CA1090255A - Stabilized compositions containing a prostaglandin e - Google Patents
Stabilized compositions containing a prostaglandin eInfo
- Publication number
- CA1090255A CA1090255A CA303,253A CA303253A CA1090255A CA 1090255 A CA1090255 A CA 1090255A CA 303253 A CA303253 A CA 303253A CA 1090255 A CA1090255 A CA 1090255A
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- Prior art keywords
- glycol
- prostaglandin
- monoester
- cis
- lower alkyl
- Prior art date
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-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
ABSTRACT
A solution containing one or more prostaglandins E, useful for therapeutic purposes, is stabilized by using as the solvent an alkylene glycol or a monoester thereof.
A solution containing one or more prostaglandins E, useful for therapeutic purposes, is stabilized by using as the solvent an alkylene glycol or a monoester thereof.
Description
s~
The present invention relates to a stabili~ed solution of one or more prostaglandins E.
The prostaglandins are a family of biologically potent lipid acids. The prostaglandins are divided into the types E, F, A, B, C and D based on ~unctions in the cyclopentane ring.
The present invention is concerned with the group of compounds known as prostaglandins E (hereinafter abbreviated as "PGE").
The prostaglandins, even when employed in very small amounts, are known to possess a wide range of pharmacological activity.
The E series of prostaglandins are known to exert both a vasodilating action and a bronchodilating action. The 20-isopropylidene derivative of prostaglandin E2 (PGE2) has been found to have only a bronchodilating activity without any other pharmacological activity and is thus ideally suited for medical use, as described in Belgian Patent Specification No. 833,577.
~owever, this derivative, like other prostaglandins E, has a problem of stability which has not yet been solved.
In general, it has been found that solutions of PGE
in most solvents lose a substantial proportion of their 1~3~3f. 9~3 pharmacological activity within a very short time, even at relatively low temperatures. For example, it has been reported that the activity of a physiological saline solution of PGEl or PGE2 is reduced to 58-62% of its original value within 15 days at 4C [Srivastava et al, Lipids, Volume 8, 592 (1973)]. It has also been reported that an ethanolic solution of PGE is unstable under the conditions in which it would normally be used and thus not only has to be stored at a temperature from -15C to -20C
but also has to be used within six months or, at most, one year of its preparation [J. Pharm. Pharmacol., Volume 23, 804 (1971);
and Am. J. Hosp. Pharm. Volume 30, 236 ~1973)].
A multitude of different types of solvent has been proposed to overcome this stability problem. Examples of the solvents proposed include: tertiary alcohols having from 4 to 10 carbon atoms, e.g. t-butanol, as described in Japanese Patent Provisional Publication No. 145515/75; vegetable oils and or acid esters, e.g. sesame oil, peanut oil, ethyl oleate or ethyl carbonate, as described in Japanese Patent Provisional Publication No. 105815/75; anhydrous but water-miscible non-protonic polar organic ; ~ 30
The present invention relates to a stabili~ed solution of one or more prostaglandins E.
The prostaglandins are a family of biologically potent lipid acids. The prostaglandins are divided into the types E, F, A, B, C and D based on ~unctions in the cyclopentane ring.
The present invention is concerned with the group of compounds known as prostaglandins E (hereinafter abbreviated as "PGE").
The prostaglandins, even when employed in very small amounts, are known to possess a wide range of pharmacological activity.
The E series of prostaglandins are known to exert both a vasodilating action and a bronchodilating action. The 20-isopropylidene derivative of prostaglandin E2 (PGE2) has been found to have only a bronchodilating activity without any other pharmacological activity and is thus ideally suited for medical use, as described in Belgian Patent Specification No. 833,577.
~owever, this derivative, like other prostaglandins E, has a problem of stability which has not yet been solved.
In general, it has been found that solutions of PGE
in most solvents lose a substantial proportion of their 1~3~3f. 9~3 pharmacological activity within a very short time, even at relatively low temperatures. For example, it has been reported that the activity of a physiological saline solution of PGEl or PGE2 is reduced to 58-62% of its original value within 15 days at 4C [Srivastava et al, Lipids, Volume 8, 592 (1973)]. It has also been reported that an ethanolic solution of PGE is unstable under the conditions in which it would normally be used and thus not only has to be stored at a temperature from -15C to -20C
but also has to be used within six months or, at most, one year of its preparation [J. Pharm. Pharmacol., Volume 23, 804 (1971);
and Am. J. Hosp. Pharm. Volume 30, 236 ~1973)].
A multitude of different types of solvent has been proposed to overcome this stability problem. Examples of the solvents proposed include: tertiary alcohols having from 4 to 10 carbon atoms, e.g. t-butanol, as described in Japanese Patent Provisional Publication No. 145515/75; vegetable oils and or acid esters, e.g. sesame oil, peanut oil, ethyl oleate or ethyl carbonate, as described in Japanese Patent Provisional Publication No. 105815/75; anhydrous but water-miscible non-protonic polar organic ; ~ 30
-2-SS
solvents, e.g. tetramethylurea, dimethyl sulphoxide, diisopropyl ketone, acetone or dimethylacetamide, as described in Belgian Patent Specification No. 790,840; and organic acid esters, e.g.
ethyl acetate, ethyl propionate or isopropyl myristate, as described in Japanese Patent Provisional Publication No. 88054/75.
Elowever, most of these solvents are physiologically unacceptable when administered directly to a living human body and none has, as yet, been used in practice. Moreover, the improvement in stability has not generally been of such a level that PGE can be stored without difficulty.
We have now surprisingly discovered that a specific class of solvents will dissolve the prostaglandins E and that the resulting solutions will retain their pharmacological activity for a considerable period of time, the improvement in stability being far greater than that achievable with prior art solvents. The class of solvents discovered by the present invention are the alkylene glycols and their monoesters.
Thus, the present invention provides a pharma-~0 ceutical composition comprising a PGE dissolved in an alkyleneglycol or a monoester thereof and also provides a method of producing such a composition by forming a solution of the PGE
in the alkylene glycol or monoester.
Although we do not wish to be limited by any theory and although, in any solution, interactions between solvent and solute are generally so complex as to defy precise analysis, we believe that the reason why the alkylene glycols and monoesters thereof provide a stable solution of PGE is as follows:
It is known that prostaglandins E tend to convert to the corresponding prostaglandin A by elimination of the hydroxy group on the five-membered ring; this is caused by the electron-attractive effect of the carbonyl group at the 9-position. The resulting prostaglandin ~ then tends to isomerize to the corresponding prostaglandin B. This process is illustrated by the following reaction scheme, in which the compound of formula (I) is PGE2 or a derivakive thereof, compound (II) is PGA2 or a derivative thereof, compound (III) is PGB2 or a derivative thereof and R represents a substituent.
. .
O
~'C~H " ~\~O~
~R ~\/
~1~ 0~
Il) 11~) OOH
1~1) ' The nature of the solvent in which the PGE is dissolved influences the hydroxy group elimination reaction;
protonic solvents tend to promote it. Thus, the ll-hydroxy group (in the 5- membered ring) of a PGE is easily eliminated in a protonic solvent; this is probably due to an intermolecular hydrogen bond formed between the 9- carbonyl group and the s.olvent. Accordingly, the elimination reaction is probably promoted by solvents having a large proton donating capacity, e.g. methanol or ethanol. It is believed that the alkylene glycols and their monoesters have limited proton donating capacity and, for this reason, do not promote the hydroxy group elimination reaction and thus provide solutions of improved stability.
Examples of prostaglandins E which can be stabilized by the method of the present invention include PGEl, PGE2 and derivatives thereof, including the corresponding ll-deoxy derivatives. Of these compounds, the invention may most usefully be applied to prostaglandins of general formula (IV):
O ' , ' .' )4\A~\r~oQR2 q3 ~ 1~ (IV) nH Q~ Rl [in which: A represents an ethylene group or a c -vinylene group; Rl and R2 are the same or different and each represents a hydrogen atom or a lower alkyl group, preferably having from 1 to 3 carbon atoms (e.g. methyl, ethyl, n-propyl or isopropyl);
and R3 and R4 are the same or different and each represents a lower alkyl group, preferably having from 1 to 3 carbon atoms (e.g. methyl, ethyl, n-propyl or isopropyl)] and the corresponding ll-deoxy derivatives, which have the general formula (V):
O
~)~A--G~ R~ (V) \~ R~
(in which A, Rl, R , R and R4 are as defined above).
Examples of compounds of the above formulae are as follows:
1. 9-Oxo-lla,15~(or~ dihydroxy-20-isopropylidene-; prost-13(trans)-enoic acid and its methyl, ethyl, n-propyl and isopropyl esters;
2. 9-Oxo-11~,15a(or~)-di.hydroxy-20-isopropylidene-prost-5(cls), 13(trans)-dienoic acid and its methyl, ethyl, n-propyl and isopropyl esters;
solvents, e.g. tetramethylurea, dimethyl sulphoxide, diisopropyl ketone, acetone or dimethylacetamide, as described in Belgian Patent Specification No. 790,840; and organic acid esters, e.g.
ethyl acetate, ethyl propionate or isopropyl myristate, as described in Japanese Patent Provisional Publication No. 88054/75.
Elowever, most of these solvents are physiologically unacceptable when administered directly to a living human body and none has, as yet, been used in practice. Moreover, the improvement in stability has not generally been of such a level that PGE can be stored without difficulty.
We have now surprisingly discovered that a specific class of solvents will dissolve the prostaglandins E and that the resulting solutions will retain their pharmacological activity for a considerable period of time, the improvement in stability being far greater than that achievable with prior art solvents. The class of solvents discovered by the present invention are the alkylene glycols and their monoesters.
Thus, the present invention provides a pharma-~0 ceutical composition comprising a PGE dissolved in an alkyleneglycol or a monoester thereof and also provides a method of producing such a composition by forming a solution of the PGE
in the alkylene glycol or monoester.
Although we do not wish to be limited by any theory and although, in any solution, interactions between solvent and solute are generally so complex as to defy precise analysis, we believe that the reason why the alkylene glycols and monoesters thereof provide a stable solution of PGE is as follows:
It is known that prostaglandins E tend to convert to the corresponding prostaglandin A by elimination of the hydroxy group on the five-membered ring; this is caused by the electron-attractive effect of the carbonyl group at the 9-position. The resulting prostaglandin ~ then tends to isomerize to the corresponding prostaglandin B. This process is illustrated by the following reaction scheme, in which the compound of formula (I) is PGE2 or a derivakive thereof, compound (II) is PGA2 or a derivative thereof, compound (III) is PGB2 or a derivative thereof and R represents a substituent.
. .
O
~'C~H " ~\~O~
~R ~\/
~1~ 0~
Il) 11~) OOH
1~1) ' The nature of the solvent in which the PGE is dissolved influences the hydroxy group elimination reaction;
protonic solvents tend to promote it. Thus, the ll-hydroxy group (in the 5- membered ring) of a PGE is easily eliminated in a protonic solvent; this is probably due to an intermolecular hydrogen bond formed between the 9- carbonyl group and the s.olvent. Accordingly, the elimination reaction is probably promoted by solvents having a large proton donating capacity, e.g. methanol or ethanol. It is believed that the alkylene glycols and their monoesters have limited proton donating capacity and, for this reason, do not promote the hydroxy group elimination reaction and thus provide solutions of improved stability.
Examples of prostaglandins E which can be stabilized by the method of the present invention include PGEl, PGE2 and derivatives thereof, including the corresponding ll-deoxy derivatives. Of these compounds, the invention may most usefully be applied to prostaglandins of general formula (IV):
O ' , ' .' )4\A~\r~oQR2 q3 ~ 1~ (IV) nH Q~ Rl [in which: A represents an ethylene group or a c -vinylene group; Rl and R2 are the same or different and each represents a hydrogen atom or a lower alkyl group, preferably having from 1 to 3 carbon atoms (e.g. methyl, ethyl, n-propyl or isopropyl);
and R3 and R4 are the same or different and each represents a lower alkyl group, preferably having from 1 to 3 carbon atoms (e.g. methyl, ethyl, n-propyl or isopropyl)] and the corresponding ll-deoxy derivatives, which have the general formula (V):
O
~)~A--G~ R~ (V) \~ R~
(in which A, Rl, R , R and R4 are as defined above).
Examples of compounds of the above formulae are as follows:
1. 9-Oxo-lla,15~(or~ dihydroxy-20-isopropylidene-; prost-13(trans)-enoic acid and its methyl, ethyl, n-propyl and isopropyl esters;
2. 9-Oxo-11~,15a(or~)-di.hydroxy-20-isopropylidene-prost-5(cls), 13(trans)-dienoic acid and its methyl, ethyl, n-propyl and isopropyl esters;
3. 9-Oxo-11~,15~(or~)-dihydroxy-17~-methyl-20-iso-propylideneprost-13(trans)-enoic acid and its methyl ethyl, n-propyl and isopropyl esters;
~ 4. 9-0~o-11~,15~(or~)-dihydroxy-17~-methyl-20-iso-; propylideneprost-5(cis),13(trans)-dienoic acid and its methyl, ethyl, n-propyl and isopropyl esters;
5. 9-Oxo-11~,15~(or~)-dihydroxy-17~-methyl-20-(1- -methylisopropylidenelprost-13(trans)-enoic acid and its methyl, ethyl, n-propyl and isopropyl esters;
s 6. 9-Oxo~ , 15~(or ~)-dihydroxy-17~-methyl-20-(1-methylisopropylidene)prost-5(cis), 13(trans)-dienoic acid and its methyl, ethyl, n-propyl and isopropyl esters;
7. 9-Oxo-lla, 15a~or ~)-dihydroxy-17~-methyl-20-(1,3-dimethylisopropylidene)prost-13(trans)-enoic acid and its methyl, ethyl, n-propyl and isopropyl estersi ; ' 8. 9-Oxo-lla, 15a(or ~)-dihydroxy-17~-methyl-20-(1,3-dimethylisopropylidene)prost-5(cis), 13(trans)-dienoic acid and its methyl, ethyl, n-propyl and isopropyl esters;
9. 9-Oxo-lla,15a(or ~)-dihydroxy-20-(1-methylisopropyl-idene)prost-13(transl-enoic acid and its methyl, ethyl, n -propyl and isopropyl esters;
10. 9-oxo-Ila, 15a(or ~)-dihydroxy-20-(1-methylisopropyl-idene)prost-5-(cis), 13(trans)-dienoic acid and its .: methyl, ethyl, n-propyl and isopropyl esters;
.
. ~ 11. 9-Oxo-lla~15a(or ~)-dihydroxy-20-(1,3-dimethyliso-propylidene)prost-13(trans)-enoic acid and its methyl, ethyl, n-propyl and isopropyl esters;
12. 9-Oxo-lla, 15~(or ~)-dihydroxy-20-(1,3-dimethyl-isopropylidene)prost~5(cls), 13(trans)-dienoic acid and its methyl, ethyl, n-propyl and isopropyl esters;
13~ 9-Oxo-15~(or ~)-hydroxy-20-isopropylideneprost-13(trans)-enoic acid and its methyl, ethyl, n-propyl and isopropyl esters;
14. 9-Oxo 15~(or ~)-hydroxy-17~-methyl-20-isopropyl-ideneprost-13(trans)-enoic acid and its methyl, ethyl, n-propyl and isopropyl esters;
15. 9-Oxo-15a(or ~)-hydroxy-20-isopropylideneprost-5-(cis), 13(trans)-dienoic acid and its methyl, ethyl, n-propyl and isopropyl esters; and 16. 9-Oxo-15~(or ~)-hydroxy~17~-methyl-20-isopropyl-ideneprost-5-(cls), 13(trans)-dienoic acid and its methyl, ethyl, n-propyl and isopropyl esters.
Of these compounds, we particularly prefer 9-oxo-lla, 15~-dihydroxy-20-isopropylideneprost-5(cis), 13(trans)-dienoic 2~i~
acid, otherwise known as 20-isopropylidene-PGE2, which has the formula (VI):
h ~ ~aH ~ (VI) Q~ .
The solvent employed in the present-invention is an alkylene glycol or monoester thereof. Examples of suitable alkylene glycols include: ethylene glycol; diethylene glycol;
triethylene glycol; propylene glycol; dipropylene glycol; 1,3-butanediol; 2,3-butanediol; 2,4-pentanediol; hexylene glycol;
2,5-hexanediol; 2,4-heptanediol; polyethylene glycols 200, 300, 400, 600, 1000, 2000, 4000 and 6000; and polypropylene glycols 200, 300, 400, 750, 1200, 2000 and 4000. The monoester employed is preferably an ester of any of the above-mentioned alkylene glycols with a lower aliphatic acid, for example ethylene glycol ~; monoacetate or propylene glycol monoacetate. It is also possible to use block copolymers of the above - listed polyethylene glycols and polypropylene glycols.
Any of these alkylene glycols and monoesters may be employed by itself or a mixture of any two or more may be used.
s~
of the alkylene glycols and monoesters exemplified above, we particularly prefer propylene glycol and polyethylene glycols 200, 300 and 400; these compounds form solutions easily and have good physiological tolerances.
Some of the alkylene glycols and monoesters thereof which may be used in the present invention are liquids at normal temperatures, whereas others are solids. Where the alkylene glycol or monoester is a liquid at ordinary temperatures, the solution of the present invention can easily be formed by dis-solving ~he PGE in it in the same way as any other solid is dissolved in a liquid which is a solvent for it. Where the alkylene glycol or monoester thereof is solid at ordinary temperatures, the preferred method of forming the solution is to dissolve the PGE in an aqueous solution of the alkylene glycol or monoester, or add water to a mixture of the PGE and the alkyl-ene glycol or monoester, and then freeze-dry the resulting aqueous solution., Alternatively, where the alkylene glycol or monoester thereof is solid at normal temperatures, a solution may be formed by heating the alkylene glycol or monoester to melt it and then dissolving the PGE in the molten glycol. The resulting solutlon is then cooled to storage temperature to form a solid solution. The temperature at which the glycol or, monoester is heated obviously depends on its melting point, but account should also be taken of the temperature stability of the PGE. It is preferred that the molten solution containing the PGE should be at about the minimum tempera'ture necessary for melting and that it should be ~ept at that temperature for the minimum necessary time. This procedure is particularly useful with polyethylene glycols 2000, 4000 and 6000 at the glycol solvent.
' There is no particular limitation upon the concentration of the PGE in the solution, although the maximum concentration will, of course, depend upon the solubility of the PGE in the selected alkylene glycol or monoester. However, 2ss for practical and economic reasons, it is preferred that sufficient PGE should be dissolved in the alkylene glycol or monoester to give a final PGE concentration of from about lOy to 1000~ per ml of the final composition, more preferably about 100~/ml.
The invention is further illustrated by the following non-limiting Examples. In these Examples, the residual activity of the PGE in solution after ageing was determined by the following biological test.
A sample of bronchial muscle excised from a guinea pig was contracted with histamine. The bronchial muscle sample was then kept at 36C and suspended in Tyrode solution aerated with a gas mixture comprising 95% by volume 2 and 5% by volume CO2, and its tension was measured. Histamine was added to the - solution to a final concentration of 10 5 g/ml and, after contra-ction of the excised muscle sample became constant, the desired test sample was added to ,determine the concentration required for 50% relaxation. The residual activity is reported as a percentage of the activity after ageing for 4 weeks at 40C to the activity of an initial test sample.
` -25~
EXAMPLES 1 to ll -lO0 mg of the prostaglandin E specified in Table 1 were charged into a l litre vessel and then sufficient of the solvent indicated in Table 1 was added to make a total volume of l litre. The activities of the resulting solutions were measured both before and after keeping at 40~C for 4 weeks.
The results are summarized in Table lo op cn ~Q ~
o ~ o~ o ) o o ;., o o ~ o ~ o ~ o ~ ~ o ~ O O a) o ~ ~ o a~
~ ~ a~
,. o ~ ~ r~ 4 ,. u~ O O a) ~ ~ p~
:~
~1 ~1 ~ : - ~
~ N C~
~ ~ u v ~
p~
~ a) a) a) a c~
~ $
~J
:~
0~ Po OQ'0~ 0~ 0~ 0 0 51 h h h h h h h ~ P~ P~ ~ ~ P~P~
:. O o O O O O O O
U~
. ,. I o o o o I o o .
zo . ~ CO ~ O
X
.
2S~
,, (~
~ ~ J o -5~
It can be seen from the Table that solutions using the alkylene glycol and monoester solvents of the present invention are substantially more stable than those using the prior art solvent, ethanol. The solvents of the present invention also compare favourably with other prior art solvents. Fo~
example, Japanese Patent Provisional Publication No. 145515/75 describes the use of t-butanol as a solvent and this shows a residual activity of 62 - 83% after 2 weeks at 50C; ageing for 2 weeks at 50C is substantially equivalent to agein~ for 4 weeks at 40C. Accordingly, it can be concluded that the solvents of the present invention are substantially better than t-butanol also.
E~AMæLE 12 :`
100 mg of 20-isopropylidene PGE2 were charged into a 1 litre vessel. 50 g of polyethylene glycol 6000 were added and then distilled water was added to a total volume of 1 lit~e. The resulting solution was divided into vials and then freeze-fried by a conventional method. The preparation thus formed showed , ~ 5~
a residual ac~ivity of 75~ after 4 weeks at 40PC.
On investigation of the freeze-dried solution, it was found that it contained residual traces of water, indicating that drying had not been complete. It was thoughtthat this trace of water had partially destroyed prostaglandin activity and resulted in the relatively low residual activity. Accordingly the experiment was repeated taking great care to remove all water during freeze-drying. This time the residual activity was 90 percent after 4 weeks at 40 degrees celsius. The importance of complete drying is thus demonstrated.
One KG of polyethylene glycol 4000 was melted at 60 degrees celsius, and then 100 mg of 20 isopropylidene PGE2 were dissolved in the melt. The resulting solution was cooled and finely divided to form a powder. This powder has a residual activity of 90 percent after 4 weeks at 40 degrees celsius.
~ 4. 9-0~o-11~,15~(or~)-dihydroxy-17~-methyl-20-iso-; propylideneprost-5(cis),13(trans)-dienoic acid and its methyl, ethyl, n-propyl and isopropyl esters;
5. 9-Oxo-11~,15~(or~)-dihydroxy-17~-methyl-20-(1- -methylisopropylidenelprost-13(trans)-enoic acid and its methyl, ethyl, n-propyl and isopropyl esters;
s 6. 9-Oxo~ , 15~(or ~)-dihydroxy-17~-methyl-20-(1-methylisopropylidene)prost-5(cis), 13(trans)-dienoic acid and its methyl, ethyl, n-propyl and isopropyl esters;
7. 9-Oxo-lla, 15a~or ~)-dihydroxy-17~-methyl-20-(1,3-dimethylisopropylidene)prost-13(trans)-enoic acid and its methyl, ethyl, n-propyl and isopropyl estersi ; ' 8. 9-Oxo-lla, 15a(or ~)-dihydroxy-17~-methyl-20-(1,3-dimethylisopropylidene)prost-5(cis), 13(trans)-dienoic acid and its methyl, ethyl, n-propyl and isopropyl esters;
9. 9-Oxo-lla,15a(or ~)-dihydroxy-20-(1-methylisopropyl-idene)prost-13(transl-enoic acid and its methyl, ethyl, n -propyl and isopropyl esters;
10. 9-oxo-Ila, 15a(or ~)-dihydroxy-20-(1-methylisopropyl-idene)prost-5-(cis), 13(trans)-dienoic acid and its .: methyl, ethyl, n-propyl and isopropyl esters;
.
. ~ 11. 9-Oxo-lla~15a(or ~)-dihydroxy-20-(1,3-dimethyliso-propylidene)prost-13(trans)-enoic acid and its methyl, ethyl, n-propyl and isopropyl esters;
12. 9-Oxo-lla, 15~(or ~)-dihydroxy-20-(1,3-dimethyl-isopropylidene)prost~5(cls), 13(trans)-dienoic acid and its methyl, ethyl, n-propyl and isopropyl esters;
13~ 9-Oxo-15~(or ~)-hydroxy-20-isopropylideneprost-13(trans)-enoic acid and its methyl, ethyl, n-propyl and isopropyl esters;
14. 9-Oxo 15~(or ~)-hydroxy-17~-methyl-20-isopropyl-ideneprost-13(trans)-enoic acid and its methyl, ethyl, n-propyl and isopropyl esters;
15. 9-Oxo-15a(or ~)-hydroxy-20-isopropylideneprost-5-(cis), 13(trans)-dienoic acid and its methyl, ethyl, n-propyl and isopropyl esters; and 16. 9-Oxo-15~(or ~)-hydroxy~17~-methyl-20-isopropyl-ideneprost-5-(cls), 13(trans)-dienoic acid and its methyl, ethyl, n-propyl and isopropyl esters.
Of these compounds, we particularly prefer 9-oxo-lla, 15~-dihydroxy-20-isopropylideneprost-5(cis), 13(trans)-dienoic 2~i~
acid, otherwise known as 20-isopropylidene-PGE2, which has the formula (VI):
h ~ ~aH ~ (VI) Q~ .
The solvent employed in the present-invention is an alkylene glycol or monoester thereof. Examples of suitable alkylene glycols include: ethylene glycol; diethylene glycol;
triethylene glycol; propylene glycol; dipropylene glycol; 1,3-butanediol; 2,3-butanediol; 2,4-pentanediol; hexylene glycol;
2,5-hexanediol; 2,4-heptanediol; polyethylene glycols 200, 300, 400, 600, 1000, 2000, 4000 and 6000; and polypropylene glycols 200, 300, 400, 750, 1200, 2000 and 4000. The monoester employed is preferably an ester of any of the above-mentioned alkylene glycols with a lower aliphatic acid, for example ethylene glycol ~; monoacetate or propylene glycol monoacetate. It is also possible to use block copolymers of the above - listed polyethylene glycols and polypropylene glycols.
Any of these alkylene glycols and monoesters may be employed by itself or a mixture of any two or more may be used.
s~
of the alkylene glycols and monoesters exemplified above, we particularly prefer propylene glycol and polyethylene glycols 200, 300 and 400; these compounds form solutions easily and have good physiological tolerances.
Some of the alkylene glycols and monoesters thereof which may be used in the present invention are liquids at normal temperatures, whereas others are solids. Where the alkylene glycol or monoester is a liquid at ordinary temperatures, the solution of the present invention can easily be formed by dis-solving ~he PGE in it in the same way as any other solid is dissolved in a liquid which is a solvent for it. Where the alkylene glycol or monoester thereof is solid at ordinary temperatures, the preferred method of forming the solution is to dissolve the PGE in an aqueous solution of the alkylene glycol or monoester, or add water to a mixture of the PGE and the alkyl-ene glycol or monoester, and then freeze-dry the resulting aqueous solution., Alternatively, where the alkylene glycol or monoester thereof is solid at normal temperatures, a solution may be formed by heating the alkylene glycol or monoester to melt it and then dissolving the PGE in the molten glycol. The resulting solutlon is then cooled to storage temperature to form a solid solution. The temperature at which the glycol or, monoester is heated obviously depends on its melting point, but account should also be taken of the temperature stability of the PGE. It is preferred that the molten solution containing the PGE should be at about the minimum tempera'ture necessary for melting and that it should be ~ept at that temperature for the minimum necessary time. This procedure is particularly useful with polyethylene glycols 2000, 4000 and 6000 at the glycol solvent.
' There is no particular limitation upon the concentration of the PGE in the solution, although the maximum concentration will, of course, depend upon the solubility of the PGE in the selected alkylene glycol or monoester. However, 2ss for practical and economic reasons, it is preferred that sufficient PGE should be dissolved in the alkylene glycol or monoester to give a final PGE concentration of from about lOy to 1000~ per ml of the final composition, more preferably about 100~/ml.
The invention is further illustrated by the following non-limiting Examples. In these Examples, the residual activity of the PGE in solution after ageing was determined by the following biological test.
A sample of bronchial muscle excised from a guinea pig was contracted with histamine. The bronchial muscle sample was then kept at 36C and suspended in Tyrode solution aerated with a gas mixture comprising 95% by volume 2 and 5% by volume CO2, and its tension was measured. Histamine was added to the - solution to a final concentration of 10 5 g/ml and, after contra-ction of the excised muscle sample became constant, the desired test sample was added to ,determine the concentration required for 50% relaxation. The residual activity is reported as a percentage of the activity after ageing for 4 weeks at 40C to the activity of an initial test sample.
` -25~
EXAMPLES 1 to ll -lO0 mg of the prostaglandin E specified in Table 1 were charged into a l litre vessel and then sufficient of the solvent indicated in Table 1 was added to make a total volume of l litre. The activities of the resulting solutions were measured both before and after keeping at 40~C for 4 weeks.
The results are summarized in Table lo op cn ~Q ~
o ~ o~ o ) o o ;., o o ~ o ~ o ~ o ~ ~ o ~ O O a) o ~ ~ o a~
~ ~ a~
,. o ~ ~ r~ 4 ,. u~ O O a) ~ ~ p~
:~
~1 ~1 ~ : - ~
~ N C~
~ ~ u v ~
p~
~ a) a) a) a c~
~ $
~J
:~
0~ Po OQ'0~ 0~ 0~ 0 0 51 h h h h h h h ~ P~ P~ ~ ~ P~P~
:. O o O O O O O O
U~
. ,. I o o o o I o o .
zo . ~ CO ~ O
X
.
2S~
,, (~
~ ~ J o -5~
It can be seen from the Table that solutions using the alkylene glycol and monoester solvents of the present invention are substantially more stable than those using the prior art solvent, ethanol. The solvents of the present invention also compare favourably with other prior art solvents. Fo~
example, Japanese Patent Provisional Publication No. 145515/75 describes the use of t-butanol as a solvent and this shows a residual activity of 62 - 83% after 2 weeks at 50C; ageing for 2 weeks at 50C is substantially equivalent to agein~ for 4 weeks at 40C. Accordingly, it can be concluded that the solvents of the present invention are substantially better than t-butanol also.
E~AMæLE 12 :`
100 mg of 20-isopropylidene PGE2 were charged into a 1 litre vessel. 50 g of polyethylene glycol 6000 were added and then distilled water was added to a total volume of 1 lit~e. The resulting solution was divided into vials and then freeze-fried by a conventional method. The preparation thus formed showed , ~ 5~
a residual ac~ivity of 75~ after 4 weeks at 40PC.
On investigation of the freeze-dried solution, it was found that it contained residual traces of water, indicating that drying had not been complete. It was thoughtthat this trace of water had partially destroyed prostaglandin activity and resulted in the relatively low residual activity. Accordingly the experiment was repeated taking great care to remove all water during freeze-drying. This time the residual activity was 90 percent after 4 weeks at 40 degrees celsius. The importance of complete drying is thus demonstrated.
One KG of polyethylene glycol 4000 was melted at 60 degrees celsius, and then 100 mg of 20 isopropylidene PGE2 were dissolved in the melt. The resulting solution was cooled and finely divided to form a powder. This powder has a residual activity of 90 percent after 4 weeks at 40 degrees celsius.
Claims (25)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A pharmaceutical composition having improved stability comprising a solution of a prostaglandin E in an alkylene glycol or a monoester.
2. A composition according to Claim 1, wherein said prostaglandin E is a compound of formula (IV):
(IV) wherein: A represents an ethylene group or a cis-vinylene group;
R1 and R2 are the same or different and each represents a hydrogen atom or a lower alkyl group; and R3 and R4 are the same or different and each represents a lower alkyl group.
(IV) wherein: A represents an ethylene group or a cis-vinylene group;
R1 and R2 are the same or different and each represents a hydrogen atom or a lower alkyl group; and R3 and R4 are the same or different and each represents a lower alkyl group.
3. A composition according to Claim 1, wherein said prostaglandin E is a compound of formula (V):
(V) wherein: A represents an ethylene group or a cis-vinylene group;
R1 and R2 are the same or different and each represents a hydrogen atom or a lower alkyl group; and R3 and R4 are the same or different and each represents a lower alkyl group.
(V) wherein: A represents an ethylene group or a cis-vinylene group;
R1 and R2 are the same or different and each represents a hydrogen atom or a lower alkyl group; and R3 and R4 are the same or different and each represents a lower alkyl group.
4. A composition according to Claim 1, wherein said prostaglandin is 9-oxo-11.alpha.,15.alpha.-dihydroxy-20-isopropylideneprost-5(cis), 13(trans)-dienoic acid.
5. A composition as claimed in any one of Claims 1, 2 and 3, wherein said alkylene glycol or monoester thereof is ethylene glycol, diethylene glycol, triethylene glycol, propylene glycol, dipropylene glycol, 1,3-butanediol, 2,3-butanediol, 2,4-pentanediol, hexylene glycol, 2,5-hexanediol, 2,4-heptanediol, ethylene glycol monoacetate, propylene glycol monoacetate, poly-ethylene glycol 200, 300, 400, 600, 1000, 2000, 4000 or 6000 or polypropylene glycol 200, 300, 400, 750, 1200, 2000 or 4000.
6. A composition as claimed in any one of Claims 1, 2, and 3, wherein the alkylene glycol is propylene glycol, polyethyl-ene glycol 200, polyethylene glycol 300 or polyethylene glycol 400.
7. A composition as claimed in Claim 1, wherein said prostaglandin E is 9-oxo-11.alpha.,15.alpha.-dihydroxy-20-isopropylideneprost-5(cis),13(trans)-dienoic acid and said alkylene glycol is propylene glycol, polyethylene glycol 200, polyethylene glycol 300 or polyethylene glycol 400.
8. A composition as claimed in any one of Claims 1, 2 or 3, wherein said solution is liquid.
9. A composition as claimed in any one of Claims 1, 2 or 3, wherein said solution is solid.
10. A process for preparing a stabilized prostaglandin E composition, which comprises forming a solution of said prostaglandin E in an alkylene glycol or monoester thereof.
11. A process according to Claim 10, wherein said prostaglandin E is a compound of formula (IV) (IV) wherein: A represents an ethylene group or a cis-vinylene group;
R1 and R2 are the same or different and each represents a hydrogen atom or a lower alkyl group; and R3 and R4 are the same or different and each represents a lower alkyl group.
R1 and R2 are the same or different and each represents a hydrogen atom or a lower alkyl group; and R3 and R4 are the same or different and each represents a lower alkyl group.
12. A process according to Claim 10, wherein said prostaglandin E is a compound of formula (V):
(V) wherein: A represents an ethylene group or a cis-vinylene group;
R1 and R2 are the same or different and each represents a hydrogen atom or a lower alkyl group; and R3 and R4 are the same or different and each represents a lower alkyl group.
(V) wherein: A represents an ethylene group or a cis-vinylene group;
R1 and R2 are the same or different and each represents a hydrogen atom or a lower alkyl group; and R3 and R4 are the same or different and each represents a lower alkyl group.
13. A process according to Claim 10, wherein said prostaglandin is 9-oxo-11.alpha.,15.alpha.-dihydroxy-20-isopropylideneprost-5(cis), 13(trans)-dienoic acid.
14. A process as claimed in any one of Claims 10, 11 and 12, wherein said alkylene glycol or monoester thereof is ethylene glycol, diethylene glycol, triethylene glycol, propylene glycol, dipropylene glycol, 1,3-butanediol, 2,3-butanediol, 2,4-pentanediol, hexylene glycol, 2,5-hexanediol, 2,4-heptanediol ethylene glycol monoacetate, propylene glycol monoacetate, polyethylene glycol 200, 300, 400, 600, 1000, 2000, 4000 or 6000 or polypropylene glycol 200, 300, 400, 750, 1200, 2000 or 4000.
15. A process as claimed in any one of Claims 10, 11 and 12, wherein the alkylene glycol is propylene glycol, poly-ethylene glycol 200, polyethylene glycol 300 or polyethylene glycol 400.
16. A process as claimed in any one of Claims 10, 11 and 12, wherein said alkylene glycol or monoester thereof is liquid at normal temperatures and the solution is formed by dissolving said prostaglandin E in said alkylene glycol or said monoester.
17. A process as claimed in any one of Claims 10, 11 and 12, wherein said alkylene glycol or monoester thereof is solid at normal temperatures and the solution is formed by preparing an aqueous solution containing said prostaglandin E
and said alkylene glycol or said monoester and freeze-drying the aqueous solution.
and said alkylene glycol or said monoester and freeze-drying the aqueous solution.
18. A process as claimed in any one of Claims 10, 11 and 12, wherein said alkylene glycol or monoester thereof is solid at normal temperatures and the solution is formed by dissolving said prostaglandin E in an aqueous solution of said alkylene glycol or said monoester and freeze-drying the aqueous solution.
19. A process for preparing a stabilized prostaglandin E composition wherein a solid alkylene glycol or a solid monoester of an alkylene glycol is melted, a prostaglandin E is dissolved in the melt, and the resulting solution is cooled.
20. A process according to Claim 19, wherein said prostaglandin E is a compound of formula (IV) (IV) wherein: A represents an ethylene group or a cis-vinylene group;
R1 and R2 are the same or different and each represents a hydrogen atom or a lower alkyl group; and R3 and R4 are the same or different and each represents a lower alkyl group.
R1 and R2 are the same or different and each represents a hydrogen atom or a lower alkyl group; and R3 and R4 are the same or different and each represents a lower alkyl group.
21. A process according to Claim 19, wherein said prostaglandin E is a compound of formula (V):
(V) wherein: A represents an ethylene group or a cis-vinylene group;
R1 and R2 are the same or different and each represents a hydrogen atom or a lower alkyl group; and R3 and R4 are the same or different and each represents a lower alkyl group.
(V) wherein: A represents an ethylene group or a cis-vinylene group;
R1 and R2 are the same or different and each represents a hydrogen atom or a lower alkyl group; and R3 and R4 are the same or different and each represents a lower alkyl group.
22. A process according to Claim 19, wherein said prostaglandin is 9-oxo-11.alpha.,15.alpha.-dihydroxy-20-isopropylideneprost-5(cis), 13(trans)-dienoic acid.
23. A process as claimed in any one of Claims 19, 20 or 21, wherein said alkylene glycol or monoester thereof is ethylene glycol, diethylene glycol, triethylene glycol, propylene glycol, dipropylene glycol, 1,3-butanediol, 2,3-butanediol, 2,4-pentanediol, hexylene glycol, 2,5-hexanediol, 2,4-heptanediol, ethylene glycol monoacetate, propylene glycol monoacetate, polyethylene glycol 200, 300, 400, 600, 1000, 2000, 4000 or 6000 or polypropylene glycol 200, 300, 400, 750, 1200, 2000 or 4000.
24. A process as claimed in any one of Claims 19, 20 or 21 wherein the alkylene glycol is polyethylene glycol 2000, 4000 or 6000.
25. A process as claimed in Claim 19, wherein the alkylene glycol is polyethylene glycol 2000, 4000, or 6000 and the prostaglandin E is 9-oxo-11.alpha.,15.alpha.-dihydroxy-20-isopropylidene-prost-5(cis), 13 (trans)-dienoic acid.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP52054679A JPS6019734B2 (en) | 1977-05-12 | 1977-05-12 | Method for producing stable prostaglandin E preparations |
| JP54679/1977 | 1977-05-12 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1090255A true CA1090255A (en) | 1980-11-25 |
Family
ID=12977466
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA303,253A Expired CA1090255A (en) | 1977-05-12 | 1978-05-12 | Stabilized compositions containing a prostaglandin e |
Country Status (7)
| Country | Link |
|---|---|
| JP (1) | JPS6019734B2 (en) |
| CA (1) | CA1090255A (en) |
| CH (1) | CH635513A5 (en) |
| DK (1) | DK210778A (en) |
| ES (1) | ES469822A1 (en) |
| NL (1) | NL7805180A (en) |
| SE (1) | SE435898B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0084865A1 (en) * | 1982-01-21 | 1983-08-03 | Syntex (U.S.A.) Inc. | Propylene glycol diester solutions of PGE-type compounds |
| US8071577B2 (en) | 2004-04-20 | 2011-12-06 | Bayer Pharma Aktiengesellschaft | Multi-phase contraceptive preparation based on a natural estrogen |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4310543A (en) * | 1980-10-09 | 1982-01-12 | Hoffmann-La Roche Inc. | Prostaglandin compositions |
| DE19541815B4 (en) * | 1995-11-09 | 2008-04-10 | Bannert, Christian, Dr. | Use of a solution of polyethylene glycol in water as an aqueous rinse solution for the prevention or treatment of viscous mucus associated with radiation and / or chemotherapy-induced mucosal disorders |
| AT515356B1 (en) * | 2014-01-30 | 2015-11-15 | Gebro Holding Gmbh | Stable alcoholic solution of alprostadil |
-
1977
- 1977-05-12 JP JP52054679A patent/JPS6019734B2/en not_active Expired
-
1978
- 1978-05-11 CH CH515878A patent/CH635513A5/en not_active IP Right Cessation
- 1978-05-12 ES ES469822A patent/ES469822A1/en not_active Expired
- 1978-05-12 NL NL7805180A patent/NL7805180A/en not_active Application Discontinuation
- 1978-05-12 DK DK210778A patent/DK210778A/en not_active Application Discontinuation
- 1978-05-12 SE SE7805499A patent/SE435898B/en not_active IP Right Cessation
- 1978-05-12 CA CA303,253A patent/CA1090255A/en not_active Expired
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0084865A1 (en) * | 1982-01-21 | 1983-08-03 | Syntex (U.S.A.) Inc. | Propylene glycol diester solutions of PGE-type compounds |
| US8071577B2 (en) | 2004-04-20 | 2011-12-06 | Bayer Pharma Aktiengesellschaft | Multi-phase contraceptive preparation based on a natural estrogen |
Also Published As
| Publication number | Publication date |
|---|---|
| CH635513A5 (en) | 1983-04-15 |
| SE435898B (en) | 1984-10-29 |
| NL7805180A (en) | 1978-11-14 |
| ES469822A1 (en) | 1978-12-16 |
| DK210778A (en) | 1978-11-13 |
| JPS53139716A (en) | 1978-12-06 |
| SE7805499L (en) | 1978-11-13 |
| JPS6019734B2 (en) | 1985-05-17 |
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