EP1263453A2 - Formulation pharmaceutique destinee a reguler la liberation dans le temps de composes biologiquement actifs a base d'une matrice polymere - Google Patents

Formulation pharmaceutique destinee a reguler la liberation dans le temps de composes biologiquement actifs a base d'une matrice polymere

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Publication number
EP1263453A2
EP1263453A2 EP01939971A EP01939971A EP1263453A2 EP 1263453 A2 EP1263453 A2 EP 1263453A2 EP 01939971 A EP01939971 A EP 01939971A EP 01939971 A EP01939971 A EP 01939971A EP 1263453 A2 EP1263453 A2 EP 1263453A2
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Prior art keywords
peptide
polymer
release
poly
samples
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Ceased
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EP01939971A
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German (de)
English (en)
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EP1263453A4 (fr
Inventor
Joachim B. Kohn
Deborah M. Schachter
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Rutgers State University of New Jersey
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Rutgers State University of New Jersey
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Ceased legal-status Critical Current

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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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7015—Drug-containing film-forming compositions, e.g. spray-on
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/593—Polyesters, e.g. PLGA or polylactide-co-glycolide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • 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)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to a new approach to the delayed or pulsed release of biologically active compounds having pharmaceutical activity, particularly peptides such as INTEGRILINTM, from a polymer matrix.
  • biologically active compounds having pharmaceutical activity particularly peptides such as INTEGRILINTM
  • peptides such as INTEGRILINTM
  • Ivermectin a water insoluble antiparasitic agent for veterinary applications
  • PLGA 50:50
  • Pulsed and delayed release of active agents from PLGA microspheres was most intensely studied by
  • the PLA or PLGA microspheres are processed using a high kinematic viscosity of polymer solution and a high ratio of polymer to aqueous solution. This produces dense microspheres, which require severe bulk erosion to release the drug. These conditions yield microspheres that have low loading (generally 1% w/w), moderate bursts, and lag times during which significant leaching of drug occurs.
  • a formulation containing a biologically active compound having a structure with hydrogen bonding sites, blended with a polymer having a structure with complementary hydrogen bonding sites, the polymer forming hydrolytic degradation products that promote the release of the biologically active compound from the polymer.
  • the formulation thus consists of two components, a polymer and an active compound blended together.
  • the present invention thus provides a formulation system that uses the degradation products of selected polymers to trigger the release of the active compound from the matrix of the polymer. Using this method, active compounds can be very simply formulated with the polymer and be programmed to be released at desired intervals, requiring no sophisticated barriers to prevent the premature release of the active agent.
  • the present invention also includes a method for the pulsatile delivery of a biologically active compound to a patent in need thereof comprising administering to the patient the formulation of the present invention.
  • This type of drug delivery is not only important for amino acid based drugs but also for hormonal based drug delivery. Fertility and birth control drug therapy for both animals and humans is not continuous, but rather cyclic in nature since these therapies work synergistically with the menstrual cycle and the corresponding hormonal flux. This is another direction in drug delivery in which this type of delayed pulsed release of an active agent would be applicable. Agricultural applications which require the timed dosing of fertilizers, weed-killers, and other active agents is another area where this invention would be important.
  • Figure 1 depicts the chemical structure of tyro sine-derived polyarylates
  • Figure 2 depicts the amino acid sequence of INTEGRILINTM
  • Figure 3 depicts release from poly(DTH adipate) films containing 30% (w/w) peptide
  • Figure 4 depicts release from D,L-PLA and poly( ⁇ -caprolactone) films containing 30% (w/w) peptide
  • Figure 5 depicts percent mass retention of poly(DTH adipate) samples containing 30% (w/w) peptide;
  • Figure 6 depicts percent mass retention data for D.L-PLA samples containing 30%
  • Figure 7 depicts percent water absorption by films of PCL and PLA containing 30% (w/w) peptide
  • Figure 8 depicts percent water absorption by films of poly(DTH adipate) both with and without peptide
  • Figure 9 depicts percent molecular weight retention of neat poly(DTH adipate) samples to that of poly(DTH adipate) containing 30% (w/w) peptide, and to that of 10% PEG/90% poly(DTH adipate);
  • Figure 10 depicts the effect of ionic strength on the release of 30% (w/w) INTEGRILINTM from poly(DTH adipate) films
  • Figure 11 depicts release from poly(DTH adipate) films containing 30% (w/w) peptide at pH 2.2 without added electrolytes;
  • Figure 15 depicts the chemical structure of poly(DTE carbonate).
  • Figure 21 depicts release of peptide from poly(DT-co-DTH adipate) matrices
  • Figure 22 depicts release of peptide from 30% (w/w) poly(DT-co-DTH adipate) films
  • Figure 23 depicts pH measurements of buffer of samples of poly(DT-co-DTH adipate) with 15% (w/w) peptide
  • Figure 24 depicts percent molecular weight retention of samples of poly(DTH adipate) containing various percentages of DT incubated in PBS at 37°C.
  • the copolymers of WO 99/24107 contain a hydrophilic monomer with a pendant carboxylic acid group, desaminotyrosyltyrosine, which degrades to form acidic degradation products.
  • the other monomer, a desaminotyrosyltyrosine ester also contains hydrogen bonding sites for retention of the active compound.
  • a water soluble yet hydrophobic dicarboxylate monomer forms polyarylate linkages between the two diols.
  • Members of the tyrosine-derived polyarylate library all share the same highly functional structural template but are distinguished from one another by subtle structural changes. The functional groups of the main template provide sites for interactions.
  • any of the copolymers that can be derived from the tyrosine-derived diphenol compounds of U.S. Patent No. 5,587,507 and the tyrosine-derived dihydroxy monomers of WO 98/36013, the disclosures of both of which are. also incorporated herein by reference, using the process of WO 99/24107 for forming free carboxylic acid moieties.
  • examples include the polycarbonates of U.S. Patent No. 5,099,060, the polyiminocarbonates of U.S. Patent No. 4,980,449, the polyphosphazenes and polyphosphates of U.S. Patent No.
  • Peptide drugs suitable for formulation with the compositions of the present invention include natural and unnatural peptides, oligopeptides, cyclic peptides, library generated oligopeptides, polypeptides and proteins, as well as peptide mimetics and partly-peptides.
  • Peptide drugs of particular interest include platelet aggregation inhibiting (PAI) peptides, which are antagonists of the cell surface glycoprotein Iib/IIIa, thus preventing platelet aggregation, and ultimately clot formation.
  • PAI platelet aggregation inhibiting
  • the absorption efficiency must be individually determined for each drug by methods well known in pharmacology. Accordingly, it may be necessary for the therapist to titer the dosage and modify the route of administration as required to obtain the optimal therapeutic effect.
  • the determination of effective dosage levels that is, the dosage levels necessary to achieve the desired result, will be within the ambit of one skilled in the art.
  • applications of compound are commenced at lower dosage levels, with dosage levels being increased until the desired effect is achieved.
  • the release rate of the drug from the formulations of this invention are also varied within the routine skill in the art to determine an advantageous profile, depending on the therapeutic conditions to be treated.
  • a typical dosage might range from about 0.001 mg/kg to about lOOOmg/kg, preferably from about 0.01 mg/kg to about 100 mg/kg, and more preferably from about 0.10 mg/kg to about 20 mg/kg.
  • the compounds of this invention may be administered several times daily, and other dosage regimens may also be useful.
  • INTEGRILINTM (antithrombotic injection) was chosen as the model peptide to explore the drug delivery applications of these materials (Figure 2).
  • This compound is a synthetic cyclic readily water-soluble heptapeptide which is a highly potent glycoprotein Ilb/HIa antagonist.
  • This compound has successfully demonstrated antithrombogenic behavior in vivo and devices fabricated by the formulation of this peptide into a polymer matrix with this property would have many useful cardiovascular applications.
  • this polymer contains an RGD sequence and therefore a device containing this peptide could possibly find applications as a component in scaffolds for tissue regeneration.
  • the blend of INTEGRILINTM and poly(DTH adipate) was described in U. S . Patent
  • Tyrosine derived polyarylates were synthesized as described in U.S. Patent No. 5,877,224 and in WO 99/24107.
  • the polymers used had molecular weights ranging between 80-120 kDa.
  • the particular polymers synthesized were poly To o s-co-DTHo.jj adipate, Poly(DT 010 -co-DTH_o 90 adipate), and poly(DT 015 -co- DTH o 85 adipate).
  • the molecular weights of the polymers used ranged from 60 - 80 kDa.
  • D,L- PLA and poly( ⁇ -caprolactone) were purchased from Medisorb and Aldrich, respectively. Both were of molecular weight 100 kDa and fabricated into release devices in the same manner as the poly(DTH adipate).
  • the peptide was obtained from COR Therapeutics, Inc.
  • Compression molded films were fabricated from a co-precipitate containing 30% peptide and 70% polymer by weight.
  • This co-precipitate was prepared by dissolving 0.15 g of peptide in 5 ml of methanol (HPLC grade) and 0.35 g polymer in 5 ml of methylene chloride (HPLC grade) and mixing the two solutions together to form a clear solution.
  • This resultant solution was added drop- wise into 100 ml of stirred ethyl ether maintained at -78 °C.
  • White spongy precipitates were formed, filtered using a sintered glass filter, and dried under vacuum. After drying the co-precipitate was compression molded at 90 °C under a pressure of 5,000 psi. Films with a thickness of 0.1 mm (+0.02 mm) were obtained.
  • the samples were removed, rinsed with deionized water, blotted with a imwipe tissue and either placed in a vial for subsequent vacuum drying for mass retention and molecular weight retention studies or used for thermal gravimetric analysis
  • TGA water uptake studies. Those devices that were not needed for gel permeation chromatography (GPC) or TGA studies were dissolved in organic solvent subsequent to drying and the peptide content extracted to ensure that all loaded peptide was accounted for.
  • thermogravimetric analysis A small sample (10 mg) was cut from a specimen and placed in an aluminum TGA pan.
  • the sample was heated under a nitrogen flow at a rate of 10 °C/min from room temperature to 225 °C.
  • the water uptake was measured by the loss in weight of the sample as it was heated from room temperature until 150 °C.
  • DSC Differential scanning calorimetry analysis
  • DSC was used to determine the melting point of the peptide.
  • a sample of approximately 2 mg of peptide was weighed out and sealed in a crimped aluminum DSC pan. The sample was heated at 12 °C/min from room temperature to 200 °C, under nitrogen flow. DSC was also used to determine whether there is a melting transition associated with the polymer films that contain 30% (w/w) peptide.
  • a sample size of 6 mg of film was sealed in a crimped aluminum DSC pan and heated at 12 °C/min until 200 °C, under nitrogen flow. Melting point of the sample was determined by the temperature at which the sharp endotherm of melting occurred. All data was analyzed using the first-run thermogram. An empty aluminum pan was used as a reference in each experiment.
  • the percent mass retention of the samples was calculated in the following manner.
  • the sample was removed from the PBS incubation medium, rinsed in deionized water, and blotted with a Kimwipe tissue. It was placed in a fresh vial and dried under vacuum for 2 weeks. Following this dessication period, it was weighed (W d ). The mass obtained following incubation and drying was compared to the initial mass (W 0 ).
  • the formula for calculating percent mass retention is the following:
  • the glass transition temperature of sets of films was measured using Dynamic Mechanical Analysis (DMA). Measurements were performed on a DMA 983 from TA Instruments in a flexural bending deformation mode of strain. Each set of films contained a different weight percentage of peptide ranging from 0% - 30% (w/w) of peptide. Samples of approximate size 5 x 10 x 1 mm were cut from the films and mounted on the instrument using low mass clamps, after calibrating the instrument with the low mass clamps. The samples were cooled using a liquid nitrogen cooling accessory to -30 °C and heated at a rate of 4 °C/min until 70 °C. The frequency was fixed at 1 Hz and the amplitude was 1 mm. The glass transition was read from the maxima of the E" peak.
  • DMA Dynamic Mechanical Analysis
  • INTEGRILINTM (4.12 mg) was placed in a 25 ml roundbottom flask. To this flask was added 50.12 mg of dithiothreitol. A minimun of 20 moles of DTT was required per disulfide bridge (this is 62 moles of DTT per disulfide bridge). Then 3 ml of water was added and flask was stoppered. The contents of flask were stirred with a magnetic stirrer. Every few hours, an aliquot of reaction mixture was removed from the flask, diluted with HPLC water, and analyzed with HPLC. As the reaction continued, the peak at 1.7 minutes corresponding to the intact peptide decreased and the peak at 2.5 minutes corresponding to the peptide with the cleaved disulfide bridge increased. Virtually all of the peptide had been reduced after stirring overnight.
  • reaction mixture was lyophilized overnight.
  • 5 ml of diethyl ether was added to dissolve the DTT and precipitate the peptide. This mixture was stirred for 3 hours and the resulting suspension was filtered using filter paper. The filtered material was dried under vacuum overnight.
  • the flexibility of the polyarylate films that contained peptide relative to those composed of the peptide and either of aliphatic polyesters can be explained by the lower glass transition temperature of the polyarylate (37 °C) as compared to that of PLA (52 °C), and the amorphous nature of the polyarylate as compared to PCL.
  • the glass transition temperature of neat poly(DTH adipate) was compared to those of poly(DTH adipate) containing 15, 20, or 30% (w/w) peptide.
  • the glass transition temperature was higher relative to the neat polymer samples.
  • the fact that there is an effect on the glass transition temperature indicates that there is a mixing on the molecular scale between the peptide and the polymer.
  • the increase in T g with the addition of the peptide confirms that there is hydrogen bonding between the peptide and the polymer.
  • Poly(DTH adipate) films containing 30% (w/w) peptide were prepared in the standard manner.
  • the pH of the incubation media remained about 7, but the ionic strength of the release media was varied.
  • the in vitro release of the peptide in HPLC water, in the standard PBS solution (10 mM phosphate buffer saline, 138 mM NaCl, 2.7 mM KC1), and in PBS buffer formulated at twice the concentration (20 mM phosphate buffer saline, 276 mM NaCl, 5.4 mM KC1) was measured and compared (Figure 10). It was observed that the rate of release of peptide was four times greater in HPLC water as compar-ed to the release rate in phosphate buffer.
  • the interaction of the peptide with the tyrosine-derived polyarylate arises from the unique structure of the polymer in which the amide bond of each repeat unit is in close proximity to the pendent ester in the same unit. This entire region can be considered as one functional group, the ⁇ -amidocarboxylate group and can act as a pocket for the hydrogen bonding of various groups on the peptide. Peptide-polymer interactions with other tyrosine-derived polymers
  • Poly(DTH dioxaoctanedioate) was the first alternate but structurally related polymer that was investigated.
  • This polymer contains the DTH repeat unit which makes it similar to poly(DTH adipate).
  • this polymer is synthesized by polymerizing DTH with dioxaoctanedioic acid ( Figure 13) instead of adipic acid.
  • the objective of this experiment was to observe the effect of a more hydrophilic tyrosine-derived polymer on the diffusion of the peptide. It would be expected that this compound is more hydrophilic than adipic acid because there are two oxygens in the backbone spacer.
  • Poly(DTE carbonate) was also formulated with 15% (w/w) peptide.
  • This polymer structure contains only the desaminotyrosyltyrosine ethyl ester with carbonate linkages and does not contain any PEG.
  • These films also showed the same behavior as the tyrosine-derived polyarylates (Figurel7). The water uptake of these films was also measured and found to be 6% by weight over the incubation period.
  • the degradation of the tyrosine-derived polyarylates proceeds via an acid hydrolysis mechanism that is similar to the hydrolysis of poly(DTE carbonate).
  • the pendent ester groups in contact with water would hydrolyze initially and the resulting acid groups would begin the hydrolysis of the backbone ester, liberating DTH and adipic acid.
  • the adipic acid contributes to the acidity within the matrix and further promotes the hydrolysis of both backbone and pendent ester groups.
  • this has been demonstrated that this is a relatively slow process, only 40% degradation occurs during a 2 month degradation period and the degradation rate begins to plateau after reaching this extent of degradation (Figure 9).
  • the addition of DT to the polymer backbone accelerates the degradation process.
  • Thermograms of these terpolymers indicated only one glass transition which was in the vicinity of the glass transition of poly(DTH adipate).
  • the appearance of only one glass transition indicates there is a miscibility between the DTH adipate and the DT adipate, not surprising since they share a very similar structure.
  • the range of temperatures over which the glass transition occurs is about 6°C. This is about the same for poly(DTH adipate) indicating that the polymer is quite homogeneous.
  • T g with increasing mole percent of DT, this is quite expected since an increase in the amount of DT could result in an increase in hydrogen bonding between the chains and thereby increasing the rigidity of the polymer (Table 1).
  • the homogeneity of the copolymer in all probability, contributes to the transparency and clarity of those films that contain peptide.
  • the incubation conditions were the same used in the above experiments.
  • the results of these experiments were a delayed release, and the length of the delay time was a function of the mole percent of DT.
  • the set of films containing 15 mole percent DT was characterized by a lag time of 20 days, after this lag time, 60% of the loaded peptide was released over a period of 40 days ( Figure 21).
  • Samples containing 10% DT were associated with a lag time of close to 60 days. This delay period was followed by a release phase where 60% of the loaded peptide was released within 30 days. Samples with 5% DT never released the peptide even after 110 days of incubation.
  • the control in this experiment was poly(DTH adipate) samples containing 15% (w/w) peptide which, also, did not release the peptide. In all samples no burst was observed and no leaching of the peptide occurred during the lag time.
  • any peptide molecules that would be hydrogen bonded to this proton would no longer be interacting with this group once the proton is lost, and therefore these peptide molecules would be lost as a burst.
  • the carboxyl-ate group of the DT might actually compete with the peptide for interaction sites on the DTH repeat unit resulting in the release from the films of the peptide molecules that lost the competition.
  • the higher the DT content in the polymer the more competition for the peptide and consequently, the size of the burst is correlated with increasing mole percent of DT.
  • the films containing 15% DT also demonstrated a second release phase at about 40 days but it is much smaller than the second release phase of the specimens containing 10% DT.
  • Samples with 5% DT again, as in the 5% DT samples containing 15% (w/w) peptide, presumably, never reached the critical pH necessary for release of the peptide, and, therefore, following the burst no more peptide was released.
  • the buffer media were analyzed for pH changes at each buffer change ( Figure 23). Since the release of the peptide depends on the lowering of the pH of the matrix a detectable lowering of the pH should coincide with the release of the peptide. As expected, those films composed of the polymer system with 15 mole percent of DT demonstrated a drop of the pH below 7.2, first. This reduction in pH began at approximately 30 days which was 10 days after release of the peptide commenced. The pH of the media remained around 7.0 for the remainder of the incubation. Samples containing 10 mole percent of DT were characterized by a drop in pH below
  • control samples of poly(DTH adipate) containing 15% (w/w) peptide were placed in buffer at a pH of 7.0. This again, was to observe whether environmental pH affects the release of the peptide. Trace release of the peptide was seen from these control samples. No difference in the behavior of these samples as compared to samples incubated in buffer at 7.4 was observed.
  • the only polymer matrix of the group of polymers investigated in these experiments that released any of the peptide with the cleaved disulfide bond was the poly(DT 015 -co- DTHQ 85 adipate) samples which contained the lower loading of peptide. These samples began the release phase after a lag time of 20 days and continued this steady release until approximately 60 days of incubation. Intact peptide was released within the first 20 days of the release phase. However from the 44 th day of incubation and beyond, fully one third of the peptide released was associated with a cleaved disulfide bond. Again, peptide with a cleaved disulfide bond was not observed in association with any other polymer system in these studies.
  • the degradation products also contain more DT and therefore critical concentration of acidic products necessary for release of the peptide is reached earlier with these samples than the polymers with 10 mole percent of DT.
  • the poly(DT-co-DTH adipate) polymers without peptide appear to degrade through the same mechanism.
  • the rates may be different especially between those polymers that contain 5 mole percent of DT and those that contain more DT but the end result appears similar.
  • After 16 weeks of incubation the polymers have all developed a significant amount of low molecular weight fractions and there does not appear to be a preference for the formation of one particular fraction over another.
  • polymers that form hydrolytic degradation products promote the release of biologically active compounds from the polymer matrix in comparison to polymers of similar structure that do not hydrolytically degrade. Neither polymer initially releases the biologically active compound. However, a delayed pulsatile release is obtained from polymers that hydrolytically degrade as the degradation products, accumulate, while significant quantities of biologically active compound are never released from the polymers that do not hydrolytically degrade.

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Abstract

L'invention concerne une formulation contenant un composé biologiquement actif ayant une structure dotée de sites de liaison hydrogène, qui est mélangé à un polymère ayant une structure dotée de sites de liaison hydrogène complémentaires, le polymère formant des produits de dégradation hydrolytiques qui favorisent la libération du composé biologiquement actif du polymère.
EP01939971A 1999-12-31 2001-01-02 Formulation pharmaceutique destinee a reguler la liberation dans le temps de composes biologiquement actifs a base d'une matrice polymere Ceased EP1263453A4 (fr)

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US17413799P 1999-12-31 1999-12-31
US174137P 1999-12-31
PCT/US2001/000030 WO2001049249A2 (fr) 1999-12-31 2001-01-02 Formulation pharmaceutique destinee a reguler la liberation dans le temps de composes biologiquement actifs a base d'une matrice polymere

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EP1263453A2 true EP1263453A2 (fr) 2002-12-11
EP1263453A4 EP1263453A4 (fr) 2008-02-20

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EP (1) EP1263453A4 (fr)
JP (1) JP2003519164A (fr)
AU (1) AU784226B2 (fr)
CA (1) CA2396037A1 (fr)
WO (1) WO2001049249A2 (fr)

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JP2003519164A (ja) 2003-06-17
AU2925501A (en) 2001-07-16
WO2001049249A2 (fr) 2001-07-12
CA2396037A1 (fr) 2001-07-12
AU784226B2 (en) 2006-02-23
WO2001049249A3 (fr) 2002-01-17
EP1263453A4 (fr) 2008-02-20

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