WO2008106144A2 - Implants destinés au traitement d'états psychiatriques - Google Patents

Implants destinés au traitement d'états psychiatriques Download PDF

Info

Publication number
WO2008106144A2
WO2008106144A2 PCT/US2008/002550 US2008002550W WO2008106144A2 WO 2008106144 A2 WO2008106144 A2 WO 2008106144A2 US 2008002550 W US2008002550 W US 2008002550W WO 2008106144 A2 WO2008106144 A2 WO 2008106144A2
Authority
WO
WIPO (PCT)
Prior art keywords
implant
disorder
poly
compound
subject
Prior art date
Application number
PCT/US2008/002550
Other languages
English (en)
Other versions
WO2008106144A3 (fr
Inventor
Steven J. Siegel
Terri B. Sebree
Original Assignee
Nupathe Inc.
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 Nupathe Inc. filed Critical Nupathe Inc.
Publication of WO2008106144A2 publication Critical patent/WO2008106144A2/fr
Publication of WO2008106144A3 publication Critical patent/WO2008106144A3/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/34—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/58—Materials at least partially resorbable by the body
    • 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
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
    • 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
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/202—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with halogen atoms, e.g. triclosan, povidone-iodine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/204—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with nitrogen-containing functional groups, e.g. aminoxides, nitriles, guanidines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/602—Type of release, e.g. controlled, sustained, slow
    • A61L2300/604—Biodegradation

Definitions

  • Schizophrenia is a serious brain disorder that affects approximately 1 % of the human population. The cause of this complex and devastating disease remains elusive, although genetic, nutritional, environmental, and developmental factors have been considered.
  • a combination of clinical, neuroimaging, and postmortem studies have implicated the dorsal prefrontal cortex (PFC) as a prominent site of dysfunction in schizophrenia.
  • PFC dorsal prefrontal cortex
  • Schizophrenia is typically characterized as a disorder of thinking and cognition, as contrasted to other disorders of mental faculties, such as mood, social behavior, and those affecting learning, memory, and intelligence. Schizophrenia is generally characterized by psychotic episodes during which an individual may lose the ability to test reality or may have hallucinations, delusions, incoherent thinking, and even disordered memory. There are varying forms of schizophrenia differing in severity, from a schizotypal disorder to a catatonic state.
  • Antipsychotic drugs were identified in the 1950's, and these drugs were found to produce a dramatic improvement in the psychotic phase of the illness. Reserpine was the first of these drugs to be used and was followed by typical antipsychotic drugs including phenothiazines, the butyrophenones, and the thioxanthenes. A new group of therapeutic drugs, typified by clozapine, has been developed and were referred to as "a typical" antipsychotics. Haloperidol has been employed extensively in the treatment of schizophrenia and is one of the currently preferred options for treatment. When these drugs are taken over the course of at least several weeks, they mitigate or eliminate delusions, hallucinations, and some types of disordered thinking.
  • the invention pertains, at least in part, to a method for treating a subject for a disorder by administering to a subject a biodegradable implant comprising an N-phenyl substituted indolyl compound
  • R and R are each independently halogen, hydroxyl, amino, thio, nitro, alkyl, alkenyl, alkynyl, aryl, or cyano;
  • P is a saturated cyclic moiety; n is 0, 1, or 2;
  • M is a heterocycle; or a pharmacuetically acceptable salt thereof.
  • the compound of formula (I) is sertindole (5-chloro-l-
  • the invention also pertains, at least in part, to a method for maintaining a therapeutic plasma level of a compound of formula (I), e.g., sertindole, in a subject.
  • the method includes administering to the subject an implant comprising a biodegradable polymer and a compound of formula (I), such that the plasma level of the compound is maintained for at least one day.
  • the invention also pertains at least in part, to a method for treating a subject for schizophrenia.
  • the method includes administering to a subject a biodegradable implant, wherein the implant comprises an effective amount of a compound of formula (I), e.g., sertindole, to treat schizophrenia.
  • a compound of formula (I) e.g., sertindole
  • the invention pertains to a method for treating a subject for a disorder treatable by administration of compounds of the invention.
  • the method includes administering to the subject a biodegradable implant, which comprises an effective amount of an N-ph
  • R 1 and R 2 are each independently hydrogen, halogen, hydroxyl, amino, thio, nitro, alkyl, alkenyl, aryl, cyano or alkynyl; P is a saturated substituted or unsubstited cyclic moiety; n is O, 1, 2, or 3;
  • M is a substituted or unsubstituted heterocycle; or a pharmacuetically acceptable salt thereof.
  • the polymer is selected so that it interacts with the N- phenyl substituted indolyl compound of formula (I) via ionic interactions. These interactions may retard the release of the compounds of the invention.
  • the implant is comprised of a polymer that is biocompatible.
  • biocompatible includes polymers which are not toxic to the human body, are not carcinogenic, and do not significantly induce inflammation in body tissues.
  • the polymer comprises polylactide or a copolymer comprising polylactide such as dl(polylactide-co-glycolide). Examples of such biodegradable polymers include those which comprise about 30 to 100% polylactide and 0 to 70% polyglycolide.
  • the copolymer and the compound of formula (I) may be fabricated into an implant via solvent casting and compression molding.
  • the individual polymers and the compound are dissolved in an organic solvent and solvent cast at a temperature at which the solvent evaporates for a period of time which allows for complete drying of the polymer-compound mixture. Complete drying can be assessed by weighing the material at the beginning of solvent casting and at the end of the solvent casting to ensure that all solvent has been evaporated. It may be noted that care should be taken to form a homogenous mixture to avoid the creation of macroscopic areas of high concentrations of the an N-phenyl substituted indolyl compound, which may result in "drug dumping.”
  • the implants of the invention may further comprise a hydrophobic coating which may comprise one or more hydrophobic polymers.
  • hydrophobic polymers include PLGA, polycapralactone (PCL), PLA, ethylcellulose, and combinations and co-polymers thereof (including, but not limited to, PLGA-co-PCL and PLA-co-PCL).
  • the hydrophobic polymers are selected to reduce water permeability of the implant and slow the release of the compound of the invention.
  • the N-phenyl substituted indolyl compound of formula (I) concentrations may range from about 5% to about 95%, from about 10% to about 80%, from about 20% to about 60%, or from about 30% to about 50% in the implant depending upon the release period.
  • subject includes animals (e.g., mammals, e.g., cats, dogs, horses, pigs, cows, sheep, rodents, rabbits, squirrels, bears, primates ⁇ e.g., chimpanzees, gorillas, and humans)) which are capable of (or currently) suffering from a pyschiatric state. It also includes transgenic animal models. In a further embodiment, the subject is a human suffering from schizophrenia.
  • treated includes therapeutic and/or prophylactic treatment of a psychiatric state. The treatment includes the diminishment or alleviation of at least one symptom associated or caused by the psychiatric state. For example, treatment can be diminishment of one or several symptoms of the psychiatric state or complete eradication of the state.
  • the negative symptoms of schizophrenia include a class of symptoms of schizophrenia which can be considered to reflect a Moss' in functional, directed thought or activity.
  • Negative symptoms of schizophrenia include affective flattening (characterized by, for example, an immobile and/or unresponsive facial expression, poor eye contact and reduced body language), alogia ("poverty of speech' or brief, laconic and/or empty replies), avolition (characterized by a reduced or absent ability to initiate and carry out goal-directed activities), anhedonia (loss of interest or pleasure), social withdrawal, apathy and other negative symptoms known to those of skill in the art.
  • the negative symptoms of schizophrenia may be assessed using any methodology known in the art including, but not limited to, the Brief Psychiatric Rating Scale (BPRS), the Positive and Negative Symptom Scale (PANSS), the Rorschach Schizophrenia Index (SCZI), and the Scale for the Assessment of Negative Symptoms (SANS). Some of these methods may also be used to assess positive symptoms (e.g., BPRS, PANSS and SCZI), although methods for specifically assessing positive symptoms are also available (e.g., the Scale for the Assessment of Positive Symptoms, or PANS).
  • the language "effective amount" of a compound of formula (I) is that amount necessary or sufficient to treat or prevent a psychiatric state in a subject, e.g.
  • the effective amount can vary depending on such factors as the size and weight of the subject, or the type of illness. For example, the choice of the compound of formula (I) or salt can affect what constitutes an "effective amount".
  • the term "effective amount” also includes the amount of a compound of formula (I), e.g., sertindole, that will render a desired therapeutic outcome, e.g., a level or amount effective to reduce symptoms of a disorder.
  • the effective amount may be the effective amount to treat a psychiatric state such as schizophrenia and/or increase periods of therapeutic effectiveness ("on" periods).
  • An amount that is "therapeutically effective" for a particular subject may depend upon such factors as a subject's age, weight, physiology, and/or the particular symptoms or condition to be treated, and will be ascertainable by a medical professional.
  • the effective amount of a compound of formula (I) is the amount necessary to achieve a plasma concentration of the compound of about 0.5 to about 100 ng/mL, of about 0.5 to about 90 ng/mL, of about 0.5 to about 80 ng/mL, of about 0.5 to about 70 ng/mL, of about 0.5 to about 60 ng/mL, of about 0.5 to about 50 ng/mL, 1 ng/ml to about 40 ng/ml, about 1 ng/ml to about-30 ng/ml, about 1 ng/ml to about 20 ng/ml, 1 ng/ml to about 15 ng/ml, or about 2.5 ng/ml to about 10 ng/ml.
  • the effective amount is effective to maintain the aforementioned plasma concentration for at least one day or longer, one week or longer, two weeks or longer, three weeks or longer, four weeks or longer, six weeks or longer, two months or longer, three months or longer, four months or longer, five months or longer, six months or longer, seven months or longer, eight months or longer, nine months or longer, ten months or longer, eleven months or longer, twelve months or longer, or over a year or longer.
  • the invention pertains to a biodegradable implant, comprising a compound of formula (I), e.g., sertindole, and a biodegradable polymer.
  • the implant comprises an effective amount of the compound of formula (I) to treat a disorder, e.g., a psychiatric disorder such as schizophrenia.
  • the compound of formula (I) is present in an amount in the implant which is effective to maintain an effective plasma level of the compound.
  • the effective plasma level is at least 1 ng/ml for at least one day, one week, one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months or twelve months or longer.
  • the plasma level of the compound of formula (I) is between about 1 ng/ml and about 100 ng/ml, about 1 ng/ml and about 90 ng/ml, about 1 ng/ml and about 80 ng/ml, about 1 ng/ml and about 70 ng/ml, about 1 ng/ml and about 60 ng/ml, about 1 ng/ml and about 50 ng/ml, about 1 ng/ml and about 40 ng/ml, about 1 ng/ml and about 30 ng/ml, about 1 ng/ml and about 20 ng/ml, or about 1 ng/ml and about 10 ng/ml.
  • the invention also includes a method for maintaining an effective plasma level of the compound of formula (I) in a subject.
  • the method includes administering to the subject an implant comprising a biodegradable polymer and a compound of formula (I), such that the plasma level of the compound is maintained for at least one day.
  • the effective amount is between about 1 ng/ml and about 100 ng/ml, about 1 ng/ml and about 90 ng/ml, about 1 ng/ml and about 80 ng/ml, about 1 ng/ml and about 70 ng/ml, about 1 ng/ml and about 60 ng/ml, 1 ng/ml and about 50 ng/ml, about 1 ng/ml and about 40 ng/ml, about 1 ng/ml and about 30 ng/ml, about 1 ng/ml and about 20 ng/ml, or about 1 ng/ml and about 10 ng/ml.
  • the plasma levels are maintained for at least one day, one week, one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months or twelve months or longer.
  • the invention also pertains to methods comprising administering second agents in combination with the biodegradable implants of the invention.
  • the second agents may be any agent which enhances or increases the effectiveness of the treatment of the disorder (such as, but not limited to, psychiatric disorders) and/or reduce inflammation at the site of administration of the biodegradable implant, or which prevents or retards oxidation of the compound of formula (I).
  • the second agents may be encapsulated within the biodegradable implant to prevent or reduce local inflammation at the site of administration.
  • the second agents may also be administered separately to the subject by any route that allows the second agents to perform their intended functions.
  • the second agents may be administered orally, parentally, topically, subcutaneously, sublingually, etc. Any of the second agents, or a combinations thereof, may also be included in the same implant(s) as the compound of formula (I) or alternatively, may be incorporated into one or more separate implants or sections thereof that do not include the compound of formula (I).
  • the implants can be manufactured using methods known in the art.
  • implants comprised of polymers that are viscose liquids at processing temperatures of 60-80 0 C (e.g., polycapralactone and the like)
  • the polymer is melted in an oven and the compound of formula (I) is mixed into the molten polymer with an electric mixer.
  • the homogenous mixture of the compound of formula (I) and the polymer is then formed into implants by pouring it into molds, and/or by compression molding and/or extrusion.
  • the compound of formula (I) and the polymer are melt mixed in a single or twin screw mixer/extruder that heats and kneads the drug and polymer prior to extrusion.
  • the implants (or sections thereof) are then formed by extrusion alone or in combination with compression molding.
  • alkyl further includes alkyl groups, which can further include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone.
  • a straight chain or branched chain alkyl has 6 or fewer carbon atoms in its backbone (e.g., Ci-C ⁇ for straight chain, C3-C6 for branched chain), and more preferably 4 or fewer.
  • preferred cycloalkyls have from 3-8 carbon atoms in their ring structure, and more preferably have 5 or 6 carbons in the ring structure.
  • C 1 -CO includes alkyl groups containing 1 to 6 carbon atoms.
  • alkyl includes both "unsubstituted alkyls" and “substituted alkyls”, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
  • substituents can include, for example, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sul
  • Cycloalkyls can be further substituted, e.g., with the substituents described above.
  • An "alkylaryl” or an “arylalkyl” moiety is an alkyl substituted with an aryl (e.g., phenylmethyl (benzyl)).
  • the term “alkyl” also includes the side chains of natural and unnatural amino acids.
  • naphthalene benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, methylenedioxophenyl, quinoline, isoquinohne, naphthridine, indole, benzofuran, purine, benzofuran, deazapurine, or indolizine.
  • aryl heterocycles may also be referred to as "aryl heterocycles", “heterocycles,” “heteroaryls” or “heteroaromatics”.
  • the aromatic ring can be substituted at one or more ring positions with such substituents as described above, as for example, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and
  • alkenyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond.
  • alkenyl includes straight-chain alkenyl groups (e.g., ethylenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, etc.), branched-chain alkenyl groups, cycloalkenyl (alicyclic) groups (cyclopropenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl), alkyl or alkenyl substituted cycloalkenyl groups, and cycloalkyl or cycloalkenyl substituted alkenyl groups.
  • alkenyl includes straight-chain alkenyl groups (e.g., ethylenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonen
  • substituents can include, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, amino carbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, al
  • a straight chain or branched chain alkynyl group has 6 or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain).
  • C 2 -C6 includes alkynyl groups containing 2 to 6 carbon atoms.
  • alkynyl includes both "unsubstituted alkynyls" and
  • substituted alkynyls refers to alkynyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
  • substituents can include, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, amino carbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino,
  • lower alkyl as used herein means an alkyl group, as defined above, but having from one to five carbon atoms in its backbone structure.
  • Lower alkenyl and “lower alkynyl” have chain lengths of, for example, 2-5 carbon atoms.
  • the alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, amino carbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate
  • hydroxy or "hydroxyl” includes groups with an -OH or -O " .
  • halogen includes fluorine, bromine, chlorine, iodine, etc.
  • heteroatom includes atoms of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur and phosphorus.
  • cyclic includes saturated or unsaturated, aromatic or non-aromatic ring moieites. Examples of saturated cyclic moieties include piperidine, piperazine, morpholine, cyclohexyl, cyclobutyl, cyclopentyl, etc.
  • Each copolymer has a distinctive period of degradation, which is determined by the ratio of lactide to glycolide and the molecular weight of the resulting molecule produced.
  • An additional polymer of polycaprolactone/polylactide (PCL/PLA) is used for in vivo testing in rats. Individual polymers and sertindole are dissolved in acetone and solvent cast at 60 0 C for up to 14 days. Solvent cast material are compression molded at 80 ° and 25,000 psi (density 1.1.+-.0.05 grams/cc).
  • mice and rats are anesthetized with ketamine/xylazine (100/10 mg/kg, i.p.). A l- cm incision is made in the skin on the dorsal aspect of the animal and an implant is placed between dermis and muscle. Removal of implants is performed with identical anesthesia and incision followed by implant retrieval. Bioactivity of sertindole implants are assessed in mice and rats. The mice received implants made of 85:15 PLGA, 65:35 PLGA, 50:50 PLGA or PCL alone or with 35% or 45% sertindole to assess the effects of implants. Following three weeks of implantation, the rats and mice are assessed for improvement. Implants are then removed and animals are allowed to recover for 48 hours prior to additional testing.

Landscapes

  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Dermatology (AREA)
  • Transplantation (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biomedical Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Molecular Biology (AREA)
  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Biological Depolymerization Polymers (AREA)

Abstract

La présente invention concerne des implants biodégradables comprenant des composés d'indolyl N-phényle substitués.
PCT/US2008/002550 2007-02-28 2008-02-27 Implants destinés au traitement d'états psychiatriques WO2008106144A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US90393407P 2007-02-28 2007-02-28
US60/903,934 2007-02-28

Publications (2)

Publication Number Publication Date
WO2008106144A2 true WO2008106144A2 (fr) 2008-09-04
WO2008106144A3 WO2008106144A3 (fr) 2008-10-30

Family

ID=39721801

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2008/002550 WO2008106144A2 (fr) 2007-02-28 2008-02-27 Implants destinés au traitement d'états psychiatriques

Country Status (1)

Country Link
WO (1) WO2008106144A2 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4883666A (en) * 1987-04-29 1989-11-28 Massachusetts Institute Of Technology Controlled drug delivery system for treatment of neural disorders
US5112838A (en) * 1989-04-11 1992-05-12 H. Lundbeck A/S Method of treating psychoses in human beings with the atypical neuroleptic 5-chloro-1-(4-fluorophenyl)-3-(1-(2-(2-imidazolidinon-1-yl)ethyl-4-piperidyl)1h-indole

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4883666A (en) * 1987-04-29 1989-11-28 Massachusetts Institute Of Technology Controlled drug delivery system for treatment of neural disorders
US5112838A (en) * 1989-04-11 1992-05-12 H. Lundbeck A/S Method of treating psychoses in human beings with the atypical neuroleptic 5-chloro-1-(4-fluorophenyl)-3-(1-(2-(2-imidazolidinon-1-yl)ethyl-4-piperidyl)1h-indole

Also Published As

Publication number Publication date
WO2008106144A3 (fr) 2008-10-30

Similar Documents

Publication Publication Date Title
US10278916B2 (en) Implants for the treatment of dopamine associated states
JP5923493B2 (ja) 注射可能なデポー組成物の調製方法
JP5893061B2 (ja) 疼痛および／または炎症の治療のためのαアドレナリン作動性受容体アゴニスト
JP2011518180A (ja) クロニジンを含んでなる、術後疼痛を治療するための方法及び組成物
JP2013527213A5 (fr)
KR20130118742A (ko) 항정신병약물 주사 가능한 데포 조성물
JP2009501798A5 (fr)
WO2008106144A2 (fr) Implants destinés au traitement d'états psychiatriques
WO2008130640A1 (fr) Implants pour le traitement d'états psychiatriques
US20150313897A1 (en) Methods for treating parkinson's disease
KR20240151740A (ko) 약물 전달 시스템 및 그 사용 방법
JP2021123559A (ja) 薬剤徐放性組成物
WO2022175977A1 (fr) Composition d'implant biodégradable et procédé d'administration à long terme de buprénorphine et utilisation associée
KR20240152304A (ko) 약물 전달 시스템 및 그 사용 방법

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08726130

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase in:

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08726130

Country of ref document: EP

Kind code of ref document: A2