EP0000291B1 - Composition pharmaceutique contre les maladies tropicales - Google Patents

Composition pharmaceutique contre les maladies tropicales Download PDF

Info

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
Authority
EP
European Patent Office
Prior art keywords
weight
compound
pharmaceutical composition
formula
acid
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
Application number
EP78300112A
Other languages
German (de)
English (en)
Other versions
EP0000291A1 (fr
Inventor
Neil Bonnette Graham
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Strathclyde
Original Assignee
University of Strathclyde
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by University of Strathclyde filed Critical University of Strathclyde
Publication of EP0000291A1 publication Critical patent/EP0000291A1/fr
Application granted granted Critical
Publication of EP0000291B1 publication Critical patent/EP0000291B1/fr
Expired legal-status Critical Current

Links

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.
  • 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.

Landscapes

  • 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)

Claims (9)

1. Une composition pharmaceutique comprenant une matrice polymérique d'un copolymère du composé de la Formule I.
Figure imgb0014
avec au moins un comonomère ayant plus d'un groupe fonctionnel sélectionné des groupes hydroxyles et carboxyles caractérisée de par le fait que la composition contient un médicament en mélange avec la matrice polymérique, qui est un composé d'azote organique de réaction basique et qui est efficace contre une maladie tropicale.
2. Une composition pharmaceutique suivant la revendication 1 dans laquelle la matrice polymérique est un copolymère de glycérol et le composé de la Formule 1 défini dans la revendication 1.
3. Une composition pharmaceutique suivant la revendication 2 dans laquelle le rapport molaire du composé de la Formule I défini dans la revendication 1 au glycérol est de 3:2.
4. Une composition pharmaceutique suivant la revendication 2 ou 3 dans laquelle le copolymère est préparé sous catalyse acide en présence du médicament de base, le catalyseur acide étant utilisé en quantité dépassant suffisamment celle nécessaire pour neutraliser le médicament de base de sorte que la copolymérisation est catalysée.
5. Une composition pharmaceutique suivant la revendication 4 dans laquelle le catalyseur est le chlorure ferrique.
6. Une composition pharmaceutique suivant la revendication 1 comprenant le produit obtenu en faisant réagir
17% en poids de glycérol
73,8% en poids d'un composé de la Formule 1 défini dans la revendication 1,
0,2% en poids de chlorure ferrique comme catalyseur, en présence de
10% en poids de cycloguanil.
7. Une composition pharmaceutique suivant la révendication 1 comprenant le produit obtenu en faisant réagir
20% en poids de glycérol,
69,8% en poids d'un composé de la Formule I défini dans la revendication 1 et
0,2% en poids de chlorure ferrique comme catalyseur, en présence de
10% en poids de sulfadiazine.
8. Une composition pharmaceutique suivant la revendication 1 comprenant le produit obtenu en faisant réagir
15% en poids de glycérol,
54,8% en poids d'un composé de la Formule défini dans la revendication 1 et
0,2% en poids de chlorure ferrique comme catalyseur, en présence de
30% en poids de sulfadiazine.
9. Une composition pharmaceutique suivant la revendication 1 comprenant le produit obtenu en faisant réagir
15% en poids de glycérol,
54,7% en poids d'un composé de la Formule I défini dans la revendication 1 et
0,3% en poids de chlorure ferrique comme catalyseur, en présence de
30% en poids de pyriméthamine.
EP78300112A 1977-06-28 1978-06-28 Composition pharmaceutique contre les maladies tropicales Expired EP0000291B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB2691877 1977-06-28
GB2691877 1977-06-28

Publications (2)

Publication Number Publication Date
EP0000291A1 EP0000291A1 (fr) 1979-01-10
EP0000291B1 true EP0000291B1 (fr) 1981-09-30

Family

ID=10251259

Family Applications (1)

Application Number Title Priority Date Filing Date
EP78300112A Expired EP0000291B1 (fr) 1977-06-28 1978-06-28 Composition pharmaceutique contre les maladies tropicales

Country Status (5)

Country Link
US (1) US4221779A (fr)
EP (1) EP0000291B1 (fr)
JP (1) JPS5441319A (fr)
DE (1) DE2861226D1 (fr)
HK (1) HK95786A (fr)

Families Citing this family (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS585316A (ja) * 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 ハイドロゲル
EP0067671B1 (fr) * 1981-06-12 1989-11-15 National Research Development Corporation Hydrogels
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
US20100074949A1 (en) 2008-08-13 2010-03-25 William Rowe Pharmaceutical composition and administration thereof
DK1773816T3 (en) 2004-06-24 2015-01-26 Vertex Pharma Modulators of ATP-binding cassette transporters
JP5409010B2 (ja) 2005-12-28 2014-02-05 バーテックス ファーマシューティカルズ インコーポレイテッド Ｎ−［２，４−ビス（１，１−ジメチルエチル）−５−ヒドロキシフェニル］−１，４−ジヒドロ−４−オキソキノリン−３−カルボキサミドの固体形態
NZ624460A (en) 2009-03-20 2015-12-24 Vertex Pharma Process for making modulators of cystic fibrosis transmembrane conductance regulator
CN104470518A (zh) 2012-02-27 2015-03-25 沃泰克斯药物股份有限公司 药物组合物及其施用
CA2963945C (fr) 2014-10-07 2023-01-10 Vertex Pharmaceuticals Incorporated Co-cristaux de modulateurs du regulateur de conductance transmembranaire de la mucoviscidose
WO2016130527A1 (fr) * 2015-02-09 2016-08-18 University Of Iowa Research Foundation Polymères d'éther cyclique substitué, et leurs conjugués et utilisations

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL271416A (fr) * 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

Also Published As

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

Similar Documents

Publication Publication Date Title
EP0000291B1 (fr) Composition pharmaceutique contre les maladies tropicales
JP2660401B2 (ja) 注射用徐放性マイクロカプセル
EP0635272B1 (fr) Copolymères absorbables liquides pour applications parenterales
Wise Handbook of pharmaceutical controlled release technology
Dahlmann et al. Synthesis and properties of biodegradable aliphatic polyesters
US4584188A (en) Hydrogels
EP0260415A2 (fr) Synthèse et utilisation de polyanhydrides à haut poids moléculaire
EP0113505B1 (fr) Polyesters hydrosolubles
EP3586825A1 (fr) Compositions pour l'administration de médicaments biodégradables
EP0797609A1 (fr) Polyesters
US4150108A (en) Injectable medicinal compositions
JPS61502760A (ja) 粘着性経皮投与層
EP0635531B1 (fr) Copolymères liquides à partir d'E-caprolactone et de lactide
WO2002092061A1 (fr) Poly(orthoesters) bioerodables issus de dicetene acetals a base de dioxolane
WO1995009613A1 (fr) Microspheres a liberation lente
US20020155092A1 (en) Phosphate based biodegradable polymers
JP2887414B2 (ja) 乳酸と酒石酸とからなる新規のコポリマー、その製造方法及びその用途
Fukuzaki et al. In vivo characteristics of high, molecular weight copoly (l-lactide/glycolide) with S-type degradation pattern for application in drug delivery systems
US5538738A (en) Retard systems for the sustained release of medicinal and/or biological valuable materials from a depot carrier material
Hou et al. Synthesis and erosion properties of PEG‐containing polyanhydrides
GB1572598A (en) Injectable medicinal compounds
US5254345A (en) Poly(orthocarbonate acetal) bioerodible polymers
Heller Control of polymer surface erosion by the use of excipients
EP0275961A2 (fr) Préparation médicale orale à libération prolongée
AU733802B2 (en) Sustainedly releasing agents for medicines and sustainedly released medicinal compositions containing the same

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AK Designated contracting states

Designated state(s): CH DE FR GB

17P Request for examination filed
GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Designated state(s): CH DE FR GB

REF Corresponds to:

Ref document number: 2861226

Country of ref document: DE

Date of ref document: 19811210

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed
PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 19950525

Year of fee payment: 18

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CH

Payment date: 19950615

Year of fee payment: 18

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 19950630

Year of fee payment: 18

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 19950721

Year of fee payment: 18

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Effective date: 19960628

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CH

Effective date: 19960630

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 19960628

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FR

Effective date: 19970228

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DE

Effective date: 19970301

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST