Classifications

• • 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.
• compositions for use in the treatment of tropical disease comprising a drug which is an organic nitrogen compound of basic reaction and which is effective against tropical disease in admixture with a polymeric matrix of a copolymer of the compound of the formula with at least one compound having more than one functional group selected from OH and COOH groups.
• 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 OH or COOH group 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 a pararosaniline, salphamethizole, dapsone, sodium Sulpgoxone, sulphedrone, sodium hydnocarpe and sodium chauimoograte.
• the compound having two or more groups selected from OH and COOF 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:
• the ratio of drug to copolymer which can be present in the compositions of this invention can vary within wide limits.
• the weight of the drug is at least about equal to the weight of copolymer, and it may be possible to have a steroid to copolymer weight ratio of up to 90:10.
• a steroid to copolymer ratio of form about 50:50 by weight to about 60:40 by weight is particularly suitable.
• compositions of this invention are prepared by copolymerising a compound of formula I hereinbefore with at least one compound having more than one group selected from 01 and COOH groups in the presence of an acidic catalyst and in the presence of a drug 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 on known detrimental effect on skin. It may be prepared according to the following reaction sequence:
• the process 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 about 60°C to 100°C, especially at about 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 allo ed 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, sulphuric acid etc, organic acids such a paratoluenesulphonic acid etc and Lewis acids such as zinc chloride, tin tetrachloride, aluminium chloride, ferric chloride etc.
• the preferred acidic catalyst is ferric chloride.
• the amount of acidic catalyst used is not critical, but it is expedient to use from about 0.01% to 2.0%, particularly from about 0.04% to about 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 groupapea 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 following is a simplified representation of the preparation of a cross-linked copolymer using the compound of formula I and glycerol: Following administration of the compositions of this invention to the body, the drug is gradually released the from 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 copolym 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.
• the density of the cross-linking can be altered.
• 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 (i.e. matrices) is that such copolymers have a so-called glassy stat (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.
• glassy stat in which they are hard and brittle
• the copolymer is gradually biodegraded, this resulting in a 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.
• 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 dispersed 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, rods and the like. 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.
• 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 I According to the method of Example I, the following ingredients were used to prepare a polymer matrix containing cycloguanil The composition was worked-up as pellets for subcutaneous implantation 6mm in diameter and 2mm thick.
• Example 1 According to the method of Example 1, the following ingredients were used to prepare a polymer matrix containing sulnhadiazine (SDA) The composition was worked-up as a powder and as an implant of the same dimensions as in Example 4.
• SDA sulnhadiazine
• the powdered product was tested in powder form of particle size (a) 53 ⁇ 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)
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• Life Sciences & Earth Sciences (AREA)
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• General Health & Medical Sciences (AREA)
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Citations (4)

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• 1978
  • 1978-06-28 DE DE7878300112T patent/DE2861226D1/de not_active Expired
  • 1978-06-28 JP JP7753778A patent/JPS5441319A/ja active Granted
  • 1978-06-28 EP EP78300112A patent/EP0000291B1/de not_active Expired
  • 1978-06-28 US US05/920,056 patent/US4221779A/en not_active Expired - Lifetime
• 1986
  • 1986-12-11 HK HK957/86A patent/HK95786A/xx unknown

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