US20010044438A1 - Pharmaceutical combinations - Google Patents

Pharmaceutical combinations Download PDF

Info

Publication number
US20010044438A1
US20010044438A1 US09/778,290 US77829001A US2001044438A1 US 20010044438 A1 US20010044438 A1 US 20010044438A1 US 77829001 A US77829001 A US 77829001A US 2001044438 A1 US2001044438 A1 US 2001044438A1
Authority
US
United States
Prior art keywords
antagonist
alpha
pharmaceutically acceptable
adrenoceptor
composition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US09/778,290
Other languages
English (en)
Inventor
Michael Wyllie
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novartis International Pharmaceutical Ltd
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=22663745&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20010044438(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Individual filed Critical Individual
Priority to US09/778,290 priority Critical patent/US20010044438A1/en
Publication of US20010044438A1 publication Critical patent/US20010044438A1/en
Assigned to NOVARTIS INTERNATIONAL PHARMACEUTICAL LTD. reassignment NOVARTIS INTERNATIONAL PHARMACEUTICAL LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: PFIZER INC.
Priority to US11/140,723 priority patent/US7138405B2/en
Abandoned legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder

Definitions

  • This invention relates to pharmaceutical combinations suitable for treating the lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) in men, which combinations contain an alpha-adrenoceptor antagonist and a muscarinic antagonist.
  • LUTS lower urinary tract symptoms
  • BPH benign prostatic hyperplasia
  • the combinations of the invention are particularly suitable for treating moderate or severe LUTS.
  • BPH is a progressive, nearly universal condition in aging men characterized by a nodular enlargement of prostatic tissue resulting, through obstruction of the urethra, in variable degrees of bladder outlet obstruction.
  • the disorder is not a major cause of death, but it is a leading cause of morbidity in elderly men and is associated with a variety of lower urinary tract symptoms.
  • LUTS in males include, inter alia, increased frequency of urination, nocturia, a poor urine stream and hesitancy or delay in starting the urine flow.
  • Chronic consequences of BPH can include hypertrophy of bladder smooth muscle, a decompensated bladder and an increased incidence of urinary tract infection.
  • BPH prostate adenoma leading to the bladder outlet obstruction
  • the development of BPH is considered to be an inescapable phenomenon for the aging male population. BPH is commonly seen in men over the age of 50 and is observed in approximately 70% of males over the age of 70.
  • the method of choice for treating BPH is the administration of alpha 1 -adrenoceptor antagonists and, to a lesser extent, surgery, usually involving transurethral resection of the prostate (TURP).
  • alpha 1 -adrenoceptor antagonists are used only in the treatment of patients with mild or moderate LUTS.
  • LUTS are recognized as arising from changes in urethral resistance induced by the enlarging prostate; the outflow of urine is restricted and secondary changes are induced in the bladder.
  • a characteristic pattern of unstable bladder contractions, also known as irritable bladder, is often observed in men with morphological BPH.
  • Noradrenaline a neurotransmitter released from sympathetic nerve terminals, contracts the prostatic smooth muscle that surrounds the urethra, increases urethral resistance and thereby reduces uroflow.
  • Alpha-adrenergic receptors (herein also referred to as “alpha-adrenoceptors” or as “alpha-receptors”) are specific protein recognition sites loaded in the peripheral and central nervous systems and other tissues throughout the body. Neurotransmitters, such as noradrenaline, control many physiological processes via an action on these receptors and thereby transmit information between cells or influence cells or influence biochemical processes within the cell. Many agents capable of modifying noradrenaline activity on alpha-adrenoceptors have been developed over the last 40 years. Drugs active at alpha-adrenoceptors can be broken down into two major classes, agonists and antagonists.
  • Antagonists of which phenylephrine and methoxamine are examples, activate the receptor system in the same way as the endogenous neurotransmitters, adrenaline and noradrenaline.
  • Antagonists of which phenoxybenzamine and prazosin are examples, do not activate the receptor, but block the actions of the endogenous neurotransmitters.
  • alpha-adrenoceptor types have been discovered over the years including alpha 1 -adrenoceptors and alpha 2 -adrenoceptors. These receptor types are now considered to be subdivided further into subtypes including alpha 1A, 1B, 1D, 1H, 1L and 1N .
  • Alpha 1 -adrenoceptors are known to mediate the contraction of vascular (arterial and venous) and prostatic smooth muscle.
  • Alpha 1 -adrenoceptor antagonists have been widely used as first line therapy for the treatment of hypertension and, more recently, for the symptomatic relief of BPH (see Kenny et al, Expert Opin in Invest Drugs, 1995, 4, 915-923).
  • Alpha-adrenoceptor antagonists are known to relieve the obstruction by causing relaxation of the prostate smooth muscle, a decrease in urethral resistance and increased uroflow.
  • male patients with the clinical symptoms of mild-moderate BPH experience a moderate improvement in symptoms.
  • the magnitude of the effect is considerably less than that achieved after surgery.
  • LUTS although traditionally associated with BPH, can be found in both men and women. It is noted that women, although they of course do not develop morphological BPH, also suffer due to unstable bladder contractions. The clinical symptoms, particularly frequency and urgency, are similar in women and men.
  • Bladder excitability is under control of the parasympathetic nervous system that releases the neurotransmitter acetylcholine. Acetylcholine acts on protein recognition sites in the bladder called antimuscarinic receptors, producing an increase in electrical excitability of the bladder and concentration of bladder muscle. Unstable bladder is known to arise due to abnormal excitability or contractility.
  • Drugs active at muscarinic receptors can be broken into two major classes, agonists and antagonists. Agonists activate the receptor system in the same way as the endogenous neurotransmitter acetylcholine. Muscarinic antagonists (herein referred to as “antimuscarinics”, of which atropine and hyoscine are examples) do not activate the receptor, but block the actions of the endogenous transmitter. Different muscarinic receptor types have been discovered over the years including M 1 , M 2 and M 3 .
  • Antimuscarinic agents are known to relieve many of the symptoms arising from unstable or irritable bladder in women experiencing urinary urge incontinence.
  • the combination of Hyoscyamine and Doxazosin has also been found to be efficacious in treating these symptoms in women (see, e.g., Serels, S., et al., Neurourology and Urodynamics, 17, 31-36 (1998)).
  • the LUTS arising from BPH-induced unstable bladder contractions in men should not be treated with antimuscarinics.
  • the use of antimuscarinics in the treatment of LUTS in men with BPH is contraindicated as urinary retention, requiring catheterization or surgery, may result (see, M. Caine, et al., Br. J. Urol., 47(2), 193-202 (1975))
  • the present invention provides a combination of an alpha-adrenoceptor antagonist and a muscarinic antagonist for use as a medicament.
  • a medicament or product
  • the medicament includes a first pharmaceutically acceptable composition containing an alpha-adrenoceptor antagonist and a second pharmaceutically acceptable composition containing a muscarinic antagonist wherein the product is a combined preparation for simultaneous, separate or sequential use of the first composition and the second composition.
  • a pharmaceutical composition which comprises an alpha-adrenoceptor antagonist, a muscarinic antagonist and a pharmaceutically acceptable carrier.
  • the composition may be used in the treatment of lower urinary tract symptoms associated with benign hyperplasia in mammals.
  • a method of treating the lower urinary tract symptoms associated with benign prostatic hyperplasia includes administering to a subject (or mammal) in need thereof an effective amount of an alpha-adrenoceptor antagonist in combination with a muscarinic antagonist.
  • the combination may be administered separately, simultaneously or sequentially.
  • references to an alpha-adrenoceptor antagonist and/or to a muscarinic antagonist shall at all times be understood to include all active forms of such agents, including the free form thereof (e.g. the free and/or base form) and also all pharmaceutically acceptable salts, polymorphs, hydrates, silicates, stereo-isomers, (e.g. diastereisomers and enantiomers) and so forth. Active metabolites of either the alpha-adrenoceptor antagonist or the muscarinic antagonist, in any form, are also included.
  • the alpha-adrenoceptor antagonist can be selective for alpha 1 -adrenoceptors or it can be non-selective, exhibiting antagonist activity at both the alpha 1 and alpha 2 receptors. Antagonists selective for the alpha 1 -adrenoceptor are preferred. In the context of the known alpha 1 -adrenoceptor subtypes, antagonists at 1A, 1B, 1D, 1H, 1N and 1L are equally preferred.
  • Suitable alpha 1 -adrenoceptor antagonists include 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline (as described in example 19 of WO 98/30560), alfuzosin, indoramin, maftopidil, tamsulosin, doxazosin, terazosin, abanoquil, prazosin and pharmaceutically acceptable salts thereof.
  • Preferred alpha 1 -adrenoceptor antagonists include 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline, doxazosin, terazosin, indoramin, abanoquil, and prazosin, and the pharmaceutically acceptable salts thereof (especially doxazosin mesylate, terazosin hydrochloride, abanoquil mesylate and prazosin hydrochloride)
  • alpha-adrenoceptor antagonists which are reported to be selective for the alpha 1 receptor include: Recordati 15/2739, SNAP 1069, SNAP 5089, RS 17053 and SL 89.0591 (Kenny, et al., Expert Opin in Invest Drugs, 4, 915-923 (1995)).
  • Suitable non-selective alpha-adrenoceptor antagonists include phentolamine, trazodone, dapiprazole and phenoxybenzamine.
  • alpha-adrenoceptor antagonists useful in this invention may be widely chosen from among those already known to the art or subsequently discovered and/or hereafter discovered and/or hereafter developed.
  • alpha-antagonists and salts thereof have been widely disclosed in the patent literature, including U.S. Pat. Nos. 5,599,810; 5,340,814; 5,508,279; 4,755,507; 4,188,390; 4,026,894; 3,511,836; 4,315,007; 3,527,761; 3,997,666; 2,503,059; 4,703,063; 3,381,009; 4,252,721 and 2,599,000, each of which is incorporated herein by reference.
  • the alpha-adrenoceptor antagonism of a compound can be determined using a number of conventional assays in vitro. Suitable assays include those disclosed in U.S. Pat. No. 5,599,810 which uses rabbit aorta to determine alpha 1 -adrenoceptor antagonist activity and U.S. Pat. No. 5,340,814 which employ rat brain cortex to determine antagonist activity. Both of these patents are incorporated herein by reference.
  • the muscarinic antagonist can be selective for M 3 receptors or it can be non-selective, exhibiting antagonism at M 1 , M 2 and M 3 . Antagonists selective for the M 3 receptor are preferred.
  • Suitable M 3 receptor selective muscarinic antagonists are darifenacin and pharmaceutically acceptable salts thereof.
  • Suitable non-selective muscarinic antagonists include atropine, fluvoxate, hyoscine, oxybutynin, tolterodine, propantheline, propiverine, trospium and the pharmaceutically acceptable salts thereof.
  • darifenacin, tolterodine and oxybutynin and pharmaceutically acceptable salts thereof are especially preferred, particularly darifenacin citrate.
  • muscarinic antagonists useful in this invention may be widely chosen from among those already known to the art or subsequently discovered and/or hereafter discovered and/or hereafter developed.
  • pyrrolidine antimuscarinic antagonists have been disclosed in the patent literature, including U.S. Pat. Nos. 5,233,053 and 5,096,890, both of which are incorporated herein by reference.
  • the muscarinic antagonist activity of a compound can be determined using a number of conventional assays in vitro (see, Wallis and Napier, Life Sci, 64, 395-401, (1997)).
  • a suitable combination is a muscarinic antagonist and a non-selective alpha-adrenoceptor antagonist.
  • Preferred combinations are a muscarinic antagonist with a selective alpha 1 -adrenoceptor antagonist and a non-selective alpha-antagonist with a muscarinic antagonist that is selective for the M 3 receptor.
  • a more preferred combination is a selective alpha 1 -adrenoceptor antagonist and a muscarinic antagonist that is selective for the M 3 receptor subtype.
  • the most preferred is the combination of any alpha-adrenoceptor antagonist with darifenacin.
  • Preferred specific combinations include doxazosin with darifenacin; 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline and darifenacin; and pharmaceutically acceptable salts thereof.
  • Administering both therapeutic agents produces an effect that is greater than that of the alpha-adrenoceptor antagonist administered alone. This is advantageous in that it allows for a smaller amount of the alpha-adrenoceptor antagonist to be administered to provide a therapeutic effect. A further advantage is that therapy can be effected for patients who, for example, do not respond adequately to the use of the alpha-adrenoceptor antagonist at what would be considered a maximal strength dose.
  • a product comprising a first pharmaceutically acceptable composition containing an alpha-adrenoceptor antagonist and a second pharmaceutically acceptable composition containing a muscarinic antagonist for use as a combined preparation for simultaneous, separate or sequential use in treating the lower urinary tract symptoms associated with benign hyperplasia in mammals.
  • the alpha-adrenoceptor antagonist in the first composition is non-selective.
  • the alpha-adrenoceptor antagonist in the first composition is selective for ⁇ 1 receptors.
  • the alpha 1 -adrenoceptor antagonist in the first composition is selected from 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinalzoline, doxazosin, tetrazosin, abanoquil, prazosin and indoramin and pharmaceutically acceptable salts thereof.
  • the muscarinic antagonist in the second composition may be non-selective.
  • the muscarinic antagonist in the second composition is selected from darifenacin, tolterodine and oxybutynin and pharmaceutically acceptable salts thereof. More preferably the muscarinic antagonist in the second composition is selective for M 3 receptors. Most preferably the muscarinic antagonist in the second composition is darifenacin and pharmaceutically acceptable salts thereof.
  • the present invention provides for the administering of each of the antagonists separately but as part of the same therapeutic treatment program or regimen, and it is contemplated that separate administration of each compound, at different times and by different routes, will sometimes be recommended. Thus the two components need not necessarily be administered at essentially the same time.
  • the alpha-adrenoceptor antagonist will be given several days prior to initiation of the muscarinic antagonist either daily or “on demand”.
  • administration is timed so that the peak pharmacokinetic effect of the alpha 1 -adrenoceptor antagonist precedes the peak pharmacokinetic effect of the muscarinic antagonist. If co-administered separately, it is also preferred that both components be administered in an oral dosage form.
  • the product may comprise a kit.
  • the kit may comprise a container for containing the separate compositions such as a divided bottle or a divided foil packet, wherein each compartment contains a plurality of dosage forms (e.g., tablets) comprising either the alpha 1 -adrenoceptor antagonist or the muscarinic antagonist.
  • dosage forms e.g., tablets
  • the kit may contain separate compartments each of which contains a whole dosage which comprises separate compositions.
  • An example of this type of kit is a blister pack wherein each individual blister contains two tablets, one tablet comprising the alpha-adrenoceptor antagonist, the other comprising the muscarinic antagonist.
  • the kit comprises directions for the administration of the separate components. Such instructions would cover situations such as:
  • the container may have deposited thereon a label that describes the contents therein and any appropriate warnings.
  • Blister packs are well known in the packaging industry and are widely used for the packaging of pharmaceutical unit dosage forms such as tablets, capsules, and the like. Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses between the plastic foil and the sheet.
  • the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. Tablet(s) or capsule(s) can then be removed by means of the opening.
  • a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen during which the tablets or capsules so specified should be ingested.
  • a memory aid is a calendar printed on the card, e.g. as follows “First Week, Monday, Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, . . . ”, etc.
  • a “daily dose” can be a single tablet or capsule or several pills or capsules to be taken on a given day.
  • a daily dose of the first compound can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa.
  • the memory aid should reflect this.
  • both the alpha-adrenoceptor antagonist and the muscarinic antagonist may be present in a single composition.
  • a pharmaceutical composition containing an alpha-adrenoceptor antagonist, a muscarinic antagonist and a pharmaceutically acceptable carrier.
  • Suitable alpha-adrenoceptor antagonists include those that are non-selective.
  • the alpha-adrenoceptor antagonist is selective for the ⁇ 1 receptor. More preferably the alpha-adrenoceptor antagonist is selected from 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline, doxazosin, tetrazosin, abanoquil, prazosin and indoramin and pharmaceutically acceptable salts thereof.
  • Suitable muscarinic antagonists include those that are non-selective.
  • the muscarinic antagonist is selected from darifenacin, tolterodine and oxybutynin and pharmaceutically acceptable salts thereof. More preferably the muscarinic antagonist is selective for M 3 receptors.
  • the muscarinic antagonist in the second composition is darifenacin and pharmaceutically acceptable salts thereof.
  • composition containing a combination of any alpha-adrenoceptor antagonist with darifenacin is particularly preferred.
  • Preferred specific combinations include: doxazosin and darifenacin; and 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline and darifenacin; and pharmaceutically acceptable salts thereof.
  • compositions of the present invention may be suitable for topical, oral, parenteral or rectal administration.
  • the compositions may be formulated to provide immediate or sustained release of the therapeutic agent.
  • Particularly suitable delayed or sustained release formulations are those disclosed in WO 97/09980.
  • the compounds of the invention can be administered alone but will generally be administered as an admixture with a suitable pharmaceutical excipient, diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • the compounds of the invention can be administered orally, buccally or sublingually in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavoring or coloring agents, for immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release applications.
  • tablets contain various excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycollate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included. Tablets may be manufactured by any standard tablet-making process, for example, direct compression or a wet or dry granulation process. The tablet cores may also be coated with one or more appropriate overcoats.
  • excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine
  • compositions of a similar type are also employed as fillers in gelatin capsules.
  • Preferred excipients in this regard include lactose, milk sugar, cellulose, starch or high molecular weight polyethylene glycols.
  • the compounds of this invention can be combined with various sweetening agents, flavoring agents, coloring agents or dyes, emulsifying agents and/or suspending agents, diluents (e.g., water, ethanol, propylene glycol, glycerin and mixtures thereof) and combinations thereof.
  • the compounds of the invention can also be administered parenterally, for example, intravenously, intra-arterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrasternally, intracranially, intramuscularly or subcutaneously, or they may be administered by infusion techniques.
  • parenteral administration they are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. If necessary, the aqueous solutions should be suitably buffered (preferably to a pH from 3 to 9).
  • the preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art.
  • the compounds of the invention can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene or polyoxypropylene compound, emulsifying wax and water.
  • they can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-oxtyldodecanol, benzyl alcohol and water.
  • the alpha-adrenoceptor antagonist and/or the muscarinic antagonist may also be used in combination with a cyclodextrin.
  • Cyclodextrins are known to form inclusion and non-inclusion complexes with drug molecules. Formation of a drug-cyclodextrin complex may modify the solubility, dissolution rate, bioavailability and/or stability property of a drug molecule. Drug-cyclodextrin complexes are generally useful for most dosage forms and administration routes.
  • the cyclodextrin may be used as an auxiliary additive, e.g., as a carrier, diluent or solubilizer.
  • Alpha-, beta- and gamma-cyclodextrins are most commonly used and suitable examples are described in WO 91/11172, WO 94/02518 and WO 98/55148.
  • the exact dose of each component administered will, of course, differ depending on the specific components prescribed, on the subject being treated, on the severity of the LUTS, on the manner of administration and on the judgement of the prescribing physician.
  • the dosages given below are a guideline and the physician may adjust doses of the compounds to achieve the treatment that the physician considers appropriate for the patient, male or female.
  • the physician must balance a variety of factors such as the age of the patient and the presence of other diseases or conditions (e.g. cardiovascular disease).
  • the muscarinic antagonist will be administered in a range of from 0.5 to 200 mg per day, preferably 10 to 125 mg per day, more preferably 25 mg to 100 mg per day.
  • the alpha-adrenoceptor antagonist will generally be administered in an amount of from 0.01 mg to 50 mg per day, preferably from 0.5 to 10 mg per day.
  • Doxazosin when in combination, will be administered in the range 0.25 mg to 16 mg per day, preferably 2 mg to 4 mg per day.
  • Tolterodine will be administered twice a day in the range 0.2 mg to 2 mg per day, preferably from 0.5 mg to 1 mg per day and darifenacin will be administered in the range 0.5 mg to 5 mg twice a day, preferably 1 mg or 2 mg. All weights quoted above refer to the weight of the compounds as the free base.
  • Immediate release doxazosin tablet Ingredient % w/w Doxazosin Mesylate 4.05 Microcrystalline Cellulose 125.28 Lactose 66.67 Sodium Starch Glycollate 2.00 Magnesium stearate 2.00 Total weight 200.00
  • Immediate release darifenacin tablet Ingredient % w/w Darifenacin hydrobromide 2.976 Microcrystalline Cellulose 131.024 Calcium phosphate dibasic 60.000 Croscarmellose sodium 4.000 Magnesium stearate 2.000 Total weight 200.000
  • Combination immediate release darifenacin/doxazosin tablet Ingredient % w/w Doxazosin Mesylate 4.05 Darifenacin hydrobromide 2.976 Microcrystalline Cellulose 125.28 Lactose 63.694 Sodium Starch Glycollate 2.00 Magnesium stearate 2.00 Total weight 200.00
  • Combination immediate release doxazosin/controlled release darifenacin tablet Ingredient % w/w Doxazosin Mesylate 4.05 Microcrystalline Cellulose 125.28 Lactose 66.67 Sodium Starch Glycollate 2.00 Magnesium stearate 4.00 Darifenacin hydrobromide 17.857 Methylhydroxypropyl cellulose 114.400 Calcium phosphate dibasic 65.743 Total weight 400.000
  • Controlled release darifenacin tablet Ingredient % w/w Darifenacin hydrobromide 17.857 Methylhydroxypropyl cellulose 114.400 Calcium phosphate dibasic 65.743 Magnesium stearate 2.000 Total weight 200.000
  • an alpha-adrenoceptor antagonist and a muscarinic antagonist can be tested clinically, typically orally, in humans.
  • Each component is administered singly at different times to a population of male patients, each component being administered in conjunction with the International Prostate Symptom Score (IPSS) questionnaire (see, Barry, et al., J. Urol., 148, 1549-1563 (1992)) which evaluated patient satisfaction.
  • IVS International Prostate Symptom Score
  • the components are co-administered in a manner such that both components co-operate pharmacokinetically, preferably such that fully effective drug plasma levels of both agents will be obtained.
  • Co-administration is evaluated according to IPSS questionnaires mentioned above, thereby providing a basis for comparison of the effects of co-administration with that for each single administration. The efficacy of the present invention is demonstrated by the results of the IPSS questionnaire.

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Urology & Nephrology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
US09/778,290 2000-02-09 2001-02-07 Pharmaceutical combinations Abandoned US20010044438A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US09/778,290 US20010044438A1 (en) 2000-02-09 2001-02-07 Pharmaceutical combinations
US11/140,723 US7138405B2 (en) 2000-02-09 2005-05-31 Pharmaceutical combinations

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US18131000P 2000-02-09 2000-02-09
US09/778,290 US20010044438A1 (en) 2000-02-09 2001-02-07 Pharmaceutical combinations

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US11/140,723 Continuation US7138405B2 (en) 2000-02-09 2005-05-31 Pharmaceutical combinations

Publications (1)

Publication Number Publication Date
US20010044438A1 true US20010044438A1 (en) 2001-11-22

Family

ID=22663745

Family Applications (2)

Application Number Title Priority Date Filing Date
US09/778,290 Abandoned US20010044438A1 (en) 2000-02-09 2001-02-07 Pharmaceutical combinations
US11/140,723 Expired - Fee Related US7138405B2 (en) 2000-02-09 2005-05-31 Pharmaceutical combinations

Family Applications After (1)

Application Number Title Priority Date Filing Date
US11/140,723 Expired - Fee Related US7138405B2 (en) 2000-02-09 2005-05-31 Pharmaceutical combinations

Country Status (12)

Country Link
US (2) US20010044438A1 (es)
EP (2) EP2266571A1 (es)
KR (2) KR20010078803A (es)
AU (3) AU1832901A (es)
CA (1) CA2334460C (es)
HU (1) HU230982B1 (es)
IL (1) IL141235A (es)
MY (1) MY164900A (es)
NZ (1) NZ509807A (es)
PE (1) PE20011167A1 (es)
TW (1) TWI287448B (es)
ZA (1) ZA200101012B (es)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007010509A2 (en) * 2005-07-22 2007-01-25 Ranbaxy Laboratories Limited Controlled release pharmaceutical composition comprising alpha-adrenergic antagonist and muscarinic antagonist
WO2007072169A2 (en) * 2005-12-20 2007-06-28 Pfizer Products Inc. Pharmaceutical combination for the treatment of luts comprising a pde5 inhibitor and a muscarinic antagonist
US20080167317A1 (en) * 2004-03-22 2008-07-10 Anita Chugh Combination Therapy
US20080242674A1 (en) * 2004-03-24 2008-10-02 Yoshinobu Yamazaki Medicine For Prevention or Treatment of Frequent Urination or Urinary Incontinence
US20100331361A1 (en) * 2007-07-20 2010-12-30 Astellas Pharma Inc. Pharmaceutical composition containing alpha-adrenergic receptor antagonist and an anti-muscarinic agent and method of improving lower urinary tract symptoms associated with prostatic hypertrophy
US20120142725A1 (en) * 2008-11-04 2012-06-07 Astellas Ireland Co., Ltd. Combined Use of an Alpha-Adrenergic Receptor Antagonist and an Anti-Muscarinic Agent
US8871275B2 (en) 2007-08-08 2014-10-28 Inventia Healthcare Private Limited Extended release compositions comprising tolterodine
WO2024107961A1 (en) * 2022-11-17 2024-05-23 Dri Biosciences Corporation Compositions and methods of treating neurological conditions

Families Citing this family (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7019012B2 (en) 2000-12-20 2006-03-28 Boehringer Ingelheim International Pharma Gmbh & Co. Kg Quinazoline derivatives and pharmaceutical compositions containing them
DE10149674A1 (de) * 2001-10-09 2003-04-24 Apogepha Arzneimittel Gmbh Orale Darreichungsformen für Propiverin oder seinen pharmazeutisch annehmbaren Salzen mit verlängerter Wirkstoffreisetzung
US7163696B2 (en) 2001-10-11 2007-01-16 Pfizer Inc. Pharmaceutical formulations
GB0124455D0 (en) * 2001-10-11 2001-12-05 Pfizer Ltd Pharmaceutical formulations
US20030185882A1 (en) * 2001-11-06 2003-10-02 Vergez Juan A. Pharmaceutical compositions containing oxybutynin
RU2311903C2 (ru) * 2001-11-07 2007-12-10 Синтон Б.В. Таблетки тамзулосина
DE10221018A1 (de) 2002-05-11 2003-11-27 Boehringer Ingelheim Pharma Verwendung von Hemmern der EGFR-vermittelten Signaltransduktion zur Behandlung von gutartiger Prostatahyperplasie (BPH)/Prostatahypertrophie
IL165370A0 (en) * 2002-06-07 2006-01-15 Astellas Pharma Inc Therapeutic agent for overactive bladder
WO2004017960A1 (en) * 2002-08-14 2004-03-04 Janssen Pharmaceutica N.V. Treatment of lower urinary tract symptoms associated with overactive bladder in men and women
GB0221582D0 (en) * 2002-09-17 2002-10-23 Pfizer Ltd Method of treatment
AU2003207089A1 (en) * 2003-02-14 2004-09-06 Takeda Pharmaceutical Company Limited Preparation for topical administration
KR100679111B1 (ko) * 2004-11-20 2007-02-07 대우약품공업주식회사 독사조신을 포함하는 서방성 정제
EP3173084B1 (en) 2005-11-11 2019-10-23 Boehringer Ingelheim International GmbH Quinazoline derivatives for the treatment of cancer diseases
WO2007109142A2 (en) * 2006-03-17 2007-09-27 Oregon Health & Science University M3 muscarinic receptor antagonists for treating tumors
CA2663599A1 (en) 2006-09-18 2008-03-27 Boehringer Ingelheim International Gmbh Method for treating cancer harboring egfr mutations
US7891492B2 (en) * 2007-08-13 2011-02-22 Carton Service, Incorporated Pharmaceutical blister card package
EP2451445B1 (en) 2009-07-06 2019-04-03 Boehringer Ingelheim International GmbH Process for drying of bibw2992, of its salts and of solid pharmaceutical formulations comprising this active ingredient
JP2015531346A (ja) 2012-09-05 2015-11-02 チェイス・ファーマスーティカルズ・コーポレーション 抗コリン作用性神経保護組成物及び方法
US9242965B2 (en) 2013-12-31 2016-01-26 Boehringer Ingelheim International Gmbh Process for the manufacture of (E)-4-N,N-dialkylamino crotonic acid in HX salt form and use thereof for synthesis of EGFR tyrosine kinase inhibitors
TWI822690B (zh) * 2017-07-20 2023-11-21 中國大陸商盛元醫藥廣州有限公司 用於治療近視之組合物及方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6083950A (en) * 1997-11-13 2000-07-04 Ranbaxy Laboratories Limited 1-(4-arylpiperazin-1-yl)-ω-[n-(α,ω-dicarboximido)]-alka nes useful as uro-selective α1-adrenoceptor blockers

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2503059A (en) 1950-04-04 Nxchj
US2599000A (en) 1950-09-02 1952-06-03 Smith Kline French Lab Nu, nu-disubstituted-beta-halo-alkylamines
IT1066857B (it) 1965-12-15 1985-03-12 Acraf Derivati della s ipiazolo 4.3 a piridina e processi per la loro preparazione
IT1094076B (it) 1978-04-18 1985-07-26 Acraf Cicloalchiltriazoli
JPS56110665A (en) 1980-02-08 1981-09-01 Yamanouchi Pharmaceut Co Ltd Sulfamoyl-substituted phenetylamine derivative and its preparation
GB8906166D0 (en) 1989-03-17 1989-05-04 Pfizer Ltd Therapeutic agents
US5233053A (en) 1989-03-17 1993-08-03 Pfizer Inc. Pyrrolidine derivatives
JPH08502977A (ja) * 1992-11-04 1996-04-02 セプラコア，インコーポレイテッド 良性前立腺増殖およびアテローム性動脈硬化の治療法ならびに（＋）ドキサゾシン組成物
GB9518953D0 (en) * 1995-09-15 1995-11-15 Pfizer Ltd Pharmaceutical formulations
GB9700504D0 (en) * 1997-01-11 1997-02-26 Pfizer Ltd Pharmaceutical compounds
AU7703700A (en) * 1999-09-22 2001-04-24 Merck & Co., Inc. Treatment of lower urinary tract symptoms and pharmaceutical compositions for use therein

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6083950A (en) * 1997-11-13 2000-07-04 Ranbaxy Laboratories Limited 1-(4-arylpiperazin-1-yl)-ω-[n-(α,ω-dicarboximido)]-alka nes useful as uro-selective α1-adrenoceptor blockers

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080167317A1 (en) * 2004-03-22 2008-07-10 Anita Chugh Combination Therapy
US20080242674A1 (en) * 2004-03-24 2008-10-02 Yoshinobu Yamazaki Medicine For Prevention or Treatment of Frequent Urination or Urinary Incontinence
WO2007010509A2 (en) * 2005-07-22 2007-01-25 Ranbaxy Laboratories Limited Controlled release pharmaceutical composition comprising alpha-adrenergic antagonist and muscarinic antagonist
WO2007010509A3 (en) * 2005-07-22 2007-08-09 Ranbaxy Lab Ltd Controlled release pharmaceutical composition comprising alpha-adrenergic antagonist and muscarinic antagonist
WO2007072169A2 (en) * 2005-12-20 2007-06-28 Pfizer Products Inc. Pharmaceutical combination for the treatment of luts comprising a pde5 inhibitor and a muscarinic antagonist
WO2007072169A3 (en) * 2005-12-20 2007-11-01 Pfizer Prod Inc Pharmaceutical combination for the treatment of luts comprising a pde5 inhibitor and a muscarinic antagonist
US20080318982A1 (en) * 2005-12-20 2008-12-25 Pfizer, Inc. Pharmaceutical Combination for the Treatment of Luts
US20100331361A1 (en) * 2007-07-20 2010-12-30 Astellas Pharma Inc. Pharmaceutical composition containing alpha-adrenergic receptor antagonist and an anti-muscarinic agent and method of improving lower urinary tract symptoms associated with prostatic hypertrophy
US8871275B2 (en) 2007-08-08 2014-10-28 Inventia Healthcare Private Limited Extended release compositions comprising tolterodine
US20120142725A1 (en) * 2008-11-04 2012-06-07 Astellas Ireland Co., Ltd. Combined Use of an Alpha-Adrenergic Receptor Antagonist and an Anti-Muscarinic Agent
WO2024107961A1 (en) * 2022-11-17 2024-05-23 Dri Biosciences Corporation Compositions and methods of treating neurological conditions

Also Published As

Publication number Publication date
IL141235A (en) 2012-04-30
HU0100586D0 (en) 2001-03-28
US7138405B2 (en) 2006-11-21
HU230982B1 (hu) 2019-08-28
AU1832901A (en) 2001-08-16
AU2009227918B2 (en) 2011-09-22
TWI287448B (en) 2007-10-01
AU2006202176A1 (en) 2006-06-15
IL141235A0 (en) 2011-08-01
CA2334460C (en) 2009-01-27
EP1123705A1 (en) 2001-08-16
US20050222165A1 (en) 2005-10-06
HUP0100586A2 (hu) 2001-11-28
ZA200101012B (en) 2002-08-06
AU2009227918A1 (en) 2009-11-12
PE20011167A1 (es) 2001-11-13
KR20010078803A (ko) 2001-08-21
KR20040032141A (ko) 2004-04-14
EP2266571A1 (en) 2010-12-29
CA2334460A1 (en) 2001-08-09
HUP0100586A3 (en) 2003-05-28
NZ509807A (en) 2002-09-27
MY164900A (en) 2018-01-30

Similar Documents

Publication Publication Date Title
US7138405B2 (en) Pharmaceutical combinations
US20080318982A1 (en) Pharmaceutical Combination for the Treatment of Luts
McKeage et al. Alfuzosin: a review of the therapeutic use of the prolonged-release formulation given once daily in the management of benign prostatic hyperplasia
CN101287462A (zh) 治疗疾病的疗法
US8088827B2 (en) Use of irbesartan for the preparation of medicinal products that are useful for treating pulmonary hypertension
Melian et al. Candesartan cilexetil plus hydrochlorothiazide combination: a review of its use in hypertension
US20240207227A1 (en) Use of a combination of sacubitril and valsartan
US20160243082A1 (en) 4-Methylpyrazole Formulations for Inhibiting Ethanol Intolerance
BG65309B1 (bg) Използване на елетриптан за профилактика на мигренозен рецидив
AU2003260373B2 (en) Treatment of lower urinary tract symptoms associated with overactive bladder in men and women
JP2003055261A (ja) 製剤組合せ
Yedinak Use of Calcium Channel Antagonists for cardiovascular disease: This CE program reviews the role of calcium channel antagonists in managing certain diseases and compares agents
CA2397244C (en) Ace inhibitor-vasopressin antagonist combinations
Agent et al. PrTARO-AMLODIPINE
US20070099850A1 (en) Combination of acetylsalicylic acid and alpha-glucosidase inhibitors
CN109069438A (zh) 包含β阻滞剂、转化酶抑制剂和抗高血压药或NSAID的药物组合物
JP2004529893A (ja) 改善されたバイオアベイラビリティーを有する組成物

Legal Events

Date Code Title Description
AS Assignment

Owner name: NOVARTIS INTERNATIONAL PHARMACEUTICAL LTD., BERMUD

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:PFIZER INC.;REEL/FRAME:014709/0987

Effective date: 20031105

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION