALLEGRA60 mg capsules, and this characteristic solubility sympathomimetic drugs, which slowly characteristics solubility SUDAFED 12 HOUR120 mg tablets.

Summary of the invention the present invention proposed pharmaceutical composition in the form of a two-layer tablet, which includes (a) a first discrete zone comprising Compositions (A), which comprises a therapeutically effective decongestant amount of sympathomimetic drugs or its pharmaceutically acceptable salt in an amount of from about 18 to about 39% by weight of the Composition (a) and the basic material of the first carrier, and the main material of the first carrier comprises a mixture of (i) Carnauba wax in an amount of from about 59 to about 81% by weight of the Composition (a) and (ii) the right, preventing the bonding agent in an amount of from about 0.25 to about 2,00% by weight of the Composition (A); where the specified key material of the first carrier provides prolonged isolation of sympathomimetic drugs, and (b) the second thesis is estvo piperidinemethanol or its pharmaceutically acceptable salt, in the amount of from about 15 to about 30% by weight of Composition (b) and the basic material of the second carrier comprising a mixture of (i) cellulose diluent in an amount of from about 27 to about 73% by weight of the Composition (C); (ii) pre-gelatinizing starch in an amount of from about 15 to about 30% by weight of the Composition (In);
(iii) a suitable dezintegriruetsja agent in an amount of from about 0.25 to about 6,00% by weight of Composition (b) and
(iv) a suitable lubricant in an amount of from about 0.25 to about 2,00% by weight of the Composition (In);
with the specified key material of the second media provides an immediate allocation piperidinemethanol or its pharmaceutically acceptable salt.

In addition, in the present invention proposed pharmaceutical composition in the form of a two-layer tablet, which includes
(a) a first discrete zone comprising Compositions (A), which comprises a therapeutically effective decongestant amount of sympathomimetic drug or its pharmaceutically acceptable salt in an amount of from about 18 to about 39% by weight of the Composition (a) and the basic material of the first carrier, and the main material of the first carrier includes a mixture of
(i) Carnauba wax in kollichestvo from about 0.25 to about 2,00% by weight of the Composition (A);
where the specified key material of the first carrier provides prolonged isolation of sympathomimetic drugs, and
(b) a second discrete zone comprising a Composition (B), which comprises a therapeutically effective antihistamine number piperidinemethanol formula:

where X represents a number in the range of from about 0 to about 5, and the individual optical isomer in an amount of from about 15 to about 30% by weight of the Composition (C), and the main material of the second carrier includes a mixture of
(i) cellulose diluent in an amount of from about 27 to about 73% by weight of the Composition (In);
(ii) pre-gelatinizing starch in an amount of from about 15 to about 30% by weight of the Composition (In);
(iii) a suitable dezintegriruetsja agent in an amount of from about 0.25 to about 6,00% by weight of Composition (b) and
(iv) a suitable lubricant in an amount of from about 0.25 to about 2,00% by weight of the Composition (In);
with the specified key material of the second media provides an immediate allocation piperidinemethanol or its pharmaceutically acceptable salt.

In addition, in the present invention proposed pharmaceutical composition in the form of a two-layer ski effective decongestant amount of sympathomimetic drugs or its pharmaceutically acceptable salt, in the amount of from about 25 to about 33% by weight of the Composition (a) and the basic material of the first carrier, and the main material of the first carrier includes a mixture of
(i) Carnauba wax in an amount of from about 66 to about 74% by weight of the Composition (a) and
(ii) appropriate, preventing the bonding agent in an amount of from about 0.50 to about 1.50% of the weight. Composition (A);
where the specified key material of the first carrier provides prolonged isolation of sympathomimetic drugs, and
(b) a second discrete zone comprising a Composition (b) which comprises a therapeutically effective antihistaminic amount of piperidinemethanol formula:

where X represents a number in the range of from about 0 to about. 5, and the individual optical isomer, in an amount of from about 15 to about 24% by weight of Composition (b) and the basic material of the second carrier, and the main material of the second carrier includes a mixture of
(i) cellulose diluent in an amount of from about 43 to about 67% by weight of the Composition (In);
(ii) pre-gelatinizing starch in an amount of from about 15 to about 24% by weight of the Composition (In);
(iii) a suitable dezintegriruetsja agent in an amount of from about 3,20 d of 1.00% by weight of the Composition (In);
with the specified key material of the second media provides an immediate allocation piperidinemethanol or its pharmaceutically acceptable salt.

Detailed description of the invention
In the sense, as used herein, the terms "connection piperidinemethanol" and "connection piperidinemethanol and their pharmaceutically acceptable salts" refers to those compounds which are described by formulas (I), (II) and (III) U.S. patent 3878217, 4254129 and 4285957, each of which is incorporated here by reference.

Connection piperidinemethanol formula (I) are those compounds which correspond to the formula:

where R1represents hydrogen or hydroxy; R2represents hydrogen or R1and R2taken together form a second bond between the carbon atoms to which are attached R1and R2; n represents a positive integer from 1 to 3; Z represents thienyl, phenyl or substituted phenyl, and the substituents in the substituted phenyl may be in ortho-, meta - or para-positions unsubstituted phenyl ring and are selected from the group consisting of a halogen atom, a straight or branched chain lower alkyl containing from 1 to 4 carbon atoms, lower Aogo heterocyclic ring, selected from the group consisting of pyrrolidino, piperidino, morpholino or N-(lower)-alkylpiperazine, or their pharmaceutically acceptable salts accession acid.

Connection piperidinemethanol formula (II) are those compounds which correspond to the formula:

where R1represents hydrogen or hydroxy; R2represents hydrogen or R1and R2taken together form a second bond between the carbon atoms to which are attached R1and R2; m represents an integer from 1 to 5; R3represents-CH3or-CH2OH; each a or b is hydrogen or hydroxy, provided that at least one of a and b is hydrogen and one of a and b is different from hydrogen if R3represents-CH3; and their pharmaceutically acceptable salts and individual optical isomers.

Connection piperidinemethanol formula (III) are those compounds which correspond to the formula:

where R1represents hydrogen or hydroxy; R2represents hydrogen or R1and R2taken together form a second bond between the carbon atoms to which are attached R1and R2; m ptarget from 1 to 6 carbon atoms and may be branched or unbranched; each a and b is hydrogen or hydroxy, provided that at least one of a and b is hydrogen; and their pharmaceutically acceptable salts and individual optical isomers.

More specifically, hydrochloride 4-[4-[4-(hydroxydiphenyl-methyl)-1-piperidinyl]-1-hydroxybutyl],-dimethylbenzoxazole acid of formula (IIIa)

where X represents a number in the range of from about 0 to about 5, and the individual optical isomers are preferred compounds piperidinemethanol. The most preferred compound piperidinemethanol is the connection hydrochloride 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzoxazole acid, where X=0 or 1.

In addition, the free base of 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzoxazole acid of formula (IIIb)

where X represents a number in the range of from about 0 to about 5, and the individual optical isomers are also preferred compounds piperitenone free reason 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl] -,-dimethylbenzoxazole acid, which can be obtained, as disclosed in international patent publication WO 95/31437, published 23 November 1995. The free base of 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl] -,-dimethylbenzoxazole acid can easily be obtained using techniques and procedures well known in the art. For example, hydrochloride 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl] -,-dimethylbenzoxazole acid are dissolved in methanol and treated with one equivalent of aqueous sodium bicarbonate. After stirring for about 5-30 minutes, the white solid is collected by filtration, washed with water and dried by air, getting dihydrate free base of 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl] -,-dimethylbenzoxazole acid.

Illustrative examples of straight or branched alkyl groups containing from 1 to 4 carbon atoms, can serve as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. Illustrative examples of straight or unless the-butyl, isobutyl, tert-butyl, n-pentyl, cyclopentyl, n-hexyl and cyclohexyl. Illustrative examples of the lower alkoxygroup containing from 1 to 4 carbon atoms, can serve as methoxy, ethoxy, propoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy. The terms "halo", "halogen" or "halide" refers to fluorine atoms, chlorine, bromine or iodine.

The term "pharmaceutically acceptable salt" refers to those salts of the formula (I), (II), (III) and (IIIa), which are practically non-toxic in the doses that are taken for achieving the desired effect and do not have independent pharmacological activity. Salt is included in the scope of the invention under such term, are pharmaceutically acceptable salts attach the appropriate inorganic or organic acids. Suitable inorganic acids are, for example, hydrochloric, Hydrobromic, sulfuric and phosphoric acid. Suitable organic acids include carboxylic acids such as acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic, tartaric, citric, reklamowa, ascorbic, maleic, hydroxymaleimide, dihydroxytoluene, benzoic, phenylacetic, 4-aminobenzotriazole and almond acid, sulfonic acids, such as methanesulfonate, econsultancy and-hydroxyethanesulfonic acid. In addition, pharmaceutically acceptable salts include salts of the compounds of formula (I), (II), (III) and (IIIa), which are formed with inorganic and organic bases, such as alkali metal salts, for example sodium, potassium and lithium salts of alkaline earth metals such as calcium and magnesium, salts of light metals of group IIIA, such as aluminum, salts of organic amines such as primary, secondary or tertiary amines, such as cyclohexylamine, ethylamine, pyridine, methylaminoethanol and piperazine. These salts get conventional methods known in the art, such as treating compounds of formula (I), (II), (III) and (IIIa) with an appropriate acid or base. Such salts can exist as hydrated and practically anhydrous form. Preferred salts accession acids are salts of hydrochloric, sulfuric and tartaric acids.

The term "stereoisomers" is a General term for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes geometric (CIS/TRANS) isomers and isomers Ruga (diastereoisomer). The term "chiral center" refers to the carbon atom is attached to four different groups. The terms "enantiomer", "enantiomeric" or "optical isomer" refers to a molecule that is incompatible with its mirror image and, therefore, is optically active, where the optical isomer or enantiomer rotates the plane of polarized light in one direction and its mirror image rotates the plane of polarized light in the opposite direction. The term "racemic mixture" or "racemic modification" refers to a mixture of equal parts of enantiomers, which is optically inactive. In the sense as used in the description, the prefix "(+)" and "(-)" is used to designate the sign of rotation of plane polarized light by the compound, with (+) refers to programada connection, and (-) refers to levogyrate.

The term "enantiomeric enrichment" refers to the increase in the number enantiomer compared with the content of its corresponding opposite enantiomer. The usual way of expressing the achieved enantiomeric enrichment introduces the concept of the "enantiomeric excess" or "EE", which is expressed by the following equation:

Various sympathomimetic drugs, such as pseudoephedrine, phenylephrine and phenylpropanolamine, considered by experts as therapeutic agents effective to relieve congestion in the nose, and usually take them together with antihistamines to relieve congestion in the nose associated with allergic rhinitis. These sympathomimetic drugs are usually effective when administered orally in a standard dosage form when receiving a standard dosage forms four times a day, and this standard dosage form provides immediate release of active drugs. For example, the recommended dose hydrochloride pseudoephedrine for adults is 60 mg every 6 hours (q.i.d.). In addition, a standard dosage form, containing sympathomimetic drugs can be prepared in such a way as to ensure the selection of active drugs in such a way as to ensure the introduction of effea in the form of a continuous selection can be 120 mg twice a day (b.i.d.).

In the sense as used in the description, the term "sympathomimetic drug" refers to sympathomimetic agents that are therapeutically effective to ensure ease congestion in the nose need in this patient. These agents include, but are not limited to, pseudoephedrine, phenylephrine and phenylpropanolamine. As is well known and acknowledged by experts, these sympathomimetic drugs can be used in accordance with the present invention in the form of free amines or their pharmaceutically acceptable salts.

Therapeutically effective decongestant amount of sympathomimetic drugs is the amount that provides the necessary antitumor therapeutic response when administered orally and which can easily identify the specialist, using conventional techniques and by observing results achieved in similar circumstances. When determining therapeutically effective decongestant amount or dose of the treating physician must consider several factors, including (but not limited to) type of mammal; its size, age and General health, the individual reaction of the patient, the spiral is a new mode, used simultaneously medicines and other related circumstances.

Therapeutically effective decongestant amount of sympathomimetic drugs may vary from about 1 to about 200 mg. Preferred amount will vary from about 5 to about 150 mg, and the most preferred amount is 120 mg when taken twice a day.

Note that a therapeutically effective decongestant amount of sympathomimetic drugs are presented in the Composition (A). The material of the carrier Composition (A) provides prolonged or continuous release of active drug, while the material of the carrier composition (C) provides an immediate release of active drugs. In the sense as used in the description, the term "prolonged isolation" refers to the property of the pharmaceutical composition, in which the absorption and bioavailability of the active drug is supported through the allocation over time, so that a therapeutically effective decongestant amount of sympathomimetic drugs are bioavailable for a long period of time. In the sense as used in the description, the term "immediate wideleaved bioavailable without long delays. The standard dose is the amount of the pharmaceutical composition, which is separately administered to the patient. In addition, the experts recognized that the pharmaceutical compositions of the present invention can be used as antihistamines, antiallergic agents, bronchodilators in the treatment of urticaria.

In the sense as used in the description, the term "patient" refers to warm-blooded animal such as a mammal in need antihistaminic, antiallergic agent, a bronchodilator agent, or requires treatment for urticaria. You should understand that humans, mice, rats and dogs included in the term "patient".

In the sense as used in the description, the term "cellulose diluent" includes microcrystalline cellulose, Avicel PH101, Avicel PH102, Avicel PH301, Avicel PH302, Avicel PH200, Avicel PH112, Avicel PH113, Avicel PH103, Avicel PH105, etc. Preferred cellulose diluent is microcrystalline cellulose Avicel PH101 and Avicel PH102 and the most preferred cellulose diluent is a combination of Avicel PH101 and Avicel PH102. Particularly preferably, a mixture of Avicel PH101 and Avicel PH 102 contained about 12% Avicel PH101 and about 88% Avicel PH102.

In the sense as used in the description, Ter the alcohol, paraffin, white wax, glycerin, lanolin, talc, mineral oil, etc. Preferred prevents the bonding agent is stearic acid.

In the sense as used in the description, the term "suitable disintegrity agent" includes nitrocresols, crosspovidone, alginic acid, sodium alginate, methacrylic acid DVB, crosslinked PVP (polyvinylpyrrolidone), microcrystalline cellulose, calibration, sodium starch glycolate, starch, pre-gelatinizing starch, etc., Preferred suitable dezintegriraat agent is nitrocresols.

In the sense used here, the term "reaching lubricating substance" includes magnesium stearate, calcium stearate, zinc stearate, stearic acid, talc, gidrirovannoe vegetable oil, etc., the Preferred lubricant is magnesium stearate.

In the sense used here, the term "suitable agent, contributing to the slide includes silicon dioxide, talc, etc., the Preferred agent promoting sliding, is silicon dioxide.

The term "very fine grinding" refers to the process of increasing the surface area of the particles soedinenii fine grinding compounds piperidinemethanol formulas (I) to(IIIb) specialist can easily carry out, for example, the method disclosed So Ortyl et A1. in WO 96/26726 published on 6 September 1996.

Very finely ground particles of connection piperidinemethanol formulas (I) to(IIIb), which have the surface area of the particles is more than about 1.0 m2/, the Preferred amount of surface area is very finely ground particles is from about 2 to 10 m2/g, most preferred amount of surface area is very finely ground particles is from about 2 to 52/g, and particularly preferred amount of the surface is very finely ground particles is about 2.2 m2/, Connection piperidinemethanol formulas (I) to(IIIb), which were not subjected to the process very fine grinding, have a surface area of particles less than about 1.0 m2/,

Therapeutically effective antihistaminic amount of a compound piperidinemethanol formula (I) to(IIIb) is the amount that provides the desired therapeutic response (i.e., antihistamines, antiallergic, bronchodilatory effect or reduce the symptoms or cure urticaria) after oral administration according to the scheme of single or multiple doses. Therapeutically effective antihistaminic number mg to about 240 mg The preferred therapeutically effective antihistaminic amount of a compound piperidinemethanol formula (I) to(IIIb) may vary from about 20 to about 70 mg, and receiving 60 mg twice a day is preferable. Therapeutically effective antihistaminic amount of coupling can easily determine the practitioner, specialist, etc. using known techniques and by observing results achieved in similar circumstances, as disclosed previously to sympathomimetic drugs.

It should be understood that a therapeutically effective antihistaminic amount of a compound piperidinemethanol formula (I) to(IIIb) is present in the Composition (C) pharmaceutical compositions of the present invention. This Composition (C) provides an immediate release of active drug.

In a preferred embodiment of the present invention, the number of connections piperidinemethanol in the Composition (B) about 60 mg of the hydrochloride of 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl] -,-dimethylbenzoxazole acid is preferred. In a preferred embodiment of the present invention, the number of sympathomimetic lackac here used the term layered tablet, it belongs to the tablet, which is made of two or more individual layers or discrete zones of pellets pressed with separate layers arranged one on top of another. Layered tablets are kind of sandwich, as can be seen the edges of each layer. Such traditional layered tablets are usually prepared, extruding the pellets on top of the previously compacted granules. This operation can be repeated to obtain a multi-layer tablets containing more than two layers. In a preferred embodiment of the present invention, the tablet consists of two layers, one layer consists of a Composition (A) and the other layer consists of a composition (B), which gives a two-layer tablet.

The pharmaceutical compositions of the present invention, the Composition (A) and Composition (B) optionally can contain one or more other pharmaceutically acceptable excipients. These excipients are therapeutically inert ingredients, such as those well known and accepted by the specialists. In the sense used here, the term "inert ingredient" refers to a therapeutically inert ingredients, which are well known to specialists-pharmacists, which can be used separately or in rascality, sweetening agents, dezintegriruetsja agents, dyes, corrigentov, antioxidants, solubilizing agents, agents for coating, etc. as disclosed in The United States Pharmacopeia, XXII, 1990 (1989 The United States Phannacopeial Convention, Inc), pp.1857-1859), which is incorporated here as a reference. For example, the following inert ingredients can be used separately or in various combinations: a binder, such as gelatin, polyvinylpyrrolidone (PVP), pre-gelatinizing starch, povidone; such diluents like calcium carbonate, lactose, starch, microcrystalline cellulose, etc. ; lubricants such as magnesium stearate, calcium stearate, zinc stearate, stearic acid, talc, gidrirovannoe vegetable oil, etc.; agents promoting sliding, such as silicon dioxide, talc, etc.; dezintegriruetsja agents such as alginic acid, methacrylic acid DVB, stitched KpocPVP, microcrystalline cellulose, nitrocresols, crosspovidone, calibration, sodium starch glycolate, starch, pre-gelatinizing starch, etc.; sweetening agents; dyes; corrigentov; antioxidants, etc.,

The preferred compositions of the present invention are such comp and magnesium stearate are present together with the hydrochloride of 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydro-Sibuti] -,-dimethylbenzoxazole acid in the layer immediately dedicated the Song (In) and Carnauba wax, stearic acid, and colloidal silicon dioxide are present hydrochloride pseudoephedrine in the layer of prolonged selection of the Composition (A).

The preferred amount of the hydrochloride of 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl-]-1-hydroxybutyl] -,-dimethylbenzoxazole acid, cellulose diluent, pre gelatinizing starch, nitrocresols and stearate in the composition (B) are combined in amounts from about 15 to about 30%, from about 27 to about 73%, from about 15 to about 30%, from about 0.25 to about 6.0%, and from about 0.25 to about 2,00% respectively by weight of the composition, more preferably from about 16 to about 24%, from about 43 to about 67%, from about 15 to about 24%, from about 3,20 to about 4,80% and from about 0.50 to about 1.00%, respectively, of the weight of the composition and most preferably about 17,09 about 61,67, about 17,09 about 3,42 and about 0.75%, respectively.

The preferred amount of the hydrochloride pseudoephedrine, Carnauba wax, flakes, stearic acid, and colloidal silicon dioxide in the Composition (A)to 3.00%, respectively, of the weight of the composition, more preferably from about 25 to about 33%, from about 66 to about 74%, from about 0.50 to about 1.50% and 0.00 to about 0.75% by weight of the composition and most preferably about 28,17, about 70,42, about 1.15 and about 0.25%, respectively.

Professionals can easily get connections piperidinemethanol formulas (I) to(IIIb), for example, using methods and
the procedure disclosed in U.S. patent 3878217, 4254129 and 4285957, which are incorporated here by reference, and in international application PCT/US93/02103, published October 28, 1993, in WO 93/21156, in international application PCT/US94/05982, published January 5, 1995, WO 95/00480 and in the international application WO 95/31437, published 23 November 1995.

The components of the pharmaceutical compositions of the present invention are combined into a two-layer tablet for oral administration standard methods known in the art, such as disclosed in the examples below (see tab. (1) the Following examples should be considered only as illustrative and in no way limit the invention. The reagents and starting materials available to professionals. Used abbreviations mean:
"rsd - percent relative standard deviation (CCA); M is molar; "mM" - millimolar; "oF - degrees Fahrenheit, "MMDD" mm RT. Art. ; "kPa - kilopascals; "psi" is pounds/cm2; "Cu" - kilo/pound.

Pilot the process of manufacturing two-layer tablets
Fabrication of two-layer tablets at pilot plant as follows. Granules hydrochloride pseudoephedrine are made by adding hydrochloride pseudoephedrine to a molten mixture of Carnauba wax and stearic acid with stirring. Liquid wax mixture is then poured into trays in a thin layer and leave to harden as the wax cools. Then congealed wax milled and mixed with colloidal silicon dioxide in the mixer, located in the bunker. Granulation hydrochloride 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl] -,-dimethylbenzoxazole acid is carried out, using high-granulator. The granules are dried in a fluidized bed dryer and milled. Add the remaining components of the mixture and mix in the mixer, located in the bunker. Two-layer tablet press using a press for two-layer tablets, and granules hydrochloride pseudoephedrine is pressed as the first layer, and the resulting mixture �45.gif">-dimethylbenzoxazole acid pressed as a second or top layer. Then the compressed tablets are covered with a sheath of transparent coatings in Accela-Cota. The whole process of manufacturing tablets takes about 33 hours to obtain an experienced party 130,000 tablets.

Granulation hydrochloride pseudoephedrine
The number of components, which is used for the manufacture of granules hydrochloride pseudoephedrine (for party 80 kg) are listed in table 2. Carnauba wax is melted under continuous stirring at about 85-90oWith tank stainless steel jacketed with hot water (Hamilton) capacity 379 l (100 Gal). The temperature of the water in the jacket was adjusted to about 100oC. After Carnauba wax melts, add the stearic acid flakes and allow them to melt. Hydrochloride pseudoephedrine sieved through a 30 mesh sieve, using vibrating pellet Stokes Oscillating Granulator. Sifted hydrochloride pseudoephedrine added slowly to the molten wax under continuous stirring using a mixer Lightnin propeller type. Adding hydrochloride pseudoephedrine temperature of the melt support approximately 90oC. After the sifted hydrochloride pseudoe 10 minutes. The approximate time of receipt of the suspension of the hydrochloride pseudoephedrine/liquid wax is 5 hours.

Then the suspension of the hydrochloride pseudoephedrine/liquid wax is poured on trays made of stainless steel to a thickness of about 0,635 cm (1/4 inch) and incubated at room temperature for curing and cooling to a temperature at which it can be touched (about 2 hours). Utverzhdennuyu matrix hydrochloride pseudoephedrine/wax stored in lined with polyethylene cardboard cylinders at room temperature for at least about 12 hours before it is shredded to make sure that the wax matrix is cooled down sufficiently.

Frozen wax crushed at the front position of the knives at 2500 rpm through a Fitzmill mill with sieve with drilled holes 0065. The crushed pellets hydrochloride pseudoephedrine loaded into a 200-liter mixer In-Bin Blending Tote. The required aspect ratio of the colloidal silica sieved through 20 mesh and add 200 l of the mixer. Components in the vessel is stirred for 70 revolutions at a speed of 18 rpm, using a mixer CMS In-Bin Blender. The resulting mixture was stored in lined with polyethylene cardboard cylinders to the pressing process. Approximate phenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzoxazole acid and the resulting mixture
Table 3 lists the ingredients and quantities used in the manufacture of granules hydrochloride 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl] -1-hydroxybutyl] -,-dimethylbenzoxazole acid and the final mixture. Granules hydrochloride 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl] -,-dimethylbenzoxazole acid get using a mixer with a high shear/granulator capacity 300 l (Fielder PMA 300 L High Shear Mixer/Granulator). Hydrochloride 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl] -1-hydroxybutyl] -,-dimethylbenzoxazole acid, nitrocresols, pre gelatinizing starch and microcrystalline cellulose (Avicel PH101) add in the filling tank and mixed dry for 5 min at a prescribed value for the impeller 110 rpm and switch off the shredder. Then to the dry mixture, add purified water at a rate of 5.7 kg/min, and the speed of the impeller is set to 110 rpm, and the speed of the grinder 3600 rpm Granules mixed in t is s in the fluidized bed dryer (Glatt Fluid Bed Dryer GPCG 30). The temperature of the incoming air support at 80oC and the dew point is determined during the 9oC. the Volumetric rate of air flow set at the beginning of 1050 m3/h and gradually reduce over time drying up to 550 m3/H. Granules are dried to a moisture content of 2-3%, which is determined using an instrument Computrac at 125oC. the Temperature of the final product is approximately 65oWith, and the entire drying process takes about 160 minutes. The final moisture content of the dried granules is approximately 2.5%.

Each of the parties granules hydrochloride 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl] -1-hydroxybutyl] -,-dimethylbenzoxazole acid separately milled through a sieve with holes 1532-0050 using a Fitzmill at medium speed with knives in the front position. The two portions of the granules are mixed together for 3 minutes in the mixer Patterson Kelley V-Blender capacity 0,142 m3(5 ft3). The crushed mixture is kept in lined with polyethylene cardboard cylinders prior to final mixing. Estimated time stage grinding and mixing the pellets hydrochloride 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl] -,-dimethylbenzoxazole acid are presented in table 3. The final mixture of the hydrochloride of 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl] -1-hydroxybutyl] -,-dimethylbenzoxazole acid get, using 200-liter In-Bin Blending Tote. In the bunker Tote load microcrystalline cellulose (Avicel PH102), nutritionnelles (Ac-Di-Sol) and previously obtained milled granule hydrochloride 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl] -,-dimethylbenzoxazole acid. The components are stirred for 140 revolutions at a speed of 18 rpm magnesium Stearate is screened through a hand sieve of 30 mesh, add in 200 litre Tote bin and stirred for 70 revolutions at a speed of 18 rpm Final mixture is kept in lined with polyethylene cardboard cylinders to the stage of pressing. Estimated time stage of the process the final mixing is 0.5 hours.

Pressing the two-layer tablets
Party of two-layer tablets are made using a rotary press for manufacturing two-layer tablets (35 Station Manesty BB4 Bi-Layer Rotary Tablet Press). Tablet press using capsulorraphy stanm). Party pills is 180000 tablets made from 76,7 kg of pellets hydrochloride pseudoephedrine and 63.2 kg finite mixture of the hydrochloride of 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl] -,-dimethylbenzoxazole acid. The average speed of extrusion is about 640 tablets/min Complete the pressing time is about 5 hours.

Granules hydrochloride pseudoephedrine pressed the first layer at a given weight 426 mg/tablet. Average given the hardness of the tablets (Tester Key Hardness Tester, tablet testing across the width of the layer hydrochloride pseudoephedrine is about (8 CR). The second layer, which consists of a finite mixture of the hydrochloride of 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl] -,-dimethylbenzoxazole acid, is added to the first layer to complete a given weight pills 777,1 mg (equivalent to 351,1 mg/tablet finite mixture of the hydrochloride of 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzoxazole acid). Two-layer tablet press to a predetermined hardness of about (20 CR) (Tester Key Hardness Tester, tabIe in 121,92 cm (48 inch) Accela-Cota (101,0 kg tablets without shell, approximately 130,000 tablets) using a spray system with two pistols at a speed of rotation of the pallet to 10.5 rpm On tablets coated using a 12% weight/weight solution for applying a transparent coating OPADRYYS-1-7006, which contains hypromellose and polyethylene glycol. Covering the suspension before use filtered through a sieve of 60 mesh. On the pill cause 25,25 kg of a solution for coating. On tablets coated at a temperature of exhaust air about 41oWith the interval 39,6-41,9oC. the temperature of the inlet air is usually 55-62oWhen the speed of the air supply 48.10 per-51,00 m3/min (1700-1800 m3/min). The rate of flow of solution to cover first is about 230 g/min and periodically increased until reaching a terminal velocity dispersion of about 390 g/min spraying solution for coating use pressure spraying air 3,515 kg/cm2(50 psi). The entire coating process takes approximately 1.5 hours.

The industrial process of manufacturing a two-layer tablets
Fabrication of two-layer tablets on an industrial scale is as follows. Granules of ghskogo wax with stirring. Liquid wax mixture is pumped through kapleobrazovanie pipe stainless steel (installation Rotoform) on a rotating chilled stainless steel belt. Frozen droplets of wax (pellet) is removed at the end of the rotating belt. Then the pellet is crushed and mixed with colloidal silicon dioxide in the mixer, located in the bunker. Granulation hydrochloride 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl] -,-dimethylbenzoxazole acid is carried out, using high-granulator. The granules are dried in a fluidized bed dryer and milled. Add the remaining components of the mixture and stirred in the mixer, located in the bunker. Two-layer tablets are pressed into the press for the manufacture of two-layer tablets, and granules hydrochloride pseudoephedrine is pressed as the first layer, and the final mixture of the hydrochloride of 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl] -1-hydroxybutyl] -,-dimethylbenzoxazole acid pressed as a second or top layer. Then the compressed tablets are covered with a sheath of transparent coatings in Acc the TII 1374000 tablets.

Granulation hydrochloride pseudoephedrine
The number of components, which is used for the manufacture of granules hydrochloride pseudoephedrine (for party 600 kg), are listed in table 4. Carnauba wax is melted under continuous stirring at about 85-90oWith tank stainless steel tank 1137 liters (300 gallons) with a shirt with hot water (Hamilton). The temperature of the water in the jacket was adjusted to approximately 120oC. After all of Carnauba wax melts, add the stearic acid flakes and allow them to melt. Hydrochloride pseudoephedrine sieved through a 30 mesh sieve, using vibrating granulator (Stokes Osciliating Granulator (Model 43-6)). Sifted hydrochloride pseudoephedrine added slowly to the molten wax under continuous stirring using a propeller mixer type (Sew-Eurodrive mixer). Adding hydrochloride pseudoephedrine temperature of the melt support approximately 92oC. After the sifted hydrochloride pseudoephedrine added to the molten wax, the temperature was raised to 95oC and continuously stirred for at least 20 minutes, the stirring is continued until the completion of stage of solidification and temperature during the stage of solidification ponderable 6 hours.

The suspension of the hydrochloride pseudoephedrine/liquid wax is pumped using a pump with a positive supply, fitted shirt with hot water (Wauakasha Model 6) lines with inner diameter of 0,688 cm (3/8 inch) stainless steel, which is provided with a jacket of hot (110oC) water in kapleobrazovanie pipe stainless steel (Sandvik Rotoform3000 Model LV). Sieve 20 mesh is located in the feed line suspension liquid wax for protection Rotoform. The Rotoformthere are openings in the shell 2.0 mm increments 8.0 mm, the bend with a triangular geometry and the slit width of 6.0 mm Rotoformheated hot water with a temperature of 110oWith a fixed cylindrical stator, which has a 2.54 cm (1 inch) slot for flow of liquid wax through the whole device.

A rotating device Rotoformhave over a rotating cooled stainless steel belt Sandvik so that drops of liquid wax mixture fell on a moving tape. Sandvik cooled stainless steel belt use for prozac cooled stainless steel strips is to 81.28 cm (32 inches). And the length of the cooling zone is 7,315 m (24 ft). The front roller of the tape is heated to 65oC. the Device Rotoformfeatures at a height of approximately 2 mm above the moving tape. The tape speed and the speed Rotoformis 21,33 m/min (70 feet), while the cooling water temperature is equal to the 15oC. Suspension of the hydrochloride pseudoephedrine/liquid wax pumped at a rate of approximately 5 kg/min on the tape. Frozen droplets of wax (pellet) with a diameter of about 5 mm unloaded at the end of the rotating tape at a temperature of about 20oC. the Pellet frozen wax milled blades in the front position at a speed of 3000 rpm through the shredder Fitzpatrick DAS06, equipped with a sieve with holes 0065. Estimated time of the process of hardening of wax and grinding stage is 3 hours.

The crushed pellets hydrochloride pseudoephedrine load in 1800 litre mixer In-Bin Blending Tote (Gallay). The required amount of colloidal silica added to 1800 l Tote. The contents of the tank is stirred for 140 revolutions at a speed of 14 rpm, using a mixer CMS In-Bin Blender. The resulting mixture was stored in lined with polyethylene cardboard tilley 1 hour.

Granulation hydrochloride 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzoxazole acid and the resulting mixture
Table 5 lists the ingredients and quantities used in the manufacture of granules hydrochloride 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl] -1-hydroxybutyl] -,-dimethylbenzoxazole acid and the final mixture. Granules hydrochloride 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzoxazole acid get using a mixer with a high shear/granulator capacity 800 l (Fielder PMA 800 L High Shear Mixer/Granulator). Hydrochloride 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl] -1-hydroxybutyl] -,-dimethylbenzoxazole acid, nitrocresols, pre gelatinizing starch and microcrystalline cellulose (Avicel PH101) add in the filling tank and mixed dry for 5 min at a prescribed value for the impeller 116 rpm and switch off the shredder. Then to the dry mixture, add purified water at a rate of 15 kg/min, is over 6 minutes after as the addition of water is terminated. The speed of the chopper is increased to 2800 rpm when setting the speed for the impeller 116 rpm and pellets stirred for additional 60 s, and then from the granulator move in the tank for drying the product from the fluidized bed.

The granules are dried in a fluidized bed dryer Glatt Fluid Bed Dryer GPCG 300. The temperature of the incoming air support at 80oC and the dew point is determined during the 9oC. the Volumetric rate of air flow set 3800 m3/h and gradually reduce over time drying to 2900 m3/H. Granules are dried to a moisture content of 2-4%, which is determined using an instrument Computrac at 115oC. the Temperature of the final product is approximately 66oWith, and the entire drying process takes about 100 minutes. The final moisture content of the dried granules is approximately 3.0 percent. The dried granules hydrochloride 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl] -,-dimethylbenzoxazole acid milled through a sieve with holes 1532-0050 using a Fitzmill at medium speed with knives in the front position. Granules are crushed in the 1800 liter mixer In-Bin Blending Tote (Gallay). Estimated time �/chr/945.gif">,-dimethylbenzoxazole acid is 5 hours.

The composition of the final mixture of the hydrochloride of 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl] -1-hydroxybutyl]-,-dimethylbenzoxazole acid are presented in table 4. In the bunker containing the crushed granules hydrochloride 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl] -,-dimethylbenzoxazole acid load microcrystalline cellulose (Avicel PH 102), nutritionnelles (Ac-Di-Sol). The contents stirred for 140 revolutions at a speed of 14 rpm, using a mixer CMS In-Bin Blender. Magnesium stearate is screened through a hand sieve of 30 mesh and add in the 1800 gallon bin, the contents stirred for 70 revolutions at a speed of 14 rpm, using a mixer CMS In-Bin Blender. The final mixture was stored in a bunker to the stage of pressing. The estimated time to process the final mixing hydrochloride 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzoxazole acid is 1 hour.

Pressing the two-layer tablets
Party of two-layer tablets will sgotovitsya, using capsulorraphy standard concave shape size 0,79 cm1,89 cm (0,3125 inch0,7500 inch). Party pills is 1374000 tablets made from 585,3 kg of pellets hydrochloride pseudoephedrine and 482,4 kg finite mixture of the hydrochloride of 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl] -,-dimethylbenzoxazole acid. The average speed of extrusion is about 1200 tablets/min Complete the pressing time is about 19 hours. As the pellets hydrochloride pseudoephedrine, and the final mixture of the hydrochloride of 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl] -1-hydroxybutyl] -,-dimethylbenzoxazole acid, is fed into the press from bins, which are used for mixing, using a setting Gallay bin drop.

Granules hydrochloride pseudoephedrine is pressed as the first layer is given a weight of 426 mg/tablet. Powder loading device for feeding pellets hydrochloride pseudoephedrine operates with a capacity of 75%. Given the thickness of the layer hydrochloride pseudoephedrine is 0,4572 cm (rate £ 0.162 inches) with an average hardness of tablets (Tester Key Hardness Tester, taxidermal)-1-piperidinyl] -1-hydroxybutyl] -,-dimethylbenzoxazole acid, is added to the first layer to complete a given weight pills 777,1 mg (equivalent to 351,1 mg/f a finite mixture of the hydrochloride of 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzoxazole acid). Powder charging device for supplying a mixture of the hydrochloride of 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl] -1-hydroxybutyl] -,-dimethylbenzoxazole acid is functioning at 100%. Two-layer tablet is pressed to a predetermined thickness 0,6096 cm (0,240 inch) with an average hardness of 20 cu (Tester Key Hardness Tester, tablet test length).

Coating
On extruded two-layer tablets are coated in 121,92 cm (48 inches) Accela-Cota, dividing by 10 parties about 106,8 kg tablets without skin (about 137400 tablets) using a spray system with three guns at a speed of rotation of the pallet 11 rpm On tablets coated using a 12% weight/weight solution for transparent coating OPADRYYS-1-7006, which contains hypromellose and polyethylene glycol. On Taberno 41oWith, usually in the range of 39.0-41,0oC. the Temperature of the incoming air usually support in the range of 55-62oWhen the speed of the air supply 48.10 per-53,80 m3/min (1700-1900 m3/min). The rate of flow of solution to cover first is about 250 g/min and periodically increased until reaching a terminal velocity dispersion of approximately 375-400 g/min spraying solution for coating use pressure spraying air 4,219 kg/cm2(60 psi). The entire coating process takes approximately 1.5 hours for each of the 10 parties. Time coating for 10 parties is 15 hours.

The method of determining the homogeneity of the content
Uniformity of content determine known in the art techniques and procedures. For example, you can use the procedure isotretinoin HPLC, in which the use of strongly basic cation exchange column Alltech Adsorbosphere XL SCX, 5 μm (50 mm4.6 mm inner diameter) located sequentially column reversed-phase Bond SB-Phenyl, 5 μm (250 mm4.6 mm inner diameter). Mobile phase, which consists of a mixture of 65:35 (V/V) methanol:buffer (0,050 M sodium acetate and of 0.075 M sodium salt of 1-OK is and 1.5 ml/min The temperature of the column support at the 35oC. Standards and samples are injected into the column using a volume of 20 µl with subsequent UV detection at 215 nm.

Ten separate samples of the tablets prepared as follows. One tablet is placed in a 100 ml volumetric flask and add 60,0 ml of methanol. The flask was closed and shaken for 60 minutes on a mechanical vibrator at high speed. After a period of shaking the flask in an ultrasonic heating bath and treated with ultrasound at 40oC for 60 minutes. During the 60 minute period of treatment with ultrasound flask is strongly shaken manually every 15 minutes, in order to facilitate the destruction of the tablets. After the initial 60-minute period of treatment with ultrasound in the flask add 35 ml of buffer (0,050 M sodium acetate and of 0.075 M sodium salt of 1-octanesulfonic acid, pH 4,60 set acetic acid), mixed and placed in an ultrasonic bath with heating for the second period of the ultrasonic treatment at 40oC for 60 minutes. During 60-minute period of treatment with ultrasound flask is strongly shaken manually every 15 minutes, in order to facilitate the destruction of the tablets. After the second period obrabotannoi temperature. After reaching room temperature, the flask is shaken/stirred, and then the main part of the floating excipients poured into a container for waste. Approximately 6-8 ml of the remaining sample solution is filtered in a small glass, using 0.45 µm Whatman GD/X filter, receiving the sample solution I. Using a measuring pipette 4.0 ml of the sample solution I put in a 50 ml-Yu volumetric flask, dilute to volume with mobile phase, receiving the sample solution II, and injected into the HPLC system. Determine the peak area for pseudoephedrine and 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl] -1-hydroxybutyl] -,-dimethylbenzoxazole acid and the percentage lable claim count for each of the active substances.

In tables 6 and 7 present the results of the homogeneity hydrochloride for 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl] -,-dimethylbenzoxazole acid hydrochloride and pseudoephedrine, respectively. Good content match confirms that each tablets contains the right amount of medicinal substance with small deviations from tablet to tablet to boot. In order to determine a good adminie than or equal to 6%, but each individual tablet must fall within the interval 85,0-115,0% Lable Claim for a sample of 10 tablets. As stated above, in the present invention proposed a pharmaceutical composition which shows good uniformity of content and where the largest deviation observed for hydrochloride 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl] -,-dimethylbenzoxazole acid, 3.5% CCA for the one-hour sample and for hydrochloride pseudoephedrine is 3.7% CCA for three-hour sample.

The method of dissolution
Characteristics of solubility is defined by experts, using known techniques and procedures. For example, testing the solubility is carried out in 900 ml of 0.001 n Hcl (pH 3,00) at 37oWith using the method with a stirrer USP (Apparatus 2, see , for example, Remington's Pharmaceutical Sciences, Mack Publishing Company (1990), 18th Ed. pp.595-596) when the rotation speed of 50 rpm Aliquots of each of the test solutions are selected and filtered through a 45 μm polyethylene filter and select aliquots at intervals 15, 30, 45, 60, 180, 300, 420 and 720 minutes. Each of the selected aliquot of solution samples analyzed by method isotretinoin HPLC using strongly basic cation is tion of a mixture of 45:55 (V/V) acetonitrile:buffer (0.05 M sodium phosphate, pH 2,000.05), and pumped through the column at a speed of 1.0 ml/min column Temperature support room. Standards and samples are injected into the column using a 10 ál injected volume with subsequent UV detection at a wavelength of 210 nm. Determine the peak areas for pseudoephedrine and 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl] -1-hydroxybutyl] -,-dimethylbenzoxazole acid and for each of the active substance calculate the percentage Lable Claim released in each time interval.

Tables 8 and 9 present the characteristics of solubility for hydrochloride 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl] -,-dimethylbenzoxazole acid hydrochloride and pseudoephedrine, respectively. Tables 10 and 11 represent the characteristics of solubility for SUDAFED 12 HOURtablets and ALLEGRAcapsules, respectively.


Claims

1. Pharmaceutical composition for alleviating congestion in the nose associated with allergic rhinitis in the form of a two-layer table is active decongestant number sympathomimetic drug or its pharmaceutically acceptable salt in an amount of from 18 to 39% by weight of the composition (A), and the base material of the first carrier, and the base material of the first carrier comprises a mixture of: (i) Carnauba wax in an amount of from 59 to 81% by weight of the composition (a) and (ii) appropriate, preventing the bonding agent in the amount of from 0.25 to 2.00% by weight of the composition (A) where the specified base material of the first carrier provides prolonged isolation of sympathomimetic drugs, and (b) a second discrete zone comprising a composition (B), which includes a therapeutically effective antihistaminic amount of piperidinemethanol or its pharmaceutically acceptable salt in an amount of from 15 to 30% by weight of the composition (C), and the base material of the second carrier, and the base material of the second media comprises a mixture of: (i) cellulose diluent in an amount of from 27 to 73% by weight of the composition (C); (ii) pre-gelatinizing starch in an amount of from 15 to 30% by weight of the composition (C); (iii) appropriate dezintegriruetsja agent in amounts of from 0.25 to 6.00% by weight of the composition (In) and (iv) a suitable lubricant in the amount of from 0.25 to 2.00% by weight of the composition (C), and the specified base material of the second media provides an immediate allocation piperidinemethanol or its pharmaceutically acceptable �p://img.russianpatents.com/img_data/61/616442.gif">
where X represents a number from 0 to 5,
and individual optical isomers.

3. Pharmaceutical composition for alleviating congestion in the nose associated with allergic rhinitis, in the form of a bilayer tablet comprising: (a) a first discrete zone comprising compositions (A), which comprises a therapeutically effective decongestant amount of sympathomimetic drug, or its pharmaceutically acceptable salt in an amount of from 25 to 33% by weight of the composition (a) and the base material of the first carrier, and the base material of the first carrier comprises a mixture of: (i) Carnauba wax in an amount of from 66 to 74% by weight of the composition (a) and (ii) appropriate, preventing the bonding agent in the amount of from 0.50 to 1.50% by weight of the composition (A),
where the specified base material of the first carrier provides prolonged isolation of sympathomimetic drugs;
(b) a second discrete zone comprising a composition (b) which comprises a therapeutically effective antihistaminic amount of piperidinemethanol formula

where X represents a number in the interval from 0 to 5,
and individual optical isomers of clichees includes a mixture of: (i) cellulose diluent in an amount of from 43 to 67% by weight of the composition (In); (ii) pre-gelatinizing starch in an amount of from 15 to 24% by weight of the composition (C); (iii) appropriate dezintegriruetsja agent in an amount of from 3,20 to 4.80% by weight of the composition (I) and (iv) a suitable lubricant in the amount of from 0.50 to 1.00% by weight of the composition (C), and the specified base material of the second media provides an immediate allocation piperidinemethanol or its pharmaceutically acceptable salt.

4. The pharmaceutical composition under item 1, characterized in that the base material of the first carrier composition (A) included suitable, providing the sliding agent in amount from 0.00 to 3.00% by weight of the composition (A).

5. The pharmaceutical composition according to p. 5, characterized in that the base material of the first carrier composition (A) included suitable, providing the sliding agent in amount from 0.00 to 0.75% by weight of the composition (A).

6. The pharmaceutical composition according to p. 5, characterized in that suitable, providing the sliding agent is colloidal silicon dioxide.

7. The pharmaceutical composition according to p. 3 or 6, wherein the sympathomimetic drug is hydrochloride pseudoephedrine.

8. The pharmaceutical composition according to p. 7, characterized in that Thu) suitable dezintegriraat agent is nitrocresols and a suitable lubricant is magnesium stearate.

9. The pharmaceutical composition according to p. 8, wherein hydrochloride pseudoephedrine, Carnauba wax, stearic acid, and colloidal silicon dioxide in the composition (A) are combined in quantities 28,17, 70,42, 1,15 and 0.25% respectively, by weight of composition (A) and piperidinemethanol, cellulose thinner, pre gelatinizing starch, nitrocresols and magnesium stearate composition (B) are combined in quantities 17,09, 61,67, 7,09, 3,42 and 0.75% by weight of composition (B).

10. The pharmaceutical composition according to p. 9, characterized in that piperidinemethanol is hydrochloride 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzoxazole acid.

11. The pharmaceutical composition according to p. 10, characterized in that the cellulose diluent includes a combination of Avicel PH101 and Avicel PH102.

12. The pharmaceutical composition according to p. 11, characterized in that the combination of Avicel PH101 and Avicel PH102 includes 12% Avicel PH101 and 88% Avicel PH102.

13. The pharmaceutical composition according to p. 12, characterized in that the hydrochloride of 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl] -1-hydroxybutyl] -,-dimethylbenzoxazole acid Ave is ical composition p. 13, characterized in that on the two-layer tablets are coated with a suitable agent to cover.

15. The pharmaceutical composition according to p. 14, characterized in that a two-layer tablet is applied as a coating OPADRYYS-1-7006.

16. The pharmaceutical composition according to p. 15, characterized in that the OPADRYYS-1-7006 is present in the amount of 2.9% by weight of the composition.

17. The pharmaceutical composition according to p. 13, characterized in that the hardness of two-layer tablets is the amount of from 15 to 25 cu.

 

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