CA1069439A - Pharmaceutical composition containing xanthine - Google Patents
Pharmaceutical composition containing xanthineInfo
- Publication number
- CA1069439A CA1069439A CA252,187A CA252187A CA1069439A CA 1069439 A CA1069439 A CA 1069439A CA 252187 A CA252187 A CA 252187A CA 1069439 A CA1069439 A CA 1069439A
- Authority
- CA
- Canada
- Prior art keywords
- composition
- xanthine derivative
- xanthine
- dimethylxanthine
- forming agent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical compound O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 title claims abstract description 37
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 12
- 229940075420 xanthine Drugs 0.000 title claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 15
- 210000003296 saliva Anatomy 0.000 claims abstract description 15
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 11
- 238000000034 method Methods 0.000 claims abstract description 8
- GEPVMDINFCTKRV-UHFFFAOYSA-N 8,8-dimethyl-3H-purine-2,6-dione Chemical class CC1(N=C2NC(NC(C2=N1)=O)=O)C GEPVMDINFCTKRV-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 4
- 239000000203 mixture Substances 0.000 claims description 23
- 239000003795 chemical substances by application Substances 0.000 claims description 15
- 229940083747 low-ceiling diuretics xanthine derivative Drugs 0.000 claims description 9
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 9
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 9
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 9
- 239000000454 talc Substances 0.000 claims description 9
- 229910052623 talc Inorganic materials 0.000 claims description 9
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 8
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 7
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 7
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 238000005469 granulation Methods 0.000 claims description 6
- 230000003179 granulation Effects 0.000 claims description 6
- 239000000843 powder Substances 0.000 claims description 5
- 244000007835 Cyamopsis tetragonoloba Species 0.000 claims description 4
- 235000019359 magnesium stearate Nutrition 0.000 claims description 4
- BYPFEZZEUUWMEJ-UHFFFAOYSA-N Pentoxifylline Chemical compound O=C1N(CCCCC(=O)C)C(=O)N(C)C2=C1N(C)C=N2 BYPFEZZEUUWMEJ-UHFFFAOYSA-N 0.000 claims description 3
- 229920002678 cellulose Polymers 0.000 claims description 3
- 239000001913 cellulose Substances 0.000 claims description 3
- 239000008187 granular material Substances 0.000 claims description 3
- 229960004559 theobromine Drugs 0.000 claims description 3
- NSMXQKNUPPXBRG-UHFFFAOYSA-N 1-(5-hydroxyhexyl)-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione Chemical group O=C1N(CCCCC(O)C)C(=O)N(C)C2=C1N(C)C=N2 NSMXQKNUPPXBRG-UHFFFAOYSA-N 0.000 claims description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 2
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 claims description 2
- 229940072056 alginate Drugs 0.000 claims description 2
- 235000010443 alginic acid Nutrition 0.000 claims description 2
- 229920000615 alginic acid Polymers 0.000 claims description 2
- 239000011118 polyvinyl acetate Substances 0.000 claims description 2
- 229920002689 polyvinyl acetate Polymers 0.000 claims description 2
- XBEDAMVJWVPVDS-UHFFFAOYSA-N 1,3-dimethyl-7-(5-oxohexyl)purine-2,6-dione Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2CCCCC(=O)C XBEDAMVJWVPVDS-UHFFFAOYSA-N 0.000 claims 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 claims 1
- 235000012222 talc Nutrition 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 2
- 239000004480 active ingredient Substances 0.000 description 14
- 150000001875 compounds Chemical class 0.000 description 5
- 230000002496 gastric effect Effects 0.000 description 4
- 210000001035 gastrointestinal tract Anatomy 0.000 description 4
- 210000004400 mucous membrane Anatomy 0.000 description 4
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 4
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 210000004051 gastric juice Anatomy 0.000 description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 229940065721 systemic for obstructive airway disease xanthines Drugs 0.000 description 2
- YAPQBXQYLJRXSA-UHFFFAOYSA-N theobromine Chemical class CN1C(=O)NC(=O)C2=C1N=CN2C YAPQBXQYLJRXSA-UHFFFAOYSA-N 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- VBWKPDAEPJUUMO-UHFFFAOYSA-N 7-(4-hydroxypentyl)-1,3-dimethylpurine-2,6-dione Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2CCCC(O)C VBWKPDAEPJUUMO-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940096529 carboxypolymethylene Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000000622 irritating effect Effects 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000008095 long lasting therapeutic effect Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- 125000005188 oxoalkyl group Chemical group 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- -1 xanthine derivatives Chemical class 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Pharmaceutical compositions A b s t r a c t A pharmaceutical composition for oral administration in dosage unit form which comprises at least one xanthine derivative selected from a) (w-1)-hydroxyalkyl-dialkylxanthines wherein the (w-1)-hydroxyalkyl group contains 5 or 6 carbon atoms and is in the 1- or 7-position, the alkyl group in the other of the 1- and 7-position contains from 1 to 12 carbon atoms and the alkyl group in the 3-position contains from 1 to 4 carbon atoms, b) (w-1)-oxoalkyl-dimethylxanthines wherein the (w-1)-oxoalkyl group contains 5 or 6 carbon atoms and is in the 1- or 7-position and c) dimethylxanthine derivatives having an additional alkyl group containing from 4 to 12 carbon atoms or a benzyl group in the 1- or 7-postion, and a saliva forming agent, each dosage unit containing at least 300 mg, of xanthine derivative and the weight ratio of xanthine derivative to saliva forming agent is in the range from 1 : 2 to 10 : 1. and a method for its preparation.
Description
This invention relates to pharmaceutical compositions for oral administration containing xanthine derivatives.
It is well kno~ that certain pharmaceutically active compounds, e.g. xanthine derivatives, particularly dimethylxanthines and derivatives thereof, have a rather high incompatibilit~ with the gastro-intestinal tract.
Pharmaceutical products containing these compounds are thus frequently presented in the ~orm of injection solutions, solution for infusion or coated tablets resistan~ to gastric juicas. In the latter pharmaceutical form, the dosage has had to be kept low to avoid incompatibility reactions and this has heretofore restricted the usefulness of oral therapy.
The irritant effect on the gastric mucous membrane is particularly strong when larger quantities of the active i~gredient are released in and come into contact with a narro~l~ circumscribed area of the mucous membrane, as is the case, for example, when a tablet rests on the gastric mucous mem-brane and decomposes there within a short time, e.g. in about 1 to 2 minutes.
The problem is only partially solved by administration of pharmaceutical preparations which are resistant to gastric juices~ since the decomposition of the pharmaceuticai for~ does not then take place until it reaches the small intestine. Moreover, with subacid and anacid patien~s, the pharma-ceutical preparation nevertheless decomposes in the stomach itself. For the reasons described above, the use of oral therapy with certain pharmaceuticals which is generally preferred because of its convenience, has been severely restricted because of the limitations imposed by the low dosage levels which can be administered safely.
Pharmaceutical compositlons for oral administration ma~ be produced b~ granulating the active ingredient with the excipients, e.g. lactose or cane sugar, to produce a fairl~ coarse granulate which, after further granula-tion is compressed into tablets. It is also possible to compress a powder , .
- .~
9~39 mixture with a moisture content of 3 to 6~ directly into tablets.
The present invention is based upon the discovery that the incom-patibility of certain pharmaceuticals with the gastro-intestinal tract may be considerably reduced by admixture of the pharmaceutical with a sufficient amount of a saliva forming agent, thereby permitting safe oral administration of such pharmaceuticals in considerably higher dosages than has been possible heretofore.
Thus according to the present invention ~here i5 provided a pharma-ceutical composition for oral administration in dosage unit form which comprises at least one xanthine derivative selected from a~ l)-hydroxy-alkyl-dialkylxanthines wherein the ~-l)-hydroxyalkyl group conkains 5 or 6 carbon atoms and is in the 1- or 7- position, the alkyl group in the other of the 1- and 7-positions contains from 1 to 12 carbon a~oms and the alkyl group in the 3-position contains from 1 to 4 carbon atoms b) (~-l)-oxoalkyl-dimethylxanthines wherein the (~-l)-oxoalkyl group contains 5 or 6 carbon `atoms and is in the 1- or 7-position and c) dimethylxanthine derivatives having a~ alkyl group containing from 4 to 12 carbon atoms or a benzyl group in the 1- or 7-position, and a saliva forming agent, each dosage unit con-taining at least 30~ mg, preferably at least 400mg, o~ xanthine derivative and the weight ratio of xanthine derivati~e to salira forming agent being in the rang~ from 1:2 to 10:1, preferably from 1 1 to 6:1.
The invention is particularly valuable for administration of water-soluble xanthine derivatives but is also useful for administration of xanthine derivatives which are not soluble in water. The invention makes it possible for pharmaceutically acitve compounds which are water-soluble and badly ~olera~ed by the stomach to be administered orally in consid~rably higher doses than has been possible heretofore, whils~ avoiding incompatibil-it~ reactions ?n the gastro-intestinal tract. This has been demons~rated as follows:
It is well kno~ that certain pharmaceutically active compounds, e.g. xanthine derivatives, particularly dimethylxanthines and derivatives thereof, have a rather high incompatibilit~ with the gastro-intestinal tract.
Pharmaceutical products containing these compounds are thus frequently presented in the ~orm of injection solutions, solution for infusion or coated tablets resistan~ to gastric juicas. In the latter pharmaceutical form, the dosage has had to be kept low to avoid incompatibility reactions and this has heretofore restricted the usefulness of oral therapy.
The irritant effect on the gastric mucous membrane is particularly strong when larger quantities of the active i~gredient are released in and come into contact with a narro~l~ circumscribed area of the mucous membrane, as is the case, for example, when a tablet rests on the gastric mucous mem-brane and decomposes there within a short time, e.g. in about 1 to 2 minutes.
The problem is only partially solved by administration of pharmaceutical preparations which are resistant to gastric juices~ since the decomposition of the pharmaceuticai for~ does not then take place until it reaches the small intestine. Moreover, with subacid and anacid patien~s, the pharma-ceutical preparation nevertheless decomposes in the stomach itself. For the reasons described above, the use of oral therapy with certain pharmaceuticals which is generally preferred because of its convenience, has been severely restricted because of the limitations imposed by the low dosage levels which can be administered safely.
Pharmaceutical compositlons for oral administration ma~ be produced b~ granulating the active ingredient with the excipients, e.g. lactose or cane sugar, to produce a fairl~ coarse granulate which, after further granula-tion is compressed into tablets. It is also possible to compress a powder , .
- .~
9~39 mixture with a moisture content of 3 to 6~ directly into tablets.
The present invention is based upon the discovery that the incom-patibility of certain pharmaceuticals with the gastro-intestinal tract may be considerably reduced by admixture of the pharmaceutical with a sufficient amount of a saliva forming agent, thereby permitting safe oral administration of such pharmaceuticals in considerably higher dosages than has been possible heretofore.
Thus according to the present invention ~here i5 provided a pharma-ceutical composition for oral administration in dosage unit form which comprises at least one xanthine derivative selected from a~ l)-hydroxy-alkyl-dialkylxanthines wherein the ~-l)-hydroxyalkyl group conkains 5 or 6 carbon atoms and is in the 1- or 7- position, the alkyl group in the other of the 1- and 7-positions contains from 1 to 12 carbon a~oms and the alkyl group in the 3-position contains from 1 to 4 carbon atoms b) (~-l)-oxoalkyl-dimethylxanthines wherein the (~-l)-oxoalkyl group contains 5 or 6 carbon `atoms and is in the 1- or 7-position and c) dimethylxanthine derivatives having a~ alkyl group containing from 4 to 12 carbon atoms or a benzyl group in the 1- or 7-position, and a saliva forming agent, each dosage unit con-taining at least 30~ mg, preferably at least 400mg, o~ xanthine derivative and the weight ratio of xanthine derivati~e to salira forming agent being in the rang~ from 1:2 to 10:1, preferably from 1 1 to 6:1.
The invention is particularly valuable for administration of water-soluble xanthine derivatives but is also useful for administration of xanthine derivatives which are not soluble in water. The invention makes it possible for pharmaceutically acitve compounds which are water-soluble and badly ~olera~ed by the stomach to be administered orally in consid~rably higher doses than has been possible heretofore, whils~ avoiding incompatibil-it~ reactions ?n the gastro-intestinal tract. This has been demons~rated as follows:
- 2 - :
.. . . . . . . .. .. . . .
,. . .: .
- :: :. '. ~ - - , . . . .
- .. -. . : ~ . .. . . .. - .. . . .- ~ .
~69~3~
Where 40~ mg of 1-(5-oxohexyl)-3,7-dimethylxanthine were administered to~ether with carriers and excipients, but withou~ a saliva forming agent, the level of this active ingredient in the blood ~as found to rise rapidly but then fall again very rapidly. This indicates that the substance is well resorbed and quickl~ eliminated b~ ~he bod~.
In contrast, where 400 mg of the same active ingredient ~ere admin-istered in the form of a pharmaceutical composition according to the inven-tion, a relativel~ constant level of the active ingredient was sustained in the blood for a long period. This indicated a gradual release of the active ingredient from the pharmaceutical composition. Although decomposition pro-ducts Qf the active ingredient are constantly eliminated in the urine, the level of the active ingredient in the blood remained relatively constant over a Iong period. This thus confirms that there is a constant release of the active ingredient after resorption from the gast~o-intestinal tract.
In tests carried out in vitro we have shown that constant quantities of the active ingredient are also released per hour into artificial gastric and intestinal juices.
SuGh in vitro and in vivo tests sho~ that a constant level of the active ingredient is resorbed from the compositions according to the inven-tion over a long period in the gastro-intestinal tract, thus guaranteeing a long-lasting therapeutic effect.
By means of the invention it is generally possible to administer safely the aforementioned xanthine derivatives in the form of individual dosage units contaim ng up to 800mg of active ingredient.
Typical uater-soluble oxoalkyl~dialkylxanthines which may be incor-porated into pharmaceutical compositions according to the invention include for example 1-~5-oxohexyl)-3,7- and 7-~5-oxohexyl)-1,3-dimethylxanthines.
Other suitable xanthines are for example 3,7-dimethylxanthines and 1,3-.- . :.. , . - . ' , . ,: , - ,.; .. .' . . ' . ' . , ,, . . , ' : . :, . . . - . : .
.. . . . . . . .. .. . . .
,. . .: .
- :: :. '. ~ - - , . . . .
- .. -. . : ~ . .. . . .. - .. . . .- ~ .
~69~3~
Where 40~ mg of 1-(5-oxohexyl)-3,7-dimethylxanthine were administered to~ether with carriers and excipients, but withou~ a saliva forming agent, the level of this active ingredient in the blood ~as found to rise rapidly but then fall again very rapidly. This indicates that the substance is well resorbed and quickl~ eliminated b~ ~he bod~.
In contrast, where 400 mg of the same active ingredient ~ere admin-istered in the form of a pharmaceutical composition according to the inven-tion, a relativel~ constant level of the active ingredient was sustained in the blood for a long period. This indicated a gradual release of the active ingredient from the pharmaceutical composition. Although decomposition pro-ducts Qf the active ingredient are constantly eliminated in the urine, the level of the active ingredient in the blood remained relatively constant over a Iong period. This thus confirms that there is a constant release of the active ingredient after resorption from the gast~o-intestinal tract.
In tests carried out in vitro we have shown that constant quantities of the active ingredient are also released per hour into artificial gastric and intestinal juices.
SuGh in vitro and in vivo tests sho~ that a constant level of the active ingredient is resorbed from the compositions according to the inven-tion over a long period in the gastro-intestinal tract, thus guaranteeing a long-lasting therapeutic effect.
By means of the invention it is generally possible to administer safely the aforementioned xanthine derivatives in the form of individual dosage units contaim ng up to 800mg of active ingredient.
Typical uater-soluble oxoalkyl~dialkylxanthines which may be incor-porated into pharmaceutical compositions according to the invention include for example 1-~5-oxohexyl)-3,7- and 7-~5-oxohexyl)-1,3-dimethylxanthines.
Other suitable xanthines are for example 3,7-dimethylxanthines and 1,3-.- . :.. , . - . ' , . ,: , - ,.; .. .' . . ' . ' . , ,, . . , ' : . :, . . . - . : .
3~
dimethylxanthines substituted by a butyl, isoamyl, hexylJ lauryl, or benzyl group in the 1- or 7-position, and also homologues of these compounds with a hydroxy or oxo group in the (~-l)-position, e.g. 1-~4-hydroxypentyl)- and 1-(5-hydroxyhexyl)-3,7-dimethylxanthines, 7-t4-hydrsxypentyl)- and 7-~5-hydroxyhexyl)-1,3-dimethylxanthines, 1-~4-oxopentyl)-, 1-~5-oxohexyl)-, 1-~2-methyl-3-oxobutyl)- and 1-~2-ethyl-3-oxobutyl)-3,7-dime~h~lxanthines and the corresponding 1,3-dimethyl compounds having the aforementioned (~
hydroxyalkyl or (~ -oxoalkyl groups in the 7-posi~ion. Suitable homologues of the above hydroxyalkyl-dimethylxanthines, are those having in the 1- or 7-position which is not occupied by a hydroxyalkyl group, instead of a methyl group, an alkyl group with 2 to 12 carbon atoms~ e.g. l-ethyl-, l-propyl-, l-butyl- and l-isobutyl-3-methyl-7-~5-hydroxyhexyl~-xanthines and 7-ethyl-, 7-propyl-, 7-butyl- and 7-isobutyl-1-~5-hydrox~rhexyl)-3-methylxan-thines, and corresponding compounds having in place of the 3-methyl graup an alkyl group ~ith 2 to 4 carbon atoms.
The saliva orming agent, which generally also acts as a swelling agent, i~ preferably guar po~der, a galactomannane, a~ alginate/ an acrylic acid polymer, for example the commercial p~oduct Caxbopol*, or a cellulose derivative, for example methyl cellulose or more especially hydroxyeth~l cellulose.
~ urther excipientS, for example polyvinyl pyrrolidone, mixtures of polyvinyl pyrrolidone with polyvinyl acetate, talc, magnesium stearate and other excipients conventionally used in tablet making, may be incorporated into the compositions as desired.
Compositions according to the invention in ~he form of tablets and tablet cores ma~ be prepared by the follo~ing method, ~hich method constitutes a further feature of the invention: admixing-one ar more xanthine derivatives * Trademark for carboxy-polymethylene ' :' ..
., . - . -., . - -- ,.. . . : . .
- . . :. ... . - ,: . ,, ., ., - ~ ,. : .. . ..
~~ L3~
as hereinbefore de-fined with a saliva forming agent in a weight ratio of xanthine derivative to saliva forming agent of from 1:2 to 10:1 preferably from 1:1 to 6:1, granulating the mixture thereby produced and compressing the granulate into tablets or tablet cores each containing at least 3~0 mg, preferably at least 400mg, of xanthine derivative.
One or more further excipients may be incorporated into the compo-sitions prior to, during or after granulation as convenient. Where tablet cores are producedJ these can be subsequently coated as desired to prepare coated tablets.
Granulation is preferably carried out as a dry granulation.
However, other conventional granulation processes may also be used.
By means of the compositions according to the invention, it is sa~e to administer orally the aforespecified xanthine derivatives in the form of solid dosage units having an active ingredient content which is at least twice as high, often from 3 to 6 times as high as the highest dosage of the same active ingredient administered hitherto. In individual cases, the dosage which may be safely administered may even be 8 times as high.
When a pharmaceutical compQsition according to the invention is swallowed and comes into contact with water or gastric juices it is ~hought that a mucous layer is spontaneously ~ormed around it which layer protects the mucous membrane fram the direct action of the hi.gh concentTation of active ingredient. When ~e tested pharmaceutical compositions according to the invention containing certain oxoalkyldialkylxanthines on humans, we found that dosages of at least 400mg~ generally from 800 to 1200 mg, and even as much as 2400 mg could be administered daily without the occurrence of any incompatibility reactions. The xanthine derivatives wi!th ~hich this invention is concerned, are used particularly in the treatment of blood flow complaints and d~velop an optimum activity a~ individual single dosage levels -~,:
.
~6~343~
above 300 mg. Such dosages could previously only be administered by infusion but as a result of the present invention ma~ now be administered by the more convenient oral route.
The following Examples serve to illustrate the preparation of pharmaceutical compositions according to the invention.
Examples In each case the various ingredients were admixed, agglomerated in a compactor, gramllated and subsequently compressed into tabl0ts or cores for coated tablets having the indicated compositions:
Example 1 a)400 mg of 1-~5-oxohexyl)-3,7-dimethyl-xanthine b)80 mg of hydroxyethyl cellulose c)10 mg of polyvinylpyrrolidone d)20 mg of talc e~5 mg of magnecium stearate Ex~mple 2 a)30a mg of 1-propyl-3-methyl-7-~5-hydroxyhexyl)-xanthine b)200 mg of hydroxyethyl cellulose c)20 mg of polyvinylpyrrolidone d~10 mg of talc e)5 mg of ~agnesium stearate Example 3 a)400 mg of 1,3-dimethyl-7-(4-hydroxypentyl)-xanthine b)100 mg of hydroxyethyl cellulose c)20 mg of polyvinylpyrrolidone d)10 mg of talc e)5 mg of magnesium stearate . :. . .-: .: . - , , :. - . : . ,. . . : . .
- - : .. ~ . . .: . ~: .. .
~ L6~t~3~3~3 Example ~
a)400 mg o 1-(5-hydroxyhexyl)-3,7-dimethylxan~hine b)100 mg of hydroxyethyl cellulose c)20 mg of polyvinylpyrrolidone d)10 mg of talc e)5 mg of magnesium stearate Example 5 a)SQ0 mg Qf l-pentyl-3,7-dimethylxanthine b)50 mg of hydroxyethyl cellulose c)5 mg o polyvinylpyrrolidone d)15 mg of talc e) 5 mg ~f ~agne i ~ 5tearate Example 6 a)800 mg of 1-hexyl-3,7-dimeth~lxanthine b)150 mg of guar powder c)20 mg of polyvinylpyrrolidone d)15 mg of talc e)5 mg qf magnesi.um stearate.
Example 7 a)800 mg of 1-(5-oxohexyl)-3~7-dimethyl xanthine b)150 mg of guar powder c)20 mg of talc d)5 mg ~f magnesi.u~ stearate .
.: ,- : . ~ . . . ~ :
.. . . :
dimethylxanthines substituted by a butyl, isoamyl, hexylJ lauryl, or benzyl group in the 1- or 7-position, and also homologues of these compounds with a hydroxy or oxo group in the (~-l)-position, e.g. 1-~4-hydroxypentyl)- and 1-(5-hydroxyhexyl)-3,7-dimethylxanthines, 7-t4-hydrsxypentyl)- and 7-~5-hydroxyhexyl)-1,3-dimethylxanthines, 1-~4-oxopentyl)-, 1-~5-oxohexyl)-, 1-~2-methyl-3-oxobutyl)- and 1-~2-ethyl-3-oxobutyl)-3,7-dime~h~lxanthines and the corresponding 1,3-dimethyl compounds having the aforementioned (~
hydroxyalkyl or (~ -oxoalkyl groups in the 7-posi~ion. Suitable homologues of the above hydroxyalkyl-dimethylxanthines, are those having in the 1- or 7-position which is not occupied by a hydroxyalkyl group, instead of a methyl group, an alkyl group with 2 to 12 carbon atoms~ e.g. l-ethyl-, l-propyl-, l-butyl- and l-isobutyl-3-methyl-7-~5-hydroxyhexyl~-xanthines and 7-ethyl-, 7-propyl-, 7-butyl- and 7-isobutyl-1-~5-hydrox~rhexyl)-3-methylxan-thines, and corresponding compounds having in place of the 3-methyl graup an alkyl group ~ith 2 to 4 carbon atoms.
The saliva orming agent, which generally also acts as a swelling agent, i~ preferably guar po~der, a galactomannane, a~ alginate/ an acrylic acid polymer, for example the commercial p~oduct Caxbopol*, or a cellulose derivative, for example methyl cellulose or more especially hydroxyeth~l cellulose.
~ urther excipientS, for example polyvinyl pyrrolidone, mixtures of polyvinyl pyrrolidone with polyvinyl acetate, talc, magnesium stearate and other excipients conventionally used in tablet making, may be incorporated into the compositions as desired.
Compositions according to the invention in ~he form of tablets and tablet cores ma~ be prepared by the follo~ing method, ~hich method constitutes a further feature of the invention: admixing-one ar more xanthine derivatives * Trademark for carboxy-polymethylene ' :' ..
., . - . -., . - -- ,.. . . : . .
- . . :. ... . - ,: . ,, ., ., - ~ ,. : .. . ..
~~ L3~
as hereinbefore de-fined with a saliva forming agent in a weight ratio of xanthine derivative to saliva forming agent of from 1:2 to 10:1 preferably from 1:1 to 6:1, granulating the mixture thereby produced and compressing the granulate into tablets or tablet cores each containing at least 3~0 mg, preferably at least 400mg, of xanthine derivative.
One or more further excipients may be incorporated into the compo-sitions prior to, during or after granulation as convenient. Where tablet cores are producedJ these can be subsequently coated as desired to prepare coated tablets.
Granulation is preferably carried out as a dry granulation.
However, other conventional granulation processes may also be used.
By means of the compositions according to the invention, it is sa~e to administer orally the aforespecified xanthine derivatives in the form of solid dosage units having an active ingredient content which is at least twice as high, often from 3 to 6 times as high as the highest dosage of the same active ingredient administered hitherto. In individual cases, the dosage which may be safely administered may even be 8 times as high.
When a pharmaceutical compQsition according to the invention is swallowed and comes into contact with water or gastric juices it is ~hought that a mucous layer is spontaneously ~ormed around it which layer protects the mucous membrane fram the direct action of the hi.gh concentTation of active ingredient. When ~e tested pharmaceutical compositions according to the invention containing certain oxoalkyldialkylxanthines on humans, we found that dosages of at least 400mg~ generally from 800 to 1200 mg, and even as much as 2400 mg could be administered daily without the occurrence of any incompatibility reactions. The xanthine derivatives wi!th ~hich this invention is concerned, are used particularly in the treatment of blood flow complaints and d~velop an optimum activity a~ individual single dosage levels -~,:
.
~6~343~
above 300 mg. Such dosages could previously only be administered by infusion but as a result of the present invention ma~ now be administered by the more convenient oral route.
The following Examples serve to illustrate the preparation of pharmaceutical compositions according to the invention.
Examples In each case the various ingredients were admixed, agglomerated in a compactor, gramllated and subsequently compressed into tabl0ts or cores for coated tablets having the indicated compositions:
Example 1 a)400 mg of 1-~5-oxohexyl)-3,7-dimethyl-xanthine b)80 mg of hydroxyethyl cellulose c)10 mg of polyvinylpyrrolidone d)20 mg of talc e~5 mg of magnecium stearate Ex~mple 2 a)30a mg of 1-propyl-3-methyl-7-~5-hydroxyhexyl)-xanthine b)200 mg of hydroxyethyl cellulose c)20 mg of polyvinylpyrrolidone d~10 mg of talc e)5 mg of ~agnesium stearate Example 3 a)400 mg of 1,3-dimethyl-7-(4-hydroxypentyl)-xanthine b)100 mg of hydroxyethyl cellulose c)20 mg of polyvinylpyrrolidone d)10 mg of talc e)5 mg of magnesium stearate . :. . .-: .: . - , , :. - . : . ,. . . : . .
- - : .. ~ . . .: . ~: .. .
~ L6~t~3~3~3 Example ~
a)400 mg o 1-(5-hydroxyhexyl)-3,7-dimethylxan~hine b)100 mg of hydroxyethyl cellulose c)20 mg of polyvinylpyrrolidone d)10 mg of talc e)5 mg of magnesium stearate Example 5 a)SQ0 mg Qf l-pentyl-3,7-dimethylxanthine b)50 mg of hydroxyethyl cellulose c)5 mg o polyvinylpyrrolidone d)15 mg of talc e) 5 mg ~f ~agne i ~ 5tearate Example 6 a)800 mg of 1-hexyl-3,7-dimeth~lxanthine b)150 mg of guar powder c)20 mg of polyvinylpyrrolidone d)15 mg of talc e)5 mg qf magnesi.um stearate.
Example 7 a)800 mg of 1-(5-oxohexyl)-3~7-dimethyl xanthine b)150 mg of guar powder c)20 mg of talc d)5 mg ~f magnesi.u~ stearate .
.: ,- : . ~ . . . ~ :
.. . . :
Claims (17)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A pharmaceutical composition for oral administration in dosage unit form which comprises at least one xanthine derivative selected from the group consisting of a) (w-l)-hydroxyalkyl-dialkylxanthines wherein the (w-l)-hydroxyalkyl group contains 5 or 6 carbon atoms and is in the 1- or 7-positions, the alkyl group in the other of the 1- and 7-positions contains from 1 to 12 carbon atoms and the alkyl group in the 3-position contains from 1 to 4 carbon atoms, b) (w-l)-oxoalkyl-dimethylxanthines wherein the (w-l)-oxoalkyl group contains 5 or 6 carbon atoms and is in the 1- or 7-position, c) dimethylxanthine derivatives having an additional alkyl group containing from 4 to 12 carbon atoms in the 1- or 7-position, and d) dimethylxanthine derivatives having an additional benzyl group in the 1-or 7-position and a saliva forming agent, each dosage unit containing at least 300 mg of xanthine derivative, and the weight ratio of xanthine derivative to saliva forming agent being in the range from 1 : 2 to 10 : 1.
2. A composition as claimed in claim 1 wherein the xanthine derivative is water-soluble.
3. A composition as claimed in claim 1 wherein each dosage unit contains at least 400 mg of xanthine derivative.
4. A composition as claimed in claim 1 or 2 or 3 wherein each dosage unit contains up to 1200 mg of an (w-1)-oxoalkyl-dimethylxanthine.
5. A composition as claimed in claim 1 or 2 or 3 wherein the xanthine derivative comprises 1-(5-oxohexyl)-3,7-dimethylxanthine or 7-(5-oxohexyl)-1, 3-dimethylxanthine and each dosage unit contains up to 1200 mg of said xanthine derivatives.
6. A composition as claimed in claim 1 or 2 or 3 wherein the saliva forming agent is selected from the group consisting of guar powder, galacto-mannane, an alginate, an acrylic acid powder and a cellulose derivative.
7. A composition as claimed in claim 1 or 2 or 3 which additionally contains a further excipient selected from polyvinyl pyrrolidone, polyvinyl acetate, talcum and magnesium stearate.
8. A composition as claimed in claim 1 or 2 or 3 in tablet form.
9. A method of preparing a pharmaceutical composition for oral admini-stration in dosage unit form comprising at least one xanthine derivative as defined in claim 1 which comprises admixing at least one xanthine derivative as defined in claim 1 with a saliva forming agent in a weight ratio of xanthine derivative to saliva forming agent from 1 : 2 to 10 : 1, granulating the mixture thereby produced and compressing the granulate into tablets or tablet cores each containing at least 300 mg of xanthine derivative.
10. A method as claimed in claim 9 wherein prior to, during or after the granulation, at least one further excipient is incorporated.
11. A method as claimed in 9 or 10 wherein the granulation is effected on a dry mixture.
12. A method as claimed in claim 9 or 10 wherein tablet cores thus produced are subsequently coated.
13. A composition as claimed in claim 1, wherein the xanthine derivative is in admixture with hydroxyethyl cellulose as the saliva forming agent.
14. A composition as claimed in claim 2 or 3, wherein the xanthine derivative is in admixture with hydroxyethyl cellulose as the saliva forming agent.
15. A composition as claimed in claim 1, 2 or 3 wherein the xanthine derivative in l-(5-hydroxyhexyl)-3,7-dimethylxanthine.
16. A composition as claimed in claim 13 wherein the xanthine deriva-tive is 1-(5-oxohexyl)-3,7-dimethylxanthine.
17. A composition as claimed in claim 13 wherein the xanthine derivative is 1-(5-hydroxyhexyl)-3,7-dimethylxanthine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA252,187A CA1069439A (en) | 1976-05-11 | 1976-05-11 | Pharmaceutical composition containing xanthine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA252,187A CA1069439A (en) | 1976-05-11 | 1976-05-11 | Pharmaceutical composition containing xanthine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1069439A true CA1069439A (en) | 1980-01-08 |
Family
ID=4105926
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA252,187A Expired CA1069439A (en) | 1976-05-11 | 1976-05-11 | Pharmaceutical composition containing xanthine |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1069439A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2157209C1 (en) * | 2000-03-23 | 2000-10-10 | Открытое акционерное общество "Химико-фармацевтический комбинат "Акрихин" | Antiaggregate agent improving cerebral circulation and method of its preparing |
| RU2229298C1 (en) * | 2003-02-13 | 2004-05-27 | Открытое акционерное общество "Химико-фармацевтический комбинат "Акрихин" | Pharmaceutical composition eliciting cardiovascular effect and method for it preparing |
-
1976
- 1976-05-11 CA CA252,187A patent/CA1069439A/en not_active Expired
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2157209C1 (en) * | 2000-03-23 | 2000-10-10 | Открытое акционерное общество "Химико-фармацевтический комбинат "Акрихин" | Antiaggregate agent improving cerebral circulation and method of its preparing |
| RU2229298C1 (en) * | 2003-02-13 | 2004-05-27 | Открытое акционерное общество "Химико-фармацевтический комбинат "Акрихин" | Pharmaceutical composition eliciting cardiovascular effect and method for it preparing |
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