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WO2002053624A1 - Polymeres reticules contenant du disulfure pour l'administration de medicaments - Google Patents

Polymeres reticules contenant du disulfure pour l'administration de medicaments Download PDF

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Publication number
WO2002053624A1
WO2002053624A1 PCT/GB2001/005787 GB0105787W WO02053624A1 WO 2002053624 A1 WO2002053624 A1 WO 2002053624A1 GB 0105787 W GB0105787 W GB 0105787W WO 02053624 A1 WO02053624 A1 WO 02053624A1
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Prior art keywords
polymer
trithiol
formula
alkyl
crosslinked
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PCT/GB2001/005787
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English (en)
Inventor
Sukhvinder Bansal
Gary Martin
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Kings College London
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Kings College London
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G83/00—Macromolecular compounds not provided for in groups C08G2/00 - C08G81/00
    • C08G83/002—Dendritic macromolecules
    • C08G83/003—Dendrimers
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4891—Coated capsules; Multilayered drug free capsule shells
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/39—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
    • C07C323/40—Y being a hydrogen or a carbon atom
    • C07C323/41—Y being a hydrogen or an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms

Definitions

  • the present invention relates to polymers which are crosslinked by means of disulphide bonds and which degrade at the low redox potential existing at various sites in the body.
  • Such polymers allow the production of delivery devices for targetted delivery of active agent to such low redox sites, which include the colon, the ischaemic heart, the brain after a stroke, rheumatoid joints and tumours. Generally, these sites are characterised by low oxygen content. Also included are novel monomers and polymers and processes of production thereof.
  • Orally administered drugs are usually intended for rapid dissolution in the upper gastrointestinal (GI) tract, where many drugs are most effectively absorbed.
  • GI gastrointestinal
  • this approach is inadequate, costly and associated with undesirable adverse effects.
  • Table 1 For the treatment of a number of localised diseases of the colon (Table 1), there is a need to develop dosage systems that release the pharmacologically active agent selectively and reproducibly exclusively within the large bowel.
  • Cancer Chemotherapeutic agents There is also interest in investigating the potential of the colon as a suitable site for the uptake of macromolecules such as peptides, proteins and oligonucleotides since enzymatic activity is markedly less than that in the small intestine.
  • the colonic delivery of drug is an appropriate strategy if it is required to delay the release of drugs after oral administration.
  • This might be of relevance for the effective treatment of diseases such as asthma and rheumatoid arthritis. Both of these diseases might be treated more effectively if a drug could be taken orally before sleep, but release of the drug is delayed until just prior to waking to provide cover for 'morning dip' in asthma or immediate pain relief for rheumatic patients. Triggered colonic release of the drug could thus have a role in such chronopharmacological events.
  • Fig. 1 A number of strategies are available to delay release of drug until the dosage form reaches the lower bowel. Some of the key physiological features of the gastrointestinal tract that have or may be utilised to induce the release of drug selectively in the colon are shown in Fig. 1.
  • Dosage forms can therefore be coated with hydrophobic or slow swelling polymers with a view to inhibiting release for a set time period to allow transit through the upper intestinal tract. This is an unreliable strategy since transit time exhibits high inter- and intra-subject variability.
  • the time for a dosage form to pass through the stomach can vary from hours to minutes and is dependent upon the size of the dosage form and whether the stomach is in a fed or fasted state.
  • the pH profile within the gastrointestinal tract offers another approach.
  • Polymers such as the Eudragit resins have been utilised as enteric coats. These provide protection to the drug as it passes through the stomach but start to disintegrate and dissolve at the lower pH extant in the small intestine.
  • the difficulty of this approach is that although the pH rises as the dosage form moves from the stomach to the small intestine, upon passing through the ileocaecal valve the pH falls again as a consequence of fatty acid fermentation. It is thus difficult to formulate the drug using a single polymer and double-coating methods have to be employed using two polymers that dissolve at different pH. This is neither easy to undertake. nor a completely reliable means of achieving colonic targeting.
  • Sophisticated dosage forms such as the Pulsincap have relied upon a combination of pH triggered dissolution followed by a controlled swelling of a hydrophilic plug. Complete reliability of such an approach has however not been proven.
  • Patent specification W091/11175 and WO96/10994 disclose disulphide bonded polymers which are cleaved by reductive medium present in the colon. These are linear polymers (not crosslinked).
  • US patent specifications 5,496,872 and 5,646,239 disclose crosslinked disulphide polymers for use as surgical cements. It is not disclosed whether the polymers degrade in the colon.
  • a first aspect of the invention provides a crosslinked polymer, the polymer being crosslinked by means of disulphide bonds, which degrades at low redox potential sites in the body.
  • the crosslinking is not necessarily exclusively by disulphide bonds and may include other types of bonding.
  • Sites in the body which may have low redox potential and are therefore targets for the present invention include the colon, the ischaemic heart, the brain post- stroke, rheumatoid joints and tumours.
  • the low redox potential generally derives for a low oxygen concentration at such sites, often due to impaired blood supply to the site.
  • cells within large solid tumours may be hypoxic (oxygen deficient) due to poor blood supply within the tumour.
  • an important application of the present invention is drug delivery to the colon where low redox conditions prevail due to microbiological processes occurring there.
  • the disulphide crosslinked polymer will degrade at the colon redox potential, but is otherwise insoluble in the fluid of the gastro intestinal tract. At the low redox potential in the colon, the disulphide bonds are reduced to thiols, thereby depolymerising and degrading these redox-sensitive polymers.
  • the degradation products and the polymer itself will be chosen to be biologically acceptable and non-toxic to the human (or animal) to which it is to be delivered.
  • the polymer can be prepared from thiol-containing monomers; or alternatively monomers/prepolymers already containing -S-S- links can be polymerised to form the crosslinked polymer.
  • the redox potential in such low redox sites is generally below -50mN, particularly below -150mN and especially below -250mN.
  • the polymer will degrade at redox potentials below these values, and especially in the ranges -50 to -700mN, particularly -200 to -600mN, and especially -300 to -600mN.
  • a second aspect of the invention provides a delivery device for delivering an active agent to low redox sites, which comprises an active agent; access to the active agent by fluid being controlled by a polymer crosslinked by disulphide bonds, which degrades at the low redox potential in the site.
  • the crosslinked disulphide polymer may be employed in a variety of delivery device constructions.
  • the polymer could be used to form a capsule to encapsulate the active agent or to embed the active agent in a polymer matrix.
  • the polymer could be used to coat a capsule, such as a water-soluble gelatin capsule containing the active agent, the coating degrading in the colon to give access of the colonic fluid to the gelatin capsule.
  • a further approach is to form the polymer into the plug of a delayed delivery device (e.g. a so- called "Pulsincap” device).
  • a delayed delivery device e.g. a so- called "Pulsincap” device.
  • Such a device generally contains an enclosure containing the active agent and closed by means of the polymer plug. Degradation of the polymer plug in the colon allows access of the colonic fluid to the active agent.
  • a third aspect of the present invention provides a trithiol of general formula (I) (but excluding the tripeptide ⁇ H 2 CysCysCysCOOH )
  • A straight or branched alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl
  • Rl H or R 1 2
  • R2 H or COR 11
  • R 1 H, alkyl, or an amino acid or peptide residue
  • R ⁇ OH, or an amino or peptide residue and alkyl is C ⁇ -C ⁇ j alkyl.
  • a and K are, of course, trivalent groups.
  • A is Q,_-C(, alkyl, and particularly is C 2 -alkyl.
  • Aryl includes benzyl and napthyl.
  • Heteroaryl includes six membered heterocycles where a CH in benzene has been replaced by NH or O (e.g. pyrrole, thiophene or furan).
  • Optional substituents include alkyl, alkoxy, OH, NH 2 , NO 2 , CHO, COOH, halo (chloro, bromo etc.) and sulphonyl.
  • Rl is -NR X 2 it is usually NH 2 or NHR 1
  • R2 is COOR it is usually COOH.
  • R 1 and R 11 may be single amino acid residues or peptide residues containing 2 to 6 amino acids.
  • a fourth aspect of the invention provides a dimer, trimer or polymer produced by polymerising the triol so as to produce one or more disulphide bonds.
  • a fifth aspect of the invention provides a process of producing a trithiol of general formula (I) where R 1 and R 2 are H and B is CONH, which comprises; i) converting a compound of formula (II)
  • a sixth aspect of the invention provides an alternative process of producing a trithiol of general formula (I) where Rl and R2 are H, which comprises; i) converting a compound of formula (II) given above to a compound of formula (IN)
  • polymerisation of trithiols be carried out under controlled conditions such as to form dimers, trimers or polymers and particular three-dimensional structures, such as dendrimers (as discussed hereafter).
  • the bacterial biochemical processes generate a cascade of electrons, which are passed from one small molecular weight carrier to another via a series of oxidation-reduction processes (Fig 3).
  • suitable molecules can provide a 'sink' for the available electrons and in the process become reduced.
  • disulphide-containing polymer molecules are present under anaerobic conditions the disulphide bonds can be reduced to thiols. It is important to appreciate that this is not dependent upon the presence of any particular bacterial species but simply occurs as a consequence of the anaerobic environment. Racial differences in patients would not be expected to be significant.
  • Disulphide bonds are commonly found in peptides and proteins and have been used as drug-glutathione conjugates which are reductively cleaved in the the colon.
  • the intrinsic stability of a disulphide relative to thiol groups is determined by the redox potential of the environment since the formation or cleavage the disulphide requires, respectively, a suitable electron acceptor (A) or donor (D)
  • Thiols are reactive only in their ionised, thiolate anion form (pKa 8-9) and the reactivity of thiols decreases by an order in magnitude with each pH unit.
  • the cross-linked disulphide polymers can in principle be manufactured using a number of strategies including the condensation of a carboxylic acid with an alcohol to afford an ester or the condensation of a carboxylic acid with an amine to afford an amide.
  • a cross-linked polymer would be produced where one or more of the monomers containing two or more functionally reactive groups are reacted.
  • An interesting approach to the synthesis of cross-linked disulphide polymers involves the formation of a disulphide with a compound containing three or more thiol groups. Alternatively co-polymerisation can be effected with compounds containing thiol groups.
  • the disulphide bond may be present in one or more of the monomers used to produce the polymer, or it may be generated during polymerisation by condensation of two thiol groups.
  • One of the design features of the polymers requires that the polymers are insoluble within the gastro-intestinal tract, and this can be achieved by avoiding charged groups in the structure at Ri, R 2 or R 3 .
  • the bi-products should be non-toxic. This design feature is achieved by the use of natural amino acids and therefore our design of disulphide polymers was based on cysteine derivatives (1, 2).
  • Rl can be a hydrogen or a substituted amine and R2 can be a hydrogen or a carboxylic acid derivative.
  • Rl can be a hydrogen or a substituted amine and R2 can be a hydrogen or a carboxylic acid derivative.
  • Rl and R2 could also incorporate appropriate groups to make different types of polymers.
  • the three free thiol groups can be utilised for the formation of the disulphides and it is also possible to synthesis co-polymer with a second monomer.
  • S-Trityl cysteine 3 was treated with trifluoroacetone to protect the amine and simultaneously activate the carboxyl group of cysteine 7.
  • Treatment of the product with S-tritylcysteamine gave the amine 8 which was acylated with S-trityl thiopropanoic acid and finally the trityl groups were removed to yield the trithiol 6 (Scheme 3).
  • Disulphide Polymers Most polymerisation reactions involve the formation of carbon-carbon, carbon- oxygen or carbon-nitrogen bonds. All of these reactions involve reactive intermediates for example activated carboxylic acid derivatives, carbocations, carboanions or free radicals. It can thus become difficult to carry out the polymerisation in the presence of the drug substance and can be a major limitation of microencapsulation procedures. Thiols can be oxidised to disulphides under mild conditions, which do not oxidise many drug substances. Disulphide polymers have considerable applications therefore as biodegradable and pharmaceutically acceptable polymers. In the general model the three free thiols are used to cross-link the polymers via disulphide bonds while the amine and carboxylic acid groups can be modified to introduce specific properties on the polymers.
  • Dendrimers are highly branched three-dimensional macromolecules, with all bonds emanating from a central core. Dendrimers have attracted considerable interest because of their unique structure. Compared to linear polymers, dendrimers have much more accurately controlled structures, with a globular shape, a single molecular weight rather than a distribution of weights and a large number of controllable 'peripheral' functionalities. These properties make dendrimers excellent evaluation candidates for as drug carriers. Dendrimers can be utilised as potential drug delivery agents in various ways. Drug molecules can be physically entrapped inside the dendrimer structure (or alternatively the drug molecule can be covalently attached to the surface or other functionalities to afford a dendrimer-drug conjugate).
  • the trithiol derivatives may be used to prepare dendrimer wedges containing thiol groups. These wedges may be oxidised in the presence of the drug substance to form a spherical dendrimer with the drug substance encapsulated in the dendrimer.
  • the synthesis of a two generation dendrimer wedge is shown in Scheme 5. It is preferred to synthesise a dendrimer wedge to at least the fourth generation or more but it will be dependent on the reactivity of the higher generations.
  • Figure 1 shows the bacterial content, pH and redox potential through the gastroinstestinal tract
  • Figure 2 shows the change in redox potential as a function of time after swallowing of a radiotelemetry capsule by a human volunteer
  • Figure 3 shows oxidation-reduction processes which occur within the colon due to the presence of various bacteria
  • Figure 4 shows dissolution profiles for disulphide polymer coated capsules.
  • 1,2,3-propanetricarboxylic acid (0.42g, 2.38 mmole) and N- hydroxybenzotriazole(lg, 7.13 mmole) were added and the reaction mixture was cooled to 0°C and dicyclohexycarbodiimide (1.6g, 7.8 mmole) was introduced in small portions and the reaction mixture stirred at 0°C for 18h.
  • the precipitated dicyclohexylurea was removed by filtration and the residue was extracted successively with citric acid (30 ml, 5 % w/v), sodium hydrogen carbonate (30 ml, 5% w/v) and water.
  • the precipitated dicyclohexylurea was removed by filtration and the residue was extracted successively with citric acid, sodium hydrogen carbonate and water. The solvent was removed under reduced pressure to give an oil, which was chromatographed on silica gel using ethylacetate :
  • Triethylamine was added to a solution of (R)-3-mercapto-N-(2-mercaptoethyl-2-(3- mercaptopropionylamino) propionamide ( 1.0 g) in aqueous methanol (95% v/v, 15 ml) and the pH of the solution was adjusted to (7.4 - 7.8).
  • a gelatin capsule containing carboxyfluoresceine and sealed with methanol was added and the solution was stirred for 18 h. The resulting capsule showed a coating of polymer, the capsule was washed with water and methanol.
  • a gelatin capsule containing carboxyfluoresceine was sealed with methanol and some string was attached to the capsule.
  • the capsule was dipped into a concentrated solution of (R)-3-mercapto-N-(2-mercaptoethyl-2-(3-mercapto propionylamino)propionamide (0.5g) in dichloromethane.
  • the capsule was then air dried and dipped into an oxidation solution of [(diacetoxyiodo) benzene]. This two- step dipping procedure was repeated twenty times to produce the coated capsule. Dissolution of the capsule was carried out under conditions of low redox.
  • the polymer can be deposited onto a conventional hard gelatin capsules or the monomer can be deposited onto the capsule followed by oxidation to polymerise the monomer. This can be performed by dipping a preformed hard gelatin capsule into the monomer solution. In past experiments, using non-optimised conditions, we found that this approach lead to a heterogeneous layer of the polymer on the capsule. This application process was improved by repeatively painting the monomer solution followed by oxidation. We have successfully utilised this latter strategy. It is also possible to spray a layer of the monomer on the preformed capsule under acidic conditions followed by air oxidation at or above pH 7.
  • Carboxyfluoresceine (as a test substance) was filled into some capsules of a size suitable for small animal studies and the capsules were sealed. A solution of the monomer in dichloromethane was painted onto the capsules followed by an oxidising solution of iodobenzenediacetate, which resulted in a coating of the polymer on the outside of the capsules. The process of coating with monomer followed by oxidising solution was repeated until a thick and homogenous coat was obtained.
  • Dissolution was carried out in 0.1 M HCl on four coated capsules using the USP paddle method
  • Dissolution from control capsules was complete within two hours in 0.1 M HCl, the longer than usual dissolution time being attributed to the treatment with solvent. There was no release of fluorescent marker from the polymer-coated capsules within two hours. The capsules were transferred to buffer pH 7.4 and dissolution continued for a further 3 h. Minimal release of marker occurred from the six capsules, although some capsules did develop pin-hole leakage. This was attributed to the crude coating technique employed in these studies. New capsules were prepared and the dissolution studies repeated in buffer using an enzyme system based upon glucose-6-dehydrogenase. Redox potentials of the order of 300 mV were produced in situ and the dissolution carried out using conditions based upon the USP paddle method.
  • the capsules under these conditions of low redox potential took on an altered appearance within 30 min.
  • the capsules contracted in size and release of fluorescent marker started within 2 h.
  • Dye was released from 'weakened' areas upon the capsule surface. More rapid release of the dye would have occurred under more vigorous stirring conditions such as those provided by retropropulsion and peristaltic movement within the colon.
  • Treatment of the capsule shell with dichloromethane undoubtedly impedes capsule dissolution in its own right and it is important to develop more refined coating procedures.
  • Figure 1 Bacterial content, pH and redox potential of, and time of transit through, the gastrointestinal tract.
  • Figure 2 The change in redox potential as a function of time. After the swallowing of a radiotelemetry capsule by a human volunteer.
  • Figure 3 Examples of oxidation-reduction processes which occur within the colon, as a consequence of the presence of bacteria.
  • Figure 4 The dissolution of control (uncoated, dichloromethane treated) and disulphide-polymer coated capsules in 0. IM HCl using the USP paddle method.

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Abstract

Cette invention se rapporte à un polymère réticulé au moyen de liaisons disulfure et dégradant à faible rédox des sites potentiels dans le corps humain (par exemple le colon, le site d'une cardiopathie ischémique, le cerveau après un accident vasculaire cérébral, des articulations rhumatoïdes, des tumeurs, notamment), ce polymère étant utilisé pour former un dispositif d'administration pour l'administration sélective d'un agent actif sur le site en question. Des monomères utiles pour la production de ces polymères réticulés à base de disulfure sont les trithiols représentés par la formule (I), où A représente alkyle droit ou ramifié, aryle substitué ou insubstitué, ou hétéroaryle substitué ou insubstitué; B représente NH, NHCO ou CONH; K représente alkyle droit ou ramifié; D représente une liaison, CONH-alkylidène ou NHCO-alkylidène; R1 représente H ou NR12; R2 représente H ou COR11; R1 représente H, alkyle, ou un résidu aminoacide ou peptide; R11 représente OH, ou un résidu amino ou peptide; et alkyle représente alkyle C¿1?-C6.
PCT/GB2001/005787 2001-01-05 2001-12-28 Polymeres reticules contenant du disulfure pour l'administration de medicaments Ceased WO2002053624A1 (fr)

Applications Claiming Priority (2)

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GB0100253.4 2001-01-05
GB0100253A GB0100253D0 (en) 2001-01-05 2001-01-05 Crosslinked disulphide containing polymers for drug delivery

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104045766A (zh) * 2014-07-01 2014-09-17 西北师范大学 基于联咪唑类离子液体的氧化还原响应性纳米粒子及其制备方法
CN106380430A (zh) * 2016-09-05 2017-02-08 吉尔生化（上海）有限公司 一种3‑(三苯甲硫基)丙酸的合成方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996010994A1 (fr) * 1994-10-05 1996-04-18 Danbiosyst Uk Ltd. Procede de preparation de polymeres specifiques sensibles au milieu reducteur du colon
US5646239A (en) * 1993-07-21 1997-07-08 Flamel Technologies Organic products containing reactive thiol functions, one method for preparing same, and biomaterials containing said products

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5646239A (en) * 1993-07-21 1997-07-08 Flamel Technologies Organic products containing reactive thiol functions, one method for preparing same, and biomaterials containing said products
WO1996010994A1 (fr) * 1994-10-05 1996-04-18 Danbiosyst Uk Ltd. Procede de preparation de polymeres specifiques sensibles au milieu reducteur du colon

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104045766A (zh) * 2014-07-01 2014-09-17 西北师范大学 基于联咪唑类离子液体的氧化还原响应性纳米粒子及其制备方法
CN104045766B (zh) * 2014-07-01 2016-08-24 西北师范大学 基于联咪唑类离子液体的氧化还原响应性纳米粒子及其制备方法
CN106380430A (zh) * 2016-09-05 2017-02-08 吉尔生化（上海）有限公司 一种3‑(三苯甲硫基)丙酸的合成方法

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