CA1180276A - Gelled pge.sub.2/triacetin solutions - Google Patents
Gelled pge.sub.2/triacetin solutionsInfo
- Publication number
- CA1180276A CA1180276A CA000421153A CA421153A CA1180276A CA 1180276 A CA1180276 A CA 1180276A CA 000421153 A CA000421153 A CA 000421153A CA 421153 A CA421153 A CA 421153A CA 1180276 A CA1180276 A CA 1180276A
- Authority
- CA
- Canada
- Prior art keywords
- pge
- pge2
- improvement according
- gel
- triacetin
- 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
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 title claims abstract description 36
- 239000001087 glyceryl triacetate Substances 0.000 title claims abstract description 18
- 235000013773 glyceryl triacetate Nutrition 0.000 title claims abstract description 18
- 229960002622 triacetin Drugs 0.000 title claims abstract description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 33
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical class CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 claims abstract description 23
- -1 e.g. Substances 0.000 claims abstract description 19
- 239000003960 organic solvent Substances 0.000 claims abstract description 19
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims abstract description 17
- 230000000087 stabilizing effect Effects 0.000 claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 6
- 229960002986 dinoprostone Drugs 0.000 claims description 29
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 claims description 20
- 239000007788 liquid Substances 0.000 claims description 14
- 239000002552 dosage form Substances 0.000 claims description 8
- 239000000654 additive Substances 0.000 claims description 3
- 230000000996 additive effect Effects 0.000 claims description 3
- 125000005908 glyceryl ester group Chemical group 0.000 claims description 3
- GMVPRGQOIOIIMI-UHFFFAOYSA-N (8R,11R,12R,13E,15S)-11,15-Dihydroxy-9-oxo-13-prostenoic acid Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CCCCCCC(O)=O GMVPRGQOIOIIMI-UHFFFAOYSA-N 0.000 claims description 2
- 229960000711 alprostadil Drugs 0.000 claims description 2
- GMVPRGQOIOIIMI-DWKJAMRDSA-N prostaglandin E1 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(O)=O GMVPRGQOIOIIMI-DWKJAMRDSA-N 0.000 claims description 2
- 239000000499 gel Substances 0.000 abstract description 43
- 239000000243 solution Substances 0.000 description 10
- 239000000463 material Substances 0.000 description 8
- 150000003180 prostaglandins Chemical class 0.000 description 8
- 239000008119 colloidal silica Substances 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 239000000203 mixture Substances 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 230000006641 stabilisation Effects 0.000 description 5
- 238000011105 stabilization Methods 0.000 description 5
- 239000003381 stabilizer Substances 0.000 description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- 239000004743 Polypropylene Substances 0.000 description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000007903 gelatin capsule Substances 0.000 description 3
- 239000003349 gelling agent Substances 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 239000004033 plastic Substances 0.000 description 3
- 229920003023 plastic Polymers 0.000 description 3
- 229920001155 polypropylene Polymers 0.000 description 3
- 230000005070 ripening Effects 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- 235000012239 silicon dioxide Nutrition 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000001069 triethyl citrate Substances 0.000 description 2
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 2
- 235000013769 triethyl citrate Nutrition 0.000 description 2
- QAOBBBBDJSWHMU-WMBBNPMCSA-N 16,16-dimethylprostaglandin E2 Chemical compound CCCCC(C)(C)[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O QAOBBBBDJSWHMU-WMBBNPMCSA-N 0.000 description 1
- FOBVMYJQWZOGGJ-XYRJXBATSA-N 17-phenyl-18,19,20-trinor-prostaglandin E2 Chemical compound C([C@H](O)\C=C\[C@@H]1[C@H](C(=O)C[C@H]1O)C\C=C/CCCC(O)=O)CC1=CC=CC=C1 FOBVMYJQWZOGGJ-XYRJXBATSA-N 0.000 description 1
- 229910002012 Aerosil® Inorganic materials 0.000 description 1
- 229910002016 Aerosil® 200 Inorganic materials 0.000 description 1
- 241000726103 Atta Species 0.000 description 1
- 101100453921 Caenorhabditis elegans kin-29 gene Proteins 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 229920001479 Hydroxyethyl methyl cellulose Polymers 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000005587 carbonate group Chemical group 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 210000003679 cervix uteri Anatomy 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 150000001940 cyclopentanes Chemical class 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 229920001903 high density polyethylene Polymers 0.000 description 1
- 239000004700 high-density polyethylene Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 150000002736 metal compounds Chemical class 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- VOVZXURTCKPRDQ-CQSZACIVSA-N n-[4-[chloro(difluoro)methoxy]phenyl]-6-[(3r)-3-hydroxypyrrolidin-1-yl]-5-(1h-pyrazol-5-yl)pyridine-3-carboxamide Chemical compound C1[C@H](O)CCN1C1=NC=C(C(=O)NC=2C=CC(OC(F)(F)Cl)=CC=2)C=C1C1=CC=NN1 VOVZXURTCKPRDQ-CQSZACIVSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000008203 oral pharmaceutical composition Substances 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- 239000005022 packaging material Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000002997 prostaglandinlike Effects 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 150000003509 tertiary alcohols Chemical class 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N urethane group Chemical group NC(=O)OCC JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
ABSTRACT
The present invention provides an improved class of stable gels of prostaglandin E compounds prepared from solutions of proslaglandin E compounds in a pharmaceutically acceptable, stabilizing organic solvent, e.g., triacetin, gelled by the addition of colloidal silicon dioxide.
The present invention provides an improved class of stable gels of prostaglandin E compounds prepared from solutions of proslaglandin E compounds in a pharmaceutically acceptable, stabilizing organic solvent, e.g., triacetin, gelled by the addition of colloidal silicon dioxide.
Description
~ ~8~)2~7~
DESCR I PTI ON
BACKGROUND OF THE IN~/ENTION
The present invention relates to novel compositions of matter and methods for using them as phanmaceutical agen~s. More particularly, the present invention relates to novel solutions of certain relatively unstable prostaglandins (prostaglandin E compounds), known to be useful for a wide variety of pharmacological purposes. Most particular~y, the present invention relates to gelled solutions of these E-type prostaglandins wherein the gelling agent is colloidal silicon di~xide and the solvent within which said prostaglandin E
compound is dissolved is an organic solvent9 especially triacetin.
Prostaglandins are a family of cyclopentan~containing fatty acids. Typically these cyclopentane derivatives contain two side chains atta~hed to adjacent positions of the cyclopentane ring (C-8 and C-12) in a trans configuration wi~h respect to one anotherr In the natur~l prostaglandins the side chain at C-8 is carboxyl-terminated, contains seven carbon atoms and is attached in the a-configurat~n when this side chain is drawn in the conventional manner. The C-12 side chain is ~-alkyl terminated, substitu~ed at C-15 by an ~hydroxyl group and attached in the ~ configuration. The carbon ato~s of the cyclopentane ring adjacent ~o the attachment of these side chains are substituted with oxygenated functional groups in the PGE ca~pounds. Specifically, in the naturally occurring PGE
cc~pounds ~he carboxyl-terminated side chain is attached to the cyclopentane ring at a position adjacen~ ~o an oxo group, while the position adjacent to the other side chain is substituted by an hydroxyl group. Hence, prostaglandin E2 can be represented by the structure o~ formula I in which carbon atom numbering is given. For a more complete description of the PGE compounds, refer to the definition of "prostaglandin like compounds of the PGE-type"
set forth in U.S. Patent 3,966,962. Accordingly, the PGE compounds, i.e., the ~-hydroxy ketone~, includes such substances as PGE2, PGE1, 15-methyl-PGE2, (15R)-l5-methyl-PGE2, 16,16-dimethyl-PGE2, 17-phenyl-18,19,20-trinor-PGE2, 16-phenoxy-17,18,19,2~tetr~nor-PGE2, 15-cyclohexyl-16,17,18,19,20-pentanor-PGE2, (11S),20-d~ethyl-PGE2, and the like.
The use of organic solvents, especially dry organic solvents, as `~ ~
7 ~
DESCR I PTI ON
BACKGROUND OF THE IN~/ENTION
The present invention relates to novel compositions of matter and methods for using them as phanmaceutical agen~s. More particularly, the present invention relates to novel solutions of certain relatively unstable prostaglandins (prostaglandin E compounds), known to be useful for a wide variety of pharmacological purposes. Most particular~y, the present invention relates to gelled solutions of these E-type prostaglandins wherein the gelling agent is colloidal silicon di~xide and the solvent within which said prostaglandin E
compound is dissolved is an organic solvent9 especially triacetin.
Prostaglandins are a family of cyclopentan~containing fatty acids. Typically these cyclopentane derivatives contain two side chains atta~hed to adjacent positions of the cyclopentane ring (C-8 and C-12) in a trans configuration wi~h respect to one anotherr In the natur~l prostaglandins the side chain at C-8 is carboxyl-terminated, contains seven carbon atoms and is attached in the a-configurat~n when this side chain is drawn in the conventional manner. The C-12 side chain is ~-alkyl terminated, substitu~ed at C-15 by an ~hydroxyl group and attached in the ~ configuration. The carbon ato~s of the cyclopentane ring adjacent ~o the attachment of these side chains are substituted with oxygenated functional groups in the PGE ca~pounds. Specifically, in the naturally occurring PGE
cc~pounds ~he carboxyl-terminated side chain is attached to the cyclopentane ring at a position adjacen~ ~o an oxo group, while the position adjacent to the other side chain is substituted by an hydroxyl group. Hence, prostaglandin E2 can be represented by the structure o~ formula I in which carbon atom numbering is given. For a more complete description of the PGE compounds, refer to the definition of "prostaglandin like compounds of the PGE-type"
set forth in U.S. Patent 3,966,962. Accordingly, the PGE compounds, i.e., the ~-hydroxy ketone~, includes such substances as PGE2, PGE1, 15-methyl-PGE2, (15R)-l5-methyl-PGE2, 16,16-dimethyl-PGE2, 17-phenyl-18,19,20-trinor-PGE2, 16-phenoxy-17,18,19,2~tetr~nor-PGE2, 15-cyclohexyl-16,17,18,19,20-pentanor-PGE2, (11S),20-d~ethyl-PGE2, and the like.
The use of organic solvents, especially dry organic solvents, as `~ ~
7 ~
-2- 4074 a means of stabilizing PGE compounds is likewise known in the art.
For example, U.S. Patent 3,966,962, referred to above, discloses the use of glyceryl triacetate or triacetin as a stabilizing solvent for PGE2 and similar PGE compounds.
Di polar aprotic sol vents such as N,N-dimethylacetamide (DMA), are also known stabilizers of PGE compounds. See U.S. Patent 3,829,579.
In addition to these organic solvents, other materials such as triethyl citrate have demonstrated an ability to stabilize PGE
compoundsO See U.S. Patent 4,211,793.
Protic organic solvents are also known stabilizers of PGE
compounds. In this regard, alcohols and glycols are known to be useful stabilizing solvents. See U.S. Patent 3,74g,800. See also U.S. Patent 3,927,197, describing tertiary alcohol stabilization of PGE com po unds.
In addition to the use of organic solvents for the stabilization of prostaglandins, further known in the art are hydrophylic gels~
especially starchy gels which stabilize PGE compounds embedded there within. In this regard, cyclodextrin clathrates, especially ~-cyclo-dextrin clathrates are known as stabilizers for PGE compounds. See U.S. Patent 3,816,393.
See also Calder, A.A. et al., "Ripening of a Cervix with Extra Amniotic Prostaglandin E2 in Viscous Gel Before Induction of Labor", British Journal of Obstetrics and Gynecology 84:264-268 (1977) which describes the use of hydroxyethyl methyl cellulose as a gelling agent for PGE2. Moreover the use of gelled cellulose as a stabilizing agent for PGE2 is described in Derwent Farmdoc CPI No. 91634B/51, abstracting Japanese Kokai 143,516, published 8 November 1979.
Besides starchy materials, polymeric materials have also been reported to be effective solid or gelled stabilizing agents for for example9 the use of polyvinyl pyrrolidone (PVP) to stabilize prostaglandin E compounds is reported in U.S. Patent 3,826,823. See also the use of polyethylene oxide cross linked with urethane group for prostaglandin formu1ation described in European published applications 16,652 and 1~,654~ Finally see also the carbohydrate polymer or cross linked carbohydrate polymers described in Derwent Farmdoc CPI No 43291C/25 abstracting Belgian Patent 881,351.
The use of colloidal silica dioxide as a gelling agent for organic so1vents is also known. See Eros, I., et al, "Applications of 0~
For example, U.S. Patent 3,966,962, referred to above, discloses the use of glyceryl triacetate or triacetin as a stabilizing solvent for PGE2 and similar PGE compounds.
Di polar aprotic sol vents such as N,N-dimethylacetamide (DMA), are also known stabilizers of PGE compounds. See U.S. Patent 3,829,579.
In addition to these organic solvents, other materials such as triethyl citrate have demonstrated an ability to stabilize PGE
compoundsO See U.S. Patent 4,211,793.
Protic organic solvents are also known stabilizers of PGE
compounds. In this regard, alcohols and glycols are known to be useful stabilizing solvents. See U.S. Patent 3,74g,800. See also U.S. Patent 3,927,197, describing tertiary alcohol stabilization of PGE com po unds.
In addition to the use of organic solvents for the stabilization of prostaglandins, further known in the art are hydrophylic gels~
especially starchy gels which stabilize PGE compounds embedded there within. In this regard, cyclodextrin clathrates, especially ~-cyclo-dextrin clathrates are known as stabilizers for PGE compounds. See U.S. Patent 3,816,393.
See also Calder, A.A. et al., "Ripening of a Cervix with Extra Amniotic Prostaglandin E2 in Viscous Gel Before Induction of Labor", British Journal of Obstetrics and Gynecology 84:264-268 (1977) which describes the use of hydroxyethyl methyl cellulose as a gelling agent for PGE2. Moreover the use of gelled cellulose as a stabilizing agent for PGE2 is described in Derwent Farmdoc CPI No. 91634B/51, abstracting Japanese Kokai 143,516, published 8 November 1979.
Besides starchy materials, polymeric materials have also been reported to be effective solid or gelled stabilizing agents for for example9 the use of polyvinyl pyrrolidone (PVP) to stabilize prostaglandin E compounds is reported in U.S. Patent 3,826,823. See also the use of polyethylene oxide cross linked with urethane group for prostaglandin formu1ation described in European published applications 16,652 and 1~,654~ Finally see also the carbohydrate polymer or cross linked carbohydrate polymers described in Derwent Farmdoc CPI No 43291C/25 abstracting Belgian Patent 881,351.
The use of colloidal silica dioxide as a gelling agent for organic so1vents is also known. See Eros, I., et al, "Applications of 0~
-3- 4074 Colloidal Silicon Dioxide in Pharmaceutical Technology, II, Gel-forming Properties of Aerosil", Gysgyszereszet 19(8), 290-5 (1975);
Chem. Abstracts 83:183331q (1975). In particular the use of colloidal silica dioxide with organic solvents for preparing gels containing pharmaceutically active materials is al so known. See Mo Sherriff and R.P. Enever, "Rheological and Drug Release Properties of Oil Gels Containing Coloidal Silicon Dioxide," J. Pharm. Sci., 68(7), 842-5 (1979).
PRIOR ART
A stable dosage form of a PGE compound in a pharmaceutically acceptablizing organic liquid is known. See U.S. Patent 3,966,962 describing the stabilization of various PGE compounds in a solution of triacetin. Utilization of gels, esp~cially hydrophylic gels, in the stabilization of PGE compounds is likewise known. See the reference cited above. Finally the use of colloidal silica dioxide as a gel forming additive to pharmaceutically acceptable stabilizing organic liquids is known. Moreover the application of such gels to the delivery of pharmaceuticals is known.
SU~IMARY OF THE INVENTION
The present invention particularly comprises:
In a stable dosage form of PGE compound consisting essentially o-f a sol ution of said PGE compound in a pharmaceutically acceptable stabilizing organic liquid, an improvement which comprises:
colloidal silicon dioxide (CSD) as a gel-forrning additive thereto in a concentration sufficient to inducP a free flowing gel.
The present invention further comprises an improvement wherein the pharmaceutically acceptable stabilizing organic solvent is a glycerol ester. More particularly, the present invention provides the improvement wherein the glycery1 ester is triacetin.
Further9 with respect to such a triacetin-based formulation the present invention further provides the improvement wherein the colloidal silicon dioxide percentage by weight in the stable dosage form is from about not less than 3 to about not more than 15 percent by weight. The preferred percentage ~y weight is about 8. Lesser percentages by weight result in gels of lesser viscosity which may not be sufficiently elegant in actual clinical application. Gels whose percentage o~ CSD by weight is greater than 8 are also useful but result in more viscous gels of reduced extendability. Since such gels 3, ~
Chem. Abstracts 83:183331q (1975). In particular the use of colloidal silica dioxide with organic solvents for preparing gels containing pharmaceutically active materials is al so known. See Mo Sherriff and R.P. Enever, "Rheological and Drug Release Properties of Oil Gels Containing Coloidal Silicon Dioxide," J. Pharm. Sci., 68(7), 842-5 (1979).
PRIOR ART
A stable dosage form of a PGE compound in a pharmaceutically acceptablizing organic liquid is known. See U.S. Patent 3,966,962 describing the stabilization of various PGE compounds in a solution of triacetin. Utilization of gels, esp~cially hydrophylic gels, in the stabilization of PGE compounds is likewise known. See the reference cited above. Finally the use of colloidal silica dioxide as a gel forming additive to pharmaceutically acceptable stabilizing organic liquids is known. Moreover the application of such gels to the delivery of pharmaceuticals is known.
SU~IMARY OF THE INVENTION
The present invention particularly comprises:
In a stable dosage form of PGE compound consisting essentially o-f a sol ution of said PGE compound in a pharmaceutically acceptable stabilizing organic liquid, an improvement which comprises:
colloidal silicon dioxide (CSD) as a gel-forrning additive thereto in a concentration sufficient to inducP a free flowing gel.
The present invention further comprises an improvement wherein the pharmaceutically acceptable stabilizing organic solvent is a glycerol ester. More particularly, the present invention provides the improvement wherein the glycery1 ester is triacetin.
Further9 with respect to such a triacetin-based formulation the present invention further provides the improvement wherein the colloidal silicon dioxide percentage by weight in the stable dosage form is from about not less than 3 to about not more than 15 percent by weight. The preferred percentage ~y weight is about 8. Lesser percentages by weight result in gels of lesser viscosity which may not be sufficiently elegant in actual clinical application. Gels whose percentage o~ CSD by weight is greater than 8 are also useful but result in more viscous gels of reduced extendability. Since such gels 3, ~
-4- 4074 tend to increase in viscosity upon storage, percentages greater than 8 are especially useful when gels are to be used prcmptly following fonmulation.
The stable dosage forms provided in accordance with the present invention are used -for the same purposes and by the same method as the prior art PG~ compounds in a pharmaceutically acceptable stabilizing organic solvent with the difference that the presen~ forms are rendered more adaptable for formul~tion and use by virtue of being in the gel form. Accordingly, dosage forms in accordance with the present invention are used for various purposes described in u.S~ Patent 3,966,962. However, the present gel com-position are ~articularly advantageous in that these materials are more readily handled and formulated than liquids~
Moreover, for example, when used for intravaginal, transcervical or intracervica7, or extraamniotic injection, the gel is prepared under sterile conditions and administered via syringe. Advantageously, the present invention provides gels whose physical characteristics and ambient temperature permit free and unobstructed flow when so administered.
More particularly, the present invention provides a highly advantageous method of effecting cervical ripening utilizing extraamniotic administration of PGE2 in a viscous gel. The methodology of employing PGE2 in such viscous gels for extraamniotic cerYical ripening is described in Calder~ A.A., et al.~ British Journal of Obstetrics and Gynecology 84:264-268 (1977), cited above.
Unlike prior art gels which required reconstitution prior to use~
the present invention provides stabi1ized gels which can be manufactured under sterile conditions, packaged and distributed to hospitals or other users without the need for reconstitution, i.e~, the addition of water, prior to use. Particularly, prostaglandin E2 prepared in the novel dosage form of the present invention can exhibit a prolonged shelf-life, i.e., greater than one year, during storage at ambient temperatureO Further, unlike hydrophilic gels of the prior art the present qels can maintain the physical integrity of the gel more completely upon administration and therefore, unlike these prior art gels, be withdrawn if necessary from the patient following extraamniotic, transcerYical application.
In preparing the gels of the present invention, the PGE compound 3:~ ~ 0 2l7 ~
The stable dosage forms provided in accordance with the present invention are used -for the same purposes and by the same method as the prior art PG~ compounds in a pharmaceutically acceptable stabilizing organic solvent with the difference that the presen~ forms are rendered more adaptable for formul~tion and use by virtue of being in the gel form. Accordingly, dosage forms in accordance with the present invention are used for various purposes described in u.S~ Patent 3,966,962. However, the present gel com-position are ~articularly advantageous in that these materials are more readily handled and formulated than liquids~
Moreover, for example, when used for intravaginal, transcervical or intracervica7, or extraamniotic injection, the gel is prepared under sterile conditions and administered via syringe. Advantageously, the present invention provides gels whose physical characteristics and ambient temperature permit free and unobstructed flow when so administered.
More particularly, the present invention provides a highly advantageous method of effecting cervical ripening utilizing extraamniotic administration of PGE2 in a viscous gel. The methodology of employing PGE2 in such viscous gels for extraamniotic cerYical ripening is described in Calder~ A.A., et al.~ British Journal of Obstetrics and Gynecology 84:264-268 (1977), cited above.
Unlike prior art gels which required reconstitution prior to use~
the present invention provides stabi1ized gels which can be manufactured under sterile conditions, packaged and distributed to hospitals or other users without the need for reconstitution, i.e~, the addition of water, prior to use. Particularly, prostaglandin E2 prepared in the novel dosage form of the present invention can exhibit a prolonged shelf-life, i.e., greater than one year, during storage at ambient temperatureO Further, unlike hydrophilic gels of the prior art the present qels can maintain the physical integrity of the gel more completely upon administration and therefore, unlike these prior art gels, be withdrawn if necessary from the patient following extraamniotic, transcerYical application.
In preparing the gels of the present invention, the PGE compound 3:~ ~ 0 2l7 ~
-5- ~074 is first dissolved in the selected organic solvent by conventional means. For example, the dissolution of PGE2 and triacetin can be readi1y achieved using a mixer fitted with a sma11 disintegrating head. During the mixing process, which usually runs to completion over the course of several minutes, cooling may be required in order to prevent heat generated by the mixing process from decomposing the PGE2 .
Thereafter the colloidal silicon dioxide is incorporated into the resulting solution by combining these two ingredients in a single vessel and mixing with a stirrer. Gelling under these conditions is ordinarily effected over the course of several minutes~
The preparation of sterile product can be accomplished by an ultrafiltration of the PGE compound in the organic solvent into a sterile area. Subsequently the colloidal silica dioxide can be heat sterilized and incorporated into the sterilized PGE conpound solution~
In accordance with the present invention9 pharmaceutical grades of both ~he organic solvent and col10idal si1icon dioxide must be selected. For example, when triace~in is the selected organic solvent, USP or food grade quality material, particularly material known to be low in heavy metal compound content3 is readily employed.
Moreover, employing triacetin low in metal ion content results in improved stability of the resulting PGE gel 7 Similarly9 colloidal silica dioxide is available as a pharmaceutical grade materia'. For examplel Ca~ot Corporation ma~^kets CAB-0-SIL M5 colloidal silica dioxide, a material used in oral pharmaceutical formulations o~ prostaglandin Ez (PROSTI1~2 compressed tablets, Upjohn). Similarly AEROSIL 200 and AEROSIL FK 320 are similar grades of colloidal silicon dioxide marketed by Degussa.
Since some organic solvents are incompatible with the use of plastic packaging material, e.g., polypropylene syringes, ordinarily a glass syringe is employed and a preselected amount of the gel placed there within. However, when triacetin is employed as the organic solvent, the preferred syringe is a plastic syringe, e.gO, polypropylene or high density polyethylene. The use of such plastic syringes is preferred in order to avoid the leaching of impurities into the formulation from the rubber-containing parts of glass syringes.
Alternatively, conventional gelatin capsules may be utilized in *trade mark ~. :18(~2 ~
Thereafter the colloidal silicon dioxide is incorporated into the resulting solution by combining these two ingredients in a single vessel and mixing with a stirrer. Gelling under these conditions is ordinarily effected over the course of several minutes~
The preparation of sterile product can be accomplished by an ultrafiltration of the PGE compound in the organic solvent into a sterile area. Subsequently the colloidal silica dioxide can be heat sterilized and incorporated into the sterilized PGE conpound solution~
In accordance with the present invention9 pharmaceutical grades of both ~he organic solvent and col10idal si1icon dioxide must be selected. For example, when triace~in is the selected organic solvent, USP or food grade quality material, particularly material known to be low in heavy metal compound content3 is readily employed.
Moreover, employing triacetin low in metal ion content results in improved stability of the resulting PGE gel 7 Similarly9 colloidal silica dioxide is available as a pharmaceutical grade materia'. For examplel Ca~ot Corporation ma~^kets CAB-0-SIL M5 colloidal silica dioxide, a material used in oral pharmaceutical formulations o~ prostaglandin Ez (PROSTI1~2 compressed tablets, Upjohn). Similarly AEROSIL 200 and AEROSIL FK 320 are similar grades of colloidal silicon dioxide marketed by Degussa.
Since some organic solvents are incompatible with the use of plastic packaging material, e.g., polypropylene syringes, ordinarily a glass syringe is employed and a preselected amount of the gel placed there within. However, when triacetin is employed as the organic solvent, the preferred syringe is a plastic syringe, e.gO, polypropylene or high density polyethylene. The use of such plastic syringes is preferred in order to avoid the leaching of impurities into the formulation from the rubber-containing parts of glass syringes.
Alternatively, conventional gelatin capsules may be utilized in *trade mark ~. :18(~2 ~
-6- 4074 formulating these gels into their finished pharmaceutic~l form. For example hard gelatin capsules are especially useful.
The pharmaceutically acceptable stabilizing organic liquid or solvents utilized in accordance with the present invention are those which are relatively non-toxic and norrirritant to body tissues which they contact and those having a capacity to stabilize PGE compounds when placed in solution therewith. One especially use~ul group of materials for this purpose are glyceryl esters~ Such compounds are either mono-, bis-, or tris- esters of glycerol and are known in the art and prepared by methods readily known in the art. For example, triacetin is one such substance. Dipolar aprotic solvents, such as DMA referred to above, are also useful liquids for this purpose.
Similarly, other polyo1 esters such as triethyl citrate are known to be useful in pharmaceutically acceptable stabilizing organic liquids for use in accordance in the present invention.
Alcohols represent another, although less preferred pharmaceu-tically acceptable stabilizing organic liquid inasmuch as the lower polyols, such as ethanol, are subject to evaporative loss of volume thereby complicating unnecessarily formulation of the resulting gel.
Accordingly, useful pharmaceutically acceptable stabilizing organic liquids or solvents utilized in accordance with the present invention include numerous known organic solvents for the stabilization of prostaglandin all of the following chemical compounds.
The stabilizing liquid to be employed in the present invention must also be pharmaceutically acceptable in the sense that the quantities employed must be essentially non-toxic and well tolerated by the animal or patient being treated. The examples above describe such liquids. Organic solvents such as benzene are, for example, unsuitable for reasons of toxicity.
The amount of colloidal silica dioxide employed in any gel depends on the nature of the organic liquid employed. However, in genera1, the minimum amount of colloidal silicon dioxide necessary is that required to give necessary minimum viscosity to the selected liquid. Ordinarily, gels are preferred which are sufficiently viscous 3~ to remain in place when administered. Similarly, the maximum percen~
tage by weight of colloidal silicon dioxide desired is that which defines the maximum desired viscosity of the gel and ordinarily limited by the ability of the gel to be extruded through syringes, 2 ~ ~i
The pharmaceutically acceptable stabilizing organic liquid or solvents utilized in accordance with the present invention are those which are relatively non-toxic and norrirritant to body tissues which they contact and those having a capacity to stabilize PGE compounds when placed in solution therewith. One especially use~ul group of materials for this purpose are glyceryl esters~ Such compounds are either mono-, bis-, or tris- esters of glycerol and are known in the art and prepared by methods readily known in the art. For example, triacetin is one such substance. Dipolar aprotic solvents, such as DMA referred to above, are also useful liquids for this purpose.
Similarly, other polyo1 esters such as triethyl citrate are known to be useful in pharmaceutically acceptable stabilizing organic liquids for use in accordance in the present invention.
Alcohols represent another, although less preferred pharmaceu-tically acceptable stabilizing organic liquid inasmuch as the lower polyols, such as ethanol, are subject to evaporative loss of volume thereby complicating unnecessarily formulation of the resulting gel.
Accordingly, useful pharmaceutically acceptable stabilizing organic liquids or solvents utilized in accordance with the present invention include numerous known organic solvents for the stabilization of prostaglandin all of the following chemical compounds.
The stabilizing liquid to be employed in the present invention must also be pharmaceutically acceptable in the sense that the quantities employed must be essentially non-toxic and well tolerated by the animal or patient being treated. The examples above describe such liquids. Organic solvents such as benzene are, for example, unsuitable for reasons of toxicity.
The amount of colloidal silica dioxide employed in any gel depends on the nature of the organic liquid employed. However, in genera1, the minimum amount of colloidal silicon dioxide necessary is that required to give necessary minimum viscosity to the selected liquid. Ordinarily, gels are preferred which are sufficiently viscous 3~ to remain in place when administered. Similarly, the maximum percen~
tage by weight of colloidal silicon dioxide desired is that which defines the maximum desired viscosity of the gel and ordinarily limited by the ability of the gel to be extruded through syringes, 2 ~ ~i
-7- 4074 catheters and the like. Accordingly a fairly narrow range of values for the percent by weight of silicon dioxide of the weight of the final gel is employed. For example, when triacetin is the pharma-ceutically acceptable stabilizing organic solvent, the preferred range for the colloidal silicon dioxide is 3-15% by weight of the resulting gel.
DESCRIPTION OF THE PREFERRED_E~BODIMENTS
The operation of the present invention is more completely understood by the following example.
Example 1 Colloidal silicon dioxide gel solution of PGE2 in triacetin Gels are prepared with between Od25 mg and 3.0 mg of PGE2 per 3 9 or 2.5 ml of gel. The following ingredients are used:
(a) PGE2 (dinoprostone PROSTIN E2, Upjohn) 0.25 mg-3.0 mg.
(b) colloidal silicon dioxide NF 200 mg - 300 mg.
(c) triacetin USP 2.7 9 -2.8 g.
PGE2 is dissolved in triacetin using a Silverson mixer fitted with a 1/2 inch disintegrating head. After mixing for 15 min using an ice bath to prevent heat disintegration of PGE2, colloidal silicon dioxide is then incorporated into the PGE2 solution until the desired - viscosity is obtained by mixing the PGE2/triacetin solution with the appropriate amount of silicon dioxide until the mixture is gelled, i~e., about 2 min. The gel thusly obtained is then packed in a 5 ml Hytac SCF glass syringe (Becton Dickinson) which had been washed, silicized, and sterilized~ Preferred, however, is the 5 ml Pharma-Plant polypropylene syringe which has been sterlized by exposure to ethylene oxidea Alternatively the gel is filled into an appropriately sized empty gelatin capsules.
30~76~
DESCRIPTION OF THE PREFERRED_E~BODIMENTS
The operation of the present invention is more completely understood by the following example.
Example 1 Colloidal silicon dioxide gel solution of PGE2 in triacetin Gels are prepared with between Od25 mg and 3.0 mg of PGE2 per 3 9 or 2.5 ml of gel. The following ingredients are used:
(a) PGE2 (dinoprostone PROSTIN E2, Upjohn) 0.25 mg-3.0 mg.
(b) colloidal silicon dioxide NF 200 mg - 300 mg.
(c) triacetin USP 2.7 9 -2.8 g.
PGE2 is dissolved in triacetin using a Silverson mixer fitted with a 1/2 inch disintegrating head. After mixing for 15 min using an ice bath to prevent heat disintegration of PGE2, colloidal silicon dioxide is then incorporated into the PGE2 solution until the desired - viscosity is obtained by mixing the PGE2/triacetin solution with the appropriate amount of silicon dioxide until the mixture is gelled, i~e., about 2 min. The gel thusly obtained is then packed in a 5 ml Hytac SCF glass syringe (Becton Dickinson) which had been washed, silicized, and sterilized~ Preferred, however, is the 5 ml Pharma-Plant polypropylene syringe which has been sterlized by exposure to ethylene oxidea Alternatively the gel is filled into an appropriately sized empty gelatin capsules.
30~76~
-8- 4074 F0 R~J LA
S ~
,~ ~ COOH
~ ~o ,-HO OH
~5
S ~
,~ ~ COOH
~ ~o ,-HO OH
~5
Claims (10)
1. In a stable dosage form of PGE-compound consisting essentially of a solution of said PGE compound in a pharmaceutically acceptable stabilizing organic liquid, an improvement which comprises:
colloidal silicon dioxide (CSD) as a gel-forming additive thereto in a concentration sufficient to induce a free flowing gel.
colloidal silicon dioxide (CSD) as a gel-forming additive thereto in a concentration sufficient to induce a free flowing gel.
2. An improvement according to claim 1 wherein said pharmaceutically acceptable, stabilizing organic solvent is a glyceryl ester.
3. An improvement according to claim 2 wherein said glyceryl ester is triacetin.
4. An improvement according to claim 3 wherein percentage by weight of CSD in said stable dosage form by weight is from about not less than 8 to about not more than 15.
5. An improvement according to claim 4 wherein said PGE compound is PGE2.
6. An improvement according to claim 4 wherein said PGE compound is (15R)-15-methyl-PGE2.
7. An improvement according to claim 4 wherein said PGE compound is 6,16-dimethyl-PGE2.
8. An improvement according to claim 4 wherein said PGE compound is (175),20-dimethyl-PGE2.
9. An improvement according to claim 4 wherein said PGE compound is 15-methyl-PGE2.
10. An improvement according to claim 4 wherein said PGE compound is PGE1.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB8203322A GB2096298B (en) | 1981-02-09 | 1982-02-05 | Refrigerator or cooler cabinets suitable for use on railroad trains |
GB8,203,322 | 1982-03-22 |
Publications (1)
Publication Number | Publication Date |
---|---|
CA1180276A true CA1180276A (en) | 1985-01-02 |
Family
ID=10528130
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA000421153A Expired CA1180276A (en) | 1982-02-05 | 1983-02-08 | Gelled pge.sub.2/triacetin solutions |
Country Status (1)
Country | Link |
---|---|
CA (1) | CA1180276A (en) |
-
1983
- 1983-02-08 CA CA000421153A patent/CA1180276A/en not_active Expired
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US4680312A (en) | Stable prostaglandin E gels utilizing colloidal silicon dioxide as a gel-forming agent | |
CA1302890C (en) | Stable ophthalmic preparations containing acetazolamide | |
US5192802A (en) | Bioadhesive pharmaceutical carrier | |
JP3678745B2 (en) | Gelatin capsule containing high concentration acetaminophen solution | |
CA1287580C (en) | Pharmaceutical preparation for obtaining a highly viscose hydrogel or suspension | |
US2703777A (en) | Ophthalmological preparations and vehicles and method of making the same | |
KR100634571B1 (en) | Process for preparing pharmaceutical compositions for use with soft gelatin formulations | |
EP0390369A2 (en) | Orally administrable ibuprofen compositions | |
HU213511B (en) | Process for producing pharmaceutical composition containing megestrol acetate | |
DE60215129T3 (en) | ESMOLOL-CONTAINING PREPARATIONS | |
DE2611183C2 (en) | Stabilized formulation of PGE-type prostaglandin-like drugs | |
US2701782A (en) | Method of making and aqueous suspension of methyl cellulose | |
CA1180276A (en) | Gelled pge.sub.2/triacetin solutions | |
CA1249223A (en) | Solid drug formulations and stable suspensions | |
JPH09509186A (en) | Fine particles containing gas, drug containing fine particles, use of drug in ultrasonic diagnosis, and method for producing particles and drug | |
EP0531529A1 (en) | Process for preparing aqueous suspension | |
US4032645A (en) | Injectable metronidazole composition | |
HU179989B (en) | Process for preparing pharmacological compositions containing r-/+/-1-/1-phenyl-ethyl/-1h-imidazol-5-carboxylic acid ethyl ester for intravenous administration | |
JPS59131684A (en) | Gel composition and manufacture of same at environmental temperature | |
US4948591A (en) | Soft capsular preparation of sodium picosulfate | |
HU228857B1 (en) | Stable formulation containing fumagillin | |
JPS58121210A (en) | Manufacture of instantaneous mouth discharging sublingual soft capsule medicine | |
KR0137647B1 (en) | Pharmaceutical composition for ophthalmic use comprising a water soluble acid addition salt of ibopamine | |
JPH0611696B2 (en) | Gelatin film composition | |
KR100201907B1 (en) | A softcapsule containing biphenyldimethyldicarboxylate (pmc) solution |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
MKEC | Expiry (correction) | ||
MKEX | Expiry |