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WO2013030692A1 - Compositions et procédés pour le traitement d'une douleur chronique - Google Patents

Compositions et procédés pour le traitement d'une douleur chronique Download PDF

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Publication number
WO2013030692A1
WO2013030692A1 PCT/IB2012/053918 IB2012053918W WO2013030692A1 WO 2013030692 A1 WO2013030692 A1 WO 2013030692A1 IB 2012053918 W IB2012053918 W IB 2012053918W WO 2013030692 A1 WO2013030692 A1 WO 2013030692A1
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WIPO (PCT)
Prior art keywords
compositions
alkyl
administration
pain
release
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PCT/IB2012/053918
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English (en)
Inventor
Mahesh Kandula
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Mahesh Kandula
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Publication of WO2013030692A1 publication Critical patent/WO2013030692A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D339/00—Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms
    • C07D339/02—Five-membered rings
    • C07D339/04—Five-membered rings having the hetero atoms in positions 1 and 2, e.g. lipoic acid
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This disclosure generally relates to compounds and compositions for the treatment of chronic pain. More particularly., this invention relates to treating subjects with a pharmaceutically acceptable dose of compounds, crystals, esters, stereoisomers, enantiomers, salts, hydrates, prodrugs, or mixtures thereof.
  • Pain is a subjective experience, influenced by physical, psychological, social , and spiritual factors. The concept of total pain acknowledges the importance of all these dimensions and that good pain relief is unlikely without attention to each aspect. Pain and diseases such as cancer are not synonymous: at least two thirds of patients experience pain at some time during the course of their illness, and most will need opioid analgesics.
  • 0OO j Opioids are a cornerstone of the management of cancer pain and postoperative pain and are used increasingly for the management of chronic non-cancer pain. Understanding the metabolism of opioids is of great practical importance to primary care clinicians. Opioid metabolism is a vita! safety consideration in older and medically complicated patients, who may be taking multiple medications and may have inflammation, impaired renal and hepatic function, and impaired immunity.
  • Chronic pain such as lower back pain
  • physicians may be more concerned with opioid metabolism in reference to development of tolerance, impairment of skills and mental function, adverse events during pregnancy and lactation, and prevention of abuse by monitoring drug and metabolite levels.
  • Pharmacokinetics contributes to the variability in response to opioids by affecting the bioavailability of a drug, the production of active or inactive metabolites, and their elimination from the body.
  • Pharmacodynamic factors contributing to variability of response to opioids include between-patient differences in speciiic opioid receptors and between-opioid differences in binding to receptor subtypes. The receptor binding of opioids is imperfectly understood; hence, matching individual patients with specific opioids to optimize efficacy and tolerability remains a trial -and-etror procedure.
  • ROS highly Reactive Oxygen Species
  • Some of the pain associated neurological disorders include injur ⁇ ', post-operative pain, osteoarthritis, rheumatoid arthritis, multiple sclerosis, spinal cord injur)', migraine, HIV related neuropathic pain, post herpetic neuralgia, diabetic neuropathy, cancer pain, fibromyalgia and lower back pain.
  • the present mvention provides compounds, compositions containing these compounds and methods for using the same to treat, prevent and/or ameliorate the effects of the conditions such as chronic pain.
  • compositions comprising of formula I or pharmaceutical acceptable salts thereof.
  • the invention also provides pharmaceutical compositions comprising one or more compounds of formisi 1 or intermediates thereof and one or more of pharmaceutically acceptable carriers, vehicles or diluents. These compositions may be used in the treatment of chronic pain and its associated complications.
  • the present invention relates to the compounds and compositions of formula I, or pharmaceutically acceptable salts thereof,
  • R 1 independently represents hydrogen, hydroxy! (-OH), methyl, amine, cycohexy! methyl ether, butoxy, propoxy, thiol, alkyi, alkyl thiol, acetyl thiol, disulfide, acyl or acylalkyl;
  • R ⁇ * each independently represents hydrogen, alkyl, methyl, ethyl, earboxyl, amine, thiol.
  • R independently represents
  • K 4 , R* each independently represent ' Null, methyl ,
  • compositions comprising at. least one compound of the invention.
  • the invention also includes pharmaceutical compositions that comprise an effective compound of the invention and a pharmaceuticiijly acceptable carrier.
  • the compositions are useful for treating or preventing chronic pain.
  • the compound of invention which provided as a pharmaceutically acceptable prodrug, a hydrate, a salt, such as a pharmaceutically acceptable salt, enantiomer, stereoisomer, or mixtures thereof.
  • jOOlSj Described herein are compounds of Formula I:
  • R 1 independently represents hydrogen, hydroxy! (-OH), methyl, amine, cycohexy! methyl ether, butoxy, propoxy, thiol, alkyi, alkyl thiol, acetyl thiol, disulfide, acyl or acylalkyl;
  • R ⁇ * each independently represents hydrogen, alkyl, methyl, ethyl, earboxyl, amine, thiol.
  • R independently represents
  • K 4 , R* each independently represent ' Null, methyl ,
  • kits comprising any of the pharmaceutical compositions disclosed herein.
  • the kit may comprise instaictions for use in the treatment of chronic pain or its related complications.
  • compositions herein comprising a pharmaceutically acceptable carrier and any of the compositions herein.
  • the pharmaceutical composition is formulated for systemic administration, oral administration, sustained release, parenteral administration, injection, subdermal administration, or transdermal administration.
  • kits comprising the pharmaceutical compositions described herein.
  • the kits may further comprise instructions for use in the treatment: of chronic pain or its related complications.
  • compositions described herein have several uses.
  • the present application provides, for example, methods of treating a patient suffering from chronic pain or its related complications manifested from metabolic conditions, chronic diseases or disorders; Hepatoiogy, Cancer, Hematological,, Orthopedic, Cardiovascular, Renal, Skin, Neurological or Ocular complications.
  • DETAILED DESCRIPTION
  • alkyl refers to the radical of saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cyc!oalky! (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cyeloalkyl-substituted aikyl groups.
  • a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30 tor straight chains, C3-C30 for branched chains), and more preferably 20 or fewer.
  • preferred c cioalk ls have from 3- 10 carbon atoms in their ring structure, and more preferably have 5, 6 or 7 carbons in the ring structure.
  • alkyl refers to a saturated linear or branched-chain monovalent hydrocarbon radical of one to twel e carbon atoms.
  • alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CB3), I - propyl (n ⁇ Pr, n ⁇ propyl, -CH2CH2CH3), 2-propyl (i-Pr, i -propyl.
  • ⁇ CH(CH3)2) 1 -butyl (n-Bu, n-butyl, - CH2CH2CH2CH3), 2-methyl-l -propyl (i-Bu, i-butyl, -CH2CH(CB3)2), 2-butyl (s-Bu, s-butyl, - CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu s t- but l, - C(CH3)3), 1 -pentyl (n-pentyi, - CH2CH2CH2CB2CH3), 2-pent l (- CH ⁇ CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2- methyl-2-butyi (- C(CH3)2CH2CH3), 3-methyl-2-butyl (-CB(CH3)CH(CH3)2), 3 -methyl- i -butyl (- CH2CH2CH(CH3)2).
  • alkynyi refers to a linear or branched monovalent hydrocarbon radical of two to twelve carbon atoms with at least one site of unsaturation, i.e., a carbon- carbon, sp triple bond. Examples include, but are not limited to, ethynyl (-OCH), propynyl ⁇ propargyl, - CH20 H), and the like.
  • alky (or “lower alkyl) as used throughout the specification., examples, and claims is intended to include both “unsubstituied alky Is" and “substituted alky!s", 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, a halogen, a hydroxy I, a carbon l (such as a carboxyl, an alkoxycarbonyl, a formy!, or an acyl), a Ihiocarbonyl (such as a thioester, a thioaeetate, or a thioformate), an alkoxyl.
  • a halogen such as a hydroxy I
  • a carbon l such as a carboxyl, an alkoxycarbonyl, a formy!, or an acyl
  • Ihiocarbonyl such as a thioester, a thioaeetate, or a thioformate
  • the substituents of a substituted alkyl may include substituted and imsubstituted forms of amino, azido, imiiio, amido, phosphoryl (including phosphonate and phosphmate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and sily! groups, as well as ethers, alky!thios, carbonyl s (including ketones, aldehydes, carboxyl tes, and esters), -CF3, -CN and the like. Exemplar ⁇ -" substituted alkyls are described below.
  • Cycloalky!s can be further substituted with alkyls, alkenyls, alkoxys, a!kylthios, aminoalk ls, carbonyl -substituted alkyls, -CF3, -CN, and the like.
  • acyr is art-recognized and refers to a group represented by the general formula h drocarbyl C(OK preferably alkyl C(O)-.
  • Aryl means a monocyclic or po!ycyclic ring assembly wherein each ring is aromatic or when fused with one or more rings forms an aromatic ring assembly. If one or more ring atoms is not carbon (e.g., N, S), the aryl is a heteroaryl. Cx aryl and Cx-Y aryl are typically used where X and Y indicate the number of carbon atoms in the ri ng.
  • acylamino is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbyl C(Q) Fk
  • acylalkyl is art-recognized and refers to an alkyl group substituted with an acyl group and may be represented, for example, by the formula hydrocarbyl C(0)alkyl.
  • lower when used in conjunction with a chemical moiety, such as, acyl, acyioxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups where there are ten or fewer non-hydrogen atoms in the substituent, preferably six or fewer.
  • alkynyl, or alkoxy substituents defined herein are respectively lower acyl lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether they appear alone or in combination with other substituents, such as in the recitations hydroxyalkyl and aralkyl (in which case, for example, the atoms within the aryl group are not counted when counti g the carbon atoms in the alkyl substituent).
  • substituted refers to moieties having substituents replacing hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in.
  • substituted is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisf the valences of the heteroatonis.
  • Substituents can include any substituents described herein, for example, a halogen, a hydroxy!, a carbonyl (such as a carboxyl, an a!koxy carbonyl, a formyl, or an acyl), a tbiocar onyl (such as a thioester, a thioacetate, or a thioforraate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an am ino, an ami do, an amidine, an inline, a cyano, a nitro, an a-zido, a sulfhydryl, an alkylthio, a sulfate, a
  • references to chemical moieties herein are understood to include substituted variants.
  • reference to an "aryl” group or moiety implicitly includes both substituted and unsubstituted variants.
  • Substituted or unsubstituted means that a given moiety may consist of only hydrogen substituents through available valencies (unsubstituted) or may further comprise one or more non-hydrogen substituents through available valencies (substituted) that are not otherwise specified by the name of the given moiety.
  • isoprop l is an exampie of an ethylene moiety that is substituted by -CH3
  • a non- hydrogen substituent may be any substituent that may be bound to an atom of the given moiety that is specified to be substituted.
  • substituents include, but are not limited to, aldehyde, alley ie, aliphatic, (Ci-io) alkyl, alk lene, alkylidene, amide, amino, aminoalkyl, aromatic, aryl, bicycloalkyl, bicycloaryl, carbamoyl, carbocyclyl carboxyl, carbonyl group, cycloaikyl, cycloalkylene, ester, halo, heterobicycioalkyl, heterocycloaikylene, lieteroaryl, heterobicycloaryl , heteroeycioalky 1 , oxo, hydroxy, iminoketone, ketone, nitro, oxaalkyl and oxoaikyl moieties, each of which ma optionally also be substituted or unsubstituted.
  • substituents include, but are not limited to, hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (Ci Jo) alkoxy, (C4-12) aryloxy, heiero (Ci- io)aryIoxy, carbonyl, oxy carbonyl, aminocarbonyl, amino, (Ci- 10) alky! amino, sulfonamide, imino, sulfonyl, sulfinyl.
  • (Ci- 10) alkyl halo (Ci-10) alkyl, hydroxy (Ci-10) alkyl, carbonyl (Ci- 10) alkyl, thiocarbonyi (CiJO) alkyl, sulfonyl (Ci-10) aJkyl, sulfinyl (Ci_io) alkyl, (CiJO) azaalkyl, imino (Ci-10) alkyl, (C3 ⁇ 12 ⁇ cycloaikyl (CI-5) alkyl.
  • the substituent is itself optionally substituted by a further substituent.
  • examples of the further substituent include, but are not limited to, hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (Ci- 10) aikoxy, (C4-I2) aryloxy, hetero (Ci- 10) aryioxy, carbonyl, oxycarbonyl, aminocarbonyl, amino, (Ci-10) alkyl amino, sulfanamide, imino, sulfonyl, su!fin l, (Ci-10) alkyl, halo (Ci- 10) alkyl, hydroxy (Ci-10) alkyl, carbonyl (Ci-10) alkyl thiocarbonyl (Ci-10) alkyl, sulfonyl (Ci- 10) alkyl, sulfmyl (Ci- 10) alkyl, (Ci ⁇ ' 10) azaalkyl, imino (Ci Jo) alkyl, (C3
  • C3-.12 cycloalkyl hetero
  • C3_ .12 cycloalkyl
  • C9-12 bicycloalkyl, heie.ro (C3- 12) bicycloalkyl (C4-12) aryl, hetero (Ci-10) aryl, (C9-12) bicycloaryl and hetero (C4- 12) bicycloaryl
  • the compounds of the present invention can be present in the form of pharmaceutically acceptable salts.
  • the compounds of the present invention can also he present in the form of pharmaceutically acceptable esters (i.e., the methyl and ethyl esters of the acids of formula 1 to be used as prodrugs).
  • the compounds of the present, invention can also be solvated, i.e. hydrated. Th solvation can be affected in the course of the manufacturing process or can take place i.e. as a consequence of hygroscopic properties of an initially anhydrous compound of formula I (hydration).
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center or centers and is described by the R- and S-sequencing rules of Cahn, Ingold and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture".
  • metabolic condition refers to an Inborn errors of metabolism (or genetic metabolic conditions) are genetic disorders that result from a defect in one or more metabolic pathways; specifically, the function of an enzyme is affected and is either deficient or completely absent. Metabolic condition associated diseases include: Hepatic, Neurologic, Psychiatric, Hematologic, Renal, Cardiovascular, Cancer, Musculoskeletal, Orthopedic and Gastrointestinal.
  • polymorph as used herein is art-recognized and refers to one crystal structure of a given compound.
  • Residue is an art-recognized term that refers to a portion of a molecule.
  • a residue of thioctic acid may be; dihydro!ipoic acid, bisnorlipoic acid, tetranoriipoic acid, 6.8-bismethylmercapto-octanoic acid, 4,6-b.ismethylmercapto- hexanoic acid, 2.4-bismethylmeracapto-butanoic acid, 4,6-bismethyimercapto-hexanoic acid.
  • parenteral administration and “administered parenteral !y” as used herein refer to modes of admini stration other than enteral and topical administration, such as injections, and include without limitation intravenous, intramuscular, intrapleural, intravascular, intrapericardial, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradenna!, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrastemai injection and infusion.
  • a "patient,' " " "subject,” or “host” to be treated by the subject method may mean either a human or non-human animal, such as primates, mammals, and vertebrates.
  • compositions, polymers and other .materials and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of mammals, human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • phrases "pharmaceutically acceptable carrier” is art-recognized, and includes, for example, pharmaceutically acceptable materials, compositions or vehicles, such as a liquid or solid ft Her. diluent, solvent or encapsulating material involved in carrying or transporting any subject composition, from one organ, or portion of the body, to another organ, or portion of the body.
  • a pharmaceutically acceptable carrier is non-pyrogenic.
  • materials which may serve as pharmaceutically acceptable carriers include: ( 1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragaeanih; (5) malt; (6) gelatin; (7) talc; (8) cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, com oil and soybean oil; (10) glycols, such as propylene glycol ; (11.) pol ols, such as glycerin, sorbitol, mannitol and polyetiiylene glycol; ( 12) esters, such as ethyi oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydrox
  • polymorph as used herein is art-recognized and refers to one crystal structure of a given compound.
  • prodrug is intended to encompass compounds that, under physiological condi ions, are converted into the therapeutically active agents of the present invention.
  • a common method for making a prodrug is to include selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule.
  • the prodrug is converted by an enzymatic activity of the host animal.
  • prophylactic or therapeutic treatment is art-recognized and includes administration to the host of one or more of the subject compositions, if it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic, i.e., it protects the host against developing the unwanted condition, whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic, (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).
  • the unwanted condition e.g., disease or other unwanted state of the host animal
  • predicting refers to assessing the probability according to which a neurological condition or disorder such as pain related diseases patient will suffer from abnormalities or complication and/or terminal nerve damage or failure and/or death (i.e. mortality) withi a defined time window (predictive window) in the future.
  • the mortality may be caused by the central nervous system or complication.
  • the predictive window is an interval in which the subject will develop one or more of the said complications according to the predicted probability.
  • the predictive window may be the entire remaining lifespan of the subject upon analysis by the method of the present- invention.
  • the predictive window is an interval of one month, six months or one, two, three, four, five or ten years after appearance of the cardiovascular complication (more preferabiy and precisely, after the sample to be analyzed by the method of the present invention has been obtained).
  • an assessment i usually not intended to be correct for 100% of the subjects to be analyzed.
  • the term requires that the assessment will be valid tbr a statistically significant portion of the subjects to be analyzed. Whether a portion is statistically significant can be determined without further ado by the person skilled in the art using various well known statistic evaluation, tools, e.g., determination of confidence intervals, p-vaiue determination.
  • Preferred confidence intervals are at least 90%, at least 95%, at least 97%, at least 98% or at least 99 %.
  • the p-values are, preferabiy, 0.1 , 0.05, 0.01, 0.005, or 0.0001 .
  • the probability envisaged by the present invention allows thai the prediction will be correct for at least 60%, at least 70%, at least 80%, or at least 90% of the subjects of a gi ven cohort.
  • treating is art -recognized and includes preventing a disease, disorder or condition from occurring in an animal which may he predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having it; inhibiting the disease, disorder or condition, e.g., impeding its progress; and relieving the disease, disorder, or condition, e.g., causing regression of the disease, disorder and/or condition.
  • Treating the disease or condition includes ameliorating at least one symptom of the particular disease or condition, even if the underlying pathophysiology is not affected, such as treating the neurological condition such as chronic pain condition of a subject, by administration of an agent even though such agent does not trea the cause of the condition.
  • the terra "treating", “treat” or “treatment” as used herein includes curative, preventative (e.g. , prophylactic), adjunct and palliative treatment.
  • Neurological diseases related to pain disorders includes such as injury, postoperative pain, osteoarthritis, rheumatoid arthritis, multiple sclerosis, spinal cord injury, migraine, HIV related neuropathic pain, post herpetic neuralgia, diabetic neuropathy, cancer pain, fibromyalgia and lower back pain or any other medical condition, is well understood in the art, and includes administration of a composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition in a subject relati ve to a subject which does not receive the composition,
  • a pharmaceutically effective amount is an art-recognized term.
  • the term refers to an amount of a salt or composition disclosed herein that produces some desired effect at a reasonable benefit/risk ratio applicable to any medical treatment, in certain embodiments, the term refers to that amount necessary or sufficient to eliminate or reduce medical symptoms for a period of time.
  • the effective amount may van' depending on such factors as the disease or condition being treated, the particular targeted constructs being administered, the size of the subject, or the severity of the disease or condition.
  • One of ordinary skill in the art may empirically determine the effective amount of a particular composition without necessitating undue experimentation.
  • the pharmaceutical compositions described herein are formulated in a manner such that said compositions will be delivered to a patient in a therapeutically effective amount, as part of a prophylactic or therapeutic treatment.
  • the desired amount of the composition to be administered to a patient will depend on absorption, inaetivation, and excretion rates of the drug as well as the delivery rate of the salts and compositions from the subject compositions, it is to be noted that dosage values may also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions. Typically, dosing will be determined using techniques known to one skilled in the art.
  • the optimal concentration and/or quantities or amounts of any particular salt or composition may be adjusted to accommodate variations in the treatment parameters.
  • treatment parameters include the clinical use to which the preparation is put, e.g., the site treated, the type of patient, e.g., human or non-human, adult or child, and the nature of the disease or condition.
  • the dosage of the subject compositions provided herein may be determined by reference to the plasma concentrations of the therapeutic composition or other encapsulated materials.
  • the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve from time 0 to infinity may be used.
  • solvate refers to a compound formed by solvation (e.g., a compound formed by the combination of solvent molecules with molecules or ions of the solute).
  • sustained release When used with respect to a pharmaceutical composition or other material, the term "sustained release" is art-recognized.
  • a subject composition which releases a substance over time may exhibit sustained release, characteristics, in contrast, to a bolus type administration in which the entire amount of the substance is made biologically available at one time.
  • one or more of the pharmaceutically acceptable exeiptents may undergo gradual or delayed degradation (e.g., through hydrolysis) with concomitant release of any material incorporated therein, e.g., an therapeutic and or biologically active salt and/or composition, for a sustained or extended period (as compared to the release from a bolus).
  • This release may result in prolonged delivery of therapeutically effective amounts of any of the therapeutic agents disclosed herein.
  • the phrase "therapeutically effective amount" is an art-recognized term.
  • the term refers to an amount of a salt or composition disclosed herein that produces some desired effect at a reasonable benefit/risk ratio applicable to any medical treatment.
  • the term refers to that amount necessary or sufficient to eliminate or reduce medical symptoms for a period of time.
  • the effective amount may vary depending on such factors as the disease or condition being treated, the particular targeted constructs being admi istered, the size of the subject, or the severity of the disease or condition. One of ordinar skill in the art may empirically determine the effective amount of a particular composition without necessitating undue experimentation.
  • the present disclosure also contemplates prodrugs of the compositions disclosed herein, as well as pharmaceutically acceptable salts of said prodrugs.
  • This application also discloses a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the composition, of a.
  • compound of Formula i may be formulated for systemic or topical or oral administration.
  • the pharmaceutical composition may be also formulated for oral administration., oral solution, injection, subderaial administration, or transdermal administration.
  • the pharmaceutical composition may further comprise at least one of a pharmaceutically acceptable stabilizer, diluent, surfactant, filler, binder, and lubricant,
  • the pharmaceutical compositions described herein will incorporate the disclosed compounds and compositions (Formula ⁇ ) to be delivered in an amount sufficient to deliver to a patient a therapeutically effective amount of a compound of formula I or composition as part of a prophylactic or therapeutic treatment.
  • the desired concentration of formula ⁇ or its pharmaceutical acceptable salts will depend on absorption, inactivation, and excretion rates of the drug as well as the delivery rate of the salts and compositions from the subject compositions. It is to be noted that dosage values may also vary with the severit of the condition to be alleviated.
  • any particular compound of formula ⁇ may be adjusted to accommodate variations in the treatment parameters.
  • treatment parameters include the clinical use to which the preparation is put, e.g., the site treated, the type of patient, e.g., human or non-human, adult or child, and the nature of the disease or condition.
  • concentration and/or amount of any compound of formula I may be readily identified by routine screening in animals, e.g., rats, by screening a range of concentration and/or amounts of the materia! in question using appropriate assays.
  • Known methods are also available to assay local tissue concentrations, diffusion rates of the salts or compositions, and local blood flow before and after administration of therapeutic formulations disclosed herein.
  • One such method is microdialysis, as reviewed by T. E. Robinson et al . s 1991, microdialysis in the neurosciences. Techniques, volume 7, Chapter 1 , The methods reviewed by Robinson may be applied, in brief, as follows. A microdialysis loop is placed in situ in a test animal. Dialysis fluid is pumped through the loop.
  • the dosage of the subject compounds of formula I provided herein may be determined by reference to the plasma concentrations of the therapeutic composition or other encapsulated materials.
  • the maximum piasma concentration (Cmax) and the area under the plasma concentration-time curve from time 0 to infinity may be used.
  • an effective dosage for the compounds of Formulas ⁇ is in the range of about 0.01 mg/kg day to about 100 mg/kg/day in single or divided doses, for instance 0.01 mg kg day to about 50 mg/kg day in single or divided doses.
  • the compounds of Formulas ⁇ may be admini stered at a dose of for example, less than 0.2 mg kg/day, 0.5 mg kg day, 1.0 mg/kg/day, 5 mg/kg/day, 10 mg kg day, 20 mg/kg/day, 30 mg kg/day, or 40 mg kg day.
  • Compounds of Formula I may also be administered to a human patient at a dose of, for example, between 0.1 nig and 1000 mg, betwee 5 mg and 80 nig, or less than 1.0, 9.0, .12.0, 20.0, 50.0, 75.0, 100, 300, 400, 500, 800, 1000 mg per day.
  • the compositions herein are administered at an amount that is less than 95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10% of the compound of formula I required for the same therapeutic benefit.
  • An effective amount of the compounds of formula I described herein refers to the amount of one of said salts or compositions which is capable of inhibiting or preventing a disease.
  • a disease For example injury, post-operative pain, osteoarthritis, rheumatoid arthritis, multiple sclerosis, spinal cord injury, migraine, HIV related neuropathic pain, post herpetic neuralgia, diabetic neuropathy, cancer pain, fibromyalgia and lower back pain.
  • An effective amount may be sufficient to prohibit, treat, alleviate, ameliorate, halt, restrain, slow or reverse the progression, or reduce the severity of a complication resulting from nerve damage or demyelization and/or elevated reactive oxidative- nitrosative species and/or abnormalities in neurotransmitter homeostasis's, in patients who are at risk for such complications.
  • these methods include both medical therapeutic (acute) and/or prophylactic (prevention) administration as appropriate
  • the amount and timing of compositions administered will, of course, be dependent on the subject being treated, on the severity of the affliction, on the manner of administration and on the judgment of the prescribing physician.
  • the dosages given above are a guideline and the physician may titrate doses of the drug to achieve the treatment that the physician considers appropriate for the patient.
  • the physician nrust balance a variet of factors such as age of the patient, presence of preexisting disease, as well as presence of other diseases.
  • compositions provided by this application may be administered to a subject in need of treatment by a variety of conventional routes of administration, including orally, topically, parenteraliy, e.g., intravenously, subcutaneou ly or intramedullary. Further, the compositions may be administered intranasa!ly, as a rectal suppository, or using a "flash" formulation, i .e., allowing the medication to dissolve in the mouth without the need to use water. Furthermore, the compositions may be administered to a subject in need of treatment by controlled release dosage forms, site specific drug delivery, transdermal drug delivery, patch (active passive) mediated drug delivery, by stereotactic injection, or in nanoparticles.
  • compositions may be administered alone or in combination with pharmaceutically acceptable carriers., vehicles or diluents, in either single or multiple doses.
  • Suitable pharmaceutical carriers, vehicles and diluents include inert solid diiuents or fillers, sterile aqueous solutions and various organic solvents.
  • the pharmaceutical compositions formed by combining the compositions and the pharmaceutically acceptable carriers, vehicles or diluents are then readily administered in a variety of dosage forms such as tablets, powders, lozenges, syrups, injectable solutions and the like.
  • These pharmaceutical compositions can, if desired, contai n additional ingredients such as flavorings, binders, excipients and the like.
  • tablets containing various excipients such as L-arginine, sodium citrate, calcium carbonate and calcium phosphate may be employed along with various disintegrates such as starch, alginic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • lubricating agents such as magnesi m stearate, sodium !auryl sulfate and talc are often useful for tahletting purposes.
  • Solid compositions of a similar type may also be employed as fillers i n soft and hard filled gelatin capsules. Appropriate materials for this include lactose or milk sugar and high molecular weight polyethylene glycols.
  • the essential active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if desired, emulsifying or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin and combinations thereof.
  • the compounds of formula 1 may also comprise enterically coated comprising of various excipients, as is well known in the pharmaceutical art.
  • solutions of the compositions may be prepared in (for example) sesame or peanut oil, aqueous propylene glycol, or in sterile aqueous solutions may be employed.
  • aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
  • the formulations for instance tablets, may contain e.g. 10 to 100, 50 to 250, I SO to 500 mg, or 350 to 800 mg e.g. 10, 50, 100, 300, 500, 700, 800 nig of the compounds of formula 1 disclosed herein, for instance, compounds of formula I or pharmaceutical acceptable salts of a compounds of Formula!
  • a composition as described herein may be administered orally, or parenterally (e.g., intravenous, intramuscular, subcutaneous or intramedullary). Topical administration may also be indicated, for example, where the patient is suffering from gastrointestinal disorder that prevent oral administration, or whenever the medication is best applied to the surface of a tissue or organ as determined by the attending physician. Localized admini stration may also be indicated, for example, when a high dose is desired at the target tissue or organ.
  • the active composition may take the form of tablets or lozenges formulated in a conventional manner.
  • the dosage administered will be dependent upon the identity of the neoplastic disease; the type of host involved, including its age, health and weight; the kind of concurrent treatment, if any; the frequency of treatment and therapeutic ratio.
  • dosage levels of the administered active ingredients are: intravenous, 0.1 to about 200 mg/kg; intramuscular, 1 to about 500 mg kg; orally, 5 to about 1000 mg/kg; intranasal instillation, 5 to about 1000 mg kg; and aerosol, 5 to about 1000 mg kg of host body weight.
  • an active ingredient can be present in the compositions of the present invention for localized use about the cutis, intranasaHy, pharyngolaryngeally, bronchially, intravagiiiallv, rectally, or ocularly in a concentration of from about 0.01 to about 50% w/w of the composition; preferably about 1 to about 20% w/w of the composition; and for parenteral use in a concentration of from about 0.05 to about 50% w/v of the composition and preferabl from about 5 to about 20% w/v.
  • compositions of the present invention are preferably presented for ad mini strati on to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders., granules., suppositories, sterile parenteral solutions or suspensions, sterile non-parenteral solutions of suspensions, and oral solutions or suspensions and the like, containing suitable quantities of an active ingredient.
  • unit dosage forms such as tablets, capsules, pills, powders., granules., suppositories, sterile parenteral solutions or suspensions, sterile non-parenteral solutions of suspensions, and oral solutions or suspensions and the like, containing suitable quantities of an active ingredient.
  • unit dosage forms such as tablets, capsules, pills, powders., granules., suppositories, sterile parenteral solutions or suspensions, sterile non-parenteral solutions of suspensions, and oral solutions or suspensions and the like, containing suitable quantities of an active ingredient.
  • Powders are prepared quite simply by comminuting the active ingredient to a suitably fine size and mixing with a similarly comminuted diluent.
  • the diluent can be an edible carbohydrate material such as lactose or starch.
  • a sweetening agent or sugar is present as well as flavoring oil,
  • Capsules are produced by preparing a powder mixture as hereinbefore described and filling into formed gelatin sheaths.
  • a lubricant such as talc, magnesium stearate, calcium stearate and the like is added to the powder mixture before the filling operation.
  • Soft gelatin capsules are prepared fay machine encapsulati n of slurry of active ingredients with an acceptable vegetable oil, light liquid petrolatum or other inert oil or triglyceride.
  • Tablets are made by preparing a powder mixture, granulating or slugging, adding a lubricant and pressing into tablets
  • the powder mixture is prepared by mixing an active ingredient, suitably comminuted, with a diluent or base such as starch, lactose, kaolin, dicalciuni phosphate and the like.
  • the powder mixture can be granulated by wetting with a binder such as corn syrup, gelatin solution, methyiceilulose solution or acacia mucilage and forcing through a screen.
  • the powder mixture can be slugged, i.e., ran through the tablet machine and the resulting imperfectly formed tablets broken into pieces (slugs).
  • the slugs can be lubricated to prevent sticking to the tablet- forming dies by means of the addition of stearic acid, a stearic salt, talc or mineral oil. The lubricated mixture is then compressed into tablets.
  • the tablet can be provided with a protective coating consisting of a sealing coat or enteric coat of shellac, a coating of sugar and methyl cellulose and pol ish coating of carnauba wax,
  • Fluid unit dosage forms for oral administration such as in syrups, elixirs and suspensions can be prepared wherein each teaspoonfuf of composition contains a predetermined amount of an active ingredient for administration.
  • the water-soluble forms can be dissolved in an aqueous vehicle together with sugar, flavoring agents and preservatives to form a syrup.
  • An elixir is prepared by using a hydroalcoholic- vehicle with suitable sweeteners together with a flavoring agent.
  • Suspensions can be prepared of the insoluble forms with a suitable vehicle with the aid of a suspending aaent suck as acacia, tragacanth, methylcel ulose and the like.
  • fluid unit dosage forms are prepared utilizing an active ingredient and a sterile vehicle, water being preferred.
  • the active ingredient depending on the form and concentration used, can be either suspended or dissolved in the vehicle.
  • the water- soiubie active ingredient can be dissoived in water for injection and filter sterilized before filling into a suitable vial or ampule and sealing.
  • adjuvants such as a iocai anesthetic, preservative and buffering agents can be dissolved in the vehicle.
  • Parenteral suspensions are prepared in substantially the same manner except that an active, ingredient is suspended in the vehicle instead of being dissoived and sterilization cannot be accomplished by filtration.
  • the active ingredient can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the active ingredient.
  • an active ingredient can be administered by means of a suppository.
  • a vehicle which has a melting point at about body temperature or one that is readily soluble can be utilized.
  • cocoa butter and various polyethylene glycols (Carbowaxes) can serve as the vehicle.
  • a fluid unit dosage form is prepared utilizing an active ingredient and a suitable pharmaceutical vehicle, preferably P.F. water, a dry powder can be formulated when insufflation is the administration of choice.
  • the active ingredients can be packaged in a pressurized aerosol container together with a gaseous or liquified propellant, for example, clichlorodifluorom ethane, carbon dioxide, nitrogen, propane, and the like, with the usual adjuvants such as cosolvents and wetting agents, as may be necessary or desirable.
  • a gaseous or liquified propellant for example, clichlorodifluorom ethane, carbon dioxide, nitrogen, propane, and the like, with the usual adjuvants such as cosolvents and wetting agents, as may be necessary or desirable.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human and animal subjects, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical diluent, carrier or vehicle.
  • the specifications for the novel unit dosage forms of this invention are dictated by and axe directly dependent on (a) the unique characteristics of the active material and the particular therapeutic effect to be achieved, and (b) the limitation inherent in the art of compounding such an active materia! for therapeutic use in humans, as disclosed in this specification, these being features of the present invention.
  • suitable unit dosage forms in accord with thi invention are tablets, capsules, troches, suppositories, powder packets, wafers, cachets, teaspoonfuis, tab!espoonfuls, dropperfuls, ampules, vials, segregated multiples of any of the foregoing, and other forms as herein described.
  • the tablets of the present invention contain one or more pharmaceutically active agents that are released therefrom upon contact of the tablet with a liquid medium, for example a dissolution medium such as gastrointestinal fluids.
  • a liquid medium for example a dissolution medium such as gastrointestinal fluids.
  • Water soluble as used herein in connection with non-polymeric materials, shall mean from sparingly soluble to very soluble, i.e., not more than 100 parts water required to dissolve 1 part of the non- polymeric, water soluble solute. See Remington, The Science and Practice of Pharmacy, pp 208-209 (2000).
  • Water soluble as used herein in connection wi h polymeric materials, shall mean that the polymer swells in water and can be dispersed at the molecular level or dissolved in water.
  • modified release shall apply to tablets, matrices, particles, coatings, portions thereof, or compositions that alter the release of an pharmaceutically active agent in any manner.
  • Types of modified release include controlled, prolonged, sustained, extended, delayed, pulsatile, repeat action, and the like. Suitable mechanisms for achieving these types of modified release include diffusion, erosion, surface area control via geometry and/or impermeable barriers, or other mechanisms known in the art.
  • the first pharmaceutically active agent and the hydrophilic polymer are mixed with a powder containing a pharmaceutically- acceptable carrier, which is also defined herein as the tablet matrix, in one embodiment, the powder has an average particle size of about 50 microns to about 500 microns, such as between 50 microns and 300 microns. Particles in this size range are particularly useful for direct compression processes.
  • the components of powder are blended together, for example as dry powders, and fed into the die cavity of an apparatus that applies pressure to form a tablet core.
  • Any suitable compacting apparatus may be used, including, but not limited to, conventional unitary or rotary tablet press.
  • the tablet core may be formed by compaction using a rotary tablet press (e.g., such as those commercially available from Fette America inc., Rockaway, .J., or Manesty Machines LTD, Liverpool, UK), in general, a metered volume of powder is filled into a die cavit (where the powder is either gravity fed or mechanically fed from a feeder) of the rotary tablet press, and the cavity rotates as part of a "die table" from the filling position to a compaction position. At the compaction position, the powder is compacted between an upper and a lower punch, then the resulting tablet core is pushed from the die cavity by the lower punch and then guided to an injection chute by a stationary "take-off bar.
  • a rotary tablet press e.g., such as those commercially available from Fette America inc., Rockaway, .J., or Manesty Machines LTD, Liverpool, UK
  • a rotary tablet press e.g., such as those commercially available from Fette America inc.,
  • the tablet core may be a directly compressed tablet core made from a powder that is substantially free of water-soluble polymeric binders and hydrated polymers. As used herein, what is meant by “substantially free” is less than 5 percent, such as less than I. percent, such as less than 0.1 percent, such as completely free (e.g., 0 percent). This composition is advantageous for minimizing processing and material costs and providing for optimal physical and chemical stability of the tablet core. In one embodiment, the density of the tablet core is greater than about 0.9 3 ⁇ 4/cc. [0092]
  • the tablet core may have one of a variety of different shapes.
  • the tablet core may be shaped as a polyhedron, such as a cube, pyramid, prism, or the like; or may have the geometr 1 of a space figure with some non-flat faces, such as a cone, truncated cone, cylinder, sphere, torus, or the like, in certain embodiments, a tablet core has one or more major faces.
  • the tablet core surface typically has opposing upper and lower faces formed by contact with the upper and Sower punch faces in the compression machine.
  • the tablet core surface typically further includes a "belly-band" located between the upper and lower faces, and formed by contact with the die walls in the compression machine.
  • the tablet core contains one or more hydropMlic polymers.
  • Suitable hydrophilic polymers include, but are not limited to, water swellable cellulose derivatives, polyalkyiene glycols, thermoplastic poSyalkylene oxides, acrylic polymers, hydrocolloids, clays, gelling starches, swelling cross-linked polymers, and mixtures thereof
  • suitable water swellable cellulose derivatives include, but are not limited to, sodium carboxymethyl cellulose, cross-linked hydroxypropylcellulose, hydroxypropyl cellulose (HPC), hydroxypropylmethylcellulose (HPMC), hydroxy i sopropy 1 eel 1 ul ose, hydroxybuty I eel I ul ose, h droxyplieny leell ul ose, hydrox ethylcellulose (HEC), hydroxypentylceilulose, hydroxypropylethylcellulose, hydroxypropyibutylcellulose, and hydroxyprop
  • suitable polyalkyiene glycols include, but are not limited to, polyethylene glycol.
  • suitable thermoplastic polyalkyiene oxides include, but are not limited to, poly(ethylene oxide).
  • suitable acrylic polymers include, but are not limited to, potassium methacrylatedivinylbenzene copolymer, polymethylmethacrylate, high-molecular weight crosslinked acrylic acid homopolymers and copolymers such as those commercially available from Noveon Chemicals under the tradename CARBOPGLTM.
  • hydrocolloids include, but are not limited to, alginates, agar, guar gum, locust bean gum, kappa carrageenan, iota carrageenan, tara, gum arable, tragacanth, pectin, xanthan gum, gellan gum, maltodextrin, gal ctomannan, pusstulan, laminarin, scleroglucan, gum arable, inulin, pectin, gelatin, whelan, rhamsan, zooglan, methylan, chitin, cyelodextrin, chitosan, and mixtures thereof.
  • Suitable clays include, but are not limited to, smectites such as bentonite, kaolin, and laponite; magnesium trisilicate; magnesium aluminum silicate; and mixtures thereof.
  • suitable gelling starches include, but are not limited to, acid hydrolyzed starches, swelling starches such as sodium starch glyeolate and derivatives thereof, and mixtures thereof.
  • suitable swelling cross-linked polymers include, but are not limited to, cross-linked polyvinyl pyrrolidone, cross-linked agar, and cross-linked carboxymethylcelluiose sodium, and mixtures thereof.
  • an osmogen is incorporated into the tablet core in order to draw water into the tablet upon contact with fluids, such as gastrointesti al fluids.
  • An osmogen as used herein is a water soluble component which preferentially draws water i nto the tablet core for the purposes of distributing the water throughout the core, so that the active ingredient contained in the core may be released.
  • the osmogen is a salt such as but .not limited to sodium chloride, potassium chloride, sodium citrate, or potassium citrate.
  • the carrier may contain one or more suitable excipients for the formulation of tablets.
  • suitable excipients include, but are not limited to, fillers, adsorbents, binders, dktntegrants, lubricants, glidants, release-modi tying excipients, superdisintegrants, antioxidants, and mixtures thereof,
  • Suitable fillers include, but are not limited to, watersoluble compressible carbohydrates such as sugars (e.g., dextrose, sucrose, maltose, and lactose), starches (e.g., corn starch), sugar-alcohols (e.g., mannitol, sorbitol, maltitol, erythritoL and xylitol), starch hydroly sates (e.g., dextrins, and maltodextrins), and water insoluble plastically deforming materials (e.g., macrocrystalline cellulose or other cellulosic derivatives), and mixtures thereof.
  • watersoluble compressible carbohydrates such as sugars (e.g., dextrose, sucrose, maltose, and lactose), starches (e.g., corn starch), sugar-alcohols (e.g., mannitol, sorbitol, maltitol, erythritoL and xy
  • Suitable adsorbents include, but are not limited to, water-insoluble adsorbents such, as dicalcium. phosphate, tri calcium phosphate, silicified macrocrystalline cellulose (e.g., such as distributed under the PROSOLV brand (PenWes Pharmaceuticals, Patterson, N Y.)), magnesium aluminometasilicate (e.g., such as distributed under the EUSIIJNTM brand (Fuji Chemical industries (USA) inc., Robfamsvi!le, N.J.), clays, silicas, bentonite, zeolites, magnesium silicates, hydrotalcite, veeg tn, and mixtures thereof.
  • water-insoluble adsorbents such, as dicalcium. phosphate, tri calcium phosphate, silicified macrocrystalline cellulose (e.g., such as distributed under the PROSOLV brand (PenWes Pharmaceuticals, Patterson, N Y.)), magnesium aluminometasi
  • Suitable binders include, but are not limited to, dry binders such as polyvinyl pyrrolidone and hydroxypropyimethylcellulose; wet binders such as water-soluble polymers, including hydrocolloids such as acacia, alginates, agar, guar gum, locust bean, carrageenan, carboxymethyicellulose, tara, gum arable, tragaeanth, pectin, xanthan, geilan, gelatin, maltodextrin, galactomannan, pusstulan, laminariti, sc!eroglucan, inulin, whelan, rhamsan, zooglan, methylan, chitin, eyclodextrm, chitosan, polyvinyl pyrrolidone, celiulosics, sucrose, and starches; and mixtures thereof.
  • Suitable disintegrants include, but are not limited to, sodium starch glycol
  • Suitable lubricants include, but ate not limited to, long chain fatty acids and their salts, such as magnesium siearate and stearic acid, talc, glycerides waxes, and mixtures thereof.
  • Suitable glidants include, but are not limited to, colloidal silicon dioxide.
  • Suitable release-modifying excipients include, but are not limited to, insoluble edible materials, pH-dependent polymers., and mixtures thereof.
  • Suitable insoluble edible materials for use as release-modifying excipients include, but are not limited to, water-insoluble polymers and low-melting hydrophobic materials, copolymers thereof, and mixtures thereof.
  • suitable water- insoluble polymers include, but are not limited to, ethylceiltrlose, polyvinyl alcohols, polyvinyl acetate, polycaprolactones, cellulose acetate and its derivatives, acrylates, methacrylates, acrylic acid copolymers, copolymers thereof and mixtures thereof.
  • Suitable low-melting hydrophobic materials include, but are not limited to, fats, fatty acid esters, phospholipids, waxes, and mixtures thereof.
  • suitable fats include, but are not limited to, hydrogenated vegetable oils such as for example cocoa butter, hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenated sunflower oil, and hydrogenated soybean oil, free fatty acids and their salts, and mixtures thereof.
  • suitable fatty acid esters include, but are not limitationci to, sucrose fatty acid esters, mono-, di ⁇ , and triglycerides, glyceryl behenate, glyceryl pa!mitostearate, glyceryl monostearate, glyceryl tristearate, glyceryl triiaurylate, glyceryl myristate, G!ycoWax- 93.2, lauroyl macrogol-32 glycerides, stearoyl macrogol-32 glycerides, and mixtures thereof.
  • Suitable phospholipids include phosphatidyl choline, phosphatidyl serene, phosphoiidyi enositol, phosphotidic acid, and mixtures thereof
  • suitable waxes include, but are not limited to, carnauba wax, spermaceti wax, beeswax, candelilla wax, shellac wax, microcr stalline wax, and paraffin wax; fat-containing mixtures such as chocolate, and mixtures thereof.
  • super disintegrants include, but are not limited to, croscarmeliose sodium, sodium starch, glycol ate and cross- linked povidone (crospovidone). In one embodiment the tablet core contains up to about 5 percent by weight of such super disintegrant.
  • antioxidants include, but are not limited to, tocopherols, ascorbic acid, sodium pyrosulfite, butyllrvdroxytoSuene, but lated hydroxy anisole, edeiie acid, and edetate salts, and mixtures thereof.
  • preservatives include, but are not limited to, citric acid, tartaric acid, lactic acid, malic acid, acetic acid, benzoic acid, and sorbte acid, and mixtures thereof
  • the osmotic tablets of the present invention include an osmotic coating.
  • An osmotic coating is one that is semipermeable thereby allows water to be drawn into the tablet core, e.g., for the purposes of releasing the active ingredient such as through a pre- made hole in the coating or through coating itself it is semipermeable membrane.
  • the osmotic coating thus, does not fully dissolve upon contact with water
  • the osmotic coating contains a water soluble component such as a water solible film former which aids in facilitating a further influx of water upon contact with water.
  • the osmotic coating is applied via spray coating.
  • Suitable spray coating techniques include spray coating via a coating pan or fluid bed process such as Wurster coating or top spray fluid bed coating as described in the text, "The Theory and Practice of Industrial Pharmacy", Lachman, Leon et, ai, 3rd ed.
  • the osmotic coating may be applied using a solution prepared with water, organic solvents, or mixtures thereof.
  • Suitable organic solvents include but are not limited to acetone, isopropanol, methylene chloride, hexane, methanol, ethanol, and mixtures thereof.
  • the poI mer(s) are dissolved in the coaling solution.
  • the polymer(s) are dispersed, as is the case when applying water Insoluble polymers via a dispersion or as is the case when using ethylcellulose dispersions.
  • the osmotic coating functions as a semipermeable membrane (e.g., allowing water or solvent to pass into the core, but being impermeable to dissolved pharmaceuti caliy active agent, thereby preventing the passage of pharmaceutically active agent therethrough)
  • the film former is selected from water insoluble polymers, pH-dependent polymers, water soluble polymers, and combinations thereof.
  • the osmottc coating includes a water insoluble polymer and a pore forming material.
  • water-insoluble polymers examples include ethylcelhilose, polyvinyl alcohols, polyvinyl acetate, polycaproiactones, cellulose acetate and its derivatives, aeryiates, methacrylates, acrylic acid copolymers, and combinations thereof, in one embodiment, the water insoluble polymer is cellulose acetate. In one embodiment, the osmotic coating includes from about 10 to about 100 weight percent of a water insoluble film former.
  • the water insoluble polymer is combined with a water soluble film former in order to create pores in the resulting semipermeable membrane.
  • suitable film formers include, but are not limited to: water soluble vinyl polymers such as pol vinylaleoboi (PVA); water soluble polycarbohydrates such as hydroxypropyl starch, hydroxyethyi starch, pullulan, meth l eth l starch, carboxy methyl starch, pre-geJatinized starches, and film-forming modified starches; water swell able cellulose derivatives such as hydroxypropyl cellulose (HPC), hydroxy propyhn ethyl cellulose (HPMC), methyl cellulose (M €), hydroxyethylmethy lceliulose (HEMC), hydroxyhutylmethylceUulose (HBMC), hydrox ethylethylcellulose (HEEC), and hydrox ethylethylcellulose (HEEC), and hydrox ethy
  • a pH dependent, polymer is incorporated into the osmotic coating.
  • the pH dependent polymer is used at a level of from about 10 to about 50 percent by weight of the osmotic coating.
  • Suitable film-forming pH- dependetrt polymers include, but are not limited to, enteric cellulose derivatives, such as for example hydroxypropyl methyl celliilose phthalate, hydroxypropyl methyleellulose acetate succinate, and cellulose acetate phthalate; natural resins such as shellac and zein; enteric acetate derivatives such as polyvinylacetate phthalate, cellulose acetate phthalate, and acetaldehyde dimethylcellulose acetate; and enteric aery late derivatives such as for example polymethacrylate-based polymers such as poly(methacryIic acid, methyl methacryiate) 1 :2 (commercially available from Rohm Pharma Gmhll under the trade
  • the osmotic coating is free of porosity (e.g., wherein the pore volume is in a pore diameter range of less than 0.01 g/ec), in one embodiment, the average pore diameter of the osmotic coating is less than about 0.2 microns (e.g., less than about 0.15 microns).
  • the osmotic coating is substantially free of an pharmaceutically active agent.
  • the osmotic coating includes ⁇ pharmaceutically active agent which is different than the pharmaceutically active agent included in the immediate release coating.
  • the osmotic coating includes a plasticizer. In one embodiment the plasticizer must be of sufficient quantity to withstand the compression force of the immediate release coating.
  • Suitable plastieizers include, but are not limited to: polyethylene glycol; propylene glycol; glycerin; sorbitol, triethyi citrate; tributyl citrate; dibtityl sebecate; vegetable oils such as castor oil, grape oil, olive oil, and sesame oil; surfactants such as polysorbaies, sodium lauryi sulfates, and dioctyl -sodium sulfosuccinates; mono acetate of glycerol; diacetate of glycerol; triacetate of glycerol; natural gums; triacetin; acetyltributyl citrate; diethyloxalate; diethylmalate; diethyl fumarate; diethylmaionate; dioctylphthalate; dibutyisuccinaie; glycerol tnbutyrate; hydrogenated castor oil; fatty acids such as lauri
  • At least about 50 percent of the cross-sectional area of the osmotic coating used in tablets of this invention is striated, such as at least about 80% of the cross-sectional area of the osmotic coating portion is striated.
  • striated means non-homogeneous with respect to appearance and with respect to the internal structure of the coating portion when viewed under any magnification and lighting conditions, at which point siriations or layers can be viewed.
  • Compressed portions of a pharmaceutical oral dosage forms do not display striated areas, wherein spray coated portions display striafions.
  • a crosssection of the osmotic coating portion is striated, and nonuniform with respect to refractive properties when observed utilizing a light microscope or a scanning electron microscope at a magnification of about 50 to about 400 times.
  • the characteristic striations are indicative of the spray-coating process consisting of multiple repetitions of the steps consisting of: (a) application via spraying of coating solution; followed by (b) warm air drying, to a tumbling bed of tablets in a revolving coating pan such that numerous layers of coating material are built up as each application of coating material dries to form a layer.
  • the thickness of an individual striated layer is the range of about 10 microns to about 15 microns.
  • the osmotic coating is semipermeable (e.g., containing a plurality of small opening) and does not require the addition of an additional opening via laser or other means, in one such embodiment, t he semi -permeable membrane of the osmotic coating also allows for the release of the active ingredient in the tablet core through the membrane in a zero-order or first-order release manner.
  • the immediate release coating has an average thickness of at least 50 microns, such as from about 50 microns to about 2500 microns; e.g., from about 250 microns to about 1000 microns, in embodiment, the immediate release coating is typically compressed at a density of more than about 0.9 g/cc, as measured by the weight and volume of that specific layer.
  • the immediate release coating contains a first portion and a second portion, wherein, at least one of the portions contains the second pharmaceutically active agent.
  • the portions cootact each other at a center axis of the tablet.
  • the first portion includes the first pharmaceutically active agent and the second portion includes the second pharmaceutically active agent.
  • the first portion contains the first pharmaceutically active agent and the second portion contains the second pharmaceutically active agent. In one embodiment, one of the portions contains third pharmaceutically active agent. In on embodiment one of the portions contains a second immediate release portion of the same pharmaceutically active agent as that contained in the tablet core.
  • the outer coating portion is prepared as a dry blend of materia! s prior to addition to the coated tablet core. In another embodiment the outer coating portion is included of a dried granulation including the pharmaceutically active agent.
  • a suitable flavor or aroma agent may be added to the outer coating.
  • suitable flavor and aroma agents include, but are not limited to, essentia! oils including distillations, solvent extractions, or cold expressions of chopped flowers, leaves, peel or pulped whole fruit containing mixtures of alcohols., esters, aldehydes and lactones; essences including either diluted solutions of essential oils, or mixtures of synthetic chemicals blended to match the natural flavor of the fruit (e.g., strawberry, raspberry, and black currant); artificial and natural flavors of brews and liquors (e.g., cognac, whisky, rum, gin.
  • tobacco, coffee, tea, cocoa, and mint fruit juices including expelled juice from washed, scrubbed fruits such as lemon, orange, and lime; mint; ginger; cinnamon; cacoe/ cocoa; vanilla, liquorice; menthol; eucalyptus; aniseeds nuts (e.g., peanuts, coconuts, hazelnuts, chestnuts, walnuts, and co!anuts), almonds; raisins, and powder, flour, or vegetable material parts including tobacco plant pans (e.g., the genus Nicotiana in amounts .not contributing significantly to a level of therapeutic nicotine), and mixtures thereof.
  • tobacco, coffee, tea, cocoa, and mint fruit juices including expelled juice from washed, scrubbed fruits such as lemon, orange, and lime; mint; ginger; cinnamon; cacoe/ cocoa; vanilla, liquorice; menthol; eucalyptus; aniseeds nuts (e.g., peanuts, coconuts, hazelnuts, chestnuts, walnuts, and co!anut
  • Formulations with different drug release mechanisms described above could be combined in a final dosage form containing single or multiple units.
  • multiple units include multilayer tablets, capsules containing tablets, beads, or granules in a solid or liquid form.
  • Typical, immediate release formulations include compressed tablets, gels, films, coatings, liquids and particles that can be encapsulated, for example, in a gelatin capsule. Many methods for preparing coatings, covering or incorporating drugs, are known in the art.
  • he immediate release dosage unit of the dosage form, i.e., a tablet, a plurality of drug-containing beads, granules or particles, or an outer layer of a coated core dosage form, contains a therapeutically effective quantity of the active agent with conventional pharmaceutical excipients.
  • the immediate release dosage unit may or may not be coated, and may or may not be admixed with the delayed release dosage unit or units (as in an encapsulated mixture of immediate release drug-containing granules, particles or beads and delayed release drug-containing granules or beads),
  • a preferred method for preparing immediate release tablets is by compressing a drugcontaining blend, e.g., blend of granules, prepared using a direct, blend, wet- granulation or dry-granulation process, immediate release tablets may also be molded rather than compressed, starting with a moist material containing a suitable water-soluble lubricant.
  • preferred tablets described herein are manufactured using compression rather than molding.
  • a preferred method for forming immediate release drug-containing blend is to mix drag particles directly with one or more excipients such as diluents (or fillers), binders, dismtegrants, lubricants, glidants, and/or colorants.
  • excipients such as diluents (or fillers), binders, dismtegrants, lubricants, glidants, and/or colorants.
  • a drug-containing blend may be prepared by using a wet- granulation or dry -granulation process. Beads containing the active agent may also be prepared by any one of a number of conventional techniques, typically starting from a fluid dispersion.
  • a typical method for preparing drug-containing beads involves blending the active agent with conventional pharmaceutical excipients such as macrocrystalline cellulose, starch, polyvinylpyrrolidone, methylce!lulose, talc, metallic sfcearates, and silicone dioxide.
  • the admixture is used to coat a bead core such as a sugar sphere (e.g., "non-parcil") having a size of approximately 20 to 60 mesh.
  • An alternative procedure forpreparing drug beads is by blending tile drug with one or more pharmaceutically acceptable excipients, such as macrocrystalline cellulose, lactose, cellulose, polyvinyl pyrrolidone, talc, magnesium stearate, and a disintegrant, extruding the blend, splteronizing the extrudate, drying and optionally coating the bead to form immediate release beads.
  • excipients such as macrocrystalline cellulose, lactose, cellulose, polyvinyl pyrrolidone, talc, magnesium stearate, and a disintegrant
  • Extended release formulations are generally prepared as diffusion or osmotic systems, for example, as described in "Remington— The Science and Practice of Pharmacy", 20th. Ed., Lippincott Williams ⁇ fe Wilkins, Baltimore, Md., 2000).
  • a diffusion system typically consists of one of two types of devices, reservoir and matrix, which are weliknown and described in die art.
  • the matrix devices are generally prepared by compressing the drug with a slowly dissolving polymer carrier into a tablet form.
  • the three major types of materials used in the preparation of matrix devices are insoluble plastics, hydrophiiic polymers, and fatty compounds.
  • Plastic matrices include, but are not limited to, methyl acrylate-methyl methacrylate, polyvinyl chloride, and polyethylene.
  • Hydrophiiic polymers include, but are not limited to, methylcellulose, hydroxypropviceliulose, hydorxypropylraethyiceilulose, sodium carboxymethylcellulose, and €a.rbopol l M 934, and polyethylene oxides.
  • Fatty compounds include, but are not limited to, various waxes such as carnauba wax and glyceryl tristearate.
  • extended release formulations can be prepared using osmotic systems or by applying a semi-permeable coating to the dosage form. In the latter case, the desired drag release profile can be achieved by combining, low permeability and high permeability coating materials i suitabl proportion.
  • An immediate release portion can be added to die extended release system by means of either applying an immediate release layer on top of the extended release core; using coating or compression processes or in a multiple unit system such as a capsule containing extended and immediate release beads.
  • Extended reiease tablets containing hydrophiiic polymers are prepared by techniques commonly known in the art such as direct compression, wet granulation, or dry granulation processes. These formulations usually incorporate polymers, diluents, binders, and lubricants as well as the active pharmaceutical ingredient.
  • the usual diluents include inert powdered substances such a different kinds of starch, powdered, cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, grain flours and similar edible powders.
  • Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives are also useful.
  • Typical tablet binders include substances such as starch, gelatin and sugars such as lactose, fructose, and glucose. Natural and synthetic gums, including acacia, alginates, meth lcellulose, and polyviny!pyrro!idine can also be used. Polyethylene glycol, hydrophiiic polymers, eth cellulose and waxes can also serve as binders.
  • a lubricant is necessary i a tablet formulation to prevent the tablet and punches from sticking in the die.
  • the lubricant is chosen from such slippery 1 solids as tale, magnesium and calcium stearate, stearic acid and trydrogenated vegetable oils.
  • Extended reiease tablets containing wax materials are generally prepared using methods known in the art such as a direct blend method, a congealing method, and an aqueous dispersion method, in the congealing method, the drug is mixed with a wax material and either spray-congealed or congealed and screened and processed.
  • Delayed release dosage fomuilatiotis are created by coating a solid dosage form with a film of a polymer which is insoluble in the acid environment of the stomach, but soluble in the neutral environment of small intestines.
  • the delayed release dosage units can be prepared, for example, by coating a drug or a drug-containing composition with a selected coating material.
  • the drug-containing composition may be a tablet for incorporation into a capsule, a tablet for use as an inner core in a "coated core” dosage form, or a plurality of drug-containing beads, particles or granules, for incorporation into either a tablet or capsule.
  • Preferred coating materials include bioerodible, gradually hydrolyzable, graduall water-soluble, and/or enzymatically degradable polymers, and may be conventional "enteric" polymers.
  • Enteric polymers as will be appreciated by those skilled in the art, become soluble in the higher pH environment of the lower gastrointestinal tract or slowly erode as the dosage form passes through the gastrointestinal tract, while enzymatieally degradable polymers are degraded by bacterial enzymes present in the lower gastrointestinal tract, particularly in the colon.
  • Suitable coating materials for effecting delayed release include, but are not limited to, celiulosic polymers such as hydroxy-propyl cellulose, hydoxyethyl cellulose, hydroxym ethyl cellulose, hydroxypropyl methyl cellulose, hydroxy-propyl methyl cellulose acetate succinate, hydroxypropylmethyl cellulose phthaiate, methylcellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthaiate, cellulose acetate trimellitate and carboxymethylcellulose sodium; acrylic acid polymers and copolymers, preferably formed from acrylic acid, methacrylic acid, methyl acrylate, ethyl aery I ate, methyl methacryJate and/or ethyl methacrylate, and other methacrylic resins that are commercially available under the tradename EUDRAGITTM (Rohm Pharma; [0086] Westerstadt, Germany ), including EUDRAG
  • EUDRAGiTTM 1 ,100D (soluble at pH 6.0 and above), EUDRAGITTM S (soluble at pH 7.0 and above, as a result of a higher degree of esterifi cation), and EUDRAGiTTM NE, RL and RS (water-insoluble polymers having different degrees of permeability and expandability); vinyl polymers and copolymets such as polyvinyl pyrrolidone, vinyl acetate, vinyl acetate phthaiate, vin l acetate crotonic acid copolymer, and ethylene-vinyi acetate copolymer; enzymaiicaily degrada le polymers such as azo polymers, pectin, chitosan, amy!ase and guar gum; zein and shellac.
  • vinyl polymers and copolymets such as polyvinyl pyrrolidone, vinyl acetate, vinyl acetate phthaiate, vin l acetate
  • Multi-layer coatings using different polymers may also be applied.
  • the preferred coating weights for particular coating materials may be readily determined by those skilled in the art by evaluating individual release profiles for tablets, beads and granules prepared with different quantities of various coating materials. It is the combination of materials, method, and form of application that produce the desired release characteristics, which one can determine only from the clinical studies.
  • the coating composition may include conventional additives, such as plasticizers, pigments, colorants, stabilizing agents, glidants, etc.
  • a plasttcizer is normally present to reduce the fragility of the coating, and will generally represent about 10 wt. % to 50 wt. % relative to the dry weight of the polymer.
  • plasticizers examples include polyethylene glycol, propylene glycol, triacetin, dimethyl ph thai ate, diethyl phtha!ate, di butyl phthalate, dihutyi sebaeate, trieihyl citrate, tri butyl citrate, triethyl acetyl citrate, castor oil and acetylated monoglycerides.
  • a stabilizing agent is preferably used to stabilize particles in the dispersion.
  • Typical stabilizing agents are noniooic emulsifiers such as sorbitan esters, polysorbaies and polyvinylpyrrolidone.
  • Glidants are recommended to reduce sticking effects during film formation and drying, and will generally represent approximately 25 wt. % to 100 wt. % of the polymer weight in the coating solution.
  • One effective glidant is talc.
  • Other glidants such as magnesium stearate and glycerol monostearat.es may also be used.
  • Pigments such as titanium dioxide may also be used.
  • Small quantities of an anti-foaming agent, such as a silicone (e.g., simethicone), may also be added to the coating composition.
  • a delayed release tablet may be formulated fay dispersing tire drug within a matrix of a suitable material such as a hydrophilic polymer or a fatty compound.
  • Suitable hydrophilic polymers include, but are not limited to, polymers or copolymers of cellulose, cellulose ester, acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, and vinyl or enzymaiicaily degradable polymers or copolymers as described above. These hydrophilic polymers are particulariy useful for providing a delayed release matrix.
  • Fatty compounds for use as a matrix material include, but axe hot limited to, waxes (e,g. carnauba wax) and glycerol tristearate. Once the active ingredient is mixed with the matri material, the mixture can be compressed into tablets.
  • a pulsed release dosage form is one that mimics a multiple dosing profile without repeated dosing and typically allows at least a iwofold reduction in dosing frequency as compared to the drug presented as a conventional dosage form (e.g., as a solution or prompt drug-releasing, conventional solid dosage form).
  • a pulsed release profile is characterized by a time period of no release (lag time) or reduced release followed by rapid drug rel ase.
  • Each dosage form contains a therapeutically effective amount of active agent.
  • approximately 30 wt. % to 70 wt. %, preferably 40 wt. % to 60 wt. %, of the total amount of active agent in the dosage form is released in the initial pulse, and, correspondingly approximately 70 wt. % to 3.0 wt. %, preferably 60 wt. % to 40 wt. %, of the total amount of active agent in the dosase form is released in the second pulse.
  • the second pulse is preferably released approximately 3 hours to less than 14 hours, and more preferably approximately 5 hours to 12 hours, following administration.
  • release of the second pulse preferably takes place approximately 3 hours to 10 hours, and more preferably approximatel 4 to 9 hours, following oral administration. Release of the third pulse occurs about 2 hours to about 8 hours following the second pulse, which is typically about 5 hours to approximately 18 hours following oral administration.
  • T e dosage form can be a closed capsule housing at least two drug-containing dosage units, each dosage unit containing one or more compressed tablets, or may contain, a plurality of beads, granules or particles, providing that each dosage unit has a different drug release profile.
  • the immediate release dosage unit releases drug substantially immediately following oral administration to provide an initial dose.
  • the delayed release dosage unit releases drug approximately 3 hours to 14 hours following oral administration to provide a second dose.
  • an optional second delayed release dosage unit releases drug about 2 hours to 8 hours following the release of the second close, which is typically 5 hours to IS hours following oral administration.
  • Another dosage form contains a compressed tablet or a capsule having a drug-- containing immediate release dosage unit, a delayed release dosage unit and an optional second delayed release dosage unit
  • the immediate release dosage unit contains a plurality of beads, granul s particles that release drug substantially immediately following oral admini tration to provide an initial dose.
  • the delayed release dosage unit contains a plurality of coated beads or granules, which release drug approximately 3 hours to 14 hours foll wing oral administration to provide a second dose.
  • An optional second delayed release dosage unit contains coated beads or granules that release drug about 2 to 8 hour following administration of the initial delayed release dose, which is typically 5 to 18 hours following oral administration.
  • the beads or granules in the delayed release dosage unites) are coated with a bioerodible polymeric material. This coating prevents the drag from being released until the appropriate time, i.e., approximately 3 hours to less than 14 hours following oral administration for the delayed release dosage unit and at least 5 hours to approximately 18 hours following oral administration for the optional second delayed release dosage unit, in this dosage form the components may be admixed in the tablet or may be layered to form a laminated tablet.
  • Another dosage form is a tablet having a drug-containing immediate release dosage unit, a delayed release dosage unit, and an optional second delayed release, dosage unit, wherein the immediate release dosage unit comprises an outer layer that releases the drug substantially immediately following oral administration.
  • the arrangement of the remaining delayed release dosage(s) depends upon whether the dosage form is designed to mimic twice daily dosing or three times daily dosing,
  • the delayed release dosage unit contains an inner core that is coated with a bioerodible polymeric material The coating is appli ed such that release of the drug occurs approximately 3 hours to less than 14 hours following oral administration.
  • the outer layer completely surrounds the inner core.
  • the (first) delayed reiease dose contains an internal layer that releases drug approximately 3 hours to less than 1 hours following oral administration. This internal iayer is surrounded by the outer layer.
  • the second delayed release dosage unit generally contains an inner core that releases the drug at least 5 hours to approximately 18 hours following oral administration.
  • the layers of this tablet starting from the external surface) contain an outer layer, an interna!
  • both the delayed release dosage unit and second delayed release dosage units are surrounded by an inner layer.
  • This inner layer is free of active agent.
  • the first delayed release pulse occurs once the inner layer is substantially eroded thereby releasing the admixture of the delayed release dosage units.
  • the dose corresponding to the (first) delayed release dosage unit is released immediately since the inner layer has prevented acces to this dose for the appropriate time, e.g., from approximately 3 hours to 10 hours.
  • the second delayed release dose is formulated to effectively delay release for at least 5 hours to approximately 18 hours following oral administration.
  • the delayed release dose is released approximately 3 hours to up to 14 hours, more preferably approximately 5 hours to up to 12 hours, following oral administration.
  • the (first) delayed release dose is released approximately 3 to 10 hours, preferably 4 hours to 9 hours, following oral administration.
  • the third dose i .e., the second delayed release close
  • a dosage form which contains a coated core-type delivery system wherein the outer layer contains an immediate release dosage unit containing an acti ve aaent. such that the active agent therein is tmmediatelv released following oral administration; an intermediate layer there under which surrounds a core; aod a core which contains immediate release beads or granules and delayed release beads or granules, suc that the second dose is provided by the immediate release beads or granules and the third dose is provided by the delayed release beads or granules,
  • subject compositions of the present application maybe lyophilized or subjected to another appropriate drying technique such as spray drying.
  • the subject compositions may be administered once, or may be divided into a number of smaller doses to be administered at varying intervals of time, depending in part on the release rate of the compositions and the desired dosage.
  • Formulations useful in the methods provided herein include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, aerosol and/or parenteral administration
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of a subject composition which may be combined with a carrier material to produce a single dose may an 1 depending upon the subject being treated, and the particular mode of administration.
  • Methods of preparing these formulations or compositions include the step of bringing into association subject compositions with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association a subject composition with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • the compounds of formula I described herei may be administered in i nhalant or aerosol formulations.
  • the inhalant or aerosol formulations may comprise one or more agents, such as adjuvants, diagnostic agents, imaging agents, or therapeutic agents useful in inhalation therapy.
  • the final aerosol formulation may for example contain 0.005-90% w/w, for instance 0.005-50%, 0,005-5% w w, or 0.01-1.0% w/w, of medicament relative to the total weight of the formulation.
  • the formulations herein contain no components which may provoke the degradation of stratospheric ozone.
  • the formuiations are substantially free of chlorofluorocarbons such as CC13F, CC12F2 and CF3CC13.
  • substantially free means less than 1% w/w based upon the propel 1 ant system, in particular less than 0.5%, for example 0.1% or less.
  • the propellant may optionally contain an adjuvant having a higher polarity and/or a higher boiling point than the propellant.
  • Polar adjuvants which may be used include (e.g., €2-6) aliphatic alcohols and poiyois such as ethanol, isopropanol and propylene glycol .
  • only small quantities of polar adjuvants e.g., 0.05-3.0% w/w
  • the formulations described herein may contain less than 1% w/w, e.g., about 0.1% w/w, of poiar adjuvant.
  • the formulations may be substantially free of polar adjuvants, such as ethanol.
  • Suitable volatile adjuvants include saturated hydrocarbons such as propane, n-butane, isobutane, pentane and isopentane and all y! ethers such as dimethyl ether.
  • up to 50% w/w of the propellant may comprise a volatile adjuvant, for example 1 to 30% w/w of a volatile saturated C 1-C6 hydrocarbon.
  • the aerosol formulations may further comprise one or more surfactants.
  • the surfactants must be physiologically acceptable upon administration by inhalation.
  • surfactants such as L-a-phosphatidylchoIme (PC), .1 ,2-dipalmitoy.lphosphatidycholine (D.PPC), oleic acid, sorbitan trioleate, sorbitan mono-oleate, sorbitan monolaurate, polyoxy ethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monooleate, natural lecithin, oleyl polyoxyethylene (2) ether, stearyl polyoxyethylene (2) ether, laitryi polyoxyethylene (4) ether, block copolymers of ox ethylene and oxypropylene, synthetic lecithin, di eth lene glycol dioleate, tetraliydrofurfuryl oieate, ethyi
  • oleic acid such as L-
  • compositions disclosed herein suitable for parenteral administration comprise one or more subject compositions in combination with one or more pharmaceutically acceptable sterile, isotonic, aqueous, or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, barters ostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents,
  • aqueous and non-aqueous carriers examples include water, ethane!, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity may be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • Formulations suitable for oral admi istration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or nonaqueous liquid, or as an oii-in-water or water-in-oii liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia), each containing a predetermined amount of a subject composition as an active ingredient.
  • Subject compositions may also be administered as a bolus, electuary, or paste.
  • the subject com osition is mixed with one or more pharmaceutically acceptable carriers and/or any of the following; (1 ) fillers or extenders, such as starches, lactose, sucrose, glucose, niannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylceiiuiose, alginates, gelatin, polyvinyl pyrrdidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin: (6) absorption accelerators, such as quaternary' ammonium compounds; (7) wetting agents, such as, for example,
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using a binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, distntegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-altering or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the subject composition moi stened with an inert liquid diluent. Tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical -formulating art.
  • Tablets may be plain, film or sugar coated, bisected, embossed, layered or sustained- release. They can be made in a variety of sizes, shapes and colors. Tablets may be swallowed, chewed or dissolved in the buccal cavity or beneath the tongue. They may be dissolved in water for local or topical application. Sterile tablets are normally used for parenteral solutions and for implantation beneath the skin.
  • tablets may contain a. number of inert materials known as excipients. They may be classified according to the role they play in the final tablet.
  • the primary composition may include one or more of a filler, binder, lisbricant and glidant.
  • Other excipients which give physical characteristics to the finished tablet are coloring agents, and flavors (especially in the case of chewable tabids).
  • excipients are added to a formulation to impart good flow and compression characteristics to the material being compressed. Such properties are imparted through pretreatment steps, such as wet granulation, slugging, spray drying spheronization or crystallization.
  • Lubricants are typically added to prevent the tableting materials from sticking to punches, minimize friction during tablet compression, and allow for removal of the compressed tablet from the die. Such lubricants are commonly included in the final tablet mix in amounts usually of about 1% by weight.
  • excipients include the following: high- compressibility to allow strong tablets to be made at low compression forces; impart cohesive qualities to the powdered material; acceptable rate of disintegration; good flow properties that can improve the flow of other excipients in the formula; and cohesiveness (to prevent tablet from crumbling during processi g, shipping and handling).
  • One formulation comprises the following: a compound of Formula 1, and a binder.
  • pharmaceutically acceptable binders include, but are not limited to, starches; celluloses and derivatives thereof, e.g., microcrystallme cellulose, hydroxypropy! cellulose hydroxy! ethyl cellulose and hydroxylpropylmethyl cellulose; sucrose; dextrose; corn syrup; polysaccharides; and gelatin.
  • the binder. e.g., may be present in an amount from about 1 % to about 40% by weight of the composition such as I % to 30% or I % to 25% or I % to 20%.
  • one, two, three or more diluents can be added to the formulations disclosed herein.
  • examples of pharmaceutically acceptable fillers and pharmaceutically accepiabie di luents include, but are not limited to, confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, lactose, mannitol, microcrystailine cellulose, powdered cellulose, sorbitol, sucrose and talc.
  • diluents are microcrystallme cellulose which is manufactured by the controlled hydrolysis of alpha-cellulose, obtained as a pulp from fibrous plant materials, with dilute mineral acid solutions. Following hydrolysis, the hydrocellulose is purified by filtration and the aqueous slurry is spray dried to form dry, porous particles of a broad size distribution.
  • Suitable microcrystailine cellulose will have an average particle size of from about 20 nni to about 200 nm. Microcrystallme cellulose is available from several suppliers. Suitable icrocrystailine cellulose includes Avicel PH.
  • the microcrystailine cellulose may be present in a tablet formulation in an amount of from about 25% to about 70% by weight. Another appropriate range of this material is from about 30% to about 35% by weight; yet another appropriate range of from about 30% to about 32% by weight.
  • Another diluent is lactose.
  • the lactose may be ground to have an av erase particle size of between about 50 um and about 500 urn pri r to formulating.
  • the lactose may be present in the tabiet formulation i n an amount of from about 5% to about 40% by weight, and can be from about 18% to about 35% by weight, for example, can be from about 20% to about 25% by weight.
  • one, two, three or more disintegrants can be added to the formulations described herein.
  • examples of pharmaceutically acceptable disintegrants include, but are not limited to, starches; clays; celluloses; alginates; gums; cross-linked polymers, e.g., cross- linked polyvinyl pyrrolidone, cross-linked calcium carboxymetbylceUul ose and cross-linked sodium earboxy methyl cellulose; soy polysaccharides; and guar gum.
  • the disintegrant e.g., may be present in an amount from about 2% to about 20%, e.g., from about 5% to about 10%, e.g., about 7% about by weight of the composition.
  • a disintegrant is also an optional bu useful component of the tablet formulation.
  • Disintegrants are included to ensure that the tablet has an acceptable rate of disintegration.
  • Typical disintegrants include starch derivatives and salts of carhoxymetbyicellulose.
  • Sodium starch glycolate is one appropriate disintegrant for this formulation.
  • the disiniegrant is present in the tablet formulation in an amount of from about 0% to about 10% by weight, and can be from about 1% to about 4% by weight, for instance front about 1.5% to about 2.5% by weight,
  • one, two, three or more lubricants can be added to the formulations disclosed herein.
  • pharmaceutically acceptable lubricants and pharmaceutically acceptable glidants include, but are not limited to, colloidal silica, magnesium trisilicate, starches, talc, tribasic calcium phosphate, magnesium stearate, aluminum stearate, calcium stearate, magnesium carbonate, magnesium oxide, polyethylene glycol, powdered cellulose and microcrystalline cellulose.
  • the lubricant e.g., may be present in an amount from about. 0.1% to about 5% by weight of the composition; whereas, the glidant, e.g., may be present in an amount from about 0.1% to about 10% by weight.
  • Lubricants are typically added to prevent the tahleting materials from sticking to punches, minimize friction during tabiet compression and allow for removal of the compressed tablet from the die. Such lubricants are commonly included in the final tablet mix in amounts usually less than i% by weight.
  • the lubricant component may be hydrophobic or hydrophilic. Examples of such lubricants include stearic acid, talc and magnesium stearate. Magnesium stearate reduces the friction between the die wall and tablet mix during the compression and ejection of the tablets. It helps prevent adhesion of tablets to the punches and dies. Magnesium stearate al so aids in the flow of the powder jn the hopper and into the die.
  • the lubricant has a particle size range of 450-550 microns and a density range of 1.00-1.80 g mL it is stable and does not polymerize within the tablets ng mix.
  • One lubricant, magnesium stearate may also be employed in the formulation.
  • the lubricant is present in the tablet formulation in an amount of from about 0.25% to about 6%; also appropriate is a level of about 0.5% to about 4% by weight; and from about 0.1% to about 2% by weight.
  • Other possible lubricants include talc, polyethylene glycol, silica and hardened vegetable oils.
  • the lubricant is not present in the formulation, but is sprayed onto the dies or the punches rather than being added directly to the formulation.
  • Liquid dosage forms for oral admini stration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs, ' Jn addition to the subject compositions, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emuisifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl, benzoate, propylene glycol, 1 ,3-butylene glycol, oils (in particular, cottonseed, corn, peanut, sunflower, soybean, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example,
  • Suspensions in addition to the subject compositions, may contain suspending agents such as, for example, ethoxy ated isostearyl alcohols, polyoxyethy!erte sorbitol, and sorbitan esters, niicroerystallme cellulose, aluminum metahydroxide, bentonite, agar- agar and tragacanth, and mixtures thereof.
  • suspending agents such as, for example, ethoxy ated isostearyl alcohols, polyoxyethy!erte sorbitol, and sorbitan esters, niicroerystallme cellulose, aluminum metahydroxide, bentonite, agar- agar and tragacanth, and mixtures thereof.
  • Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a. subject composition with one or more suitable non-irritating carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax, or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will, melt in the appropriate body cavity and release the encapsulated compounds) and composition ⁇ ).
  • suitable non-irritating carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax, or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will, melt in the appropriate body cavity and release the encapsulated compounds
  • composition ⁇ suitable non-irritating carriers
  • suitable non-irritating carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax, or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will, melt in
  • Dosage forms for transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants.
  • a subjec composition may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.
  • the complexes may include lipophilic and hydrop ilic groups to achieve the desired water solubility and transport properties.
  • the ointments, pastes, creams and gels may contain, in addition to subject compositions, other carriers, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragaeanth, cellulose derivatives, polyethylene glycols, silicones, beritonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays may contain, in addition to a subject composition, exci ients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of such substances.
  • Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile it substituted hydrocarbons, such as butane and propane.
  • a transdermal patch may comprise an outer backing toil, a matrix and a protective liner wherein a) the composition or compositions are present in the matrix in a solution (which may be oversaturated), b) the matrix may contain 1 to 5% activated Si 02, and c) the matrix, may have a moisture content of less than 0.7%. Moisture- free matrix patches which contain activated silicon dioxide in the matrix show an enhanced drug release into the skin.
  • a transdermal patc may comprise: a substrate sheet comprising a composite film formed of a resin composition comprising 100 parts by weight of a polyvinyl chloride-poiyurethane composite and 2-10 parts by weight of a styreiie-ethylene-butylene-styrene copolymer, a first adhesive layer on- the one side of the composite film, and a polyalkyiene terephthalate film adhered to the one side of the composite film by means of the first adhesive layer, a primer layer which comprises a saturated polyester resin and is formed on the surface of the polyalkyiene terephthalate film; and a second adhesive layer comprising a styrene-diene-styrene block copolymer containing a pharmaceutical agent layered on the primer layer,
  • a method for the manufacture of the above-mentioned substrate sheet comprises preparing the above resin composition molding the resin composition into a composite film by a calendar process, and then adhering a
  • the pharmaceutical compositions herein can be packaged to produce a "reservoir type" transdermal patch wi th or wi thout a rate-limiting patch membrane.
  • the size of the patch and or the rate limiting membrane can be chosen to deliver the transdermal flux rates desired.
  • Such a transdermal patch can consist of a polypropylene/polyester impervious backing member heat-sealed to a polypropylene porous/permeable membrane with a reservoir there between.
  • the patch can include a pharmaceutically acceptable adhesive (such as a acrylate, silicone or rubber adhesi ve) on the membrane layer to adhere the patch to the skin of the host, e.g., a mammal such as a human.
  • a release liner such as a polyester release liner can also be provided to cover the adhesive layer prior to application of the patch to the skin as is conventional in the art.
  • This patch assembly can be packaged in an aluminum foil or other suitable pouch, again as is conventional in the art.
  • compositions herein can be formulated into a "matrix-type" transdermal patch.
  • Drug Delivery Systems Characteristics and Biomedical Application R. L Juliano, ed,, Oxford University Press. N Y, ( 1980); and Controlled Drug Delivery,
  • the drug-matrix could be formed utilizing various polymers, e.g. silicone, polyvinyl alcohol.
  • the "drug matrix” may then be packaged into an appropriate transdermal patch.
  • Another type of patch comprises incorporating the drug directly in a pharmaceutically acceptable adhesive and laminating the drug-containing adhesive onto a suitable backing member, e.g. a polyester backing membrane.
  • the drug should be present at a concentration which will not affect the adhesive properties, and at the same time deliver the required clinical dose.
  • Transdermal patches may be passive or active. Passive transdermal drug delivery systems currently available, such as the nicotine, estrogen and .nitroglycerine patches, deliver small-molecule drugs. Many of the newly developed proteins and peptide drugs are too large to be delivered through passive transdermal patches and may be delivered using technology such as electrical assist (iontophoresis) for large-molecule drugs.
  • Iontophoresis is a technique employed for enhancing the flu of ionized substances through membranes by application of electric current.
  • An iontophoretic membrane is given in U.S. Pat. No. 5,080,646 to Theeuwes.
  • the principal mechanisms by which iontophoresis enhances molecular transport across the skin are (a) repelling a charged ion. from an electrode of the same charge, (b) electroosmosis, the convective movement of solvent that occurs through a charged pore in response the preferential passage of counter-ions when an electric field is applied or (c) increase skin permeability due to application of electrical current.
  • kits it may be desirable to administer in the form of a kit, it may comprise container for containing the separate compositions such as a divided bottle or a divided foil packet.
  • the kit comprises directions for the administration of the separate components.
  • the kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician.
  • An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like).
  • Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a plastic material that may be transparent.
  • the recesses have the size and shape of the tablets or capsules to be packed.
  • the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against, the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed.
  • the tablets or capsules are sealed in the recesses between the plastic- foil and the sheet.
  • the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure o the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet, or capsule can then he removed via said opening.
  • Acid 9 (10 mmol) was taken in a RB added benzene and cooled to 0 °C and added thionyl chloride (13 mmol) dropwtse and stirred the reaction mixture at same temperature for 4 h. After completion of the reaction as indicated by TLC, benzene was distilled and the crude acid chloride 10 was used for the next step.
  • Step -8 Synthesis of Compound 1.2:
  • Step -2 Synthesis of Compound -6:
  • sample refers to a sample of a body fluid, to a sample of separated cells or to a sample from a tissue or an organ.
  • Samples of body fluids can be obtained by well known techniques and include, preferably, samples of blood, plasma, serum, or urine, more preferably, samples of blood, plasma or serum.
  • Tissue or organ samples may be obtained from any tissue or organ by, e.g., biopsy.
  • Separated cells may be obtained from the body fluids or the tissues or organs by separating techniques such as centrifugation or cell sorting.
  • cell-, tissue- or organ samples are obtained from those cells, tissues or organs which express or produce the peptides referred to herein.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Pain & Pain Management (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des procédés de formule (I) ou leurs sels pharmaceutiquement acceptables, ainsi que les polymorphes, les &nantiomères, les stéréoisomères, les solvates et les hydrates de ceux-ci. Ces sels peuvent être formulés en tant que compositions pharmaceutiques. Les compositions pharmaceutiques peuvent être formulées pour une administration perorale, une administration transdermique, à travers les transmuceuses, en tant que sirops, par voie topique, à libération prolongée, à libération entretenue, ou par injection. De telles compositions peuvent être utilisées pour le traitement de troubles ou états neurologiques, tels qu'une douleur ou ses complications associées.
PCT/IB2012/053918 2011-08-30 2012-07-31 Compositions et procédés pour le traitement d'une douleur chronique WO2013030692A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011015360A1 (fr) * 2009-08-06 2011-02-10 Laboratorios Del Dr. Esteve, S.A. Composés pharmaceutiques comprenant de l'o-desméthyl-tramadol et des inhibiteurs cox

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011015360A1 (fr) * 2009-08-06 2011-02-10 Laboratorios Del Dr. Esteve, S.A. Composés pharmaceutiques comprenant de l'o-desméthyl-tramadol et des inhibiteurs cox

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SUSAN L. MERCER ET AL.: "Opioids and Efflux Transporters.Part 3: P-Glycoprotein Substrate Activity of 3-Hydroxyl Addition to Meperidine Analogs", BIOORG MED CHEM LETT., vol. 18, no. 12, 15 June 2008 (2008-06-15), pages 3638 - 3640, XP022707448, DOI: doi:10.1016/j.bmcl.2008.04.046 *

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