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WO2004084881A1 - METHODES DE TRAITEMENT DE TROUBLES INTESTINAUX FONCTIONNELS UTILISANT DES MODULATEURS DE LA SOUS-UNITE $G(A)2$G(D) DES CANAUX CALCIQUES AVEC DES MODULATEURS DES MUSCLES LISSES - Google Patents

METHODES DE TRAITEMENT DE TROUBLES INTESTINAUX FONCTIONNELS UTILISANT DES MODULATEURS DE LA SOUS-UNITE $G(A)2$G(D) DES CANAUX CALCIQUES AVEC DES MODULATEURS DES MUSCLES LISSES Download PDF

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Publication number
WO2004084881A1
WO2004084881A1 PCT/US2004/008701 US2004008701W WO2004084881A1 WO 2004084881 A1 WO2004084881 A1 WO 2004084881A1 US 2004008701 W US2004008701 W US 2004008701W WO 2004084881 A1 WO2004084881 A1 WO 2004084881A1
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component
esters
prodrugs
amides
salts
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WO2004084881B1 (fr
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Matthew Oliver Fraser
Karl Bruce Thor
Edward C. Burgard
Lee R. Brettman
Steven B. Landau
Daniel J. Ricca
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Dynogen Pharmaceuticals Inc
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Dynogen Pharmaceuticals Inc
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Priority to US10/549,998 priority Critical patent/US20060276542A1/en
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Publication of WO2004084881B1 publication Critical patent/WO2004084881B1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate

Definitions

  • the invention relates to methods for treating functional bowel disorders, particularly Irritable Bowel Syndrome, using smooth muscle modulators and ⁇ 2 ⁇ subunit calcium channel modulators.
  • Functional Bowel Disorders refer to disorders or diseases where the primary abnormality is an altered physiological function of the bowels, rather than an identifiable structural or biochemical cause. While the term bowel is commonly defined as the small and large intestines, the phrase "functional bowel disorder” is generally held to encompass disorders or diseases related to the xnid or lower gastrointestinal tract, which includes the stomach as well as the intestines. Specific FBD's are Irritable Bowel Syndrome (IBS), functional abdominal bloating, functional constipation, functional diarrhea, and unspecified functional bowel disorder (see, Drossman D. et al.
  • FBDs are diagnosed by characteristic symptoms being present for at least 12 weeks during the preceding 12 months in the absence of a structural or biochemical explanation (see, Thompson et al, Gut, 45 (Suppl. II):II43-II47 (1999)).
  • Individual FBDs IBS, functional abdominal bloating, functional constipation, and functional diarrhea
  • Unspecified FBD presents as a bowel disorder lacking the specific criteria for the other FBDs.
  • IBS Inflammatory bowel syndrome
  • BS is the most common disease diagnosed by gastioenterologists and one of the most common disorders seen by all physicians. Since IBS has no characteristic pathophysiological abnormality, the diagnosis is mainly based on symptom analysis, such as by the Manning criteria (1978) or the Rome I (1989) and Rome II (1999) criteria.
  • symptoms associated with IBS include abdominal pain, abnormal stool frequency, abnormal stool form, abnormal stool passage, mucorrhea, and bloating or feeling of abdominal distension.
  • a diagnosis of LBS is generally supported through cumulative presence of the symptoms described above.
  • Treatment options for IBS generally encompass multiple approaches that are customized to the patient depending upon the severity of the symptoms. Patients diagnosed with mild IBS symptoms are often counseled about managing sitess and making diet and lifestyle changes. Patients diagnosed with moderate IBS are similarly counseled with the added recommendation of fiber supplements. Depending on the symptoms, moderate IBS patients can also be advised to use antidiarrheals, laxatives, or anticholinergic agents. Typical antidiarrheals include loperamide (hnodium ® ), attapulgite (Kiaopectate ® ), and diphenoxylate (Lotomil ® ).
  • Typical laxatives include bisacodyl (Dulcolax ® ), senna (Senokot ® ), polyethylene 3350 (MiralaxTM), and bulk-forming fiber laxatives, such as psyllium (Metamucil ® ), calcium polycarbophil (Equalactin ® ), methylcellulose (Citrucel ® ), and fructan (Fiber Choice ® ).
  • An example of an anticholinergic used in treating IBS is dicyclomine (Bentyl ® ). Patients diagnosed with severe IBS may receive, in addition to the above, treatment with antidepressants, including tricyclics and selective serotonin reuptake inhibitors (SSRIs).
  • Severe LBS may also be treated with medication having 5-HT 3 activity, such as alosetron (Lotronex ® ), or 5-HT activity, such as tegaserod (Zelnorm ® ).
  • 5-HT 3 activity such as alosetron (Lotronex ® ), or 5-HT activity, such as tegaserod (Zelnorm ® ).
  • Tricyclic antidepressants such as amitriptyline (Amitril ® or Elavil ® ), imipramine (Tofranil ® ), and doxepin (Adapin ® ), are used in treating IBS symptoms because of the anticholinergic and analgesic properties they exhibit independent of their psychotropic effects.
  • the present invention presents a significant advantage over these treatments via increased efficacy and decreased side effects. Because detrimental side effects are lessened, the present invention also has the benefit of improving patient compliance.
  • compositions and methods for treating functional bowel disorders, particularly IBS are provided.
  • Compositions of the invention comprise c 2 ⁇ subunit calcimn channel modulators in combination with one or more compounds with smooth muscle modulatory effects.
  • 2 ⁇ subunit calcimn channel modulators include GABA analogs (e.g., gabapentin and pregabalin), fused bicyclic or tricyclic amino acid analogs of gabapentin, and amino acid compounds.
  • Compounds with smooth muscle modulatory effects include antimuscarinics, ⁇ 3 adrenergic agonists, spasmolytics, neurokinin receptor antagonists, bradykinin receptor antagonists, and nitric oxide donors.
  • Compositions of the invention include combinations of the aforementioned compounds as well as pharmaceutically acceptable, pharmacologically active acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, and derivatives thereof.
  • compositions are administered in therapeutically effective amounts to a patient in need thereof for treating functional bowel disorders. It is recognized that the compositions may be administered by any means of administration as long as an effective amount for the treatment of symptoms associated with functional bowel disorders.
  • the compositions may be formulated, for example, for sustained, continuous, or as-needed administration.
  • One advantage of the present invention is that at least one detrimental side effect associated with single administration of an ⁇ 2 ⁇ subunit calcium channel modulator or a smooth muscle modulator is lessened by concurrent administration of an ⁇ 2 ⁇ subunit calcium channel modulator with a smooth muscle modulator. When an ⁇ : 2 ⁇ subunit calcium channel modulator is administered in combination with a smooth muscle modulator, less of each agent is needed to achieve therapeutic efficacy.
  • the present invention presents a significant advantage over these treatments via increased efficacy and decreased side effects. Because detrimental side effects are lessened, the present invention also has the benefit of improving patient compliance.
  • Figure 3 depicts the results of isobologram studies as determined by utilizing group means to determine effective doses. The common maximal effect for either drug alone was a return to 43% of saline control. The line connecting the two axes at the effective dose for each drug alone represents theoretical additivity.
  • Figure 4 depicts the results of isobologram studies using a common maximal effect of individual animals using a return to 31%) of saline control values. Data are presented as Mean ⁇ SD.
  • compositions and methods for treating functional bowel disorders comprise a therapeutically effective dose of a compound with smooth muscle modulatory effects in combination with an ⁇ 2 ⁇ subunit calcium channel modulator, such as gabapentin or pregabalin.
  • a compound with smooth muscle modulatory effects include, but are not limited to, antimuscarinics, ⁇ 3 adrenergic agonists, spasmolytics, neurokinin receptor antagonists, bradykinin receptor antagonists, and nitric oxide donors.
  • the methods are accomplished by administering, for example, a compound with smooth muscle modulatory effects, such as oxybutynin, in combination with an ⁇ 2 ⁇ subunit calcium channel modulator and/or another compound that interacts with 0!
  • compositions and formulations that contain quantities of a compound with smooth muscle modulatory effects in combination with an ⁇ ⁇ subunit calcium channel modulator and/or other compounds that interact with ⁇ 2 ⁇ subunit-containing calcium channels are encompassed.
  • sensations or symptoms that a patient subjectively describes as producing or resulting in pain.
  • active agent and "pharmacologically active agent” are used interchangeably herein to refer to a chemical compound that induces a desired effect, i.e., in this case, treatment of functional bowel disorders.
  • the primary active agents herein are ⁇ 2 ⁇ subunit calcium channel modulators and/or smooth muscle relaxants.
  • the present invention comprises a combination therapy wherein an c 2 ⁇ subunit calcium channel modulator is administered with one or more smooth muscle modulator.
  • Such combination therapy may be carried out by administration of the different active agents in a single composition, by concurrent administration of the different active agents in different compositions, or by sequential administration of the different active agents.
  • the combination therapy may also include situations where the ⁇ 2 ⁇ subunit calcimn channel modulator or the smooth muscle modulator is already being administered to the patient, and the additional component is to be added to the patient's drug regimen, as well as where different individuals (e.g., physicians or other medical professionals) are administering the separate components of the combination to the patient. Included are derivatives and analogs of those compomids or classes of compounds specifically mentioned that also induce the desired effect.
  • ⁇ 2 ⁇ subunit calcium channel modulator refers to an agent that is capable of interacting with the c 2 ⁇ subunit of a calcium channel, including a binding event, including subtypes of the ⁇ 2 ⁇ calcium channel subunit as disclosed in Klugbauer et al. (1999) J Neurosci.19: 684-691, to produce a physiological effect, such as opening, closing, blocking, up-regulating functional expression, down-regulating functional expression, or desensitization, of the channel.
  • the term "o; 2 ⁇ subunit calcium channel modulator” is intended to include GABA analogs including gabapentin and pregabalin,, fused bicyclic or tricyclic amino acid analogs of gabapentin, amino acid compounds, and other compounds that interact with the o; 2 ⁇ calcium channel subunit as disclosed further herein, as well as acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, and derivatives thereof. Further, it is understood that any salts, esters, amides, prodrugs, active metabolites or other derivatives are pharmaceutically acceptable as well as pharmacologically active.
  • peptidomimetic is used in its conventional sense to refer to a molecule that mimics the biological activity of a peptide but is no longer peptidic in chemical nature, including molecules that lack amide bonds between amino acids, as well as pseudo-peptides, semi-peptides and peptoids.
  • Peptidomimetics according to this invention provide a spatial arrangement of reactive chemical moieties that closely resembles the three-dimensional arrangement of active groups in the peptide on which the peptidomimetic is based. As a result of this similar active-site geometry, the peptidomimetic has effects on biological systems that are similar to the biological activity of the peptide.
  • smooth muscle modulator refers to any compound that inhibits or blocks the contraction of smooth muscles, including but not limited to antimuscarinics, ⁇ 3 adrenergic agonists, spasmolytics, neurokinin receptor antagonists, bradykinin receptor antagonists, and nitric oxide donors. Smooth muscle modulators can be “direct” (also known as “musculotropic”) or “indirect” (also known as “neurotropic”). "Direct smooth muscle modulators” are smooth muscle modulators that act by inhibiting or blocking contractile mechanisms within smooth muscle, including but not limited to modification of the interaction between actin and myosin.
  • “Indirect smooth muscle modulators” are smooth muscle modulators that act by inhibiting or blocking neurotransmission that results in the contraction of smooth muscle, including but not limited to blockade of presynaptic facilitation of acetylcholine release at the axon terminal of motor neurons terminating in smooth muscle.
  • the term "anticholinergic agent” as used herein refers to any acetylcholine receptor antagonist, including antagonists of nicotinic and/or muscarinic acetylcholine receptors.
  • the term “antinicotinic agent” as used herein is intended any nicotinic acetylcholine receptor antagonist.
  • antimuscarinic agent as used herein is intended any muscarinic acetylcholine receptor antagonist. Unless otherwise indicated, the terms “anticholinergic agent,” “antinicotinic agent,” and
  • antimuscarinic agent are intended to include anticholinergic, antinicotinic, and antimuscarinic agents as disclosed further herein, as well as acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, and derivatives thereof. Further, it is understood that any acids, salts, esters, amides, prodrugs, active metabolites or other derivatives are pharmaceutically acceptable as well as pharmacologically active.
  • ⁇ 3 adrenergic agonist is used in its conventional sense to refer to a compound that binds to and agonizes ⁇ 3 adrenergic receptors.
  • ⁇ 3 adrenergic agonist is intended to include ⁇ 3 adrenergic agonist agents as disclosed further herein, as well as acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, and derivatives thereof. Further, it is understood that any acids, salts, esters, amides, prodrugs, active metabolites or other derivatives are pharmaceutically acceptable as well as pharmacologically active.'
  • the term “spasmolytic” (also l ⁇ iown as "antispasmodic”) is used in its conventional sense to refer to a compound that relieves or prevents muscle spasms, especially of smooth muscle.
  • spasmolytic is intended to include spasmolytic agents as disclosed further herein, as well as acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, and derivatives thereof. Further, it is understood that any salts, esters, amides, prodrugs, active metabolites or other derivatives are pharmaceutically acceptable as well as pharmacologically active.
  • neurokinin receptor antagonist is used in its conventional sense to refer to a compound that binds to and antagonizes neurokinin receptors. Unless otherwise indicated, the term “neurokinin receptor antagonist” is intended to include neurokinin receptor antagonist agents as disclosed further herein, as well as acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, and derivatives thereof. Further, it is understood that any acids, salts, esters, amides, prodrugs, active metabolites or other derivatives are pharmaceutically acceptable as well as pharmacologically active.
  • bradykinin receptor antagonist is used in its conventional sense to refer to a compound that binds to and antagonizes bradykinin receptors. Unless otherwise indicated, the term “bradykinin receptor antagonist” is intended to include bradykinin receptor antagonist agents as disclosed further herein, as well as acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, and derivatives thereof. Further, it is understood that any acids, salts, esters, amides, prodrugs, active metabolites or other derivatives are pharmaceutically acceptable as well as pharmacologically active.
  • nitric oxide donor is used in its conventional sense to refer to a compound that releases free nitric oxide when administered to a patient. Unless otherwise indicated, the term “nitric oxide donor” is intended to include nitric oxide donor agents as disclosed further herein, as well as acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, and derivatives thereof. Further, it is understood that any acids salts, esters, amides, prodrugs, active metabolites or other derivatives are pharmaceutically acceptable as well as pharmacologically active.
  • Constipation is used in its conventional sense to mean infrequent or difficult evacuation of feces.
  • Diarrhea is used in its conventional sense to mean a frequent and generally profuse discharge of loose or fluid evacuations from the intestines without straining.
  • treating and “treatment” as used herein refer to relieving the symptoms or other clinically observed sequelae for clinically diagnosed disorders as described herein, including functional bowel disorders, such as LBS.
  • an "effective” amount or a “therapeutically effective amount” of a drug or pharmacologically active agent is meant a nontoxic but sufficient amount of the drug or agent to provide the desired effect, i.e., relieving the symptoms associated with functional bowel disorders, as explained above.
  • the effective amount of a drug or pharmacologically active agent will vary depending on the route of administration, the selected compound, and the species to which the drug or pharmacologically active agent is administered, as well as the age, weight, and sex of the individual to which the drug or pharmacologically active agent is administered. It is also recognized that one of skill in the art will determine appropriate effective amounts by taking into account such factors as metabolism, bioavailability, and other factors that affect plasma levels of a drug or pharmacologically active agent following administration within the unit dose ranges disclosed further herein for different routes of administration.
  • pharmaceutically acceptable such as in the recitation of a “pharmaceutically acceptable carrier,” or a “pharmaceutically acceptable acid addition salt,” is meant a material that is not biologically or otherwise undesirable, i.e., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is 2004/084881 contained.
  • “Pharmacologically active” (or simply “active") as in a “pharmacologically active” derivative or metabolite refers to a derivative or metabolite having the same type of pharmacological activity as the parent compound.
  • pharmaceutically acceptable refers to a derivative (e.g., a salt or an analog) of an active agent, it is to be understood that the compound is pharmacologically active as well, i.e., therapeutically effective for treating functional bowel disorders as defined herein.
  • continuous dosing is meant the chronic administration of a selected active agent.
  • as-needed dosing also known as “pro re nata” “prn” dosing, and “on demand” dosing or administration is meant the administration of a single dose of the active agent at some time prior to commencement of an activity wherein suppression of the painful and non-painful symptoms of a functional bowel disorder, particularly IBS in normal and spinal cord injured patients, would be desirable.
  • Administration can be immediately prior to such an activity, including about 0 minutes, about 10 minutes, about 20 minutes, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, or about 10 hours prior to such an activity, depending on the formulation.
  • short-term is intended any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes after drug administration.
  • rapid-offset is intended any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes after drug administration.
  • controlled release is intended to refer to any drug-containing formulation in which release of the drug is not immediate, i.e., with a “controlled release” formulation, oral administration does not result in immediate release of the drug into an absorption pool.
  • the term is used interchangeably with "non-immediate release” as defined in Remington: The Science and Practice of Pharmacy, Twentieth Ed. (Philadelphia, Pa.: Lippincott Williams & Wilkins, 2000).
  • the "absorption pool” represents a solution of the drug administered at a particular absorption site, and k r , k a , and k e are first-order rate constants for: 1) release of the drug from the formulation; 2) absorption; and 3) elimination, respectively.
  • controlled release includes any nonimmediate release formulation, including but not limited to sustained release, delayed release and pulsatile release formulations.
  • sustained release is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that preferably, although not necessarily, results in substantially constant blood levels of a drug over an extended time period such as up to about 72 hours, about 66 hours, about 60 hours, about 54 hours, about 48 hours, about 42 hours, about 36 hours, about 30 hours, about 24 hours, about 18 hours, about 12 hours, about 10 hours, about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, or about 1 hour after drug administration.
  • the te ⁇ n "delayed release” is used in its conventional sense to refer to a drug formulation that provides for an initial release of the drug after some delay following drug administration and that preferably, although not necessarily, includes a delay of up to about 10 minutes, about 20 minutes, about 30 minutes, about 1 hour, about 2 horns, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, or about 12 hours.
  • pulsatile release is used in its conventional sense to refer to a drug formulation that provides release of the drug in such a way as to produce pulsed plasma profiles of the drug after drug administration.
  • immediate release is used in its conventional sense to refer to a drug formulation that provides for release of the drug immediately after drug administration.
  • immediate release is used in its conventional sense to refer to a drug formulation that provides for release of the drug immediately after drug administration.
  • transdermal drug delivery delivery by passage of a drug through the skin or mucosal tissue and into the bloodstream.
  • topical administration is used in its conventional sense to mean delivery of a topical drug or pharmacologically active agent to the skin or mucosa.
  • oral administration is used in its conventional sense to mean delivery of a drug through the mouth and ingestion through the stomach and digestive tract.
  • inhalation administration is used in its conventional sense to mean delivery of an aerosolized form of the drug by passage through the nose or mouth during inhalation and passage of the drug through the walls of the lungs.
  • intracranial administration is used in its conventional sense to mean delivery of a drug directly into the bladder.
  • parenteral drug delivery is meant delivery by passage of a drug into the blood stream without first having to pass through the alimentary canal, or digestive tract.
  • Parenteral drug delivery may be "subcutaneous,” referring to delivery of a drug by administration under the skin.
  • Another form of parenteral drug delivery is “intramuscular,” referring to delivery of a drug by administration into muscle tissue.
  • parenteral drug delivery is “intradermal,” referring to delivery of a drug by administration into the skin.
  • An additional form of parenteral drug delivery is “intravenous,” referring to delivery of a drug by administration into a vein.
  • An additional form of parenteral drug delivery is "intra-arterial,” referring to delivery of a drug by administration into an arteiy.
  • parenteral drug delivery is "transdermal,” referring to delivery of a drug by passage of the drug through the skin and into the bloodstream.
  • parenteral drug delivery is “intrathecal,” referring to delivery of a drug directly into the into the intrathecal space (where fluid flows around the spinal cord).
  • Still another form of parenteral drug delivery is “transmucosal,” referring to administration of a drug to the mucosal surface of an individual so that the drug passes through the mucosal tissue and into the individual's blood stream.
  • Transmucosal drug delivery may be "buccal” or “tiansbuccal,” referring to delivery of a drug by passage through an individual's buccal mucosa and into the bloodstream.
  • transmucosal drug delivery is "lingual” drug delivery, which refers to delivery of a drug by passage of a drug through an individual's lingual mucosa and into the bloodstream.
  • lingual refers to delivery of a drug by passage of a drug through an individual's lingual mucosa and into the bloodstream.
  • sublingual refers to delivery of a drug by passage of a drug through an individual's sublingual mucosa and into the bloodstream.
  • transmucosal drug delivery is “nasal” or “intranasal” drug delivery, referring to delivery of a drug through an individual's nasal mucosa and into the bloodstream.
  • transmucosal drug delivery herein is “rectal” or “transrectal” drug delivery, referring to delivery of a drug by passage of a drug through an individual's rectal mucosa and into the bloodstream.
  • Another form of transmucosal drug delivery is “urethral” or “transuretliral” delivery, referring to delivery of the drug into the urethra such that the drug contacts and passes through the wall of the urethra.
  • An additional form of transmucosal drug delivery is “vaginal” or “transvaginal” delivery, referring to delivery of a drug by passage of a drug through an individual's vaginal mucosa and into the bloodstream.
  • An additional form of transmucosal drug delivery is “perivaginal” delivery, referring to delivery of a drug through the vaginolabial tissue into the bloodstream.
  • a selected active agent is administered to a patient suffering from a functional bowel disorder.
  • a therapeutically effective amount of the active agent maybe administered orally, intravenously, subcutaneously, transmucosally (including buccally, sublingually, transurethrally, and rectally), topically, transdermally, by inhalation, intravesically, intrathecally or using any other route of administration.
  • Functional Bowel Disorders are generally defined as collections of functional symptoms that are attributable to the mid or lower gastrointestinal tract.
  • a FBD is diagnosed by characteristic symptoms for at least 12 weeks during the preceding 12 months, and such symptoms include abdominal pain, bloating, distention, and various symptoms of disordered defecation.
  • the FBDs are commonly divided into symptom specific disorders including functional diarrhea, functional constipation, functional abdominal bloating, Irritable Bowel Syndrome (D3S), which often encompasses symptoms present in each of the other individual disorders, and unspecified functional bowel disorder. Additional disorders often classified as FBDs include functional dyspepsia and functional abdominal pain syndrome. Irritable Bowel Syndrome
  • IBS is a biopsychosocial disorder with variable symptoms wherein a disturbance in the interaction between intestinal motility and sensation, the brain, and the autonomic nervous system produces the syndrome.
  • LBS is characterized by a group of symptoms where abdominal pain or discomfort is associated with a change in bowel pattern, such as loose stool, more frequent bowel movements, diarrhea, and/or constipation, in the absence of demonstrable organic pathology.
  • IBS presents no specific motility or structural correlates, it remains a clinically defined illness defined by either the Manning or Rome II Criteria.
  • the Manning criteria were originally established in 1978 to distinguish IBS from organic bowel disease (Manning A P, Thompson W G, Heaton K W, Morris A F. Towards a positive diagnosis of the irritable bowel. Br. Med. J. 1978; 2:653-4). The criteria are:
  • the Rome II criteria for IBS include reports for at least 12 weeks in the preceding 12 months, which need not be consecutive, of abdominal pain or discomfort that has two of three features:
  • hyperalgesia refers to the situation in which normal visceral sensations are experienced at lower intraluminal volumes. While for a finding of allodynia, pain or discomfort is experienced at volumes usually producing normal internal sensations (see, for example, Mayer E.A. and Gebhart, G.F., Basic and Clinical Aspects of Chronic Abdominal Pain, Vol 9, 1 ed. Amsterdam: Elsevier, 1993:3-28).
  • IBS is a functional bowel disorder in which abdominal pain or discomfort is associated with defecation or a change in bowel habit. Therefore, IBS has elements of an intestinal motility disorder, a visceral sensation disorder, and a central nervous disorder. While the symptoms of IBS have a physiological basis, no physiological mechanism unique to IBS has been identified. In some cases, the same mechanisms that cause occasional abdominal discomfort in healthy individuals operate to produce the symptoms of IBS. The symptoms of IBS are therefore a product of quantitative differences in the motor reactivity of the intestinal tract, and increased sensitivity to stimuli or spontaneous contractions. hi addition to the above diagnosis tools, IBS patients can be categorized according to symptoms and severity.
  • Chronic diarrhea which is associated with abdominal pain and which is not attributable to an organic cause is referred to as "irritable bowel syndrome with a diarrhea predominance" or diarrhea predominant IBS (Hasler et al., 1995, In: Textbook of Gastroenterology, 2nd ed., Yamada, Ed., J. B. Lippincott Co., Philadelphia, pp. 1832-1855).
  • Patients exhibit diarrhea predominant IBS if their usual bowel movement frequency is more than three times per day, or if their ususal form of stool is loose and not hard, or if they frequently feel the sense of urgency and do not strain at the stools.
  • Patient not described as exhibiting diarrhea predominant IBS or constipation predominant IBS can be termed as exhibiting non-specific or alternating constipation/diarrhea LBS.
  • Functional abdominal bloating or abdominal distention, is characterized by a feeling of fullness or bloating throughout the abdomen in the absence of further symptoms associated with another functional gastrointestinal disorder.
  • Functional abdominal bloating is often considered co-morbid with IBS, but studies indicate functional abdominal bloating alone occurs in about 15% of community-based populations, usually with a female predominance.
  • Functional abdominal bloating is often absent during waking hours and worsens throughout the day. Diagnostic criteria include at least 12 weeks, which need not be consecutive, in the preceding 12 months of: (1) feeling of abdominal fullness, bloating, or visible distension; and (2) insufficient criteria for a diagnosis of functional dyspepsia, IBS, or other functional disorder.
  • Functional constipation is generally characterized by infrequent bowel movements, passage of hard stools, difficulty in passing stools, and seemingly incomplete defecation. While not wishing to be bound by theory, functional constipation may arise from motility problems, including a decrease in the number of high amplitude propagating contractions in the large intestine.
  • Diagnostic criteria include: at least 12 weeks, which need not be consecutive, in the preceding 12 months of two or more of: (1) straining in greater than one-fourth of defecations; (2) lumpy or hard stools in greater than one-fourth of defecations; (3) sensation of incomplete evacuation in greater than one-fourth of defecations; (4) sensation of anorectal obstruction/blockade in greater than one-fourth of defecations; manual maneuvers (e.g. digital evacuation, support of the pelvic floor) to facilitate greater than one- fourth of defecations; and/or (6) less than three defecations per week.
  • Functional Diarrhea Functional diarrhea usually presents as frequent, loose, or watery stools and a subjective sense of urgency, often without the presence of pain. Without wishing to be bound by theory, one cause of functional diarrhea is believed to be an excessive number of high amplitude propagating contractions, which reduce the amount of time food residues remain in the large intestine for water to be reabsorbed. Diagnostic criteria include: at least 12 weeks, which need not be consecutive, in the preceding 12 months of: (1) liquid (mushy) or watery stool; (2) present greater than three-fourths of the time; and (3) no abdominal pain.
  • Functional Abdominal Pain Syndrome is also known as chronic idiopathic abdominal pain or chronic functional abdominal pain. These terms are generally used to describe pain for at least six months that is poorly related to bowel function and is associated with some loss of daily activities. Diagnostic criteria for FAPS include at least six months of: (1) continuous or nearly continuous abdominal pain; and (2) no or only occasional relation of pain with physiological events (e.g. eating, defecation, menses); and (3) some loss of daily functioning; and (4) the pain is not feigned; and (5) insufficient criteria exists for diagnosing other functional gastrointestinal disorders that would explain the abdominal pain.
  • Functional dyspepsia is a functional bowel disorder in which chronic or recurrent symptoms are centered in the upper abdomen without presence of other known disease, such as infection, inflammation, or ulcer. Symptoms include pain and discomfort, which is meant to represent other symptoms, such as early satiety, nausea, vomiting, or bloating. There are two primary motor dysfunctions that can be described in relation to functional dyspepsia. First, more than 30% of adults with functional dyspepsia (or non-ulcer dyspepsia) have impaired gastric emptying. Second, impaired gastric accommodation is also frequent.
  • the mammalian nervous system comprises a central nervous system (CNS, comprising the brain and spinal cord) and a peripheral nervous system (PNS, comprising sympathetic, parasympathetic, sensory, motor, and enteric neurons outside of the brain and spinal cord).
  • CNS central nervous system
  • PNS peripheral nervous system
  • an active agent according to the present invention is intended to act centrally (i.e., exert its effects via action on neurons in the CNS)
  • the active agent must either be administered directly into the CNS or be 2004/084881 capable of bypassing or crossing the blood-brain barrier.
  • the blood-brain barrier is a capillary wall structure that effectively screens out all but selected categories of substances present in the blood, preventing their passage into the CNS.
  • the unique morphologic characteristics of the brain capillaries that make up the blood-brain barrier are: 1) epithelial-like high resistance tight junctions which literally cement all endothelia of brain capillaries together within the blood-brain barrier regions of the CNS; and 2) scanty pinocytosis or transendothelial channels, which are abundant in endothelia of peripheral organs. Due to the unique characteristics of the blood-brain barrier, hydrophilic drugs and peptides that readily gain access to other tissues in the body are barred from entry into the brain or their rates of entry are very low.
  • the blood-brain barrier can be bypassed effectively by direct infusion of the active agent into the brain, or by intranasal administration or inhalation of formulations suitable for uptake and retrograde transport of the active agent by olfactory neurons.
  • the most common procedure for administration directly into the CNS is the implantation of a catheter into the ventricular system or intrathecal space.
  • the active agent can be modified to enhance its transport across the blood-brain barrier. This generally requires some solubility of the drug in lipids, or other appropriate modification known to one of skill in the art.
  • the active agent may be truncated, derivatized, latentiated (converted from a hydrophilic drug into a lipid-soluble drug), conjugated to a lipophilic moiety or to a substance that is actively transported across the blood-brain barrier, or modified using standard means known to those skilled in the art. See, for example, Pardridge, Endocrine Reviews 7: 314-330 (1986) and U.S. Pat. No. 4,801,575.
  • an active agent according to the present invention is intended to act exclusively peripherally (i.e., exert its effects via action either on neurons in the PNS or directly on target tissues)
  • the principle of blood-brain barrier permeability can therefore be used to design active agents with selective potency for peripheral targets.
  • a lipid-insoluble drug will not cross the blood-brain barrier, and will not produce effects on the CNS.
  • a basic drug that acts on the nervous system may be altered to produce a selective peripheral effect by quaternization of the drug, which decreases its lipid solubility and makes it 2004/084881
  • the charged antimuscarinic drug methscopalamine bromide has peripheral effects while the uncharged antimuscarinic drug scopolamine acts centrally.
  • active agents of the present invention using well-known standard chemical synthetic techniques to add a lipid impermeable functional group such a quaternary amine, sulfate, carboxylate, phosphate, or sulfonium to prevent transport across the blood-brain barrier. Such modifications are by no means the only way in which active agents of the present invention may be modified to be impermeable to the blood-brain barrier; other well known pharmaceutical techniques exist and would be considered to fall within the scope of the present invention.
  • Compounds useful in the present invention include any active agent as defined elsewhere herein.
  • active agents include, for example, ⁇ 2 ⁇ subunit calcium channel modulators, including GABA analogs (e.g. gabapentin and pregabalin), as described elsewhere herein, as well as smooth muscle modulators, including antimuscarinics, ⁇ 3 adrenergic agonists, spasmolytics, neurokinin receptor antagonists, bradykinin receptor antagonists, and nitric oxide donors, as described elsewhere herein.
  • Voltage gated calcium channels also known as voltage dependent calcium channels, are multi-subunit membrane-spanning proteins which permit controlled calcium influx from an extracellular environment into the interior of a cell.
  • Opening and closing (gating) of voltage gated calcium channels is controlled by a voltage sensitive region of the protein containing charged amino acids that move within an electric field. The movement of these charged groups leads to conformational changes in the structure of the channel resulting in conducting (open/activated) or non-conducting (closed/inactivated) states.
  • Voltage gated calcium channels are present in a variety of tissues and are implicated in several vital processes in animals. Changes in calcium influx into cells mediated through these calcium channels have been implicated in various human diseases such as epilepsy, stroke, brain trauma, Alzheimer's disease, multi-infarct dementia, other classes of dementia, Korsakoff s disease, neuropathy caused by a viral infection of the brain or spinal cord (e.g., human immunodeficiency viruses, etc.), amyotrophic lateral sclerosis, convulsions, seizures, Huntington's disease, amnesia, or damage to the nervous system resulting from reduced oxygen supply, poison, or other toxic substances (See, e.g., U.S. Pat. No. 5,312,928).
  • Voltage gated calcium channels have been classified by their electrophysiological and pharmacological properties as T, L, N, P and Q types (for reviews see McCleskey et al. (1991) Curr. Topics Membr. 39:295-326; and Dunlap et al. (1995) Trends. Neurosci. 18:89-98). Because there is some overlap in the biophysical properties of the high voltage-activated channels, pharmacological profiles are useful to further distinguish them. L-type channels are sensitive to dihydropyridine agonists and antagonists.
  • N-type channels are blocked by the peptides ⁇ -conotoxin GVIA and ⁇ -conotoxin MVIIA, peptide toxins from the cone shell mo Husks, Conus geographus and Conus magus, respectively.
  • P-type channels are blocked by the peptide ⁇ -agatoxin IVA from the venom of the fumiel web spider, Agelenopsis aperta, although some studies have suggested that ⁇ -agatoxin IVA also blocks N-type channels (Sidach at al. (2000) J. Neurosci. 20: 7174-82).
  • Q-type high voltage-activated calcium channel
  • Voltage gated calcium channels are primarily defined by the combination of different subunits: oi ⁇ , ⁇ 2 , ⁇ , ⁇ , and ⁇ (see Caterall (2000) Annu. Rev. Cell. Dev. Biol. 16: 521-55).
  • Ca v 2 channels form a distinct family with less than 40% amino acid sequence identity with Ca v lc ⁇ subunits (see Caterall, Annu. Rev. Cell. Dev. Biol, supra).
  • Cloned Ca v 2.1 subunits conduct P- or Q-type currents that are inhibited by ⁇ -agatoxin IVA (see Caterall, Annu. Rev. Cell. Dev. Biol, supra; Sather et al. (1993) Neuron 11: 291-303; Stea et al. (1994) Proc. 2004/084881
  • Ca v 2.2 subunits conduct N-type calcium currents and have a high affinity for ⁇ - cono toxin GVIA, ⁇ -conotoxin MVHA, and synthetic versions of these peptides including Ziconotide (see Caterall, Annu. Rev. Cell. Dev. Biol, supra; Dubel et al. (1992) Proc. Natl Acad. Sci. USA 89:5058-62; Williams et al. (1992) Science 257: 389-95).
  • GABA Gamma-aminobutyric acid
  • GABA analogs are compounds that are derived from or based on GABA. GABA analogs are either readily available or readily synthesized using methodologies known to those of skill in the art. Exemplary GABA analogs include gabapentin and pregabalin. Gabapentin (Neurontin, or l-(aminomethyl) cyclohexaneacetic acid) is an anticonvulsant drug with a high binding affinity for some calcium channel subunits, and is represented by the following structure:
  • Gabapentin is one of a series of compounds of formula:
  • Gabapentin and the related drug pregabalin may interact with the ⁇ 2 ⁇ subunit of calcium channels (Gee et al. (1996) J. Biol. Chem. 271: 5768-5776).
  • gabapentin has been shown to block the tonic phase of nociception induced by formalin and carrageenan, and exerts an inhibitory effect in neuropathic pain models of mechanical hyperalgesia and mechanical/thermal allodynia (Rose et al. (2002) Analgesia 57: 451-462). Double- blind, placebo-controlled trials have indicated that gabapentin is an effective treatment for painful symptoms associated with diabetic peripheral neuropathy, post- herpetic neuralgia, and neuropathic pain (see, e.g., Backonja et al. (1998) JAMA 280:1831-1836; Mellegers et al. (2001) Clin. J. Pain 17:284-95).
  • Pregabalin (S)-(3-aminomethyl)-5-methylhexanoic acid or (S)-isobutyl GABA, is another GABA analog whose use as an anticonvulsant has been explored (Bryans et al (1998) J. Med. Chem. 41:1838-1845). Pregabalin has been shown to possess even higher binding affinity for the ⁇ 2 ⁇ subunit of calcium channels than gabapentin (Bryans et al (1999) Med. Res. Rev. 19:149-177).
  • GABA analogs and fused bicyclic or tricyclic amino acid analogs of gabapentin that are useful in the present invention include:
  • GABA analogs according to the following structure as described in U.S. Pat. No. 4,024,175, or salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, or derivatives thereof,
  • GABA analogs according to the following structure as described in U.S. Pat. No. 5,563,175, or salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, or derivatives thereof, wherein Ri is a straight or branched alkyl group having from 1 to 6 carbon atoms, phenyl, or cycloalkyl having from 3 to 6 carbon atoms; R is hydrogen or methyl; and R 3 is hydrogen, methyl or carboxyl; Substituted amino acids according to the following structures as described in U.S. Patent No. 6,316,638, or salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, or derivatives thereof,
  • Ri to R 10 are each independently selected from hydrogen or a straight or branched alkyl of from 1 to 6 carbons, benzyl, or phenyl; m is an integer of from 0 to 3; n is an integer from 1 to 2; o is an integer from 0 to 3; p is an integer from 1 to 2; q is an integer from 0 to 2; r is an integer from 1 to 2; s is an integer from 1 to 3; t is an integer from 0 to 2; and u is an integer from 0 to 1;
  • GABA analogs as disclosed in PCT Publication No. WO 93/23383 or salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, or derivatives thereof;
  • GABA analogs as disclosed in Bryans et al. (1998) J Med. Chem. 41:1838-1845 or salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, or derivatives thereof; 8. GABA analogs as disclosed in Bryans et al. (1999) Med. Res. Rev.
  • Ri and R 2 are independently hydrogen or hydroxy;
  • X is selected from the group consisting of hydroxy and Q 2 -G- where:
  • G is -O-, -C(O)O- or -NH-;
  • Q x is a group derived from a linear oligopeptide comprising a first moiety D and further comprising from 1 to 3 amino acids, and wherein said group is cleavable from the amino acid compound under
  • D is a GABA analog moiety
  • Z is selected from the group consisting of:
  • pH which moiety is selected from the group consisting of -COOH, -SO 3 H, -SO 2 H, -P(O)(OR 16 )(OH), -OP(O)(OR 16 )(OH), - OSO 3 H and the like, and where R is selected from the group consisting of alkyl, substituted
  • oligopeptide comprising a first moiety D' and 881 further comprising from 1 to 3 amino acids, and wherein said group is cleavable under physiological conditions;
  • D' is a GABA analog moiety; or a pharmaceutically acceptable salt thereof; provided that when X is hydroxy, then Z is a group of formula -M-Q x ; 10.
  • Cyclic amino acid compounds as disclosed in PCT Publication No. WO 99/08670 or salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, or derivatives thereof; 11. Cyclic amino acids according to the following structures as disclosed in
  • R is hydrogen or a lower alkyl
  • Ri to R 14 are each independently selected from hydrogen, straight or branched alkyl of from 1 to 6 carbons, phenyl, benzyl, fluorine, chlorine, bromine, hydroxy, hydroxymethyl, amino, aminomethyl, trifluoromethyl,- C0 H,-C0 2 R 15 ,-CH 2 CO 2 H,-CHC0 R 15 , -OR 15 wherein R !5 is a straight or branched alkyl of from 1 to 6 carbons, phenyl, or benzyl, and Ri to R 8 are not simultaneously hydrogen; 12.
  • Bicyclic amino acids according to the following structures as disclosed in published U.S. Patent Application Serial No.
  • 60/160725 including those disclosed as having high activity as measured in a radioligand binding assay using [3H]gabapentin and the ⁇ 2 ⁇ subunit derived from porcine brain tissue, or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, and derivatives thereof,
  • agents useful in the present invention include any compound that binds to the ⁇ 2 ⁇ subunit of a calcium channel.
  • GABA analogs which display binding affinity to the ⁇ 2 ⁇ subunit of calcium channels and that are therefore useful in the present invention include, without limitation, cis-(lS,3R)-( l-(aminomethyl)-3- methylcyclohexane)acetic acid, cis-(lR,3S)-(l-(aminomethyl)-3- methylcyclohexane)acetic acid, l ⁇ ,3o 5Q:-(l-aminomethyl)-(3,5- dimethylcyclohexane)acetic acid, (9-(aminomethyl)bicyclo[3.3.1 ]non-9-yl)acetic acid, and (7-(aminomethyl)bicyclo[2.2.1]hept-7-yl)acetic acid (Bryans et al.
  • compositions and formulations encompassing GABA analogs and cyclic amino acid analogs of gabapentin and that would be useful in the present invention include compositions disclosed in PCT Publication No. WO 99/08670, U.S. Patent No. 6,342,529, controlled release formulations as disclosed in U.S. Application No. 20020119197 and U.S. Patent No. 5,955,103, and sustained release compounds and formulations as disclosed in PCT Publication No. WO 02/28411 , PCT Publication No. WO 02/28881, PCT Publication No. WO 02/28883, PCT Publication No. WO 02/32376, PCT Publication No. WO 02/42414, U.S. Application No. 20020107208, U.S. Application No. 20020151529, and U.S. Application No. 20020098999.
  • Acetylcholine is a chemical neurotransmitter in the nervous systems of all animals.
  • Cholinergic neurotransmission refers to neurotransmission that involves acetylcholine, and has been implicated in the control of functions as diverse as locomotion, digestion, cardiac rate, "fight or flight” responses, and learning and memory (Salvaterra (Feb. 2000) Acetylcholine. hi Encyclopedia of Life Sciences. London: Nature Publishing Group, http:/www.els.net).
  • Receptors for acetylcholine are classified into two general categories based on the plant alkaloids that preferentially interact with them: 1) nicotinic (nicotine binding); or 2) muscarinic (muscarine binding) (See, e.g., Salvaterra, Acetylcholine, supra).
  • acetylcholine receptors may be further divided into subclasses based upon differences in their pharmacological and electrophysiological properties.
  • nicotinic receptors are composed of a variety of subunits that are used to identify the following subclasses: 1) muscle nicotinic acetylcholine receptors; 2) neuronal nicotinic acetylcholine receptors that do not bind the snake venom ⁇ -bungarotoxin; and 3) neuronal nicotinic acetylcholine receptors that do bind the snake venom ⁇ -bungarotoxin (Dani et al.
  • muscarinic receptors may be divided into five subclasses, labeled M1-M5, and preferentially couple with specific G-proteins (Mi, M 3 , and M 5 with G q ; M 2 and M 4 with Gj/G 0 ) (Nathanson (July 1999) Muscarinic Acetylcholine Receptors. In Encyclopedia of Life Sciences. London: Nature Publishing Group, http:/www.els.net).
  • M1-M5 muscarinic receptors may be divided into five subclasses, labeled M1-M5, and preferentially couple with specific G-proteins (Mi, M 3 , and M 5 with G q ; M 2 and M 4 with Gj/G 0 ) (Nathanson (July 1999) Muscarinic Acetylcholine Receptors. In Encyclopedia of Life Sciences.
  • agents useful in the present invention include any anticholinergic agent, specifically, any antimuscarinic agent.
  • Particularly useful in the methods of the present invention is oxybutynin, also known as 4-diethylaminio-2-butynyl phenylcyclohexyglycolate. It has the following structure:
  • Ditropan (oxybutynin chloride) is the d,l racemic mixture of the above compound, which is known to exert antispasmodic effect on smooth muscle and inhibit the muscarinic action of acetylcholine on smooth muscle.
  • Metabolites and isomers of oxybutynin have also been shown to have activity useful according to the present invention. Examples include, but are not limited to N-desethyl-oxybutynin and S-oxybutynin (see, e.g., US Patent Nos. 5,736,577 and 5,532,278).
  • Additional compounds that have been identified as antimuscarinic agents and are useful in the present invention include, but are not limited to: a. Darifenacin (Daryon ® ) or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, and derivatives thereof; b. Solifenacin or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, and derivatives thereof; c. YM-905 (solifenacin succinate) or acids, salts, enantiomers, 5 analogs, esters, amides, prodrugs, active metabolites, and derivatives thereof; d. Solifenacin monohydrochloride or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, and derivatives thereof;
  • Flavoxate hydrochloride (Urispas ® ) or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, and derivatives thereof; k. d,l (racemic) 4- diethylamino-2-butynyl phenylcyclohexylglycolate or acids, salts, enantiomers, 30 analogs, esters, amides, prodrugs, active metabolites, and derivatives thereof; 1.
  • KRP-197 (4-(2-methylimidazolyl)-2,2-diphenylbutyramide) or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, and derivatives thereof; y. Fesoterodine or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, and derivatives thereof; and z. SPM 7605 (the active metabolite of Fesoterodine), or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, and derivatives thereof.
  • Adrenergic receptors are cell-surface receptors for two major catecholamine hormones and neurotransmitters: noradrenaline and adrenaline. (Malbon et al. (Feb. 2000) Adrenergic Receptors. In Encyclopedia of Life Sciences. London: Nature Publishing Group, http:/www.els.net). Adrenergic receptors have been implicated in critical physiological processes, including blood pressure control, myocardial and smooth muscle contractility, pulmonary function, metabolism, and central nervous system activity (See, e.g., Malbon et al, Adrenergic Receptors, supra).
  • ⁇ Two classes of adrenergic receptors have been identified, and ⁇ , that may be further subdivided into three major families (al, o2, and ⁇ ), each with at least three subtypes (al A, B, and, D; ⁇ 2 A, B, and C; and ⁇ l, ⁇ 2, and ⁇ 3) based upon their binding characteristics to different agonists and molecular cloning techniques.
  • al, o2, and ⁇ subtypes
  • ⁇ 3 adrenergic receptors have been implicated in bladder function (See, e.g., Takeda et al. (2002) Neuourol Urodyn. 21: 558-65; Takeda et al. (2000) J Pharmacol. Exp. Ther. 293: 939-45.
  • Other agents useful in the present invention include any ⁇ 3 adrenergic agonist agent.
  • Compounds that have been identified as ⁇ 3 adrenergic agonist agents and are useful in the present invention include, but are not limited to: a.
  • TT-138 and phenylethanolamine compounds as disclosed in US Patent No. 6,069,176, PCT Publication No. WO 97/15549 and available from Mitsubishi Pharma Corp., or acids, salts, esters, amides, prodrugs, active metabolites, and other derivatives thereof; b. FR-149174 and propanolamine derivatives as disclosed in US Patent Nos. 6,495,546 and 6,391,915 and available from Fujisawa Pharmaceutical Co., or acids, salts, esters, amides, prodrugs, active metabolites, and other derivatives thereof; c.
  • KUC-7483 available from Kissei Pharmaceutical Co., or acids, salts, esters, amides, prodrugs, active metabolites, and other derivatives thereof, d. 4'-hydroxynorephedrine derivatives such as 2- 2-chloro-4-
  • GS 332 (Sodium (2R)-[3-[3-[2-(3 Chlorophenyl)-2- hydroxyethylamino] cyclohexyl]phenoxy] acetate) as disclosed in Iizuka et al. (1998) J. Smooth Muscle Res. 34: 139-49 or acids, salts, esters, amides, prodrugs, active metabolites, and other derivatives thereof;
  • BRL-37,344 (4-[-[(2-hydroxy-(3-chlorophenyl) ethyl)- amino]propyl]phenoxyacetate) as disclosed in Tsujii et al. (1998) Physiol. Behav. 63: 723-8 and available from Glaxo SmithKline or acids, salts, esters, amides, prodrugs, active metabolites, and other derivatives thereof;
  • Pindolol (l-(lH-Indol-4-yloxy)-3-[(l-methylethyl)amino]- 2-propanol) as disclosed in Blin et al (1994) Mol.Pharmacol 44: 1094 or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, and 20 derivatives thereof; o.
  • SR 59230A ⁇ C1 (l-(2-Ethylphenoxy)-3-[[(l 1 S)-l,2,3,4- tetrahydro-l-naphthalenyl]amino]-(2iS)-2-propanol hydrochloride) as disclosed in Manara et al (1995) 30 Pharmacol. Comm. 6: 253 and Manara et al. (1996) Br. J.
  • Spasmolytics are compounds that relieve or prevent muscle spasms, especially of smooth muscle. In general, spasmolytics have been implicated as having efficacy in the treatment of bladder disorders (See. e.g., Takeda et al. (2000) J Pharmacol. Exp. Ther. 293: 939-45).
  • spasmolytic agents include any spasmolytic agent.
  • Compounds that have been identified as spasmolytic agents and are useful in the present invention include, but are not limited to: a. ⁇ - ⁇ -diphenylacetic acid-4-( ⁇ -methyl-piperidyl) esters as disclosed in US Patent No. 5,897,875 or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, and derivatives thereof; b. Human and porcine spasmolytic polypeptides in glycosylated form and variants thereof as disclosed in US Patent No. 5,783,416 or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, and derivatives thereof; c. Dioxazocine derivatives as disclosed in US Patent No.
  • Pancreatic spasmolytic polypeptides as disclosed in US Patent No. 4,370,317 or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, and derivatives thereof;
  • Triazinones as disclosed in US Patent No. 4,203,983 or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, and derivatives thereof;
  • 2-(4-Bi ⁇ henylyl)-N-(2-diethylamino alky ⁇ )propionamide as disclosed in US Patent No. 4,185,124 or acids, salts, 25 enantiomers, analogs, esters, amides, prodrugs, active metabolites, and derivatives thereof;
  • Piperazino-pyrimidines as disclosed in US Patent No.
  • the identification of further compounds that have spasmolytic activity and would therefore be useful in the present invention can be determined by performing bladder strip contractility studies as described in US Patent No. 6,207,852; Noronha-Blob et al. (1991) J Pharmacol. Exp. Ther.256: 562-567; and/or Kachur et al. (1988) J Pharmacol Exp. Ther.247: 867-872.
  • Tachykinins are a family of structurally related peptides that include substance P, neurokinin A (NKA) and neurokinin B (NKB). Neurons are the major source of TKs in the periphery. An important general effect of TKs is neuronal stimulation, but other effects include endothelium-dependent vasodilation, plasma protein extravasation, mast cell recruitment and degranulation and stimulation of inflammatory cells (See Maggi, C. A. (1991) Gen. Pharmacol, 22: 1-24). hi general, tachykinin receptors have been implicated in bladder function (See, e.g., Kamo et al. (2000) Eur. J. Pharmacol. 401: 235-40 and Omhura et al. (1997) Urol. Int. 59: 221- 5).
  • Substance P activates the neurokinin receptor subtype referred to as NKi.
  • Substance P is an undecapeptide that is present in sensory nerve terminals. Substance P is known to have multiple actions that produce inflammation and pain in the periphery after C-fiber activation, including vasodilation, plasma extravasation and degranulation of mast cells (Levine, J. D. et. al. (1993) J Neurosci. 13: 2273).
  • Neurokinin A is a peptide which is colocalized in sensory neurons with substance P and which also promotes inflammation and pain. Neurokinin A activates the specific neurokinin receptor referred to as NK 2 (Edmonds-Alt, S., et. al. (1992) Life Sci. 50: PL101).
  • TKs are powerful spasmogens acting through only the NK 2 receptor in the human bladder, as well as the human urethra and ureter (Maggi, C. A. (1991) Gen. Pharmacol, 22: 1-24).
  • Suitable neurokinin receptor antagonists for use in the present invention that act on the NKi receptor include, but are not limited to: l-imino-2-(2- methoxy-phenyl)-ethyl)-7,7-diphenyl-4-perhydroisoindolone(3aR ,7aR) ("RP 67580"); 2S,3 S-cis-3-(2-methoxybenzylamino)-2-benzhydrylquinuclidine (“CP 96,345"); and (aR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10, ll-tetrahydro-9- methyl-5-(4-methylphenyl)-7H-[l ,4]diazocino[2, 1 -g] [1 ,7]naphthyridine-6, 13- dione)("TAK-637").
  • Suitable neurokinin receptor antagonists for use in the present invention that act on the NK 2 receptor include but are not limited to: ((S)-N-methyl-N- 4-(4-acetylamino-4-phenylpiperidino)-2-(3 ,4-dichloropheny l)butylbenzamide ("SR 48968”); Met-Asp-Trp-Phe-Dap-Leu ("MEN 10,627”); and cyc(Gln-Trp-Phe-Gly- Leu-Met) ("L 659,877").
  • Suitable neurokinin receptor antagonists for use in the present invention also include acids, salts, esters, amides, prodrugs, active metabolites, and other derivatives of any of the agents mentioned above.
  • the identification of further compomids that have neurokinin receptor antagonist activity and would therefore be useful in the present invention can be determined by performing binding assay studies as described in Hopkins et al. (1991) Biochem. Biophys. Res. Comm. 180: 1110-1117; and Aharony et al. (1994) Mol. Pharmacol. 45: 9-19.
  • Bradykinin receptors generally are divided into bradykinin ! (Bi) and bradykinin 2 (B 2 ) subtypes. Studies have shown that acute peripheral pain and inflammation produced by bradykinin are mediated by the B 2 subtype whereas bradykinin-induced pain in the setting of chronic inflammation is mediated via the Bi subtype (Perkins, M. N., et. al. (1993) Pain 53: 191-97); Dray, A., et. al. (1993)
  • bradykinin receptors have been implicated in bladder function (See, e.g., Meini et al. (2000) Eur. J. Pharmacol. 388: 177-82 and Belichard et al. (1999) Br. J. Pharmacol. 128: 213-9).
  • Other agents useful in the present invention include any bradykinin receptor antagonist agent.
  • Suitable bradykinin receptor antagonists for use in the present invention that act on the Bi receptor include but are not limited to: des-arg 10 HOE 140 (available from Hoechst Pharmaceuticals) and des-Arg 9 bradykinin (DABK).
  • Suitable bradykinin receptor antagonists for use in the present invention that act on the B 2 receptor include but are not limited to: D-Phe 7 -BK; D-Arg-(Hyp 3 -Thi 5,8 -D-Phe 7 )-BK ("NPC 349”); D-Arg-(Hyp 3 -D-Phe 7 )-BK ("NPC 567”); D-Arg-(Hyp 3 -Thi 5 -D-Tic 7 - Oic 8 )-BK ("HOE 140"); H-DArg-Arg-Pro-Hyp-Gly-Thi-c(Dab-DTic-Oic- Arg)c(7gamma-10alpha)("MENl 1270”); H-DArg-Arg-Arg-Pro-Hyp-Gly-Tlii-Ser-DTic- Oic-Arg-OH("Icatibant”); (E)-3-(6-acetamido-3-pyridyl
  • Suitable neurokinin receptor antagonists for use in the present invention also include acids, salts, esters, amides, prodrugs, active metabolites, and other derivatives of any of the agents mentioned above.
  • the identification of further compounds that have bradykinin receptor antagonist activity and would therefore be useful in the present invention can be determined by performing binding assay studies as described in Manning et al. (1986) J Pharmacol. Exp. Ther. 237: 504 and US Patent No. 5,686,565.
  • Nitric oxide donors may be included in the present invention particularly for their anti-spasm activity.
  • Nitric oxide (NO) plays a critical role as a molecular mediator of many physiological processes, including vasodilation and regulation of normal vascular tone. The action of NO is implicated in intrinsic local vasodilation mechanisms. NO is the smallest biologically active molecule known and is the mediator of an extraordinary range of physiological processes (Nathan (1994) Cell 78: 915-918; Thomas (1997) Neurosurg. Focus 3: Article 3).
  • NO is also a known physiologic antagonist of endothelin-1, which is the most potent known mammalian vasoconstrictor, having at least ten times the vasoconstrictor potency of angiotensin II (Yanagisawa et al. (1988) Nature 332: 411-415; Kasuya et al. (1993) J. Neurosurg. 79: 892-898; Kobayashi et al, (1991) Neurosurgery 28: 673-679).
  • the biological half-life of NO is extremely short (Morris et al. (1994) Am. J. Physiol. 266: E829- E839; Nathan (1994) Cell 78: 915-918). NO accounts entirely for the biological 2004/084881
  • EDRF endothelium-derived relaxing factor
  • NOS NO synthase
  • L-arginine an enzyme known as NO synthase (NOS) catalyzes the conversion of L-arginine to NO which acts as a diffusible second messenger and mediates responses in adjacent smooth muscle cells.
  • NO is continuously formed and released by the vascular endothelium under basal conditions which inhibits contractions and controls basal coronary tone and is produced in the endothelium in response to various agonists (such as acetylcholine) and other endothelium dependent vasodilators.
  • various agonists such as acetylcholine
  • NOS activity and the resultant levels of NO are key molecular targets controlling vascular tone (Muramatsu et. al. (1994) Cor on. Artery Dis. 5: 815-820).
  • nitric oxide donor agent any nitric oxide donor agent.
  • Suitable nitric oxide donors for the practice of the present invention include but are not limited to: a. Nitroglycerin or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, and derivatives thereof; b. Sodium nitroprusside or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, and derivatives thereof; c. FK 409 (NOR-3) or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, and derivatives thereof; d.
  • FR 144420 (NOR-4) or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, and derivatives thereof; e. 3-morpholinosydnonimine or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, and derivatives thereof; f. Linsidomine chlorohydrate (“SLN-1”) or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, and derivatives thereof; g.
  • S-nitroso-N-acetylpenicillamine or acids, salts, 5 enantiomers, analogs, esters, amides, prodrugs, active metabolites, and derivatives thereof
  • SNAP S-nitroso-N-acetylpenicillamine
  • AZD3582 CINOD lead compound, available from NicOx S.A.
  • NCX 4016 available from NicOx S.A.
  • acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, and derivatives thereof 10
  • NCX 4016 available from NicOx S.A.
  • NCX 701 available from NicOx S.A. or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active 15 metabolites, and derivatives thereof
  • NCX 1022 available from NicOx S.A. or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, and derivatives thereof
  • HCT 1026 available from NicOx S.A.
  • NCX 1000 available from NicOx S.A. or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active 30 metabolites, and derivatives thereof
  • NCX 1020 available from NicOx S.A. or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, and derivatives thereof
  • q. AZD 4717 available from NicOx S.A.
  • NCX 1510/NCX 1512 available from NicOx S.A.
  • D-lactic acid is the same as (-)-lactic acid
  • L-lactic acid is the same as (+)-lactic acid.
  • each of a pair of enantiomers are identical except that they are non- superimposable mirror images of one another.
  • a specific stereoisomer may also be refe ⁇ ed to as an enantiomer, and a mixture of such isomers is often called an enantiomeric, or racemic, mixture.
  • Stereochemical purity is important in the pharmaceutical field, where many of the most often prescribed drugs exhibit chirality.
  • the L-enantiomer of the beta-adrenergic blocking agent, propranolol is known to be 100 times more potent than its D-enantiomer.
  • optical purity is important in the pharmaceutical drug field because certain isomers have been found to impart a deleterious effect, rather than an advantageous or inert effect.
  • D- enantiomer of thalidomide is a safe and effective sedative when prescribed for the control of morning sickness during pregnancy, whereas its corresponding L- enantiomer is believed to be a potent teratogen.
  • (R,R) and (S,S) are an example of a pair of enantiomers (mirror images of each other), which typically share chemical properties and melting points just like any other enantiomeric pair.
  • the mirror images of (R,R) and (S,S) are not, however, superimposable on (R,S) and (S,R).
  • Solifenacin is described in U.S. Patent No. 6,174,896 and is represented by the following chemical formula:
  • Solifenacin succinate (development number YM-905) is a salt form of solifenacin that is co-promoted as Vesicare ® by Yamanouchi Pharmaceutical Co., Ltd. (through Yamanouchi Pha ⁇ na America) and GlaxoSmitliKline as an investigational muscarinic antagonist. Solifenacin was discovered and developed by Yamanouchi, and a New Drug Application was submitted to the U.S. Food and Drug Administration by YPA in December 2002 for solifenacin succinate.
  • any diastereomer or enantiomer of an active agent, as disclosed herein, can be administered to treat functional bowel disorders in patients in need of such treatment.
  • Formulations of the present invention may include, but are not limited to, continuous, as needed, short-term, rapid-offset, controlled release, sustained release, delayed release, and pulsatile release formulations.
  • Compositions of the invention comprise o; 2 ⁇ subunit calcium channel modulators in combination with one or more compounds with smooth muscle modulatory effects, including antimuscarinics (particularly those that do not have an amine embedded in an 8-azabicyclo[3.2.1]octan-3-ol skeleton), ⁇ 3 adrenergic agonists, spasmolytics, neurokinin receptor antagonists, bradykinin receptor antagonists, and nitric oxide donors.
  • the compositions are administered in therapeutically effective amounts to a patient in need thereof for treating functional bowel disorders.
  • compositions may be administered by any means of administration as long as an effective amount for treating functional bowel disorders, is delivered.
  • Any of the active agents may be administered in the form of a salt, ester, amide, prodrug, active metabolite, derivative, or the like, provided that the salt, ester, amide, prodrug or derivative is suitable phannacologically, i.e., effective in the present method.
  • Salts, esters, amides, prodrugs and other derivatives of the active agents may be prepared using standard procedures known to those skilled in the art of synthetic organic chemistry and described, for example, by J. March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 4th Ed. (New York: Wiley-Interscience, 1992).
  • acid addition salts are prepared from the free base using conventional methodology, and involves reaction with a suitable acid.
  • suitable acids for preparing acid addition salts include both organic acids, e.g., acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicylic acid, and the like, as well as inorganic acids, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • An acid addition salt may be reconverted to the free base by treatment with a suitable base.
  • Particularly preferred acid addition salts of the active agents herein are salts prepared with organic acids.
  • preparation of basic salts of acid moieties which may be present on an active agent are prepared in a similar manner using a pharmaceutically acceptable base such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, trimethylamine, or the like.
  • Preparation of esters involves functionalization of hydroxyl and/or carboxyl groups that may be present within the molecular structure of the drug.
  • esters are typically acyl-substituted derivatives of free alcohol groups, i.e., moieties that are derived from carboxylic acids of the formula RCOOH where R is alkyl, and preferably is lower alkyl.
  • Esters can be reconverted to the free acids, if desired, by using conventional hydrogenolysis or hydrolysis procedures.
  • Amides and prodrugs may also be prepared using techniques known to those skilled in the art or described in the pertinent literature. For example, amides may be prepared from esters, using 2004/084881
  • Suitable amine reactants or they may be prepared from an anhydride or an acid chloride by reaction with ammonia or a lower alkyl amine.
  • Prodrugs are typically prepared by covalent attachment of a moiety, which results in a compound that is therapeutically inactive until modified by an individual's metabolic system.
  • One set of formulations for gabapentin are those marketed by Pfizer Inc. under the brand name Neurontin ® .
  • Neurontin ® Capsules, Neurontin ® Tablets, and Neurontin ® Oral Solution are supplied either as imprinted hard shell capsules containing 100 mg, 300 mg, and 400 mg of gabapentin, elliptical film-coated tablets containing 600 mg and 800 mg of gabapentin or an oral solution containing 250 mg/5 mL of gabapentin.
  • the inactive ingredients for the capsules are lactose, cornstarch, and talc.
  • the 100 mg capsule shell contains gelatin and titanium dioxide.
  • the 300 mg capsule shell contains gelatin, titanium dioxide, and yellow iron oxide.
  • the 400 mg capsule shell contains gelatin, red iron oxide, titanium dioxide, and yellow iron oxide.
  • the inactive ingredients for the tablets are poloxamer 407, copolyvidonum, cornstarch, magnesium stearate, hydroxypropyl cellulose, talc, candehlla wax and purified water.
  • the inactive ingredients for the oral solution are glycerin, xylitol, purified water and artificial cool strawberry anise flavor.
  • gabapentin and formulations are generally described in the following patents: US 6,683,112; US 6,645,528; US 6,627,211; US 6,569,463; US 6,544,998; US 6,531,509; 6,495,669; US 6,465,012; US 6,346,270; US 6,294,198; US 6,294,192; US 6,207,685; US 6,127,418; US 6,024,977; US 6,020,370; US 5,906,832; US 5,876,750; and US 4,960,931.
  • Ditropan ® tablets are supplied containing 5 mg/tablets of the active ingredient, oxybutynin chloride, and the inactive ingredients anhydrous lactose, microcrystalline cellulose, calcium stearate, and FD&C blue #1 lake.
  • Ditropan ® syrup is supplied as 5mg/5mL of the active ingredient, oxybutynin chloride, and the inactive ingredients citric acid, FD&C green #3, flavor, glycerin, methylparaben, sodium citrate, sorbitol, sucrose, and water.
  • Ditropan XL® is an extended release tablet form of Ditropan ® supplied containing either 5 mg (pale yellow color) of oxybutynin chloride, 10 mg (pink color) of oxybutynin chloride, or 15 mg (gray color) of oxybutynin chloride.
  • Inactive ingredients are cellulose acetate, hydroxypropyl methylcellulose, lactose, magnesium stearate, polyethylene giycol, 2004/084881
  • polyethylene oxide polyethylene oxide, synthetic iron oxides, titanium dioxide, polysorbate 80, sodium chloride, and butylated hydroxytoluene.
  • Oxybutynin is also supplied by Watson Pharmaceuticals under the brand name Oxytrol ® (oxybutynin transdermal system).
  • Oxytrol ® is a transdermal patch designed to deliver oxybutynin continuously and consistently over a 3 to 4 day interval. It is supplied as a 39 cm 2 patch containing 36 mg of oxybutynin, which is designed to deliver 3.9 mg/day. The patch is worn continuously, and a new patch is applied every 3 to 4 days.
  • a formulation useful in the present invention comprises a combination of gabapentin and oxybutynin chloride.
  • the combination can be supplied in various pharmaceutical composition and dosage forms as described herein.
  • One formulation for supplying the combination is in a tablet formulation. Additional formulations for the combination of the present invention, such as capsules, syrups, etc. are also envisioned for delivery of the combination, and any description of tablet formulations is in no way meant to be limiting of possible delivery modes for the combination of the present invention.
  • Tablet formulations useful for supplying the gabapentin/oxybutynin combination useful in the present invention can comprise, in addition to the active ingredients in combination, functional excipients.
  • excipients as are useful for preparing pharmaceutical compositions in a tablet formulation are known in the art and include compounds known to be useful as fillers, binders, lubricants, disintegrants, diluents, coatings, plastizers, glidants, compression aids, stabilizers, sweeteners, solubilizers, and other excipients that would be known to one of skill in the pha ⁇ naceutical arts.
  • the active ingredients of the combination useful in the present invention are known in the art and include compounds known to be useful as fillers, binders, lubricants, disintegrants, diluents, coatings, plastizers, glidants, compression aids, stabilizers, sweeteners, solubilizers, and other excipients that would be known to one of skill in the pha ⁇ nac
  • the relative ratio of the active ingredients of the combination for use in the present invention is about 1:1 to about 1 :800, oxybutynin and gabapentin respectively, more preferably about 2.5:200 to 2.5:800, oxybutynin and gabapentin respectively.
  • the ratio of oxybutynin to gabapentin in the combination is about 2.5:50, about 2.5:100, about 2.5:150, about 2.5:200, about 2.5:250, about 2.5:300, about 2.5:350, about 2.5:400, about 2.5:450, about 2.5:500, about 2.5:550, about 2.5:600, about 2.5:650, about 2.5:700, about 2.5:750, or about 2004/084881
  • the ratio of oxybutynin to gabapentin in the combination is about about 1.25:50, about 1.25:100, about 1.25:150, about 1.25:200, about 1.25:250, about 1.25:300, about 1.25:350, about 1.25:400, about 1.25:450, about 1.25:500, about 1.25:550, about 1.25:600, about 1.25:650, about 1.25:700, about 1.25:750, or about 1.25:800.
  • the ratio of oxybutynin to gabapentin in the combination is about about 5:50, about 5:100, about 5:150, about 5:200, about 5:250, about 5:300, about 5:350, about 5:400, about 5:450, about 5:500, about 5:550, about 5:600, about ⁇ 5:650, about 5:700, about 5:750, or about 5:800.
  • formulations for preparing tablets comprising gabapentin and oxybutynin in combination suitable for use in the present invention are provided below in Tables 1 and 2.
  • Tablets according to the above formulations can be prepared according to a number of possible methods.
  • One method used in preparing a tablet comprising a formulation as provided above includes the following steps: 2004/084881
  • active agents may be prepared using standard techniques known to those skilled in the art of synthetic organic chemistry, or may be deduced by reference to the pertinent literature.
  • chiral active agents may be in isomerically pure form, or they may be administered as a racemic mixture of isomers .
  • compositions and dosage forms include tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, transdermal patches, gels, powders, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration and the like. Further, those of ordinary skill in the art can readily deduce that suitable formulations involving these compositions and dosage forms, including those formulations as described elsewhere herein.
  • Oral dosage forms include tablets, capsules, caplets, solutions, suspensions and/or syrups, and may also comprise a plurality of granules, beads, powders or pellets that may or may not be encapsulated.
  • Such dosage forms are prepared using conventional methods known to those in the field of pharmaceutical formulation and described in the pertinent texts, e.g., in Remington: The Science and Practice of Pharmacy, supra). Tablets and capsules represent the most convenient oral dosage forms, in which case solid pharmaceutical carriers are employed.
  • Tablets may be manufactured using standard tablet processing procedures and equipment.
  • One method for forming tablets is by direct compression of a powdered, crystalline or granular composition containing the active agent(s), alone or in combination with one or more carriers, additives, or the like.
  • tablets can be prepared using wet-granulation or dry-granulation processes. Tablets may also be molded rather than compressed, starting with a moist or otherwise tractable material; however, compression and granulation techniques are prefe ⁇ ed.
  • tablets prepared for oral administration using the method of the invention will generally contain other materials such as binders, diluents, lubricants, disintegrants, fillers, stabilizers, surfactants, preservatives, coloring agents, flavoring agents and the like. Binders are used to impart cohesive qualities to a tablet, and thus ensure that the tablet remains intact after compression.
  • Suitable binder materials include, but are not limited to, starch (including com starch and pregelatinized starch), gelatin, sugars (including sucrose, glucose, dextrose and lactose), polyethylene giycol, propylene giycol, waxes, and natural and synthetic gums, e.g., acacia sodium alginate, polyvinylpyrrolidone, cellulosic polymers (including hydroxypropyl cellulose, hydroxypropyl methylcellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, and the like), and Veegum. Diluents are typically necessary to increase bulk so that a practical size tablet is ultimately provided.
  • Suitable diluents include dicalcium phosphate, calcium sulfate, lactose, cellulose, kaolin, mannitol, sodium chloride, dry starch and powdered sugar.
  • Lubricants are used to facilitate tablet manufacture; examples of suitable lubricants include, for example, vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and oil of theobroma, glycerin, magnesium stearate, calcium stearate, and stearic acid. Stearates, if present, preferably represent at no more than approximately 2 wt. % of the drug-containing core.
  • Disintegrants are used to facilitate disintegration of the tablet, and are generally starches, clays, celluloses, algins, gums or crosslinked polymers.
  • Fillers include, for example, materials such as silicon dioxide, titanium dioxide, alumina, talc, kaolin, powdered cellulose and microcrystalline cellulose, as well as soluble materials such as 2004/084881
  • the dosage form may also be a capsule, in which case the active agent- containing composition may be encapsulated in the form of a liquid or solid (including particulates such as granules, beads, powders or pellets).
  • Suitable capsules may be either hard or soft, and are generally made of gelatin, starch, or a cellulosic material, with gelatin capsules preferred. Two-piece hard gelatin capsules are preferably sealed, such as with gelatin bands or the like.
  • a liquid carrier is necessary to dissolve the active agent(s).
  • the carrier must be compatible with the capsule material and all components of the pharmaceutical composition, and must be suitable for ingestion.
  • Solid dosage forms may, if desired, be coated so as to provide for delayed release.
  • Dosage forms with delayed release coatings may be manufactured using standard coating procedures and equipment. Such procedures are known to those skilled in the art and described in the pertinent texts (See, for e.g., Remington: The Science and Practice of Pharmacy, supra).
  • a delayed release coating composition is applied using a coating pan, an airless spray technique, fluidized bed coating equipment, or the like.
  • Delayed release coating compositions comprise a polymeric material, e.g., cellulose butyrate phthalate, cellulose hydrogen phthalate, cellulose proprionate phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate, dioxypropyl methylcellulose succinate, carboxymethyl ethylcellulose, hydroxypropyl methylcellulose acetate succinate, polymers and copolymers formed from acrylic acid, methacrylic acid, and/or esters thereof.
  • a polymeric material e.g., cellulose butyrate phthalate, cellulose hydrogen phthalate, cellulose proprionate phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate, dioxypropyl
  • sustained release dosage forms provide for drug release over an extended time period, and may or may not be delayed release.
  • sustained release dosage forms are formulated by dispersing a drug within a matrix of a gradually bioerodible (hydrolyzable) material such as an insoluble plastic, a hydrophilic polymer, or a fatty compound, or by coating a solid, drug-containing dosage form with such a material.
  • a gradually bioerodible (hydrolyzable) material such as an insoluble plastic, a hydrophilic polymer, or a fatty compound
  • Insoluble plastic matrices may be comprised of, for example, polyvinyl chloride or polyethylene.
  • Hydrophilic polymers useful for providing a sustained release coating or matrix cellulosic polymers include, without limitation: cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropylmethyl cellulose phthalate, hydroxypropylcellulose phthalate, cellulose hexahydrophthalate, cellulose acetate hexahydrophthalate, and carboxymethylcellulose sodium; acrylic acid polymers and copolymers, preferably formed from acrylic acid, methacryhc acid, acrylic acid alkyl esters, methacryhc acid alkyl esters, and the like, e.g.
  • Fatty compounds for use as a sustained release matrix material include, but are not limited to, waxes generally (e.g., carnauba wax) and g
  • Transmucosal Compositions and Dosage Forms Although the present compositions may be administered orally, other modes of administration are suitable as well. For example, transmucosal administration may be advantageously employed. Transmucosal administration is carried out using any type of formulation or dosage unit suitable for application to mucosal tissue.
  • the selected active agent may be administered to the buccal mucosa in an adhesive tablet or patch, sublingually admimstered by placing a solid dosage form under the tongue, lingually administered by placing a solid dosage form on the tongue, administered nasally as droplets or a nasal spray, administered by inhalation of an aerosol formulation, a non-aerosol liquid formulation, or a dry powder, placed within or near the rectum ("transrectal" formulations), or admimstered to the urethra as a suppository, ointment, or the like.
  • Preferred buccal dosage forms will typically comprise a therapeutically effective amount of an active agent and a bioerodible (hydrolyzable) polymeric carrier that may also serve to adhere the dosage form to the buccal mucosa.
  • the buccal dosage unit is fabricated so as to erode over a predete ⁇ nined time period, wherein drug delivery is provided essentially throughout. The time period is typically in the range of from about 1 hour to about 72 hours.
  • Preferred buccal delivery preferably occurs over a time period of from about 2 hours to about 24 hours.
  • Buccal drug delivery for short term use should preferably occur over a time period of from about 2 hours to about 8 hours, more preferably over a time period of from about 3 hours to about 4 hours.
  • buccal drug delivery preferably will occur over a time period of from about 1 hour to about 12 hours, more preferably from about 2 hours to about 8 hours, most preferably from about 3 hours to about 6 hours.
  • Sustained buccal drug delivery will preferably occur over a time period of from about 6 hours to about 72 hours, more preferably from about 12 hours to about 48 hours, most preferably from about 24 hours to about 48 hours.
  • Buccal drug delivery avoids the disadvantages encountered with oral drug administration, e.g., slow absorption, degradation of the active agent by fluids present in the gastrointestinal tract and/or first-pass inactivation in the liver.
  • the "therapeutically effective amount" of the active agent in the buccal dosage unit will of course depend on the potency of the agent and the intended dosage, which, in turn, is dependent on the particular individual undergoing treatment, the specific indication, and the like.
  • the buccal dosage unit will generally contain from about 1.0 wt. % to about 60 wt. % active agent, preferably on the order of from about 1 wt. %> to about 30 wt. % active agent.
  • the bioerodible (hydrolyzable) polymeric carrier it will be appreciated that virtually any such carrier can be used, so long as the desired drug release profile is not compromised, and the carrier is compatible with the active agents to be administered and any other components of the buccal dosage unit.
  • the polymeric carrier comprises a hydrophilic (water-soluble and water-swellable) polymer that adheres to the wet surface of the buccal mucosa. Examples of polymeric carriers useful herein include 2004/084881
  • acrylic acid polymers and co e.g., those known as "carbomers”
  • Carbopol® which may be obtained from B. F. Goodrich, is one such polymer.
  • suitable polymers include, but are not limited to: hydrolyzed polyvinylalcohol; polyethylene oxides (e.g., Sentry Polyox® water soluble resins, available from Union Carbide); polyacrylates (e.g., Gantrez®, which may be obtained from GAF); vinyl polymers and copolymers; polyvinylpyrrolidone; dextran; guar gum; pectins; starches; and cellulosic polymers such as hydroxypropyl methylcellulose, (e.g., Methocel®, which may be obtained from the Dow Chemical Company), hydroxypropyl cellulose (e.g., Klucel®, which may also be obtained from Dow), hydroxypropyl cellulose ethers (see, e.g., U.S.
  • the additional components include, but are not limited to, disintegrants, diluents, binders, lubricants, flavoring, colorants, preservatives, and the like.
  • disintegrants include, but are not limited to, cross- linked polyvinylpyrrolidones, such as crospovidone (e.g., Polyplasdone® XL, which may be obtained from GAF), cross-linked carboxylic methylcelluloses, such as croscarmelose (e.g., Ac-di-sol®, which may be obtained from FMC), alginic acid, and sodium carboxymethyl starches (e.g., Explotab®, which may be obtained from
  • Suitable diluents are those which are generally useful in pharmaceutical formulations prepared using compression techniques, e.g., dicalcium phosphate dihydrate (e.g., Di-Tab®, which may be obtained from Stauffer), sugars that have been processed by cocrystallization with dextrin (e.g., co-crystallized sucrose and dextrin such as Di- Pak®, which may be obtained from Amstar), calcium phosphate, cellulose, kaolin, mannitol, sodium chloride, dry starch, powdered sugar and the like. Binders, if used, are those that enhance adhesion.
  • dicalcium phosphate dihydrate e.g., Di-Tab®, which may be obtained from Stauffer
  • dextrin e.g., co-crystallized sucrose and dextrin such as Di- Pak®, which may be obtained from Amstar
  • Binders if used, are those that enhance adhesion.
  • binders include, but are not limited to, starch, gelatin and sugars such as sucrose, dextrose, molasses, and lactose.
  • Particularly preferred lubricants are stearates and stearic acid, and an optimal lubricant is magnesium stearate.
  • Sublingual and lingual dosage forms include tablets, creams, ointments, lozenges, pastes, and any other solid dosage form where the active ingredient is 004/084881
  • the tablet, cream, ointment or paste for sublingual or lingual delivery comprises a therapeutically effective amount of the selected active agent and one or more conventional nontoxic carriers suitable for sublingual or lingual drug administration.
  • the sublingual and lingual dosage forms of the present invention can be manufactured using conventional processes.
  • the sublingual and lingual dosage units are fabricated to disintegrate rapidly.
  • the time period for complete disintegration of the dosage unit is typically in the range of from about 10 seconds to about 30 minutes, and optimally is less than 5 minutes.
  • the additional components include, but are not limited to binders, disintegrants, wetting agents, lubricants, and the like.
  • binders that may be used include water, ethanol, polyvinylpyrrolidone; starch solution gelatin solution, and the like.
  • Suitable disintegrants include dry starch, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic monoglyceride, lactose, and the like.
  • Wetting agents, if used, include glycerin, starches, and the like. Particularly preferred lubricants are stearates and polyethylene giycol.
  • the formulation comprises a urethral dosage form containing the active agent and one or more selected carriers or excipients, such as water, silicone, waxes, petroleum jelly, polyethylene giycol ("PEG”), propylene giycol (“PG”), liposomes, sugars such as mannitol and lactose, and/or a variety of other materials, with polyethylene giycol and derivatives thereof particularly preferred.
  • carriers or excipients such as water, silicone, waxes, petroleum jelly, polyethylene giycol (“PEG”), propylene giycol (“PG”), liposomes, sugars such as mannitol and lactose, and/or a variety of other materials, with polyethylene giycol and derivatives thereof particularly preferred.
  • transurethral permeation enhancer in the urethral dosage foi .
  • suitable transurethral permeation enhancers include dimethylsulfoxide (“DMSO”), dimethyl formamide (“DMF”), N, N-dimethylacetamide (“DMA”), decyhnethylsulfoxide (“C 10 MSO”), polyethylene giycol monolaurate (“PEGML”), glycerol monolaurate, lecithin, the 1 -substituted azacycloheptan-2-ones, particularly l-n-dodecylcyclazacycloheptan-2-one (available under the trademark Azone® from Nelson Research & Development Co., Irvine, Calif.), SEP A® (available from 2004/084881
  • Transurethral drug administration can be carried out in a number of different ways using a variety of urethral dosage forms.
  • the drug can be introduced into the urethra from a flexible tube, squeeze bottle, pump or aerosol spray.
  • the drug may also be contained in coatings, pellets or suppositories that are absorbed, melted or bioeroded in the urethra, hi certain embodiments, the drug is included in a coating on the exterior surface of a penile insert.
  • the drug be delivered from at least about 3 cm into the urethra, and preferably from at least about 7 cm into the urethra. Generally, delivery from at least about 3 cm to about 8 cm into the urethra will provide effective results in conjunction with the present method.
  • Urethral suppository formulations containing PEG or a PEG derivative may be conveniently formulated using conventional techniques, e.g., compression molding, heat molding or the like, as will be appreciated by those skilled in the art and as described in the pertinent literature and pharmaceutical texts. (See, e.g., Remington: The Science and Practice of Pharmacy, supra), which discloses typical methods of preparing pharmaceutical compositions in the form of urethral suppositories.
  • the PEG or PEG derivative preferably has a molecular weight in the range of from about 200 to about 2,500 g/mol, more preferably in the range of from about 1,000 to about 2,000 g/mol.
  • Suitable polyethylene giycol derivatives include polyethylene giycol fatty acid esters, for example, polyethylene giycol monostearate, polyethylene giycol sorbitan esters, e.g., polysorbates, and the like.
  • urethral suppositories contain one or more solubilizing agents effective to increase the solubility of the active agent in the PEG or other transurethral vehicle.
  • the dosage form comprises a biocompatible, biodegradable material, typically a biodegradable polymer.
  • a biodegradable polymer examples include polyesters, polyalkylcyanoacrylates, polyorthoesters, polyanhydrides, albumin, gelatin and starch.
  • these and other polymers can be used to provide biodegradable microparticles that enable controlled and sustained drug release, in turn minimizing the required dosing frequency.
  • the urethral dosage form will preferably comprise a suppository that is on the order of from about 2 to about 20 mm in length, preferably from about 5 to about 10 mm in length, and less than about 5 mm in width, preferably less than about 2 mm in width.
  • the weight of the suppository will typically be in the range of from about 1 mg to about 100 mg, preferably in the range of from about 1 mg to about 50 mg.
  • the size of the suppository can and will vary, depending on the potency of the drug, the nature of the formulation, and other factors.
  • Transurethral drug delivery may involve an "active" delivery mechanism such as iontophoresis, electroporation or phonophoresis.
  • active delivery mechanism such as iontophoresis, electroporation or phonophoresis.
  • Devices and methods for delivering drugs in this way are well known in the art.
  • Iontophoretically assisted drug delivery is, for example, described in PCT Publication No. WO 96/40054, cited above. Briefly, the active agent is driven through the urethral wall by means of an electric current passed from an external electrode to a second electrode contained within or affixed to a urethral probe.
  • transrectal dosage forms include rectal suppositories, creams, ointments, and liquid formulations (enemas).
  • the suppository, cream, ointment or liquid fo ⁇ nulation for transrectal delivery comprises a therapeutically effective amount of the selected phosphodiesterase inhibitor and one or more conventional nontoxic carriers suitable for transrectal drug administration.
  • the transrectal dosage forms of the present invention can be manufactured using conventional processes.
  • the transrectal dosage unit can be fabricated to disintegrate rapidly or over a period of several hours. The time period for complete disintegration is preferably in the range of from about 10 minutes to about 6 hours, and optimally is less than about 3 hours.
  • the additional components include, but are not limited to, stiffening agents, antioxidants, preservatives, and the like.
  • stiffening agents include, for example, paraffin, white wax and yellow wax.
  • Prefe ⁇ ed antioxidants, if used, include sodium bisulfite and sodium metabisulfite. 2004/084881
  • vaginal or perivaginal dosage forms include vaginal suppositories, creams, ointments, liquid formulations, pessaries, tampons, gels, pastes, foams or sprays.
  • the suppository, cream, ointment, liquid formulation, pessary, tampon, gel, paste, foam or spray for vaginal or perivaginal delivery comprises a therapeutically effective amount of the selected active agent and one or more conventional nontoxic carriers suitable for vaginal or perivaginal drug administration.
  • the vaginal or perivaginal forms of the present invention can be manufactured using conventional processes as disclosed in Remington: The Science and Practice of Pharmacy, supra (see also drug formulations as adapted in U.S. Patent Nos.
  • the vaginal or perivaginal dosage unit can be fabricated to disintegrate rapidly or over a period of several hours.
  • the time period for complete disintegration is preferably in the range of from about 10 minutes to about 6 hours, and optimally is less than about 3 hours.
  • Other components may also be incorporated into the vaginal or perivaginal dosage forms described herein.
  • the additional components include, but are not limited to, stiffening agents, antioxidants, preservatives, and the like. Examples of stiffening agents that may be used include, for example, paraffin, white wax and yellow wax. Preferred antioxidants, if used, include sodium bisulfite and sodium metabisulfite.
  • compositions for intranasal administration are generally liquid formulations for administration as a spray or in the form of drops, although powder formulations for intranasal administration, e.g., insufflations, are also known, as are nasal gels, creams, pastes or ointments.
  • the active agent can be formulated into a solution, e.g., water or isotonic saline, buffered or unbuffered, or as a suspension.
  • such solutions or suspensions are isotonic relative to nasal secretions and of about the same pH, ranging e.g., from about pH 4.0 to about pH 7.4 or, from about pH 6.0 to about pH 7.0.
  • Buffers should be physiologically compatible and include, simply by way of example, phosphate buffers.
  • various devices are available in the art for the generation of drops, droplets and sprays, including droppers, squeeze bottles, and manually and electrically powered intranasal pump dispensers.
  • Active agent containing intranasal carriers may also include nasal gels, creams, pastes or ointments with a viscosity of, e.g., from about 10 to about 6500 cps, or greater, depending on the desired sustained contact with the nasal mucosal surfaces.
  • Such carrier viscous formulations may be based upon, simply by way of example, alkylcelluloses and/or other biocompatible carriers of high viscosity well known to the art (see e.g., Remington: The Science and Practice of Pharmacy, supra).
  • Formulations for inhalation may be prepared as an aerosol, either a solution aerosol in which the active agent is solubilized in a carrier (e.g., propellant) or a dispersion aerosol in which the active agent is suspended or dispersed throughout a carrier and an optional solvent.
  • a carrier e.g., propellant
  • a dispersion aerosol in which the active agent is suspended or dispersed throughout a carrier and an optional solvent.
  • Non-aerosol formulations for inhalation may take the form of a liquid, typically an aqueous suspension, although aqueous solutions may be used as well.
  • the carrier is typically a sodium chloride solution having a concentration such that the formulation is isotonic relative to normal body fluid
  • the liquid formulations may contain water and/or excipients including an antimicrobial preservative (e.g., benzalkonium chloride, benzethonium chloride, chlorobutanol, phenylethyl alcohol, thimerosal and combinations thereof), a buffering agent (e.g., citric acid, potassium metaphosphate, potassium phosphate, sodium acetate, sodium citrate, and combinations thereof), a surfactant (e.g., polysorbate 80, sodium lauryl sulfate, sorbitan monopalmitate and combinations thereof), and/or a suspending agent (e.g., agar, bentonite, microcrystalline cellulose
  • Topical formulations may be in any form suitable for application to the body surface, and may comprise, for example, an ointment, cream, gel, lotion, solution, 004/084881
  • Preferred topical fo ⁇ nulations herein are ointments, creams and gels.
  • Ointments are semisolid preparations that are typically based on petrolatum or other petroleum derivatives.
  • the specific ointment base to be used is one that will provide for optimum drug delivery, and, preferably, will provide for other desired characteristics as well, e.g., emolliency or the like.
  • an ointment base should be inert, stable, nonirritating and nonsensitizing.
  • ointment bases may be grouped in four classes: oleaginous bases; emulsifiable bases; emulsion bases; and water-soluble bases.
  • Oleaginous ointment bases include, for example, vegetable oils, fats obtained from animals, and semisolid hydrocarbons obtained from petroleum.
  • Emulsifiable ointment bases also known as absorbent ointment bases, contain little or no water and include, for example, hydroxystearin sulfate, anhydrous lanolin and hydrophilic petrolatum.
  • Emulsion ointment bases are either water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions, and include, for example, cetyl alcohol, glyceryl monostearate, lanolin and stearic acid.
  • Preferred water-soluble ointment bases are prepared from polyethylene glycols of varying molecular weight (See, e.g., Remington: The Science and Practice of Pharmacy, supra).
  • Creams are viscous liquids or semisolid emulsions, either oil-in-water or water-in-oil.
  • Cream bases are water-washable, and contain an oil phase, an emulsifier and an aqueous phase.
  • the oil phase also called the "internal” phase, is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol.
  • the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant.
  • the emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant.
  • gels-are semisolid, suspension-type systems contain organic macromolecules distributed substantially uniformly throughout the carrier liquid, which is typically aqueous, but also, preferably, contain an alcohol and, optionally, an oil.
  • organic macromolecules i.e., gelling agents, are crosslinked acrylic acid polymers such as the "carbomer” family of polymers, e.g., 2004/084881
  • carboxypolyalkylenes that may be obtained commercially under the Carbopol® trademark.
  • hydrophilic polymers such as polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers and polyvinylalcohol
  • cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methylcellulose
  • gums such as tragacanth and xanthan gum; sodium alginate; and gelatin, hi order to prepare a uniform gel, dispersing agents such as alcohol or glycerin can be added, or the gelling agent can be dispersed by trituration, mechanical mixing, and/or stirring.
  • solubilizers may be used to solubilize certain active agents.
  • a permeation enhancer in the formulation; suitable enhancers are as described elsewhere herein.
  • the compounds of the invention may also be administered through the skin or mucosal tissue using conventional transdermal drug delivery systems, wherein the agent is contained within a laminated structure (typically referred to as a transdermal
  • the drug composition is contained in a layer, or "reservoir,” underlying an upper backing layer.
  • the laminated structure may contain a single reservoir, or it may contain multiple reservoirs.
  • the reservoir is comprised of a polymeric matrix of a pharmaceutically acceptable contact adhesive material that serves to affix the system to the skin during drug delivery.
  • suitable skin contact adhesive materials include, but are not limited to, polyethylenes, polysiloxanes, polyisobutylenes, polyacrylates, polyurethanes, and the like.
  • the drug-containing reservoir and skin contact adhesive are separate and distinct layers, with the adhesive underlying the reservoir which, in this case, may be either a polymeric matrix as described above, or it may be a liquid or hydrogel reservoir, or may take some other form.
  • the material selected for the backing material should be selected so that it is substantially impermeable to the active agent and any other materials that are present, the backing is preferably made of a sheet or film of a flexible elastomeric material.
  • polymers that are suitable for the backing layer include polyethylene, polypropylene, polyesters, and the like.
  • the laminated structure includes a release liner, hnmediately prior to use, this layer is removed from the device to expose the basal surface thereof, either the drug reservoir or a separate contact adhesive layer, so that the system may be affixed to the skin.
  • the release liner should be made from a drug/vehicle impermeable material.
  • Transdermal drug delivery systems may in addition contain a skin permeation enhancer. That is, because the inherent permeability of the skin to some drugs may be too low to allow therapeutic levels of the drug to pass through a reasonably sized area of unbroken skin, it is necessary to coadminister a skin permeation enhancer with such drugs.
  • Suitable enhancers are well known in the art and include, for example, those enhancers listed above in transmucosal compositions.
  • Parenteral administration is generally characterized by injection, including intramuscular, intraperitoneal, intravenous (IV) and subcutaneous injection.
  • injectable formulations can be prepared in conventional forms, either as liquid solutions or suspensions; solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions.
  • sterile injectable suspensions are formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable formulation may also be a sterile injectable solution or a suspension in a nontoxic parenterally acceptable diluent or solvent.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • Intravesical administration if used, is generally characterized by administration directly into the bladder and may include methods as described elsewhere herein. Other methods of intravesical administration may include those described in U.S. Patent Nos. 6,207,180 and 6,039,967, as well as other methods that are known to one of skill in the art.
  • Intrathecal administration if used, is generally characterized by administration directly into the intrathecal space (where fluid flows around the spinal cord).
  • APT Intrathecal treatment system available from Medtronic, Inc.
  • APT Intrathecal uses a small pump that is surgically placed under the skin of the abdomen to deliver medication directly into the intrathecal space.
  • the medication is delivered through a small tube called a catheter that is also surgically placed.
  • the medication can then be administered directly to cells in the spinal cord involved in conveying sensory and motor signals.
  • the SynchroMed ® Infusion System has two parts that are both placed in the body during a surgical procedure: the catheter and the pump.
  • the catheter is a small, soft tube. One end is connected to the catheter port of the pump, and the other end is placed in the intrathecal space.
  • the pump is a round metal device about one inch (2.5 cm) thick, three inches (8.5 cm) in diameter, and weighs about six ounces (205 g) that stores and releases prescribed amounts of medication directly into the intrathecal space. It is made of titanium, a lightweight, medical-grade metal.
  • the reservoir is the space inside the pump that holds the medication.
  • the fill port is a raised center portion of the pump through which the pump is refilled.
  • the doctor or a nurse inserts a needle through the patient's skin and through the fill port to fill the pump.
  • Some pumps have a side catheter access port that allows the doctor to inject other medications or sterile solutions directly into the catheter, bypassing the pump.
  • the SynchroMed ® pump automatically delivers a controlled amount of medication through the catheter to the intrathecal space around the spinal cord, where it is most effective.
  • the exact dosage, rate and timing prescribed by the doctor are entered in the pump using a programmer, an external computer-like device that controls the pump's memory. Information about the patient's prescription is stored in the pump's memory. The doctor can easily review this information by using the programmer.
  • the programmer communicates with the pump by radio signals that allow the doctor to tell how the pump is operating at any given time.
  • the doctor also can use the programmer to change your medication dosage.
  • Methods of intrathecal administration may include those described above available from Medtronic, as well as other methods that are known to one of skill in the art.
  • XenoPort Inc. utilizes technology that takes existing molecules and re-engineers them to create new chemical entities (unique molecules) that have improved pharmacologic properties to either: 1) lengthen the short half-life of a drug; 2) overcome poor absorption; and/or 3) deal with poor drug distribution to target tissues.
  • Techniques to lengthen the short half-life of a drug include the use of prodrugs with slow cleavage rates to release drugs over time or that engage transporters in small and large intestines to allow the use of oral sustained delivery systems, as well as drugs that engage active transport systems.
  • Xenoport's XP13512 is a transported Prodrug of gabapentin that has been engineered to utilize high capacity transport mechanisms located in both the small and large intestine and to rapidly convert to gabapentin once in the body.
  • XP13512 was shown in preclinical and clinical studies to produce dose proportional blood levels of gabapentin across a broad range of oral doses, and to be absorbed efficiently from the large intestine.
  • Some other controlled release technologies rely upon methods that promote or enhance gastric retention, such as those developed by Depomed Inc.
  • Depomed has developed tablets that swell in the stomach during the postprandial or fed mode so that they are treated like undigested food. These tablets therefore sit safely and neutrally in the stomach for 6, 8, or more hours and deliver drug at a desired rate and time to upper gastrointestinal sites.
  • Examples of such controlled release fo ⁇ nulations that are suitable for use with the present invention and that rely upon gastric retention during the postprandial or fed mode, include tablets, dosage forms, and drug delivery systems in the following US patents assigned to Depomed Inc.: US 6,488,962; US 6,451,808; US 6,340,475; US 5,972,389; US 5,582,837; and US 5,007,790.
  • Examples of such controlled release formulations that are suitable for use with the present invention and that rely upon gastric retention during the postprandial or fed mode, include tablets, dosage forms, and drug delivery systems in the following published US and PCT patent applications assigned to Depomed Inc.: US20030147952; US20030104062; US20030104053; US20030104052; US20030091630; US20030044466; US20030039688; US20020051820; WO0335040; WO0335039; WO0156544; WO0132217; WO9855107; WO9747285; and WO9318755.
  • controlled release systems include those developed by ALZA Corporation based upon: 1) osmotic technology for oral delivery; 2) transdermal delivery via patches; 3) liposomal delivery via intravenous injection; 4) osmotic 2004/084881
  • ALZA oral delivery systems include those that employ osmosis to provide precise, controlled drug delivery for up to 24 hours for both poorly soluble and highly soluble drugs, as well as those that deliver high drug doses meeting high drug loading requirements.
  • ALZA controlled transdermal delivery systems provide drug delivery through intact skin for as long as one week with a single application to improve drug absorption and deliver constant amounts of drug into the bloodstream over time.
  • ALZA liposomal delivery systems involve lipid nanoparticles that evade recognition by the immune system because of their unique polyethylene giycol (PEG) coating, allowing the precise delivery of drugs to disease-specific areas of the body.
  • PEG polyethylene giycol
  • ALZA also has developed osmotically driven systems to enable the continuous delivery of small drugs, peptides, proteins, DNA and other bioactive macromolecules for up to one year for systemic or tissue-specific therapy.
  • ALZA depot injection therapy is designed to deliver biopharmaceutical agents and small molecules for periods of days to a month using a nonaqueous polymer solution for the stabilization of macromolecules and a unique delivery profile.
  • controlled release formulations, tablets, dosage forms, and drug delivery systems that are suitable for use with the present invention are described in the following published US patent application and PCT applications assigned to ALZA Corporation: US20010051183; WO0004886; WO0013663; WO0013674;
  • WO9958115 and WO9962496.
  • Another drug delivery technology suitable for use in the present invention is that disclosed by DepoMed, Inc. in U.S. Patent No. 6,682,759, which discloses a method for manufacturing a pharmaceutical tablet for oral administration combining both immediate-release and prolonged-release modes of drug delivery.
  • the tablet according to the method comprises a prolonged-release drug core and an immediate- release drug coating or layer, which can be insoluble or sparingly soluble in water.
  • the method limits the drug particle diameter in the immediate-release coating or layer to 10 microns or less.
  • the coating or layer is either the particles themselves, applied as an aqueous suspension, or a solid composition that contains the drug particles incorporated in a solid material that disintegrates rapidly in gastric fluid.
  • Andrx Corporation has also developed drug delivery technology suitable for use in the present invention that includes: 1) a pelletized pulsatile delivery system (“PPDS”); 2) a single composition osmotic tablet system (“SCOT”); 3) a solubility modulating hydrogel system (“SMHS”); 4) a delayed pulsatile hydrogel system (“DPHS”); 5) a stabilized pellet delivery system (“SPDS”); 6) a granulated modulating hydrogel system (“GMHS”); 7) a pelletized tablet system (“PELTAB”); 8) a porous tablet system (“PORTAB”); and 9) a stabilized tablet delivery system (“STDS”).
  • PPDS pelletized pulsatile delivery system
  • STT single composition osmotic tablet system
  • SMHS solubility modulating hydrogel system
  • DPHS delayed pulsatile hydrogel system
  • SPDS stabilized pellet delivery system
  • GMHS granulated modulating hydrogel system
  • PELTAB pelletized tablet system
  • PORTAB porous tablet system
  • PPDS uses pellets that are coated with specific polymers and agents to control the release rate of the microencapsulated drug and is designed for use with drugs that require a pulsed release.
  • SCOT utilizes various osmotic modulating agents as well as polymer coatings to provide a zero-order drug release.
  • SMHS utilizes a hydrogel-based dosage system that avoids the "initial burst effect" commonly observed with other sustained-release hydrogel formulations and that provides for sustained release without the need to use special coatings or structures that add to the cost of manufacturing.
  • DPHS is designed for use with hydrogel matrix products characterized by an initial zero-order drug release followed by a rapid release that is achieved by the blending of selected hydrogel polymers to achieve a delayed pulse.
  • SPDS incorporates a pellet core of drug and protective polymer outer layer, and is designed specifically for unstable drugs, while GMHS incorporates hydrogel and binding polymers with the drug and forms granules that are pressed into tablet form.
  • PELTAB provides controlled release by using a water insoluble polymer to coat discrete drug crystals or pellets to enable them to resist the action of fluids in the gastrointestinal tract, and these coated pellets are then compressed into tablets.
  • PORTAB provides controlled release by incorporating an osmotic core with a continuous polymer coating and a water soluble component that expands the core and creates microporous channels through which drug is released.
  • STDS includes a dual layer coating technique that avoids the need to use a coating layer to separate the enteric coating layer from the omeprazole core.
  • controlled release formulations, tablets, dosage forms, and drug delivery systems that are suitable for use with the present invention are described in the following published US and PCT patent applications assigned to Andrx Corporation: US20010024659; US20020115718; US20020156066; WO0004883; WO0009091; WO0012097; WO0027370; WO0050010; WO0132161; WO0134123; WO0236077; WO0236100; WO02062299; WO02062824; WO02065991; WO02069888; WO02074285; WO03000177; WO9521607; WO9629992; WO9633700; WO9640080; WO9748386; WO9833488; WO9833489; WO9930692; WO9947125; and WO9961005.
  • Some other examples of drug delivery approaches focus on non-oral drug delivery, providing parenteral, transmucosal, and topical delivery of proteins, peptides, and small molecules.
  • the Atrigel ® drug delivery system marketed by Atrix Laboratories Inc. comprises biodegradable polymers, similar to those used in biodegradable sutures, dissolved in biocompatible carriers. These pharmaceuticals may be blended into a liquid delivery system at the time of manufacturing or, depending upon the product, may be added later by a physician at the time of use.
  • Such drug delivery systems include Atrix's Eligard ® , Atridox ® / Doxirobe ® , Atrisorb ® FreeFlowTM/ Atrisorb ® -D FreeFlow, bone growth products, and others as described in the following published US and PCT patent applications assigned to Atrix Laboratories Inc.: US RE37950; US 6,630,155; US 6,566,144; US 6,610,252; US 6,565,874; US 6,528,080; US 6,461,631; US 6,395,293; US 6,261,583; US 6,143,314; US 6,120,789; US 6,071,530; US 5,990,194; US 5,945,115; US 5,888,533; US 5,792,469; US 5,780,044; US 5,759,563; US 5,744,153; US 5,739,176; US 5,736,152; US 5,733,950; US 5,702,716; US 5,681,873; US 5,660,849; US 5,599,552
  • Atrix Laboratories hie. also markets technology for the non-oral transmucosal delivery of drugs over a time period from minutes to hours.
  • Atrix's BEMA (Bioerodible Muco-Adhesive Disc) drug delivery system comprises pre- formed bioerodible discs for local or systemic delivery. Examples of such drug delivery systems include those as described in US Patent No. 6,245,345.
  • SMP Solvent Particle System
  • MCA Micrococutaneous Absorption System
  • MCA® forms a tenacious film for either wet or dry surfaces where: 1) the product is applied to the skin or mucosal surface; 2) the product forms a tenacious moisture- resistant film; and 3) the adhered film provides sustained release of drug for a period from hours to days.
  • BCPTM Biocompatible Polymer System
  • BCPTM Biocompatible Polymer System
  • MCA® forms a tenacious film for either wet or dry surfaces where: 1) the product is applied to the skin or mucosal surface; 2) the product forms a tenacious moisture- resistant film; and 3) the adhered film provides sustained release of drug for a period from hours to days.
  • BCPTM Biocompatible Polymer System
  • MCA® forms a tenacious film for either wet or dry surfaces where: 1) the product is applied to the skin or mucosal surface; 2) the product forms a tenacious moisture- resistant film; and 3) the adhered film provides sustained release of drug for a period from hours to days.
  • BCPTM Biocompatible Polymer System
  • Additional fo ⁇ nulations and compositions that include oxybutynin and are useful in the present invention include those as described in the following US patents and published US and PCT patent applications: US 5,834,010; US 5,601,839; and US 5,164,190.
  • the concentration of the active agent in any of the aforementioned dosage fo ⁇ ns and compositions can vary a great deal, and will depend on a variety of factors, including the type of composition or dosage form, the corresponding mode of administration, the nature and activity of the specific active agent, and the intended drug release profile.
  • Preferred dosage forms contain a unit dose of active agent, i.e., a single therapeutically effective dose.
  • a "unit dose" requires an active agent concentration that provides a unit dose in a specified quantity of the formulation to be applied.
  • the unit dose of any particular active agent will depend, of course, on the active agent and on the mode of administration.
  • the unit dose for oral, transmucosal, topical, transdermal, and parenteral administration will be in the range of from about 1 ng to about 10,000 mg, about 5 ng to about 9,500 mg, about 10 ng to about 9,000 mg, about 20 ng to about 8,500 mg, about 30 ng to about 7,500 mg, about 40 ng to about 7,000 mg, about 50 ng to about 6,500 mg, about 100 ng to about 6,000 mg, about 200 ng to about 5,500 mg, about 300 ng to about 5,000 mg, about 400 ng to about 4,500 mg, about 500 ng to about 4,000 mg, about 1 ⁇ g to about 3,500 mg, about 5 ⁇ g to about 3,000 mg, about 10 ⁇ g to about 2,600 mg, about 20 ⁇ g to about 2,575 mg, about 30 ⁇ g to about 2,550 mg, about 40 ⁇ g to about 2,500 mg, about 50
  • the unit dose for oral, transmucosal, topical, transdermal, and parenteral administration will be equal to or greater than about 1 ng, about 5 ng, about 10 ng, about 20 ng, about 30 ng, about 40 ng, about 50 ng, about 100 ng, about 200 ng, about 300 ng, about 400 ng, about 500 ng, about 1 ⁇ g, about 5 ⁇ g, about 10 ⁇ g, about 20 ⁇ g, about 30 ⁇ g, about 40 ⁇ g, about 50 ⁇ g, about 100 ⁇ g, about 200 ⁇ g, about 300 ⁇ g, about 400 ⁇ g, about 500 ⁇ g, about .5 mg, about 1 mg, about 1.25 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, about 5 mg, about 10 mg
  • the unit dose for intrathecal administration will be in the range of from about 1 fg to about 1 mg, about 5 fg to about 500 ⁇ g, about 10 fg to about 400 ⁇ g, about 20 fg to about 300 ⁇ g, about 30 fg to about 200 ⁇ g, about 40 fg to about 100 ⁇ g, about 50 fg to about 50 ⁇ g, about 100 fg to about 40 ⁇ g, about 200 fg to about 30 ⁇ g, about 300 fg to about 20 ⁇ g, about 400 fg to about 10 ⁇ g, about 500 fg to about 5 ⁇ g, about 1 pg to about 1 ⁇ g, about 5 pg to about 500 ng, about 10 pg to about 400 ng, about 20 pg to about 300 ng, about 30 pg to about 200 ng, about 40 pg to about
  • the unit dose for intrathecal administration will be equal to or greater than about 1 fg, about 5 fg, about 10 fg, about 20 fg, about 30 fg, about 40 fg, about 50 fg, about 100 fg, about 200 fg, about 300 fg, about 400 fg, about 500 fg, about 1 pg, about 5 pg, about 10 pg, about 20 pg, about 30 pg, about 40 pg, about 50 pg, about 100 pg, about 200 pg, about 300 pg, about 400 pg, about 500 pg, about 1 ng, about 5 ng, about 10 ng, about 20 ng, about 30 ng, about 40 ng, about 50 ng, about 100 ng, about 200 ng, about 300 ng, about 400 ng, about 500 pg, about 1 ng, about 5 ng, about 10 ng, about 20 ng, about 30 ng, about 40 ng, about 50 ng
  • the present invention also encompasses a pharmaceutical formulation encompassing oxybutyinin, wherein the unit dose for oral, transmucosal, topical, transdermal, and parenteral administration of said oxybutynin will be in an amount equal to or less than about 5 mg, about 4.5 mg, about 4 mg, about 3.5 mg, about 3 mg, about 2.5 mg, about 2 mg, about 1.5 mg, about 1.25 mg, about 1.0 mg, or about .5 mg.
  • ⁇ 2 ⁇ subunit calcium channel modulators when combined with smooth muscle modulators, dosages of ⁇ ⁇ subunit calcium channel modulators and smooth muscle modulators that have been known in the art or predicted not to be effective for treating functional bowel disorders are effective when administered according to the methods of the present invention.
  • a therapeutically effective amount of a particular active agent administered to a given individual will, of course, be dependent on a number of factors, including the concentration of the specific active agent, composition or dosage form, the selected mode of administration, the age and general condition of the individual being treated, the sex of the individual, the severity of the individual's condition, and other factors known to the prescribing physician.
  • a therapeutically effective amount according to the present invention can include an amount effective to show a reduction in the frequency or intensity of at least one symptom associated with the functional bowel disorder.
  • an effective amount of the active agents of the present invention would be an amount effective at reducing abdominal pain or discomfort associated with bowel movements.
  • a further example of an effective amount of the active agents of the present invention for treating a patient with IBS would be an amount effective for reducing the onset or frequency of loose stool.
  • at least one detrimental side effect associated with single administration of an ⁇ 2 ⁇ subunit calcium channel modulator or a smooth muscle modulator is lessened by concurrent administration of an ⁇ 2 ⁇ subunit calcium channel modulator with a smooth muscle modulator.
  • side effects for oxybutynin, an antimuscarinic smooth muscle modulator include dry mouth, sensitivity to bright light, blurred vision, dry eyes, decreased sweating, flushing, upset stomach, constipation, and drowsiness.
  • an c 2 ⁇ subunit calcium channel modulator such as gabapentin
  • significantly less of each agent is needed to achieve therapeutic efficacy (e.g., less than the 5 mg dose of oxybutynin currently marketed in the United States and also less than the 2.5 mg dose of oxybutynin currently marketed in Europe). Because detrimental side effects are lessened, the present invention also has the benefit of improving patient compliance.
  • a packaged kit contains the pharmaceutical formulation to be administered, i.e., a pharmaceutical formulation containing a therapeutically effective amount of an ⁇ ⁇ subunit calcium channel modulator in combination with one or more compounds with smooth muscle modulatory effects for treating functional bowel disorders, a container, preferably sealed, for housing the formulation during storage and prior to use, and instructions for carrying out drug administration in a manner effective for treating functional bowel disorders.
  • the instructions will typically be written instructions on a package insert and/or on a label.
  • the kit may also include a device for administering the formulation.
  • Formulations may be any suitable formulations as described herein.
  • formulations may be an oral dosage form containing a unit dosage of a selected active agent.
  • the kit may contain multiple formulations of different dosages of the same agent.
  • the kit may also contain multiple formulations of different active agents.
  • the kit may contain formulations suitable for sequential, separate and/or simultaneous use in treating functional bowel disorders, and instructions for carrying out drug administration where the formulations are administered sequentially, separately and/or simultaneously in treating functional bowel disorders.
  • the kit may also contain at least one component selected from an 0! 2 ⁇ subunit calcium channel modulator and a smooth muscle modulator; a container housing said component or components during storage and prior to administration; and instructions for carrying out drug administration of an ⁇ 2 ⁇ subunit calcium channel modulator with a smooth muscle modulator in a manner effective to treat functional bowel disorders.
  • a kit may be useful, for example, where the ⁇ i ⁇ subunit calcium channel modulator or the smooth muscle modulator is already being administered to the patient, and the additional component is to be added to the patient's drug regimen.
  • Such a kit may also be useful where different individuals (e.g., physicians or other medical professionals) are administering the separate components of the combination of the present invention,
  • kits may be independently held in one or more containers-- such as bottles, syringes, plates, wells, blister packs, or any other type of pharmaceutical packaging.
  • the processing of an insurance claim for the coverage of a given medical treatment or drug therapy involves notification of the insurance company, or any other entity, that has issued the insurance policy against which the claim is being filed, that the medical treatment or drug therapy will be performed. A determination is then made as to whether the medical treatment or drug therapy that will be perfonned is covered under the terms of the policy. If covered, the claim is then processed, which can include payment, reimbursement, or application against a deductable.
  • the present invention encompasses a method for processing an insurance claim under an insurance policy for an ⁇ 2 ⁇ subunit calcium channel modulator and an antimuscarinic or pharmaceutically acceptable salts, esters, amides, prodrugs, or active metabolites thereof used in the treatment functional bowel disorders, particularly IBS, wherein said ⁇ ⁇ subunit calcium channel modulator and antimuscarinic or pharmaceutically acceptable salts, esters, amides, prodrugs, or active metabolites thereof are administered sequentially or concurrently in different compositions.
  • This method comprises: 1) receiving notification that treatment using said ⁇ 2 ⁇ subunit calcium channel modulator and said antimuscarinic or pharmaceutically acceptable salts, esters, amides, prodrugs or active metabolites thereof will be performed or notification of a prescription; 2) determining whether said treatment using said ⁇ 2 ⁇ subunit calcium channel modulator and said antimuscarinic or pharmaceutically acceptable salts, esters, amides, prodrugs or active metabolites is covered under said insurance policy; and 3) processing said claim for treatment of said functional bowel disorders using said ⁇ 2 ⁇ subunit calcium channel modulator and said antimuscarinic or pharmaceutically acceptable salts, esters, amides, prodrugs, or active metabolites thereof, including payment, reimbursement, or application against a deductable.
  • a particularly preferred ⁇ 2 ⁇ subunit calcium channel modulator is gabapentin, while a particularly preferred antimuscarinic is oxybutynin.
  • This method also encompasses the processing of claims for and c 2 ⁇ subunit calcium channel modulator, particularly gabapentin, or an antimuscarinic, particularly oxybutynin, when either has been prescribed separately or concurrently for the treatment of functional bowel disorders, particularly LBS.
  • a variety of assays can be used to assess visceromotor and pain responses to rectal distension. See, for example, Gunter et al, Physiol. Behav., 69(3): 379-82
  • Gastroenterology (Suppl 1), 120(5): A19-A20 (2001) and Guntermann et al, Eur.
  • Visceral pain can lead to visceral reactions which can manifest themselves as, for example, contractions of the abdominal muscles.
  • the number of contractions of the abdominal muscles occurring after a mechanical pain stimulus produced by distending the large intestine can thus be a measurement for determining visceral sensitivity to pain.
  • the inhibiting action of a test agent on distension-induced contractions can be tested in rats.
  • the distension of the large intestine with an introduced balloon can be used as the stimulus; the contraction of the abdominal muscles can be measured as the response.
  • a latex balloon is introduced and inflated sequentially in a stepwise fashion to about 50-100 mbar for about 5-10 minutes.
  • the contractions of the abdominal muscles are counted. About 20 minutes after subcutaneous administration of the test agent, this measurement is repeated.
  • the action of the test agent is calculated as a percentage reduction in the counted contractions compared with the control (i.e., non-sensitized rats).
  • VISCEROMOTOR RESPONSE TO COLORECTAL DISTENSION The ability of a treatment to reverse acetic acid-induced colonic hypersensitivity in a rodent model of irritable bowel syndrome can be assessed by the following method. Animals
  • Rats are housed under standard conditions. Following one week of acclimatization to the animal facility, the rats are brought to the laboratory and handled daily for another week to get used to the environment and the research associate performing the experiments.
  • Acetic acid-induced colonic hypersensitivity in rats has been described by Langlois et al, Eur. J. Pharmacol, 318: 141-144 (1996) and Plourde et al, Am. J. Physiol. 273: G191-G196 (1997).
  • a low concentration of acetic acid 1.5 ml, 0.6%) was administered intracolonically to sensitize the colon without causing histological damage to the colonic mucosa as described in previous studies (Gunter et al, supra).
  • Drug(s) or vehicle alone are administered to the rats 30 min prior to initiation of the protocol for colorectal distension.
  • Injection volume was 0.2mL using 100% propylene giycol as the vehicle.
  • Three consecutive colorectal distensions at 15, 30 or 60 mmHg applied at 10-min intervals were recorded.
  • Visceromotor responses were evaluated as the number of abdominal muscle contractions recorded during the 10- min periods of colorectal distension.
  • Non-sensitized and sensitized uninjected control animals serve to demonstrate the lower and upper levels of response, respectively.
  • the investigation of gastrointestinal motility can be based on either the in vivo recording of mechanical or electrical events associated intestinal muscle contractions in whole animals or the activity of isolated gastrointestinal intestinal muscle preparations recorded in vitro in organ baths (see, for example, Yaun et al, Br. J. Pharmacol, 112(4):1Q95-11QQ (1994), Jin et al, J. Pharm. Exp. Ther., 288(1): 93-97 (1999) and Venkova et al, J. Pharm. Exp. Ther., 300(3): 1046-1052 (2002)).
  • the in vivo recordings, especially in conscious freely moving animals have the advantage of characterizing motility patterns and propulsive activity that are directly relevant to the motor function of the GI tract.
  • in vitro studies provide data about the mechanisms and site of action of agents directly affecting contractile activity and are a classic tool to distinguish between effects on the circular and /or longitudinal intestinal smooth muscle layers.
  • Ambulatory telemetric motility recordings provide a suitable way to investigate intestinal motility in conscious animals during long-lasting time periods.
  • Telemetric recording of colonic motility has been introduced to study propagating contractile activity in the unprepared colon of conscious freely moving animals.
  • Yucatan mini-pigs present an excellent animal model for motility investigations, based on the anatomical and functional similarities between the gastrointestinal tract in the human and the mini-pig.
  • young mini-pigs undergo a surgical procedure to establish a permanent chronic cecal fistula.
  • McRorie et al Dig. Dis. Sci. 43: 957-963 (1998); Kuge et al, Dig. Dis. Sci. 47: 2651-6 (2002)).
  • the data obtained in each recording session can be used to define the mean amplitude and the total number of propagating contiactions, the number of high and low velocity propagating contractions, the number of long and short duration propagating contractions and to estimate the relative shares of each type contractions as % of total contractile activity.
  • mice Female rats are administered, TNBS in ethanol or saline (control), intiacolonically.
  • a ventral incision is made on the ventral surface of the neck, a jugular catheter is inserted and secured with ligatures, and the skin wound is closed with suture.
  • An intra-colonic balloon-tipped catheter fashioned from condom reservoir tip and tubing is inserted anally and positioned with the balloon at approximately 4 cm from the anal verge. Connection via 3-way stopcock to a syringe pump and pressure transducer allows for simultaneous balloon volume adjustment and pressure recording.
  • Fine wire electrodes are inserted into the external anal sphincter (EAS) and the abdominal wall musculature to pe ⁇ nit electromyographic (EMG) recording. With this preparation, intra-colonic pressure, colonic motility, colonic sensory thresholds via abdominal EMG firing, and EAS firing frequency and amplitude is quantified in both control and irritated animals.
  • Isolated smooth muscle preparations can be used also to study length-tension relationships, which provide characteristics of the active and passive properties of the smooth muscle.
  • the model used in this example provides a method of determining the ability of a drug(s) to normalize accelerated colonic transit induced by water avoidance stress (WAS).
  • WAS water avoidance stress
  • This model provides a method of evaluating the effectiveness of a compound in a specific patient group of IBS sufferers where stress induced colonic motility is considered a significant contributing factor.
  • Preliminary testing in the water avoidance stress model confirmed that there exists an association between stress and altered colonic motility.
  • Fecal pellet output is measured by counting the total number of fecal pellets produced during 1 hour of WAS. Animals
  • Rats Male male F-344 rats, supplied by Charles River Laboratories and weighing 270-350 g, were used to complete this study. The rats were housed 2 per cage under standard conditions. Following one to two weeks of acclimatization to the animal facility, the rats were brought to the laboratory and handled daily for another week to acclimatize them to laboratory conditions and to the research associate who performed the studies. All procedures used in this study were approved in accordance with facility standards.
  • Procedure WAS causes an acceleration of colonic transit, which can be quantified by counting the number of fecal pellets, produced during the stress procedure.
  • Rats were placed for 1-hour into a sitesss chamber onto a raised platform 7.5 cm x 7.5 cm x 9 cm (L x W x H) in the center of a stress chamber filled with room temperature 10 water 8 cm in depth.
  • the stress chamber was constructed from a rectangular plastic tub (40.2 x 60.2 x 31.2 cm).
  • the objective of this study was to determine the ability of an ⁇ 2 ⁇ subunit calcium channel modulator in combination with a smooth muscle modulator to reverse the reduction in bladder capacity seen following continuous infusion of dilute acetic acid, an irritative model.
  • the cu ⁇ ent study utilized gabapentin as an exemplary ⁇ 2 ⁇ subunit calcium channel modulator, and oxybutynin as an exemplary a smooth muscle modulator.
  • Drugs were dissolved in normal saline at 1, 3 and 10 mg/ml for oxybutynin and 30, 100 and 300 mg/ml for gabapentin. In these studies, individual doses and combinations may be subsequently refe ⁇ ed to as Low, Mid and High.
  • mice Female rats (250-300 g body weight) were anesthetized with urethane (1.2 g/kg) and a saline- filled catheter (PE-50) was inserted into the jugular vein for intravenous drug administration. Via a midline lower abdominal incision, a flared-tipped PE 50 catheter was inserted into the bladder dome for bladder filling and pressure recording. The abdominal cavity was moistened with saline and closed by covering with a thin plastic sheet in order to maintain access to the bladder for emptying purposes. Fine silver or stainless steel wire electrodes were inserted into the external urethral sphincter (EUS) percutaneously for electromyography (EMG).
  • EUS external urethral sphincter
  • Bladder capacity data for each animal were normalized to "% Recovery from Irritation," and this index was used as the measure of efficacy.
  • Data from experiments in which each of the drugs were administered alone were utilized to create theoretical populations of additive effects for each dose (low, mid and high), and these were compared by one-tailed t-test (individual dose comparisons) and by 2- Way ANOVA (across doses) to the actual combination drug data.
  • the means and standard deviations of each individual treatment's "dose-matched" (low, middle, and high) responses were added together to estimate the mean and standard deviation of the theoretical additive populations for which to compare to the actual data obtained from the combination experiments.
  • N (Nantimuscarinic + N ⁇ 2 ⁇ subunit modulator) - 1 • P ⁇ 0.050 was considered significant. Only rats that showed between a 50-90% reduction in bladder capacity at the third vehicle measurement when compared to pre-irritation saline control values were utilized for numerical analyses.
  • Isobologram construction consisted of two methods, both utilizing the same data, but plotting the results either as group means or by individual responses.
  • group mean data the common maximal effect reached by both drugs alone and the combinations listed in the above table was a return to 43% of saline control bladder capacity values.
  • target value was 31% of saline control.
  • the purpose of this study was to determine concentrations of gabapentin, oxybutynin and desethyl oxybutynin in rat plasma samples over a 2 hour period following either 3 mg/kg oxybutynin, 100 mg/kg gabapentin, or the combination of those 2 drugs at those doses using a liquid chromatography with tandem mass spectrometric detection (LC/MS/MS) method.
  • LC/MS/MS liquid chromatography with tandem mass spectrometric detection
  • mice Female rats (250-300 g body weight) were anesthetized with urethane (1.2 g/kg) and a saline-filled catheter (PE-50) was inserted into the jugular vein for intravenous drug administration.
  • PE-50 saline-filled catheter
  • Plasma samples 200 ⁇ l; K3 EDTA were taken on ice at 4 time points (15, 30 60 and 120 minutes) following intravenous drug administration. Samples were spun at 1600 RPM for 7 minutes, plasma was drawn off and stored at -80 C until chromatographic analysis. Pharmacokinetic Chromatographic Analysis
  • Oxybutynin-D ⁇ chloride and baclofen were used as internal standards.
  • Calculations were performed using Excel Version 8.0e. Some reported values may differ in the last reported digit from values calculated directly from the report tables due to the rounding that has been applied.
  • Pharmacokinetic Analysis The maximum concentration (C max ) in rat plasma and the time to reach maximum concentiation (T max ) were obtained by visual inspection of the raw data. Pharmacokinetic parameters calculated included half-life (ti /2 ), time to maximum plasma concentration (T max ), area under the concentration- time curve from time 0 to the last time point (AUCo-t), area under the concentration- time curve from 0 to infinity (AUC 0- ⁇ ), volume of distribution (V z ), and clearance (CL). Pharmacokinetic parameters were calculated by using WinNonlin Professional Edition (Pharsight Corporation, Version 3.3).
  • Treatment Animal (mg/kg) (ng/mL) (minutes) (min*ng/mL) (min*ng/mL) (minutes) (mLkg) (mLmin/kg)
  • Treatment Animal (mg/kg) (ng/mL) (minutes) (min*ng/mL) (min*ng/mL) (minutes) (mL kg) (mL/min/kg)
  • AUC 0 - Area under the plasma concentration-time curve up to infinity.

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Abstract

L'invention concerne une méthode d'utilisation de modulateurs de la sous-unité α2δ des canaux calciques ou d'autres composés qui interagissent avec la sous-unité α2δ des canaux calciques en association avec un ou plusieurs composés présentant des effets modulateurs des muscles lisses pour traiter des troubles intestinaux fonctionnels chez des patients nécessitant ce traitement. Selon la présente invention, les modulateurs de la sous-unité α2δ des canaux calciques comprennent des analogues de GABA comprenant la gabapentine et la prégabaline, des analogues acides aminés fusionnés bicycliques ou tricycliques de gabapentine et des composés d'acides aminés. Les composés ayant des effets modulateurs des muscles lisses comprennent des antimuscariniques, des agonistes β3 adrénergiques, des spasmolytiques, des antagonistes du récepteur de neurokinine, des antagonistes du récepteur de bradykinine et des donneurs de monoxyde d'azote.
PCT/US2004/008701 2003-03-21 2004-03-22 METHODES DE TRAITEMENT DE TROUBLES INTESTINAUX FONCTIONNELS UTILISANT DES MODULATEURS DE LA SOUS-UNITE $G(A)2$G(D) DES CANAUX CALCIQUES AVEC DES MODULATEURS DES MUSCLES LISSES Ceased WO2004084881A1 (fr)

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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996037202A1 (fr) * 1995-05-22 1996-11-28 Alza Corporation Forme galenique contenant de l'oxybutynine
WO1999008670A1 (fr) * 1997-08-20 1999-02-25 Guglietta, Antonio Analogues de gaba utilises pour prevenir et traiter des lesions gastro-intestinales
WO2001001983A1 (fr) * 1999-07-02 2001-01-11 Warner-Lambert Company Combinaison synergique de gabapentine et de pregabaline
WO2001024792A1 (fr) * 1999-10-07 2001-04-12 Warner-Lambert Company Complexes medicamenteux d'antagoniste de recepteur nk1 et d'analogue structurel gaba
WO2001037832A2 (fr) * 1999-11-24 2001-05-31 Aventis Pharma S.A. Association de riluzole et de gabapentine et son utilisation comme medicament
WO2003000642A2 (fr) * 2001-06-21 2003-01-03 Nicox S.A. Medicaments contre les douleurs chroniques
WO2003070237A1 (fr) * 2002-02-22 2003-08-28 Warner-Lambert Company Llc Combinaisons d'un ligand alpha-2-delta avec un inhibiteur selectif de cyclooxygenase-2
WO2004054560A1 (fr) * 2002-12-13 2004-07-01 Warner-Lambert Company Llc Ligand alpha-2-delta pour traiter des symptomes des voies urinaires inferieures

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996037202A1 (fr) * 1995-05-22 1996-11-28 Alza Corporation Forme galenique contenant de l'oxybutynine
WO1999008670A1 (fr) * 1997-08-20 1999-02-25 Guglietta, Antonio Analogues de gaba utilises pour prevenir et traiter des lesions gastro-intestinales
WO2001001983A1 (fr) * 1999-07-02 2001-01-11 Warner-Lambert Company Combinaison synergique de gabapentine et de pregabaline
WO2001024792A1 (fr) * 1999-10-07 2001-04-12 Warner-Lambert Company Complexes medicamenteux d'antagoniste de recepteur nk1 et d'analogue structurel gaba
WO2001037832A2 (fr) * 1999-11-24 2001-05-31 Aventis Pharma S.A. Association de riluzole et de gabapentine et son utilisation comme medicament
WO2003000642A2 (fr) * 2001-06-21 2003-01-03 Nicox S.A. Medicaments contre les douleurs chroniques
WO2003070237A1 (fr) * 2002-02-22 2003-08-28 Warner-Lambert Company Llc Combinaisons d'un ligand alpha-2-delta avec un inhibiteur selectif de cyclooxygenase-2
WO2004054560A1 (fr) * 2002-12-13 2004-07-01 Warner-Lambert Company Llc Ligand alpha-2-delta pour traiter des symptomes des voies urinaires inferieures

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
CHOVET MARIA: "Gastrointestinal functional bowel disorders: New therapies", CURRENT OPINION IN CHEMICAL BIOLOGY, vol. 4, no. 4, August 2000 (2000-08-01), pages 428 - 432, XP001155578, ISSN: 1367-5931 *
DE SARRO G ET AL: "Gabapentin potentiates the antiseizure activity of certain anticonvulsants in DBA/2 mice.", EUROPEAN JOURNAL OF PHARMACOLOGY. 22 MAY 1998, vol. 349, no. 2-3, 22 May 1998 (1998-05-22), pages 179 - 185, XP002291581, ISSN: 0014-2999 *
FELIX R: "Voltage-dependent Ca<2+> channel [alpha]2[delta] auxiliary subunit: Structure, function and regulation", RECEPTORS AND CHANNELS 1999 NETHERLANDS, vol. 6, no. 5, 1999, pages 351 - 362, XP009034843, ISSN: 1060-6823 *
FIELD MARK J ET AL: "Gabapentin and the neurokinin1 receptor antagonist Cl-1021 act synergistically in two rat models of neuropathic pain.", JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol. 303, no. 2, November 2002 (2002-11-01), pages 730 - 735, XP002294267, ISSN: 0022-3565 *
KATZUNG BG: "Basic & Clinical Pharmacology, Eighth edition", 2001, LANGE MEDICAL BOOKS/MCGRAW-HILL, UNITED STATES OF AMERICA, XP002291582 *

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