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EP0000291B1 - A pharmaceutical composition for tropical diseases - Google Patents

A pharmaceutical composition for tropical diseases Download PDF

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Publication number
EP0000291B1
EP0000291B1 EP78300112A EP78300112A EP0000291B1 EP 0000291 B1 EP0000291 B1 EP 0000291B1 EP 78300112 A EP78300112 A EP 78300112A EP 78300112 A EP78300112 A EP 78300112A EP 0000291 B1 EP0000291 B1 EP 0000291B1
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weight
compound
pharmaceutical composition
formula
acid
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German (de)
French (fr)
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EP0000291A1 (en
Inventor
Neil Bonnette Graham
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University of Strathclyde
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University of Strathclyde
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • A61K9/204—Polyesters, e.g. poly(lactide-co-glycolide)
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to pharmaceutical compositions for the treatment of tropical disease.
  • Tropical diseases for example, malaria and leprosy, have hitherto been prevented and treated by periodic administration of a dose of a drug to combat offending parasites present in the body.
  • the drug is generally administered orally or by injection, and passes through the body so that frequent dosage is necessary.
  • An object of this invention is to provide a composition which is effective against tropical disease and which can provide a prolonged supply of a drug to a body with infrequent administration.
  • a pharmaceutical composition comprising a polymeric matrix of a copolymer of the compound of Formula I. with at least one comonomer having more than one functional group selected from hydroxyl and carboxyl groups, characterised in that the composition contains in admixture with the polymeric matrix a drug which is in organic nitrogen compound of basic reaction and which is effective against a tropical disease.
  • Drugs of particular effectiveness are, cycloguanil, pyrimethamine and sulphadiazine.
  • Drugs which are effective against tropical disease normally contain nitrogen atoms and are consequently basic in character. This can cause considerable problems in the preparation of the composition of this invention as the copolymerisation reaction between the compound of formula I and the compound or compounds having more than one functional group selected from OH and COOH groups is acid catalysed; thus, admixture of such a drug with the copolymerisation reactants can result in a neutralisation reaction between the drug and the acid catalyst with consequent prevention or restriction of the copolymerisation.
  • compositions of this invention are malaria, leprosy, schistosomiasis and clonorchiasis.
  • Examples of drugs which can be used in the present composition to combat these and other tropical diseases are quinine, sulphonamides, chlorphenyl derivatives, chloroguanide, pyrimethamine, trimethoprim, quinoline derivatives such as pamaquine, chloroquine, pentaquine, primaquine and amodiaquine, pararosaniline, sulphamethizole, quinacrine, dapsone, sodium sulphoxone, sulphetrone, sodium hydnocarpate and sodium chaulmoograte.
  • the compound having two or more groups selected from OH and COOH groups is preferably a compound which occurs naturally in and/or is benign to the human body.
  • Examples of compounds containing two or more groups selected from OH and COOH groups which can be used in the present invention are:
  • compositions of this invention are prepared by copolymerising a compound of formula I as hereinbefore defined with at least one compound having more than one group selected from OH and COOH groups in the presence of an acidic catalyst and in the presence of an organic nitrogen compound of basic reaction which is effective against tropical disease.
  • the compound of formula I hereinbefore which is a mixture of stereoisomers, is a colourless liquid having a high boiling point, a very low level of oral toxicity and no known detrimental effect on skin. It may be prepared according to the following reaction sequence:
  • the processes provided by the present invention may be carried out by simply mixing the compound of formula I with a compound having two or more groups selected from OH and COOH groups or with a mixture of such compounds in the presence of an acidic catalyst, advantageously at an elevated temperature such as from 60°C to 100°C, especially at 80°C, and then adding to the resulting mixture and homogeneously distributing therein the appropriate amount of the desired drug.
  • the mixture thus obtained can then be allowed to cure, suitably at an elevated temperature.
  • the drug should not react with the catalyst, and it may therefore be in the form of a salt, for example its hydrochloride, or be insoluble in the reaction medium.
  • This can be effected, for example, by the addition of an amount of a primary, secondary or tertiary amine such as triethylamine, a quaternary ammonium hydroxide or a basic inorganic oxide or hydroxide sufficient to neutralise the activity of the acidic catalyst.
  • the drug preferably in salt form or in dispersion, can then be added to and homogeneously distributed in the resulting mixture and subsequently the copolymerisation can be allowed to proceed to completion by the addition of further acidic catalyst.
  • Suitable acidic catalysts which may be used in the present process include inorganic acids such as hydrochloric acid and sulphuric acid, organic acids such as a paratoluenesulphonic acid etc and Lewis acids such as zinc chloride, tin tetrachloride, aluminium chloride and ferric chloride.
  • the preferred acidic catalyst is ferric chloride.
  • the amount of acidic catalyst used is not critical, but it is expedient to use from 0.01 % to 2.0%, particularly from 0.04% to 1.0% based on the total weight of the mixture.
  • the ratio of the compound of formula I to the compound having two or more groups selected from OH and COOH groups can be varied. It is convenient to use stoichiometric amounts, although the use of amounts which deviate considerably from stoichiometry is also possible.
  • the copolymerisation may also be carried out in the presence of an inert pharmaceutically acceptable solvent or an inert pharmaceutically acceptable oil, whereby the nature of the resulting medicinal composition is modified.
  • An example of such an oil is olive oil.
  • the inert pharmaceutically acceptable solvent or oil may be added as such or it may serve as a solvent or dispersant for other components of the copolymerisation mixture.
  • the drug may be dissolved or dispersed in the inert pharmaceutically acceptable solvent or oil.
  • the drug is gradually released therefrom over a prolonged period and, at the same time, the copolymer is biodegraded to substances which can be readily disposed of by the body.
  • the copolymer is preferably one formed between the compound of formula I and a compound which occurs naturally in and/or is benign to the human body. Hydrolysis, especially acid hydrolysis, of such copolymers yields predominantly the latter compounds themselves.
  • the hydrolysis fragments of the compound of formula I are the following: all of which are readily oxidisable for disposal by the body.
  • the rate of release of the drug from a composition provided by this invention can be controlled by a variety of methods. For example, in a copolymer prepared using given components the density of the cross-linking can be altered. Again, for example, the nature and amount of inert pharmaceutically acceptable solvent or oil which may be present in the composition can be varied.
  • compositions provided by the present invention which are based on cross-linked copolymers are based on cross-linked copolymers (i.e. matrices) is that such copolymers have a so-called glassy state (in which they are hard and brittle) and a rubber-like state, the change from the glassy state to the rubber-like state occurring at the so-called glass transition temperature.
  • the drug is gradually released and, at the same time, the copolymer is gradually biodegraded, this resulting in gradual reduction of the glass transition temperature.
  • the glass transition temperature is reached the rubber-like state occurs and the copolymer becomes more rapidly biodegraded.
  • body temperature there is a rapid onset in the degradation. It will accordingly be evident that it is highly desirable to provide compositions based on cross-linked copolymers which initially have a glass transition temperature which lies somewhat above body temperature.
  • compositions provided by the present invention may be administered for example by subcutaneous or intramuscular injection or implantation.
  • a composition of appropriate particle size can be dispensed in a pharmaceutically acceptable carrier material adapted for subcutaneous or intramuscular administration.
  • a pharmaceutically acceptable carrier material adapted for subcutaneous or intramuscular administration.
  • the rate of release of the drug can be controlled.
  • Forms adapted for implantation include, for example, pellets, films, discs and rods. Such implant forms can be prepared in a conventional manner.
  • composition of the invention a combination of drugs to obtain most effective prophylaxis or treatment of a tropical disease.
  • a solution of the ferric chloride in the glycerol is warmed to 80°C and the compound I is added dropwise while warming and stirring between the additions.
  • Compound I is initially incompatible with the glycerol, but by gradual additions and warming until the mixture becomes one phase, a stage is reached when the glycerol mixture will more readily accept the additions of compound I and become homogeneous.
  • the mixture is removed from the heating source and the amodiaquine is added to form a dispersion in the monomer mixture.
  • a temperature of 80°C is maintained until polymerisation is complete and the desired polymer matrix is obtained containing 5% of amodiaquine by weight.
  • the dispersion referred to in the preceding paragraph can be used to prepare discs for implantation as follows:
  • Example 1 According to the procedure described in Example 1, the following ingredients were used to prepare a polymer matrix containing amodiaquine.
  • Example 1 According to the method of Example 1, the following ingredients were used to prepare a composition comprising a dispersion of 25.8% of sulphamethizole in a polymer matrix.
  • Example 1 According to the method of Example 1, the following ingredients were used to prepare a polymer matrix containing cycloguanil
  • composition was worked-up as pellets for subcutaneous implantation 6 mm in diameter and 2 mm thick.
  • composition was worked-up as a powder and as an implant of the same dimensions as in Example 4.
  • the powdered product was tested in powder form of particle size (a) ⁇ 53p and (b) 53 ⁇ 96 ⁇ .
  • the powder (a) was suspended in glycerol and injected into the test mice: powder (b) was implanted. Prolonged protection in excess of five months of the test mice against the action of Plasmodium Bergei has been observed.
  • Example 1 According to the method of Example 1, the following ingredients were used to prepare a polymer matrix containing pyrimethamine.
  • the product was formed into a pellet for subcutaneous implantation into test mice.
  • the mice were protected against Plasmodium Bergei for periods in excess of three months.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

  • The present invention relates to pharmaceutical compositions for the treatment of tropical disease.
  • Tropical diseases, for example, malaria and leprosy, have hitherto been prevented and treated by periodic administration of a dose of a drug to combat offending parasites present in the body. The drug is generally administered orally or by injection, and passes through the body so that frequent dosage is necessary.
  • Our French Published Application No. A-2 336 936 describes a pharmaceutical composition which consists of a polymeric matrix in which there is admixed a steroidal material.
  • An object of this invention is to provide a composition which is effective against tropical disease and which can provide a prolonged supply of a drug to a body with infrequent administration.
  • According to the present invention there is provided a pharmaceutical composition comprising a polymeric matrix of a copolymer of the compound of Formula I.
    Figure imgb0001
    with at least one comonomer having more than one functional group selected from hydroxyl and carboxyl groups, characterised in that the composition contains in admixture with the polymeric matrix a drug which is in organic nitrogen compound of basic reaction and which is effective against a tropical disease.
  • Drugs of particular effectiveness are, cycloguanil, pyrimethamine and sulphadiazine.
  • Drugs which are effective against tropical disease normally contain nitrogen atoms and are consequently basic in character. This can cause considerable problems in the preparation of the composition of this invention as the copolymerisation reaction between the compound of formula I and the compound or compounds having more than one functional group selected from OH and COOH groups is acid catalysed; thus, admixture of such a drug with the copolymerisation reactants can result in a neutralisation reaction between the drug and the acid catalyst with consequent prevention or restriction of the copolymerisation.
  • Strongly basic drugs, if soluble in the copolymerisation reaction medium, therefore inhibit the copolymer formation, and this can be overcome either (a) by selecting an insoluble drug or rendering the drug insoluble and forming a dispersion rather than a solution, or (b) by using the drug in the form of its salt, preferably fully neutralised.
  • The use of soluble bases requires very large amounts of acid catalyst for the copolymerisation.
  • Examples of tropical disease which can be prevented or treated by compositions of this invention are malaria, leprosy, schistosomiasis and clonorchiasis.
  • Examples of drugs which can be used in the present composition to combat these and other tropical diseases are quinine, sulphonamides, chlorphenyl derivatives, chloroguanide, pyrimethamine, trimethoprim, quinoline derivatives such as pamaquine, chloroquine, pentaquine, primaquine and amodiaquine, pararosaniline, sulphamethizole, quinacrine, dapsone, sodium sulphoxone, sulphetrone, sodium hydnocarpate and sodium chaulmoograte.
  • The compound having two or more groups selected from OH and COOH groups is preferably a compound which occurs naturally in and/or is benign to the human body. Examples of compounds containing two or more groups selected from OH and COOH groups which can be used in the present invention are:
    • (a) among the compounds having two or more OH groups, glycerol, sorbitol, erythritol, inositol, glycols based on polyethylene oxide, 4,4'-dihydroxyphenyl-2,2-propane, 1,2-dihydroxy-benzene, 1,3-dihydroxy-benzene, 1,4-dihydroxybenzene, 1,2,3-trihydroxy-benzene, 1,2,4-trihydroxy-benzene, and 1,3,5-trihydroxy-benzene;
    • (b) among the compounds having at least one OH group and at least one COOH group, lactic acid, malic acid, 2-hydroxyisobutyric acid, 10-hydroxydecanoic acid, 12-hydroxyoctadecanoic acid, 12-hydroxy-(cis)-9-octadecenoic acid, 2-hydroxycyclo-hexanecarboxylic acid (hexahydrosalicylic acid), 2-hydroxy-2-phenyl-(D)-propionic acid, di-phenylhydroxyacetic acid, ascorbic acid, citric acid, tartaric acid, 2-hydroxy-3-methyl-(D) succinic acid, 2-hydroxybenzoic acid, 3-hydroxybenzoic acid, 4-hydroxybenzoic acid, 2,3-dihydroxybenzoic acid, 2,4-dihydroxybenzoic acid, 2,5-dihydroxybenzoic acid, 2,6-dihydroxybenzoic acid, 2,3,4-trihydroxybenzoic acid, 2,4,5-trihydroxybenzoic acid, 2,4,6-trihydroxybenzoic acid and 3,4,5-trihydroxybenzoic acid;
    • (c) among the compounds having two or more COOH groups, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, 1,2-cyclohexanedicarboxylic acid, 1,3-cyclohexanedicarboxylic acid, 1,4-cyclo-hexanedicarboxylic acid, phthalic acid, isophthalic acid and terephthalic acid.
  • According to the present invention, the compositions of this invention are prepared by copolymerising a compound of formula I as hereinbefore defined with at least one compound having more than one group selected from OH and COOH groups in the presence of an acidic catalyst and in the presence of an organic nitrogen compound of basic reaction which is effective against tropical disease.
  • The compound of formula I hereinbefore, which is a mixture of stereoisomers, is a colourless liquid having a high boiling point, a very low level of oral toxicity and no known detrimental effect on skin. It may be prepared according to the following reaction sequence:
    Figure imgb0002
  • The processes provided by the present invention may be carried out by simply mixing the compound of formula I with a compound having two or more groups selected from OH and COOH groups or with a mixture of such compounds in the presence of an acidic catalyst, advantageously at an elevated temperature such as from 60°C to 100°C, especially at 80°C, and then adding to the resulting mixture and homogeneously distributing therein the appropriate amount of the desired drug. The mixture thus obtained can then be allowed to cure, suitably at an elevated temperature.
  • It is preferable that the drug should not react with the catalyst, and it may therefore be in the form of a salt, for example its hydrochloride, or be insoluble in the reaction medium.
  • In certain circumstances it may be desirable to interrupt the copolymerisation during the initial mixing of the compound of formula l with a compound having two or more groups selected from OH and COOH groups or with a mixture of such compounds. This can be effected, for example, by the addition of an amount of a primary, secondary or tertiary amine such as triethylamine, a quaternary ammonium hydroxide or a basic inorganic oxide or hydroxide sufficient to neutralise the activity of the acidic catalyst. The drug preferably in salt form or in dispersion, can then be added to and homogeneously distributed in the resulting mixture and subsequently the copolymerisation can be allowed to proceed to completion by the addition of further acidic catalyst.
  • Suitable acidic catalysts which may be used in the present process include inorganic acids such as hydrochloric acid and sulphuric acid, organic acids such as a paratoluenesulphonic acid etc and Lewis acids such as zinc chloride, tin tetrachloride, aluminium chloride and ferric chloride. The preferred acidic catalyst is ferric chloride. The amount of acidic catalyst used is not critical, but it is expedient to use from 0.01 % to 2.0%, particularly from 0.04% to 1.0% based on the total weight of the mixture.
  • The ratio of the compound of formula I to the compound having two or more groups selected from OH and COOH groups can be varied. It is convenient to use stoichiometric amounts, although the use of amounts which deviate considerably from stoichiometry is also possible.
  • The copolymerisation may also be carried out in the presence of an inert pharmaceutically acceptable solvent or an inert pharmaceutically acceptable oil, whereby the nature of the resulting medicinal composition is modified. An example of such an oil is olive oil. The inert pharmaceutically acceptable solvent or oil may be added as such or it may serve as a solvent or dispersant for other components of the copolymerisation mixture. Thus, for example, the drug may be dissolved or dispersed in the inert pharmaceutically acceptable solvent or oil.
  • The following is a simplified representation of the preparation of a cross-linked copolymer using the compound of formula I and glycerol:
    Figure imgb0003
  • Following administration of the compositions of this invention to the body, the drug is gradually released therefrom over a prolonged period and, at the same time, the copolymer is biodegraded to substances which can be readily disposed of by the body. As mentioned earlier, the copolymer is preferably one formed between the compound of formula I and a compound which occurs naturally in and/or is benign to the human body. Hydrolysis, especially acid hydrolysis, of such copolymers yields predominantly the latter compounds themselves. In the case of a copolymer prepared using glycerol as illustrated hereinbefore, the hydrolysis fragments of the compound of formula I are the following:
    Figure imgb0004
    Figure imgb0005
    all of which are readily oxidisable for disposal by the body.
  • The rate of release of the drug from a composition provided by this invention can be controlled by a variety of methods. For example, in a copolymer prepared using given components the density of the cross-linking can be altered. Again, for example, the nature and amount of inert pharmaceutically acceptable solvent or oil which may be present in the composition can be varied.
  • A particular feature of compositions provided by the present invention which are based on cross-linked copolymers (i.e. matrices) is that such copolymers have a so-called glassy state (in which they are hard and brittle) and a rubber-like state, the change from the glassy state to the rubber-like state occurring at the so-called glass transition temperature. Following administration of such a composition having the copolymer in the glassy state the drug is gradually released and, at the same time, the copolymer is gradually biodegraded, this resulting in gradual reduction of the glass transition temperature. When the glass transition temperature is reached the rubber-like state occurs and the copolymer becomes more rapidly biodegraded. Thus, if the glass transition temperature reaches body temperature, there is a rapid onset in the degradation. It will accordingly be evident that it is highly desirable to provide compositions based on cross-linked copolymers which initially have a glass transition temperature which lies somewhat above body temperature.
  • The compositions provided by the present invention may be administered for example by subcutaneous or intramuscular injection or implantation. In the case of forms for injection a composition of appropriate particle size can be dispensed in a pharmaceutically acceptable carrier material adapted for subcutaneous or intramuscular administration. By appropriate choice of particle size and particle size distribution in the dispersant the rate of release of the drug can be controlled. Forms adapted for implantation include, for example, pellets, films, discs and rods. Such implant forms can be prepared in a conventional manner.
  • In many cases it is of advantage to include in the composition of the invention a combination of drugs to obtain most effective prophylaxis or treatment of a tropical disease.
  • The following Examples describe embodiments of the present invention.
    • Example 1
  • The following ingredients were used to prepare a pharmaceutical composition consisting of a polymer matrix having a mole ratio of compound I to glycerol of 3:2
    Figure imgb0006
  • A solution of the ferric chloride in the glycerol is warmed to 80°C and the compound I is added dropwise while warming and stirring between the additions. Compound I is initially incompatible with the glycerol, but by gradual additions and warming until the mixture becomes one phase, a stage is reached when the glycerol mixture will more readily accept the additions of compound I and become homogeneous.
  • After stoichiometric amounts of compound I to glycerol have been reached, the mixture is removed from the heating source and the amodiaquine is added to form a dispersion in the monomer mixture. A temperature of 80°C is maintained until polymerisation is complete and the desired polymer matrix is obtained containing 5% of amodiaquine by weight.
  • The dispersion referred to in the preceding paragraph can be used to prepare discs for implantation as follows:
    • Prior to the final polymerisation stage, the dispersion is spread on a film of polyethylene, covered with a second film of polyethylene and placed in a press which, when closed, leaves a gap between the polyethylene films of the desired thickness for the copolymer matrix. A temperature of 80°C is applied until polymerisation is complete. The film of amodiaquine/polymer matrix is punched while still soft to produce flat discs and, after hardening has taken place, the polyethylene backing is peeled off.
    Example 2
  • According to the procedure described in Example 1, the following ingredients were used to prepare a polymer matrix containing amodiaquine.
    Figure imgb0007
  • This produced a composition containing 20% by weight of amodiaquine dispersed in the polymer matrix.
    • Example 3
  • According to the method of Example 1, the following ingredients were used to prepare a composition comprising a dispersion of 25.8% of sulphamethizole in a polymer matrix.
    Figure imgb0008
    • Example 4
  • According to the method of Example 1, the following ingredients were used to prepare a polymer matrix containing cycloguanil
    Figure imgb0009
  • The composition was worked-up as pellets for subcutaneous implantation 6 mm in diameter and 2 mm thick.
  • In tests on mice prolonged effectiveness against Plasmodium Bergei has been observed over periods in excess of three months.
    • Example 5
  • According to the method of Example 1, the following ingredients were used to prepare a polymer matrix containing sulphadiazine (SDA)
    Figure imgb0010
  • The composition was worked-up as a powder and as an implant of the same dimensions as in Example 4.
  • The powdered product was tested in powder form of particle size (a) <53p and (b) 53―96µ. The powder (a) was suspended in glycerol and injected into the test mice: powder (b) was implanted. Prolonged protection in excess of five months of the test mice against the action of Plasmodium Bergei has been observed.
    • Example 6
  • According to the method of Example 1, the following ingredients were used to prepare a polymer matrix containing pyrimethamine.
    Figure imgb0011
  • The product was formed into a pellet for subcutaneous implantation into test mice. The mice were protected against Plasmodium Bergei for periods in excess of three months.

Claims (9)

1. A pharmaceutical composition comprising a polymeric matrix of a copolymer of the compound of Formula I.
Figure imgb0012
with at least one comonomer having more than one functional group selected from hydroxyl and carboxyl groups, characterised in that the composition contains in admixture with the polymeric matrix a drug which is an organic nitrogen compound of basic reaction and which is effective against a tropical disease.
2. A pharmaceutical composition according to claim 1, in which the polymeric matrix is a copolymer of glycerol and the compound of Formula defined in claim 1.
3. A pharmaceutical composition according to claim 2, in which the molar ratio of the compound of Formula I defined in claim 1 to glycerol is 3:2.
4. A pharmaceutical composition according to claim 2 or 3, in which the copolymer is prepared under acid catalysis in the presence of the basic drug, the acidic catalyst being used in an amount sufficiently in excess of that required to neutralise the basic drug so as to catalyse the copolymerisation.
5. A pharmaceutical composition according to claim 4, in which the catalyst is ferric chloride.
6. A pharmaceutical composition as claimed in claim 1 consisting of the product obtained by reacting
17% by weight of glycerol,
73.8% by weight of a compound of Formula I defined in claim 1,
0.2% by weight of ferric chloride as a catalyst, in the presence of
10% by weight of cycloguanil.
7. A pharmaceutical composition as claimed in claim 1 consisting of the product obtained by reacting
20% by weight of glycerol,
69.8% by weight of a compound of Formula I defined in claim 1, and
0.2% by weight of ferric chloride as a catalyst, in the presence of
10% by weight of sulphadiazine.
8. A pharmaceutical composition as claimed in claim 1 consisting of the product obtained by reacting
15% by weight of glycerol,
54.8% by weight of a compound of Formula I defined in claim 1, and
0.2% by weight of ferric chloride, as a catalyst, in the presence of
30% by weight of sulphadiazine.
9. A pharmaceutical composition as claimed in claim 1 consisting of the product obtained by reacting
15% by weight of glycerol,
54.7% by weight of a compound of Formula I defined in claim 1, and
0.3% by weight of ferric chloride as a catalyst, in the presence of
30% by weight of pyrimethamine.
EP78300112A 1977-06-28 1978-06-28 A pharmaceutical composition for tropical diseases Expired EP0000291B1 (en)

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GB2691877 1977-06-28

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EP0000291B1 true EP0000291B1 (en) 1981-09-30

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Families Citing this family (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0067671B1 (en) * 1981-06-12 1989-11-15 National Research Development Corporation Hydrogels
JPS585316A (en) * 1981-06-12 1983-01-12 ナショナル・リサーチ・ディベロップメント・コーポレイション hydrogel
DE3279999D1 (en) * 1981-09-30 1989-11-30 Nat Res Dev Compositions comprising encapsulated particles
DE3278126D1 (en) * 1981-09-30 1988-03-31 Nat Res Dev Sustained release compositions
GB8319766D0 (en) * 1983-07-22 1983-08-24 Graham N B Controlled release device
US4639366A (en) * 1984-06-06 1987-01-27 Merck & Co., Inc. Polymers containing pendant acid functionalities and labile backbone bonds
US5342624A (en) * 1989-02-16 1994-08-30 British Technology Group Ltd. Dispensing device
NZ239370A (en) * 1990-08-22 1994-04-27 Merck & Co Inc Bioerodible implantable controlled release dosage form comprising a poly(ortho ester) or a polyacetal with an active agent incorporated into the chain backbone
NZ587549A (en) 2004-06-24 2012-10-26 Vertex Pharma 6-Amino-indole derivatives and processes for their preparation
CA2635581C (en) 2005-12-28 2017-02-28 Vertex Pharmaceuticals Incorporated Solid forms of n-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US12458635B2 (en) 2008-08-13 2025-11-04 Vertex Pharmaceuticals Incorporated Pharmaceutical composition and administrations thereof
US20100074949A1 (en) 2008-08-13 2010-03-25 William Rowe Pharmaceutical composition and administration thereof
PL2408750T3 (en) 2009-03-20 2016-02-29 Vertex Pharma Process for making modulators of cystic fibrosis transmembrane conductance regulator
AU2013226076B2 (en) 2012-02-27 2017-11-16 Vertex Pharmaceuticals Incorporated Pharmaceutical composition and administration thereof
KR20170063954A (en) 2014-10-07 2017-06-08 버텍스 파마슈티칼스 인코포레이티드 Co-crystals of modulators of cystic fibrosis transmembrane conductance regulator
US20180066081A1 (en) * 2015-02-09 2018-03-08 University Of Iowa Research Foundation Substituted cyclic ether polymers and conjugates and uses thereof

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL134014C (en) * 1960-11-16 1900-01-01
US3318846A (en) * 1963-05-10 1967-05-09 Shell Oil Co Resinous products from unsaturated heterocyclic compounds and method for preparing the same
GB1105457A (en) * 1963-12-03 1968-03-06 Ici Ltd Thermohardening resin compositions
US3911098A (en) * 1974-02-11 1975-10-07 American Cyanamid Co Medicament carrier
GB1572598A (en) * 1975-12-29 1980-07-30 Univ Strathclyde Injectable medicinal compounds

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DE2861226D1 (en) 1981-12-10
EP0000291A1 (en) 1979-01-10
US4221779A (en) 1980-09-09
HK95786A (en) 1986-12-19
JPS5441319A (en) 1979-04-02
JPS6148483B2 (en) 1986-10-24

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