Xanthines in pharmaceutical preparations and for stabilization of vitamins

Claim 2

A THERAPEUTICALLY-ACTIVE AND PHARMACEUTICALLYACCEPTABLE SOLIDIFIED HOMOGENOUS INTIMATE ADMIXTURE OF A. AT LEAST ONE PHARMACEUTICALLY-ACTIVE SUBSTANCE AND B. AT LEAST ONE MOLTEN PHARMACEUTICALLY-ACTIVE SUBSTANCE; AT LEAST ONE ACTIVE SUBSTANCE OF WHICH IS MORE RAPIDLY AND AT LEAST ONE OF WHICH IS MORE SLOWLY ADSORBABLE; THE SOLIDIFIED HOMOGENOUS ADMIXTURE COMPRISING, AS TWO OF THE PHARMACEUTICALLY-ACTIVE SUBSTANCES:

Claim 3

A XANTHINE WHICH IS SUBSTITUTED IN EACH OF TWO OF THE 13- AND 7-POSITIONS BY AN ALKYL GROUP HAVING AT MOST TWO CARBON ATOMS AND IS SUBSTITUTED IN THE REMAINING OF SAID POSITIONS BY: A. A HYDROCARBON GROUP HAVING FROM 3 TO 20 CARBON ATOMS AND BEING BOUND BY AN ACYCLIC CARBON ATOM WHICH IS PART OF SUCH GROUP, OR B. AN ALIPHATIC HYDROCARBON GROUP SUBSTITUTED BY AT LEAST ONE SUBSTITUENT SELECTED FROM THE GROUP CONSISTING OF HYDROXY AND OXO, THE HYDROCARBON GROUP HAVING FROM 6 TO 20 CARBON ATOMS, BEING SATURATED OR OLEFINICALLY UNSATURATED, AND BEING BOUND BY AN ACYCLIC CARBON ATOM WHICH IS PART OF SUCH GROUP; AND II. A MEMBER SELECTED FROM THE GROUP CONSISTING OF NICOTINIC ACID, A THERAPEUTICALLY-ACTIVE DERIVATIVE OF NICOTINIC ACID, A UNSTABLE VITAMIN AND A THERAPEUTICALLY-ACTIVE EQUIVALENT THEREOF SELECTED FROM THE GROUP CONSISTING OF A SALT, AN ESTER AND A PROVITAMIN THEREOF; THE XANTHINE BEING PRESENT IN THE ADMIXTURE IN A PROPORTION SUFFICIENT TO STABILIZE ANY UNSTABLE VITAMIN THEREIN.

Claim 4

A XANTHINE WHICH IS SUBSTITUTED IN EACH OF TWO OF THE 13- AND 7-POSITIONS BY AN ALKYL GROUP HAVING AT MOST TWO CARBON ATOMS AND IS SUBSTITUTED IN THE REMAINING OF SAID POSITIONS BY: A. A HYDROCARBON GROUP HAVING FROM 3 TO 20 CARBON ATOMS AND BEING BOUND BY AN ACYCLIC CARBON ATOM WHICH IS PART OF SUCH GROUP, OR B. AN ALIPHATIC HYDROCARBON GROUP SUBSTITUTED BY AT LEAST ONE SUBSTITUENT SELECTED FROM THE GROUP CONSISTING OF HYDROXY AND OXO, THE HYDROCARBON GROUP HAVING FROM 6 TO 20 CARBON ATOMS, BEING SATURATED OR OLEFINICALLY UNSATURATED, AND BEING BOUND BY AN ACYCLIC CARBON ATOM WHICH IS PART OF SUCH GROUP; AND II. A MEMBER SELECTED FROM THE GROUP CONSISTING OF NICOTINIC ACID, A THERAPEUTICALLY-ACTIVE DERIVATIVE OF NICOTINIC ACID, A UNSTABLE VITAMIN AND A THERAPEUTICALLY-ACTIVE EQUIVALENT THEREOF SELECTED FROM THE GROUP CONSISTING OF A SALT, AN ESTER AND A PROVITAMIN THEREOF; THE XANTHINE BEING PRESENT IN THE ADMIXTURE IN A PROPORTION SUFFICIENT TO STABILIZE ANY UNSTABLE VITAMIN THEREIN.

Claim 5

oxo,

Claim 6

oxo,

Claim 7

an aliphatic hydrocarbon group substituted by at least one substituent selected from the group consisting of hydroxy and oxo, the hydrocarbon group having from 6 to 20 carbon atoms, being saturated or olefinically unsaturated, and being bound by an acyclic carbon atom which is part of such group, at least 50 percent by weight of the total comprised of each vitamin and each substituted xanthine being in molten state in which any remainder of the components is homogeneously incorporated, and the substituted xanthine being in excess; and b. solidifying the resulting admixture into substantially solid state.

Claim 8

an aliphatic hydrocarbon group substituted by at least one substituent selected from the group consisting of hydroxy and oxo, the hydrocarbon group having from 6 to 20 carbon atoms, being saturated or olefinically unsaturated, and being bound by an acyclic carbon atom which is part of such group, at least 50 percent by weight of the total comprised of each vitamin and each substituted xanthine being in molten state in which any remainder of the components is homogeneously incorporated, and the substituted xanthine being in excess; and b. solidifying the resulting admixture into substantially solid state.

Claim 9

oxo,

Claim 10

oxo,

Claim 11

oxo,

Claim 12

oxo,

Claim 13

A therapeutically-active and pharmaceutically-acceptable preparation comprising a solidified admixture according to claim 1 wherein the xanthine is substituted in one of the 1-, 3- and 7-positions by: a. alkyl having from 5 to 15 carbon atoms, b. phenyl-substituted saturated aliphatic hydrocarbon, c. hydroxyalkyl having from 7 to 15 carbon atoms or d. oxoalkyl having from 7 to 15 carbon atoms.

Claim 14

A delayed release therapeutically-active and pharmaceutically-acceptable preparation comprising an admixture according to claim 1 which consists essentially of said pharmaceutically-active substances, at least one of which is more rapidly and at least one of which is more slowly therapeutically active, at least one therapeutically active substance being homogeneously incorporated in another, both being intimately mixed, the said at least two active substances being physiologically acceptable and pharmaceutically as well as chemically compatible under the conditions of the homogeneous incorporation and having activities which are not antagonistic.

Claim 15

phenyl and

Claim 16

phenyl and

Claim 17

phenyl and

Claim 18

phenyl and

Claim 19

phenyl and

Claim 20

phenyl and

Claim 21

cycloalkyl with from 5 to 7 ring atoms, each substituted hydrocarbon group having, altogether, at most 20 carbon atoms and wherein each substituent of the xanthine is bound thereto by an acyclic carbon atom which is part thereof.

Claim 22

cycloalkyl with from 5 to 7 ring atoms, each substituted hydrocarbon group having, altogether, at most 20 carbon atoms and wherein each substituent of the xanthine is bound thereto by an acyclic carbon atom which is part thereof.

Claim 23

cycloalkyl with from 5 to 7 carbon atoms, each substituted hydrocarbon group having, altogether, at most 20 carbon atoms and wherein each substituent of the xanthine is bound thereto by an acyclic carbon atom which is part thereof at least 50 percent by weight of the total comprised of each vitamin and of each substituted xanthine is in molten state in which any remainder of the components is homogeneously incorporated, and the substituted xanthine is in excess; B. solidifying the resulting admixture into substantially solid state.

Claim 24

cycloalkyl with from 5 to 7 carbon atoms, each substituted hydrocarbon group having, altogether, at most 20 carbon atoms and wherein each substituent of the xanthine is bound thereto by an acyclic carbon atom which is part thereof at least 50 percent by weight of the total comprised of each vitamin and of each substituted xanthine is in molten state in which any remainder of the components is homogeneously incorporated, and the substituted xanthine is in excess; B. solidifying the resulting admixture into substantially solid state.

Claim 25

cycloalkyl with from 5 to 7 ring atoms, each substituted hydrocarbon group having, altogether, at most 20 carbon atoms and wherein each substituent of the xanthine is bound thereto by an acyclic carbon atom which is part thereof; in which combination the xanthine compound is present in an excess and wherein the vitamin is homogeneously distributed in said substituted xanthine compound in the form of an intimate solid mixture of these components.

Claim 26

cycloalkyl with from 5 to 7 ring atoms, each substituted hydrocarbon group having, altogether, at most 20 carbon atoms and wherein each substituent of the xanthine is bound thereto by an acyclic carbon atom which is part thereof; in which combination the xanthine compound is present in an excess and wherein the vitamin is homogeneously distributed in said substituted xanthine compound in the form of an intimate solid mixture of these components.

Claim 27

A delayed release therapeutically-active and pharmaceutically-acceptable preparation comprising an admixture according to claim 1 and wherein one of the pharmaceutically-active substances is nicotinic acid or a therapeutically-active derivative thereof.

Claim 28

A delayed-release pharmaceutically-acceptable preparation according to claim 4 wherein the admixture consists essentially of a solidified intimate admixture of a. at least one member selected from the group consisting of nicotinic acid and a therapeutically-active derivative thereof and b. molten 1-hexyl-3,7-dimethylxanthine.

Claim 29

A pharmaceutically-acceptable stabilized vitamin preparation comprising an admixture according to claim 1 and wherein one of the pharmaceutically-active substances is an unstable vitamin stabilized by the xanthine.

Claim 30

A preparation according to claim 6 wherein one of the pharmaceutically-active substances is an unstable vitamin stabilized by the xanthine, wherein the xanthine is present in an excess and wherein the vitamin is homogeneously distributed in said xanthine in the form of an intimate solid mixture of these components.

Claim 31

A delayed-release pharmaceutically-acceptable stabilized vitamin preparation according to claim 6 wherein the admixture consists essentially of a solidified intimate admixture of a. at least one absorbable therapeutically-active vitamin selected from the group consisting of vitamin A, vitamin B1, vitamin B6, vitamin C and vitamin E and b. an effective vitamin-stabilizing amount of molten 1-hexyl-3, 7-dimethylxanthine.

Claim 32

A delayed-release pharmaceutically-acceptable stabilized vitamin preparation according to claim 6 wherein the admixture consists essentially of a solidified intimate admixture of a. at least one absorbable therapeutically-active vitamin selected from the group consisting of vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin C, vitamin D3 and vitamin E and b. an effective vitamin-stabilizing amount of molten 1-hexyl-3,7-dimethylxanthine.

Claim 33

A preparation according to claim 6 comprising a combination of at least one vitamin stabilized with at least one pharmacologically-acceptable substituted xanthine which is substituted in each of two of the 1-, 3- and 7-positions by an alkyl group having at most 2 carbon atoms and is substituted in the remaining of said positions by a. an aliphatic unsubstituted hydrocarbon group with from 3 to 20 carbon atoms and which is saturated or contains at most 3 olefiniC bonds, b. substituted (a), at least one substituent of which is a member selected from the group consisting of

Claim 34

In a process for producing a pharmaceutical preparation exhibiting delayed release of an active substance, the improvement which consists essentially of: a. intimately mixing at least two therapeutically-active and pharmaceutically-acceptable substances, at least one of which is more rapidly absorbable than another and at least one of which is in molten state, each other therapeutically-active substance being homogeneously incorporated into any such substance in molten state; b. solidifying the resulting admixture and c. forming the solidified admixture into a solid pharmaceutical preparation wherein each therapeutically-active substance is homogeneously admixed with each other such substance, and all active substances are compatible for concurrent administration; two of the therapeutically-active and pharmaceutically-acceptable substances being: I. a xanthine which is substituted in each of two of the 1-, 3-and 7-positions by an alkyl group having at most two carbon atoms and is substituted in the remaining of said positions by: a. a hydrocarbon group having from 3 to 20 carbon atoms and being bound by an acyclic carbon atom which is part of such group, or an aliphatic hydrocarbon group substituted by at least one substituent selected from the group consisting of hydroxy and oxo, the hydrocarbon group having from 6 to 20 carbon atoms, being saturated or olefinically unsaturated, and being bound by an acyclic carbon atom which is part of such group; and II. a member selected from the group consisting of nicotinic acid, a therapeutically-active derivative of nicotinic acid, an unstable vitamin and a therapeutically-active equivalent thereof selected from the group consisting of a salt, an ester and a provitamin thereof; the xanthine being present in the admixture in a proportion sufficient to stabilize any unstable vitamin therein.

Claim 35

In a process for producing a pharmaceutical preparation exhibiting delayed release of an active substance, the improvement which consists essentially of: a. intimately mixing at least two therapeutically-active and pharmaceutically-acceptable substances, at least one of which is more rapidly absorbable than another and at least one of which is in molten state, each other therapeutically-active substance being homogeneously incorporated into any such substance in molten state; b. solidifying the resulting admixture and c. forming the solidified admixture into a solid pharmaceutical preparation wherein each therapeutically-active substance is homogeneously admixed with each other such substance, and all active substances are compatible for concurrent administration; two of the therapeutically-active and pharmaceutically-acceptable substances being: I. a xanthine which is substituted in each of two of the 1-, 3-and 7-positions by an alkyl group having at most two carbon atoms and is substituted in the remaining of said positions by: a. a hydrocarbon group having from 3 to 20 carbon atoms and being bound by an acyclic carbon atom which is part of such group, or an aliphatic hydrocarbon group substituted by at least one substituent selected from the group consisting of hydroxy and oxo, the hydrocarbon group having from 6 to 20 carbon atoms, being saturated or olefinically unsaturated, and being bound by an acyclic carbon atom which is part of such group; and II. a member selected from the group consisting of nicotinic acid, a therapeutically-active derivative of nicotinic acid, an unstable vitamin and a therapeutically-active equivalent thereof selected from the group consisting of a salt, an ester and a provitamin thereof; the xanthine being present in the admixture in a proportion sufficient to stabilize any unstable vitamin therein.

Claim 36

A process according to claim 11 wherein non-liquid therapeutically-active substances absorbable at different rates are intimately mixed under pressure.

Claim 37

A process according to claim 11 wherein the therapeutically-active substances comprise at least one unstable vitamin or a therapeutically-active equivalent thereof.

Claim 38

A process according to claim 11 wherein the therapeutically-active substances comprise nicotinic acid or a therapeutically-active derivative thereof.

Claim 39

A process according to claim 11 wherein the molten and solidified admixture is granulated and filled into capsules, or extruded under pressure into shaped tablet dosage forms.

Claim 40

A process according to claim 11 wherein the therapeutically-active substances are: a. from 50 to 200 parts by weight of an alkyldimethylxanthine and b. from 10 to 50 parts by weight of nicotinic acid or a salt thereof.

Claim 41

A process according to claim 11 wherein the solidified admixture resulting from step (b) consists essentially of said therapeutically-active substances.

Claim 42

A process according to claim 11 wherein one of the therapeutically-active substances is a xanthine which is substituted in each of two of the 1-, 3- and 7-positions by an alkyl group having at most 2 carbon atoms and is substituted in the remaining of said positions by a. an aliphatic unSubstituted hydrocarbon group with from 3 to 20 carbon atoms and which is saturated or olefinically unsaturated with at most 3 olefinic bonds, b. substituted (a), at least one substituent of which is a member selected from the group consisting of

Claim 43

A process according to claim 11 for producing a pharmaceutically-acceptable vitamin preparation exhibiting delayed release of active vitamin substance and which process consists essentially of: a. intimately mixing an effective vitamin-stabilizing amount of a molten dimethylxanthine compound selected from the group consisting of 1-hexyl-3,7 -dimethylxanthine, 1 -oxohexyl-3,7-dimethylxanthine, and 7-( Beta -hydroxyethyl)-1,3-dimethylxanthine with at least one absorbable therapeutically-active vitamin substance selected from the group consisting of nicotinic acid, vitamin A, vitamin B1, vitamin B2 , vitamin B6, vitamin C, vitamin D3 and vitamin E; b. solidifying the obtained mixture; and c. forming the solidified mixture into a solid vitamin pharmaceutical preparation.

Claim 44

A process according to claim 19 wherein the dimethylxanthine is 1-oxohexyl-3,7-dimethylxanthine.

Claim 45

A process according to claim 19 wherein the dimethylxanthine is 7-( Beta -hydroxyethyl)-1,3-dimethylxanthine.

Claim 46

A process according to claim 19 wherein the dimethylxanthine is 1-hexyl-3,7-dimethylxanthine.

Claim 47

A vitamin stabilization process which comprises: a. intimately mixing at least two pharmacologically-acceptable components, one such component comprising at least one unstable vitamin and another such component comprising an effective vitamin-stabilizing amount of at least one substituted xanthine, the xanthine being substituted in each of two of the 1-, 3- and 7-positions by an alkyl group having at most two carbon atoms and being substituted in the remaining of said positions by:

Claim 48

A vitamin stabilization process which comprises: a. intimately mixing at least two pharmacologically-acceptable components, one such component comprising at least one unstable vitamin and another such component comprising an effective vitamin-stabilizing amount of at least one substituted xanthine, the xanthine being substituted in each of two of the 1-, 3- and 7-positions by an alkyl group having at most two carbon atoms and being substituted in the remaining of said positions by:

Claim 49

A process according to claim 23 wherein the vitamin is at least one member selected from the group consisting of vitamin A, vitamin C, vitamin E and a vitamin of the B-vitamins.

Claim 50

A vitamin stabilization process according to claim 23 which comprises: A. intimately mixing at least two pharmacologically-acceptable components, one such component comprising at least one unstable vitamin and another such component comprising at least one substituted xanthine, which is substituted in each of two of the 1-, 3- and 7-positions by an alkyl group having at most 2 carbon atoms and is substituted in the remaining of said positions by a. an aliphatic unsubstituted hydrocarbon group with from 3 to 20 carbon atoms and which is saturated or contains at most 3 olefinic bonds, b. substituted (a), At least one substituent of which is a member selected from the group consisting of

Claim 51

A process according to claim 25 wherein the vitamin is vitamin A, vitamin C, vitamin E, a vitamin of the B-vitamins, a vitamin of the D-vitamins, or a combination thereof.

Claim 52

A process according to claim 25 wherein the vitamin/substituted-xanthine ratio is at most 30 percent by weight.

Claim 53

A process according to claim 25 for producing a pharmaceutically-acceptable stabilized vitamin preparation, which process consists essentially of intimately mixing an effective vitamin-stabilizing amount of molten 1-hexyl-3,7-dimethylxanthine with at least one absorbable therapeutically-active vitamin substance selected from the group consisting of vitaminA, vitamin B1, vitamin B2, vitamin B6, vitamin C, vitamin D3 and vitamin E, solidifying the obtained mixture and forming it into a solid stabilized vitamin pharmaceutical preparation.