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WO1997014419A1 - Administration percutanee d'inhibiteurs des recepteurs alpha-adrenergiques - Google Patents

Administration percutanee d'inhibiteurs des recepteurs alpha-adrenergiques Download PDF

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Publication number
WO1997014419A1
WO1997014419A1 PCT/US1995/014620 US9514620W WO9714419A1 WO 1997014419 A1 WO1997014419 A1 WO 1997014419A1 US 9514620 W US9514620 W US 9514620W WO 9714419 A1 WO9714419 A1 WO 9714419A1
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WO
WIPO (PCT)
Prior art keywords
methyl
compound
methoxyphenyl
propylcarbamoyl
piperazinyl
Prior art date
Application number
PCT/US1995/014620
Other languages
English (en)
Inventor
Giancarlo Santus
Aeri Kim
Michael L. Francoeur
Ulrike Bremer
Original Assignee
Flora Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Flora Inc. filed Critical Flora Inc.
Priority to AU41534/96A priority Critical patent/AU4153496A/en
Priority to PCT/US1995/014620 priority patent/WO1997014419A1/fr
Publication of WO1997014419A1 publication Critical patent/WO1997014419A1/fr

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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
    • A61K31/495—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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • A61K9/7061—Polyacrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7069—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained otherwise than by reactions only involving carbon to carbon unsaturated bonds, e.g. polysiloxane, polyesters, polyurethane, polyethylene oxide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7084—Transdermal patches having a drug layer or reservoir, and one or more separate drug-free skin-adhesive layers, e.g. between drug reservoir and skin, or surrounding the drug reservoir; Liquid-filled reservoir patches

Definitions

  • Adrenergic nerve fibers comprise the majority of the postganglionic nerve fibers, having norepinephrine as the primary neurotransmitter. Autonomic nerve impulses induce adrenergic responses in many bodily organs. The responses are varied, including blood vessel constriction, constriction of the stomach, intestinal, and genito-urinary sphincters, bronchial muscle relaxation and increased heart rate.
  • alpha adrenergic blocking agents Agents that block responses to adrenergic nerve activity through interaction with alpha-adrenoceptors are referred to as alpha adrenergic blocking agents.
  • the blocking agents selectively inhibit responses to adrenergic sympathetic nerve activity and to epinephrine and other sympathomimetic drugs.
  • the response to sympathomimetic amines such as norepinephrine and isoproterenol was first used to categorize adrenergic receptors.
  • the alpha receptors are potently affected by norepinephrine and very poorly affected by isoproterenol.
  • the beta receptors are poorly affected by norepinephrine and potently affected by isoproterenol.
  • Alpha-adrenergic receptors (or alpha adrenoceptors) , including the alpha_ and alpha 2 subtypes, are found in many locations throughout the body.
  • the alpha-adrenergic blocking agents ⁇ alpha-blockers have been suggested to have, or have a variety of therapeutic uses, including the treatment of prostate and genito-urinary disorders such as benign prostatic hyperplasia (BPH) ; peripheral vascular disorders, including Raynaud's disease, acrocyanosis, frost bite, acute arterial occlusion, phlebitis, phlebothrombosis, diabetic gangrene, causalgia, shock and pheochromocytoma; hair loss; and hypertension, see Goodman and Gilman, The Pharmacological Basis of Therapeutics 7th Ed, 1985, MacMillan and Co., the contents of which are hereby incorporated by reference.
  • transdermal administration of active agents offers many of the benefits of i.v. infusion, including direct entry of the drug into the systemic circulation and continual release of the drug. Transdermal delivery is also particularly advantageous for drugs having short half-lives, as maintenance of the required blood levels of these drugs required a higher frequency of bolus dose administration of the drug.
  • Transdermal delivery of active compounds also provides a non-invasive method for the controlled release and delivery of an active agent. This is advantageous as compared to non-controlled release methods, which may result in underdosing or overdosing of the drug.
  • Other advantages of transdermal drug delivery may include reduction in dosing frequency, reduced fluctuation in circulating drug levels, increased patient compliance and convenience, and a more uniform effect.
  • Transdermal delivery also avoids some of the disadvantages associated with oral drug delivery, such as gastrointestinal irritation.
  • many drugs have been difficult to administer transdermally, due to the low skin flux or permeation rates of the drug and the amount of drug that must be delivered for therapeutic efficacy.
  • X represents a nitrogen, oxygen or sulfur atom, or an amino or alkylamino group, a sulfinyl or sulfonyl group;
  • R s represents a hydrogen or halogen atom or a nitro, amino, acylamino, alkylsulfonylamino, alkylamino, dialkylamino, cyano, hydroxy, alkoxy or alkyl group;
  • R7 represents a hydrogen atom or an alkoxy group
  • Y represents one of the following groups, each of which is depicted with its left hand end being the end which attaches to the heterobicyclic ring and its right hand end being the end which attaches to the group Z:
  • B represents one of the following groups: (Bl)
  • n 1 or 2 and A represents a phenyl group optionally substituted by one or more substituents (preferably at position 2) selected from the group consisting of alkoxy, alkyl, halogen, hydroxy, or A represents a 2-pyrimidinyl group or a bicyclic ring of formula
  • R- 0 and R independently represents a hydrogen atom or an alkoxy or alkylthio group
  • R 12 represents a hydrogen atom or an alkyl group and n is 2 or 3
  • R, 2 has the meaning defined under B3 and R 13 represents a hydrogen atom or an alkoxy group
  • R 12 has the meaning defined under B3.
  • the invention further includes prodrugs of the formula I compounds, e.g., the derivatives of compounds of formula I bearing reactive groups such as NH, NH 2 and in par ⁇ ticular OH (i.e., at positions W, R 2 , R 3 , R 6 , Z, B,, B 2 ) prepared for various purposes, e.g., to improve the pharmaco-kinetic properties (adsorption, distribution, metabolism, plasmatic half-life, etc.) of said compounds of formula I, which can be administered in this "masked” or prodrug form and are liberated, exerting their pharmaco ⁇ logical action, in mammals receiving them.
  • prodrug derivatives have the following structure
  • J is a bond, an oxygen or sulfur atom, or a NH group
  • F represents an alkyl group (optionally containing hetero atoms such as 0, S, N or substituted nitrogen) , a carbocyclic group or heterocyclic group, optionally substituted with amino, alkylamino, dialkylamino, dialkylaminoalkyl, carboxy, alkoxycarbonyl, carboxamido.
  • J is a bond and F is CH 3 , (CH 3 ) 3 C,
  • B' represents a dialkylamino group or a cyclic amino group, optionally containing other heteroatoms such as N, 0 or S. Also included in the invention are derivatives having the formula:
  • prodrug derivatives are those obtained by the derivatization of "acidic" NH groups (Ny) such as those present in Y3, Y10, Y14, Y19, Y22, Y27, Y33, Y36 and Y41, yielding derivatives having the formula:
  • the invention also includes the enantiomers, diastereoisomers, N-oxides and pharmaceutically acceptable salts of these compounds, as well as metabolites of these compounds having the same type of activity (hereafter some ⁇ times referred to as "active metabolites” and prodrugs of said "active metabolites”) .
  • the invention provides a method of treating benign prostatic hyperplasia, the method comprising the transdermal administration of a therapeutically effective amount of the comounds having Formula I.
  • a transdermal patch for the delivery of compounds having Formula I to the skin of a patient comprising a backing layer, a drug depot including a compound having Formula I and a permeation enhancer composition, and a means for affixing the patch to the skin of the patient.
  • the permeation enhancer composition comprises a combination of permeation enhancers, including at least one plasticizer type enhancer, and may also include at least one solvent type enhancer.
  • a method for administering the compounds having Formula I to an individual in therapeutically effective amounts comprising the transdermal delivery of the active compounds together with a permeation enhancer, so as to deliver at least about 0.01 mg of the active compound per kg of body weight per day to the individual.
  • Figure 1 shows the contrasting levels of drug in a system after conventional oral delivery and transdermal delivery.
  • Figure 2 shows a cross section of a simple adhesive patch having an impermeable backing layer, a drug containing adhesive layer, and a release liner.
  • Figure 3 shows a cross section of a monolithic matrix transdermal patch having an impermeable backing layer, a drug depot comprising a polymer matrix in which drug is dispersed, a peripheral adhesive layer, a release liner.
  • the patch may also contain a porous membrane.
  • Figure 4 shows a cross section of a reservoir type transdermal patch having an impermeable backing, a drug depot, a porous membrane, an adhesive layer, and a release liner.
  • the backing layer and the membrane are sealed at their peripheral edges, thus defining a drug depot.
  • drug means "any compound within the generic definition of formula I" as defined above, including the free base, pharmaceutically acceptable salts of these compounds hydrates, anhydrous form, and prodrugs thereof.
  • bioavailability is the extent to which the drug reaches its site of action, or the extent to which the drug reaches a biological fluid (such as blood, and typically the general circulation) from which the drug has access to the site of action. For example, if a drug is metabolized in the liver or excreted in bile, some of the drug taken orally will be inactivated before it can reach the general circulation and exert its desired therapeutic effect. Bioavailability is defined in terms of a specific drug moiety, usually the active therapeutic entity, which may be the unchanged drug, or as with prodrugs, a metabolite.
  • terapéuticaally effective level refers to the minimal blood level of drug required to achieve a therapeutic effect.
  • pharmaceutically acceptable or “therapeutically acceptable” refers to a substance which does not interfere with the effectiveness or the biological activity of the active ingredients and which is not toxic to the host or patient.
  • adrenergic blockade indicates that the particular response system affected is that which normally involves the catecholamine neurohumoral transmitters, epinephrine (adrenaline) and norepinephrine (noradrenaline, levarterenol) .
  • adrenergic refers to any of the cellular apparatus concerned with the elaboration, storage, release, transmission, reception or action of these catecholamines or to their mimetics.
  • the locus of an adrenergic blocking agent might be any one of these sites.
  • Transdermal delivery of drugs offers a means of circumventing the problems of overdosing and underdosing that are associated with conventional drug delivery methods.
  • the transdermal delivery of drugs can be designed so that the rate of delivery of the drug closely follows the rate of the clearance of the drug from the environment, thus keeping constant levels of drug in the blood, and reducing drug waste and overdosing problems.
  • Figure 1 displays the blood levels from transdermal as well as conventional oral delivery of drugs over a period of time, indicating the controlled release and delivery aspect of transdermal delivery, and the achievement of therapeutically effective levels of a drug for a prolonged duration.
  • transdermal drug delivery also provides a comfortable, convenient and non-invasive method of administering drugs. Gastrointestinal irritation and other side-effects associated with oral drug delivery may be reduced or eliminated, and patient anxiety regarding invasive delivery methods, such as needles, is also eliminated.
  • Alpha adrenoceptors may be characterized as the alpha, or alpha 2 subtypes. The receptor subtypes are functionally categorized. Blockage of alpha, receptors inhibit vasoconstriction induced by endogenous catecholamines. Blockade of alpha, receptors also inhibits vasoconstriction and the increase in blood pressure produced by the administration of a sympathomimetic amine.
  • pre-synaptic alpha 2 receptors inhibits the release of norepinephrine from peripheral sympathetic nerve endings.
  • Blockade of these alpha 2 receptors with selective antagonists can increase sympathetic outflow and potentiate the release of norepinephrine, leading to activation of alpha, and beta, receptors in the heart and peripheral vasculature, leading to an increase in blood pressure, as described in Goodman and Gilman, supra.
  • post-synaptic and extra- synaptic receptors have been recently found, whose activation by catecholamines leads to an increase in blood pressure (E. Sylvester Vizi (1989) Med. Res. Review 6:431- 449 and references cited therein) .
  • Therapeutic agents may be either selective or non-selective alpha blockers.
  • Non-selective alpha blockers include phenoxybenzamine, phentolamine, and ergot alkaloids.
  • the non-selective alpha blockers may be used in the treatment of essential hypertension, renal hypertension, and peripheral vascular disorders in which there is an adrenergically- mediated vasospastic component such as Raynaud's disease, acrocyanosis, frost bite, acute arterial occlusion, pseudo obstruction of the bowel, phlebitis, phlebothrombosis, diabetic gangrene, causalgia, shock, pheochromocytoma, treatment of migraine, and as stimulants of post-partum uterine contractions.
  • an adrenergically- mediated vasospastic component such as Raynaud's disease, acrocyanosis, frost bite, acute arterial occlusion, pseudo obstruction of the bowel, phlebitis, phlebothrombo
  • Alpha blockers selective for the alpha, receptor subtype include alfuzosin, tamsulosin, prazosin, and terazosin. The use of these compounds to block the alpha, adrenergic impulses causes decreased vascular resistance and decreased blood pressure.
  • Selective alpha, blockers may be used in the treatment of essential hypertension, renal hypertension, peripheral vascular disorders in which there is an adrenergically- mediated vasospastic component such as Raynaud's disease, acrocyanosis, frost bite, acute arterial occlusion, phlebitis, phlebothrombosis, congestive heart failure, diabetic gangrene, causalgia, shock and pheochromocytoma.
  • an adrenergically- mediated vasospastic component such as Raynaud's disease, acrocyanosis, frost bite, acute arterial occlusion, phlebitis, phlebothrombosis, congestive heart failure, diabetic gangrene, causalgia, shock and pheochromocytoma.
  • alpha-adrenergic blockers are effective in the treatment of the symptoms associated with BPH, Caine et al., Br. J. Urol. (1976) 138: 979 - 983.
  • the alpha blocker terasozin has also been suggested for the treatment of BPH, as reviewed in Hansen, B.J. and T. Hald, Eur. Urol. (1993) 24 (suppl) : 41 - 49.
  • BPH is a disease frequently found in older men, and may be present in up to 80% of males older than 60 years of age.
  • obstructive urinary symptoms including hesitancy and difficulty in initiation of urination, in interruption and quality of flow, weakening of the urinary stream, and sensations of incomplete emptying.
  • patients experience irritative urinary symptoms, such as nocturia, increased frequency, and urgency.
  • oral doses of terasozin have been suggested to be effective in the treatment of BPH, concerns remain over potential high dose side effects such as postural hypotension and loss of consciousness, see for example, Goodman and Gilman, The Pharmacological Basis of Therapeutics, supra.
  • the preferred system for administration of these compounds according to the present invention is a transdermal patch.
  • 5- [2- [[2- (o-Ethoxyphenoxy) -ethyl]amino]propyl] -2- methoxybenzenesulfonamide (also known as amusulosin, amsulosin, YM12617, YM617 or tamsulosin) is a selective alpha, receptor blocker.
  • the structure of tamsulosin is shown in Formula II below.
  • Tamsulosin reduces the contraction of the rabbit and guinea pig prostrate, urethra, and vesical trigone, and of the human urethra and vesical trigone, Hyundai et al., Alpha -1 Adrenoceptor antagonist effect of the optical isomers of YM12617 in rabbit lower urinary tract and prostate, J. Clin. Pharmacol. Exptl. Therapeutics (1986) 239(2): 512 - 516, and Honda et al. Further studies on ( ⁇ ) - YM12617, a potent and selective ⁇ ⁇ -adrenoceptor antagonist and its individual optical enantiomers, Arch. Pharmacol. (1987) 336: 295 - 302. Thus, tamsulosin is expected to have activity in diseases where bladder, prostate, or vasosphincter musculature is compromised, for example, erectile dysfunction, BPH, dysuria or urinary incontinence.
  • Alfuzosin N- [3- [ (4-Amino-6, 7dimethoxy-2- quinazolinyl) methylamino]propyl] tetrahydro-2- furancarboxamide, is a quinazoline derivative and is a selective alpha, blocker with antihypertensive activity, and direct peripheral vasodilating properties.
  • Radioligand binding and phosphate accumulation studies demonstrate that alfuzosin possesses similar affinity for both alpha 1A and alpha, B adrenoceptors and lacks any relevant selectivity for alpha, subtypes, Michel, M.C. et al., Naunyn-Schmiedeberg's Arch. Pharmacol. (1993) 348: 385 - 395.
  • the structure of alfuzosin is shown in Formula III.
  • Alfuzosin also shows activity in altering the phenylephrine induced contractions on preparations of smooth muscle originating from the trigone muscle at the base of the bladder.
  • alfuzosin is expected to have activity in diseases where bladder, prostate, or vasosphincter musculature is compromised, for example, erectile dysfunction, BPH and dysuria or urinary incontinence.
  • Alfuzosin is typically administered as the racemic mixture.
  • the R and S enantiomers are equally potent in antagonizing phenylephrine, a sympathomimetic agent - induced contraction in both rabbit trigone and urethral ring tissues, Wilde et al., Drugs (1993) 45(3) 410 - 429.
  • Typical dosages of alfuzosin are in the range of about 4 - 15 mg of the racemic mixture per day.
  • the mean oral bioavailability of alfuzosin is 64%, Wilde et al., supra, and the plasma half life of the drug is reported as between 4 - 9 hours, thus necessitating a twice or three times daily oral dosage regimen to maintain a constant therapeutically effective plasma blood level, S. Lieto di Priolo et al., Dose-Titration Study of Alfuzosin, a New Alphaj -Adrenoceptor Blocker in Essential Hypertension, Eur. J. Clin Pharmacol (1988) 35: 25-30.
  • Terazosin [1- (4-amino-6,7-dimethoxy-2- quinazonlinyl) -4- [tetrahydro-2-furanyl)carbonyl]piperazine] is a selective alpha, blocker with anti-hypertensive activity, as described in Titmarsh, S., et al. (1987) Drugs 33:461-477.
  • the structure of terazosin is shown in the Merck Index, 11th Edition, the contents of which are incorporated by reference, and in Formula IV.
  • the preferred compounds useful in practicing the subject invention are, 8 (3- [4- (2-methoxyphenyl) -1- piperazinyl] -propylcarbamoyl) -3-methyl-4-oxo-2-phenyl-4H-1- benzopyran, compound V; 2-cyclohexyl-8- ⁇ 3- [4- (2- methoxyphenyl) -l-piperazinyl] -propylcarbamoyl ⁇ -3-methyl-4- oxo-4H-l-benzopyran, compound VI; 8- ⁇ 3- [4- (2-methoxyphenyl) - 1-piperazinyl]propylcarbamoyl ⁇ -3-methyl-4-oxo-2- trifluoromethyl-4H-l-benzopyran, compound VII; 8- ⁇ 3-[4-(5- chloro-2-methoxyphenyl) -1-piperazinyl] -propylcarbamoyl ⁇ -3-
  • the compounds having Formula I are anti-adrenergic compounds, as described in U.S. Patent 5,403,842, for Benzo- pyran and Benzothiopyran Dervatives, Issued: April 4, 1995; U.S. Application Serial No. 08/067,861, filed: May 26, 1993, for Bicyclic Heterocyclic Derivatives; and U.S. Application Serial No. 08/299,188, filed August 31, 1994, for Bicyclic Heterocyclic Derivatives.
  • Compounds having Formula I can be prepared by following the procedures outlined in these references.
  • the compounds having Formula I and in particular Compounds V-XI have a high affinity and selectivity for the alpha, adrenergic receptors, and exhibit high selectivity for the mammalian lower urinary tract. That is, the compounds are substantially more active in antagonizing urethral contractions than in lowering blood pressure.
  • alpha, antagonists such as prazosin do not exhibit such selectivity, and in fact cause hypotension as a most common side effect.
  • the active compounds of the invention are useful for the treatment of hypertension and micturition troubles associated with obstructive disorders of the lower urinary tract, including benign prostatic hyperplasia.
  • the active ingredients are also useful as anti-hypertensive agents.
  • the compounds of the invention demonstrate antagonistic effects against contractions of rat bladder strip induced by potassium chloride, as described in PCT Publication No. WO/93,17007, the contents of which are hereby incorporated by reference. This effect may be attributed to a calcium antagonistic activity, and renders the active ingredient useful as antispasmodics of the lower urinary tract, and thus useful in the treatment of urinary incontinence, urge syndrome, and the like.
  • the alpha blockers are present as mesylate (CH 3 S0 3 " ) salts.
  • Many salt forms of active compounds for example inorganic, sulfonic and carboxylic acid salts tend to increase the melting point of the drug over the neutral free base form, thereby improving the stability and processing of basic drugs.
  • the choice of salt form may alter the solubility of the compound. Changing from a neutral form of a drug to a salt form affects the pH of the resulting solution, and a number of physical parameters, including melting point, molecular weight, stability, hygroscopicity and solubility.
  • salts prepared from strong acids are freely soluble in water. Strong acids are those with a pK, of less than 2, and are completely ionized in solution. According to the present invention, salts of strong alkane- or arenesulfonic acids may be used in pharmaceutical compositions to provide counterions for the manipulation of the performance of basic salt drugs.
  • Suitable alkane- or arenesulfonic acid anions include sulfate, tosylate (para-toluenesulfonate) , mesylate (methanesulfonate) , napsylate (1-napthalene-2-sulfonate) , besylate (benzene sulfonate) and maleate.
  • Table 1 provides the melting point and molecular weight of the free base, hydrochloride, and mesylate salt forms of selected alpha blockers of the present invention.
  • Table 2 provides the solubility of the free base forms of the alpha blocker, Compound V, in various vehicles. Solubility of free base is indicated as ⁇ g per ml of medium. PBS indicates phosphate buffered saline (20 mM phosphate and 0.9% NaCl) .
  • enhancer is meant to encompass any enhancer or combination of enhancers that increases the flux of a substance across a mammalian stratum corneum.
  • the enhancer that results in the highest skin flux is often specific to a particular drug and what works for one drug may not work for another.
  • concentration of enhancer and the particular combination of enhancers must be tailored to each drug to achieve the maximum skin flux.
  • permeation enhancers There are numerous possible permeation enhancers that can be used and they are typically categorized into two groups, solvent-type enhancers and plasticizing-type enhancers.
  • Plasticizer-type enhancers refers to fatty acids, fatty acid esters, fatty alcohols and similar hydrophobic compounds that are capable of increasing the permeability of drugs to the stratum corneum. Without limiting the scope of the present invention, the following is proposed as the mechanism of action of the plasticizer-type enhancers. It is believed that the function of the plasticizer-type enhancers is to migrate into the upper stratum corneum layers of the skin and disrupt the lipids which occupy the extracellular spaces of the stratum corneum. The stratum corneum layer, although only 25 - 50 microns thick, is the principal barrier to transdermal permeation. The plasticizer-type enhancers that migrate into the skin serve to increase the mobility and diffusion of the drug into the skin.
  • Plasticizer-type enhancers generally will have a molecular weight of greater than 150 but less than 1000.
  • the plasticizer-type enhancers should also be relatively water insoluble or they will leach into the subcutaneous tissue layers below the stratum corneum.
  • plasticizer-type enhancers with water solubility of less than 0.5 wt % are preferred, and more preferably 0.2 wt % or less.
  • Enhancers may also be classified according to their Hildebrand solubility parameters.
  • the Hildebrand solubility parameter measures the cohesive forces and sum of all intermolecular attractive forces related to the extent of mutual solubility of many chemical species. See, eg. the CRC Handbook of Solubility Parameters and other Cohesion Parameters, CRC Press, Inc., Boca Raton, Florida (1985). Relative hydrophilicity increases with the value of the Hildebrand solubility parameter ( ⁇ ) . For example, the skin has a ⁇ value of 10, while water has a ⁇ value of 23.4.
  • plasticizer type enhancers have a ⁇ value of between about 5 and 10.
  • a preferred group of plasticizer-type enhancers includes lower alkyl and alkoxy esters of pharmaceutically acceptable fatty acids, fatty acid esters, fatty alcohols, and similar hydrophobic compounds.
  • the term 'lower alkyl and lower alkoxy' refers to alkyl and alkoxy groups having up to and including 7 carbon atoms and preferably, up to and including 4 carbon atoms.
  • alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl and heptyl.
  • alkoxy groups include the oxides corresponding to the above alkyl groups.
  • suitable fatty acid esters include saturated or unsaturated fatty acid esters, including isopropyl myristate, isopropyl palmitate, and the methyl and ethyl esters of oleic and lauric acid.
  • Suitable fatty alcohols include stearyl alcohol and oleyl alcohol.
  • Suitable fatty acids include saturated and unsaturated fatty acids, including oleic acid, lauric acid, myristic acid, palmitic acid, stearic acid, linoleic acid, and palmitoleic acid.
  • plasticizer-type enhancers such as diethyl hexyl phthalate, octyldocecyl myristate, isostearyl isostearate, caprylic/capric triglycerides including polyethylene glycol esters of caprylic/capric acids, propylene glycol laurate (Lauroglycol) , Miglyol (propylene glycol diester caproic, caprylic, capric, lauric acid) , Lexol PG-865 (propylene glycol diester decanoic, octanoic acid) , propylene glycol myristate (mirpyl) , corn oil polyethylene glycol - 6 esters (
  • a preferred plasticizer-type enhancer for use with the mesylate salt of Compound V include caprylic/capric acids triglyceride PEG-4 esters, available as Labrafac Hydro WL 1219, (Gattefosse, Westwood, N.J.) which contains a mixture of saturated polyglycolyzed glycerides consisting of glycerides and polyethylene glycol esters of caprylic and capric acids.
  • the plasticizer-type enhancers may be used alone or in combination.
  • a particularly preferred enhancer combination including the caprylic/capric triglycerides for use with the mesylate salt of Compound V is an enhancer vehicle consisting essentially of ethanol: caprylic/capric triglycerides polyethylene glycol-4 ester: propylene glycol:isopropyl myristate in a 1:1:1:1 ratio.
  • solvent - type enhancer generally refers to relatively hydrophilic compounds having molecular weights of less than about 200 that are capable of increasing the permeability of drugs to the stratum corneum. Solvent-type enhancers typically exhibit solubility parameters between about 10 and 24, and preferably between about 10 and 18. Solvent-type enhancers are often better enhancers because they generally provide higher flux rates for a given permeant than plasticizer-type enhancers.
  • the solvent type enhancers will comprise a pharmaceutically-acceptable lower alkyl alcohol, aryl alcohol, or polyol, for example, ethanol, propanol, butanol, benzyl alcohol, glycerin, or propylene glycol.
  • the solvent-type enhancer is a 2-pyrrolidone or alkyl derivative thereof, such as N-methyl-2-pyrrolidone, 3- hydroxy-N-methyl-2-pyrrolidone, and pyroglutamic acid esters.
  • ethylene glycol ethers include, but are not limited to, ethylene glycol monoalkyl ethers, such as ethylene glycol monomethyl ether (also known as methyl cellosolve) , ethylene glycol dialkyl ethers, such as ethylene glycol dimethyl ether (also known as dimethyl cellosolve) , and ethylene glycol monoalkyl ether esters, such as ethylene glycol monoethyl ether acetate (also known as cellosolve acetate) .
  • ethylene glycol monoalkyl ethers such as ethylene glycol monomethyl ether (also known as methyl cellosolve)
  • ethylene glycol dialkyl ethers such as ethylene glycol dimethyl ether (also known as dimethyl cellosolve)
  • ethylene glycol monoalkyl ether esters such as ethylene glycol monoethyl ether acetate (also known as cellosolve acetate) .
  • polyethylene glycol ethers include, but are not limited to, diethylene glycol monoalkyl ethers, such as diethylene glycol monobutyl ether (also known as butyl ethyl Cellosolve or butyl carbitol) , diethylene glycol dialkyl ethers; and diethylene glycol monoalkyl ether esters, such as diethylene glycol monoethyl ether acetate (also known as Carbitol acetate) , and transcutol (diethylene glycol monoethyl ether) .
  • diethylene glycol monoalkyl ethers such as diethylene glycol monobutyl ether (also known as butyl ethyl Cellosolve or butyl carbitol)
  • diethylene glycol dialkyl ethers diethylene glycol dialkyl ethers
  • diethylene glycol monoalkyl ether esters such as diethylene glycol monoethyl ether acetate (also known as Carbitol a
  • Preferred solvent type enhancers have a molecular weight of less than about 150. They are also relatively hydrophilic, generally being greater than 2 wt% soluble in water, and are preferably greater than 10 wt% soluble in water. Most preferred solvent type enhancers are completely water miscible. One of skill in the art would appreciate that the solvent type enhancers may be used alone or in combination.
  • solvent type enhancers may be useful in delivering large amounts of therapeutic agents through the skin, when used alone, larger amounts of the solvent enhancer must often be applied continuously to achieve a prolonged therapeutic effect, to the extent that they themselves are permeable through the skin. As such, skin irritation may occur.
  • plasticizer-type enhancers when used in combination with one or more solvent-type enhancers, drugs can be delivered through the stratum corneum at therapeutically effective levels.
  • Such an enhancer mixture achieves high delivery rates of the drug with relatively dilute solutions of the solvent-type enhancer. This tends to eliminate the irritation that occurs when solvent-type enhancers are used alone at high concentrations.
  • the function of the solvent type enhancer is to rapidly diffuse into the stratum corneum layer of the skin, making it possible for the larger, less mobile plasticizer type enhancers to enter the stratum corneum layer.
  • the small size and hydrophilic nature of the solvent type enhancers makes them very effective in this role.
  • the design of the transdermal patch for use according to the invention involves several factors including the permeability of drug to the skin, the dose of the drug required for the desired therapeutic application, the enhancers used to promote delivery of the drug, and the flux rate of drug and enhancer formulations required to achieve a therapeutic effect.
  • Each active compound has unique physical and chemical properties that influence the design of the patch for effective delivery of the active compound to the patient.
  • Various patch designs may be used in accordance with the present invention, as exemplified in Figures 2 through 4.
  • the optimal patch configuration and enhancer combination and concentration is assessed experimentally in vi tro using two common methods, skin permeation testing and dissolution release tests.
  • dissolution release test the transdermal device is placed in a volume of receiving fluid sufficient to maintain sink conditions, which is stirred continuously and is maintained at a constant temperature. The cumulative amount of drug or enhancer released into the receiving medium is measured as a function of time. This test allows for confirmation of drug release from the transdermal device as well as a gross discrimination in drug release as a function of transdermal device components and formulation composition. However, the majority of screening is provided via in vi tro skin tests. These tests provide a more realistic picture of the device performance in vivo.
  • test solution or the transdermal device is placed in contact with the skin which is in contact with a receiving phase, usually saline.
  • a receiving phase usually saline.
  • the amount of drug permeating throughout the skin is determined by monitoring the drug concentration in the receiving phase as a function of time. See, for example, Ritschel and Barkhaus (1987) Meth. and Find. Exptl. Clin. Pharmacol. 9: 673-676.
  • Enhancer selection and composition may be optimized by empirical testing.
  • the transdermal patch for the delivery of Compound V is a simple adhesive patch, as shown in Figure 2.
  • the patch 1 comprises an impermeable backing layer 2, a release liner 3, and a drug/adhesive containing matrix 6.
  • the impermeable backing layer 2 defines the top of the drug delivery device, i.e., the side furthest away from the skin when the device is in use.
  • the backing forms an occlusive layer that prevents the loss of drug and/or enhancers to the environment and protects the patch from contamination from the environment.
  • the backing layer may be opaque so as to protect the drug from light.
  • the backing layer can be made from standard commercially available films for medical use, such as those supplied by 3M Corporation, St. Paul, MN; Dow Chemical, Midland, MI; or AF Packaging, Winston-Salem, NC.
  • Suitable materials which can be used to form the backing layer include films or sheets of polyolefin, polyester, polyurethane, polyvinyl alcohol, polyvinylidene, polyamide, ethylene-vinylacetate copolymer, ethylene-ethylacrylate copolymer, and the like, metal-vapor deposited films or sheets thereof, rubber sheets or films, expanded synthetic resin sheets or films, unwoven fabrics, fabrics, knitted fabrics, paper, and foils. These materials can be used individually or as laminates. These films can be pigmented or metalized.
  • Preferred backing layers include Scotchpak ® 1006 and 1009, skin-colored aluminized polyester films of approximately 70 - 80 ⁇ in thickness, and 3M-1012, a transparent polyester film laminate, all of which are available from 3M Corporation.
  • the patch may include a peel strip or release liner 3 to cover the surface of the pressure-sensitive adhesive during storage, and prevent evaporative loss of the drug or enhancer(s) .
  • the release liner may be formed with dimples for decreasing contacting surface with the adhesive layer, and it may also be formed with a pull-tab for making it easier for removing it from the device.
  • the peel strip may be made from any impermeable film, such as is specified for the backing layer. Additionally it may be made from metal foil, Mylar ® polyethylene terephthalate, or any material normally used for this purpose in the art that is compatible with the drug and the chosen adhesive.
  • suitable compositions for the release liner include siliconized polyester, poly (1, 1- dihydroperfluoroctylmethacrylate) , fumed silica in silicone rubber, end-capped siliconized polyethylene terephthalate, polytetrafluoroethylene, cellophane, a film of polyvinyl chloride having titanium dioxide dispersed therein, and the like.
  • Preferred release liners include a silicon coated Release Technology 381B and fluoropolymer coated polyester films, such as 3M Scotchpak ® 1022 film.
  • the drug depot layer is comprised of the drug and an adhesive, the layer attaching directly to the skin of the patient after the peel strip or release liner is removed.
  • the drug depot layer also comprises one or more enhancers.
  • the selection of the adhesive is important to the proper functioning of the transdermal delivery device. This is particularly true if a plasticizer-type enhancer is placed in the adhesive layer. Specifically, the adhesive layer must retain its functioning properties in the presence of the plasticizer-type and solvent-type enhancers, as well as upon exposure to the alpha blocker. However, often enhancers or other formulation ingredients can compromise the physicochemical and functional properties of an adhesive. Significant loss of cohesive strength can result in undesirable effects such as an increase in tack, cold flow beyond the edge of the patch, transfer of the adhesive to the protective release liner during removal, or adhesive residue left on the skin following removal of the patch. Alternatively, in some cases, the patch loses adhesion altogether and falls off.
  • the adhesive layer of the devices described herein contain a high level of plasticizer-type enhancer, typically from about 5 to about 50 wt% of a plasticizer-type enhancer, based on the adhesive layer, and preferably from about 10 to about 40 wt%, and more preferably from about 25 to about 35 wt%, the proper selection of the adhesive is important for the performance of these transdermal delivery devices.
  • the adhesives employed in the transdermal delivery systems described herein will have shear values greater than 2, with the higher values being preferred; plasticity values between about 1 and 4, and preferably greater than 1.5, with the higher values being preferred; tack values between about 50 and 1000, with the lower values being preferred; a dynamic loss modulus between about 10' 5 and 10 "7 at frequencies of 10" 2 rad/sec and between 10 "5 and 10 "7 at frequencies of 10 2 rad/sec; and a dynamic storage modulus between about 10" 5 and 10 "7 at frequencies of 10 "2 rad/sec and between 10 'J and 10 "7 at frequencies of 10 2 rad/sec. See Chang (1991) J. Adhesion 34:189-200 and European Patent Publication No. 524,776.
  • Cross-linked acrylate-based adhesives such as those available from Avery Chemical Division, Mill Hall, PA and National Starch and Chemical Company, Bridgewater, NJ, are able to withstand relatively high loading of enhancers, both solvent-type and plasticizer-type, while still maintaining these performance parameters.
  • These adhesives generally contain about 1 to about 5 wt% of acrylic acid, about 5 to about 20 wt% of a C 4 to a C, 2 alkyl acrylate or alkyl methacrylate.
  • the adhesives also can contain about 0.1 to about 5 wt% of a cross-linking monomer.
  • Preferred adhesive for delivery of Compound V of the present invention are acrylate-based adhesives.
  • Acrylate- based adhesives for use according to the present invention include Avery 2533 and Avery-460HPX adhesives (available from Avery Chemical Division (U.S.), Mill Hall, PA), Duro- tak ® 87-2516, 87-2852, and 87-2287 (available from National Starch, Bridgewater, NJ) , and Monsanto's Gelva GE 1753.
  • the acrylate adhesives Avery 2533 and Avery 460-HPX are similar acrylate adhesives with varying levels of cross linking.
  • the Durotak ® 87-2516, 87-2852 and 87-2287 are acrylic solution pressure sensitive adhesives, with the 2516 and 2852 being cross-linking and the 2287 being non- crosslinking.
  • Figure 3 shows a monolithic matrix patch, an alternative embodiment of the transdermal patch of the invention.
  • the patch 4 comprises an impermeable backing layer 2, a release liner 3, a monolithic matrix layer 14 comprising a polymer matrix in which drug is dispersed, and a peripheral adhesive layer 12.
  • the patch may also include an optional porous membrane layer.
  • the patch may have an adhesive layer that is co-extensive with the skin facing surface of the patch.
  • the monolithic matrix layer 14 comprises the drug, and one or more enhancers dispersed in a polymeric matrix.
  • the monolithic matrix layer may also comprise additional components such as diluents, stabilizers, vehicles, biocides, antioxidants, anti-irritants and the like.
  • a preferred embodiment of the monolithic matrix patch is a monolithic matrix patch with a peripheral adhesive annular ring and a drug depot having a hydrogel matrix or a foam matrix.
  • a further embodiment of the invention is the reservoir type patch which allows a higher loading level of active material, and usually, a higher loading level of enhancer.
  • An example of the reservoir type patch is shown in Figure 4.
  • the patch 7 is comprised of an impermeable backing layer 2 which is sealed at its periphery to an inert membrane 8, thereby defining between these two layers a drug depot 5.
  • An adhesive layer 9 is affixed to the skin facing side of the patch.
  • the patch also comprises a release liner 3.
  • the drug depot contains the drug, and optionally one or more enhancers or gelling components.
  • a membrane separates the drug reservoir from the adhesive layer.
  • the membrane is a non-rate controlling membrane.
  • a non-rate controlling membrane is one in which the rate of permeation of the enhancer(s) and drug through the membrane is greater than their permeation rate through the skin or any other portion of the device (typically two to five times greater or more) .
  • a non- rate controlling membrane is extremely permeable to the enhancer(s) and the drug contained in the reservoir.
  • the membrane may be a rate- controlling membrane.
  • a rate-controlling membrane is one in which the rate of permeation of the enhancer(s) and the drug through the membrane is less than or equal to their permeation rate through the skin or any other portion of the device. Rate-controlling membranes are described, for example, in U.S. Patent Nos. 4,460,372 and 4,379,454.
  • the membrane may comprise a microporous or porous material.
  • Microporous membranes have a distinct pore structure with pores ranging in diameter from approximately 0.08 to 0.5 microns, preferably from about 0.1 and 0.4 microns, and more preferably from about 0.2 and 0.4 microns.
  • suitable microporous membranes include polyethylene and polypropylene films, nylon, and nitrocellulose film.
  • a preferred membrane material is Cotran ® 9710, which is a polyethylene membrane, 50 ⁇ m in thickness, with a void volume of greater than 10%, available from 3M Corporation.
  • Other embodiments of the present invention will utilize other microporous polyethylene membranes, such as Celgard K-256, available from Hoechst- Celanese, Charlotte, NC.
  • Porous membranes have pores greater than about 3 microns in diameter. Such materials are available as woven and non-woven fabrics, such as non- woven polyester #9770 from Dexter Corp. (Windsor Locks,
  • the membrane and the backing layer are sealed at their peripheral edges to form the drug reservoir.
  • This seal should be substantially fluid-tight to prevent drug leakage from the reservoir through the seal between the backing layer and the membrane.
  • peripheral edges refer to the areas that are sealed together to define the drug reservoir. Therefore, extraneous membrane and backing layer material may extend outwardly from the drug reservoir and peripheral edge.
  • the drug reservoir contains a solution, suspension, or gel of the drug and the permeation enhancers, as well as diluents, such as water, and vehicles or other additives.
  • the drug can be dispersed in the solution, suspension, or gel in either a dissolved or undissolved state.
  • a gelling agent may be incorporated into the reservoir or monolithic matrix to increase the viscosity and rheological characteristics of the drug and enhancers.
  • the agent also serves to prevent settling of the dispersed drug during storage.
  • a viscosity range of about 100 to 100,000 centipoise for the combination of materials forming the reservoir is necessary in order to produce the drug delivery device using form-filling technology, as described in greater detail below.
  • the gelling agent comprises a pharmaceutically- acceptable material that is capable of increasing viscosity of the reservoir solution.
  • the drug delivery devices described herein will employ cellulosic materials as the gelling agent.
  • suitable cellulosic materials include cellulose, cellulose derivatives, alkylcellulose, hydroxy- (lower alkyl) cellulose derivatives where the alkyl group contains one to six carbons, carboxyalkylcellulose and the like.
  • Other gelling agents include PVP, CMC, Klucel, alginates, kaolinate, bentonite, or montmorillonite, other clay fillers, stearates, silicon dioxide particles, carboxy polymethylene, ethylene maleic anhydride, polyacrylamide, and poly (methyl vinyl ether maleic anhydride.)
  • a preferred embodiment of the present invention utilizes a hydroxy- (lower alkyl) cellulose as the gelling agent.
  • hydroxypropylcellulose will be employed in an amount from about 0.1 to about 20 wt%, based on the reservoir fill solution, and preferably from about 0.5 to about 10 wt%.
  • the gelling agent is present in about 2 wt%.
  • the reservoir or matrix layer also may include diluents, stabilizers, vehicles, biocides, antioxidants, anti-irritants and the like.
  • diluents For example, water is frequently utilized as a diluent in the reservoir type patches. Typically water will be present in the reservoir in an amount not greater than about 50 wt%, based on the reservoir fill solution; preferably, not greater than 40 wt%.
  • Other diluents which will frequently find use in the drug delivery devices described herein include glycerine and propylene glycol.
  • a pressure-sensitive adhesive layer is affixed to the membrane opposite to the backing layer.
  • the adhesive layer should interact minimally with the drug; it should adhere firmly to the membrane, but removably to the peel strip; it should stick securely to the wearer for extended periods, yet allow the transdermal delivery device to be removed with minimum discomfort; and it should not give rise to undue skin irritation, allergic reactions or other dermatological problems. These properties must be maintained from the time of patch manufacture, throughout storage, and up to and throughout the time of application.
  • An alternative embodiment of the reservoir patch has a peripheral adhesive, wherein the area of the adhesive layer is not co-extensive with the active releasing area of the patch, but rather forms an annular ring around the active releasing area of the patch.
  • the delivery of the drug thus is not primarily through the adhesive layer of the patch, although some lateral diffusion may occur within the patch, resulting in delivery of active substance through the adhesive at the periphery of the patch.
  • the shape of the peripheral adhesive region will vary with the shape of the patch, but will generally comprise the outer perimeter of the patch, in order that an adequate adhesive seal is maintained between the skin and the patch to prevent the patch from falling off.
  • the percentage of the patch that comprises the peripheral adhesive portion depends on the type of adhesive, the type of backing layer, the length of time the patch will be worn, and the weight and loading of drug in the patch. Such determinations will be apparent to the skilled artisan.
  • the patches Prior to use, the patches typically are stored in laminate foil pouches, both to prevent contamination and to avoid drug and/or enhancer(s) loss.
  • laminate foil pouches are standard in the industry, and are described in copending United States Patent Application Serial No., 08/060,907, the contents of which are expressly incorporated by reference.
  • the patch may be assembled by any of the techniques known in the art for producing transdermal patches.
  • the patches may be of various shapes, but the round shape is preferred as it contains no corners and thus is less easily detached from the skin.
  • the dosage units produced may have various sizes. A total surface area in the range of 1 to 200 cm 2 is contemplated, with 5 - 30 cm 2 being preferred.
  • the active drug delivery surface area may be somewhat less than the total surface area, for example, in the peripheral adhesive type reservoir patch.
  • the active drug delivery surface area is in the range of 1 - 190 cm 2 , with 5 - 30 cm 2 being preferred.
  • the percentage by weight of the drug in the solution, hydrogel or matrix may be varied according to the desired loading of the finished patch.
  • the drug content of the finished matrix can vary widely, from about 0.1 to about 70 wt%.
  • the transdermal patch is applied such that a dose is an amount from 0.1 to 200 mg per day, depending on the therapeutic application.
  • dosages for obstructive disorders of the lower urinary tract are between 0.001 and 20 mg/kg/of body weight per day, with preferred dosages being between 0.05 and 1 mg/kg of body weight per day, and most preferred dosages being at least approximately 0.3 mg/kg of body weight per day.
  • the dosage of Compound V will generally be between 0.01 and 20 mg/kg of body weight per day, with preferred dosages being between 0.1 and 5 mg/kg of body weight per day, and a most preferred dosage being at least approximately 1 mg/kg of body weight per day.
  • the general dosage is between 0.10 and 20 mg/kg of body weight per day, with a preferred dosage being 0.02 - 10 mg/kg of body weight per day, and a most preferred dosage being at least approximately 2 mg/kg of body weight per day.
  • the dosage is generally between 0.01 - 20 mg/kg of body weight per day, with a preferred dosage being between 0.05 - 5 mg/kg body weight per day, with a most preferred dosage being at least approximately 0.5 mg/kg body weight per day.
  • the dosage may, however, be more or less depending on factors including therapeutic application, the age of the patient, and the patient's tolerance to the drug, if any. Such dosage changes may be determined by the physician in each case.
  • Example 1 Preparation of 8-(3- f4- (2-methoxyphenyl) -1- piperazinyl1 -propylcarbamoyl ⁇ -3-methyl-4-oxo-2-phenyl-4H-1- benzopyran.
  • a mixture of 6.28 g of 1- (2-methoxyphenyl)piperazine and 5.34 g of 8- (3-chloropropylcarbamoyl) -3-methyl-4-oxo-2- phenyl-4H-1-benzopyran was heated at 180°C for 5 hours. After cooling, the dark mass was purified by flash chromatography on silica gel, eluting with dichloromethane /methanol 100:3.
  • Example 1 The residue (A) of Example 1 was dissolved in boiling ethanol. The solution was filtered, acidified with ethanolic hydrogen chloride, and stood overnight at 20-25°C. The crude product was collected by filtration and crystallized from ethanol to give 5 g of the title compound, m.p. (177) 182-186°C.
  • the amine can also be condensed at room temperature with an equimolar amount of the corresponding free acid in the presence of N,N' -dicyclohexylcarbodiimide and 4-dimethylaminopyridine in a solvent such as dichloromethane, chloroform, tetrahydrofuran or dimethylformamide.
  • Example 4 Preparation of 8- ⁇ 3- .4- (2-methoxyphenyl) -1- piperazinyl] -propylcarbamoyl ⁇ -3-methyl-4-oxo-2-phenyl-4H-1- benzopyran monomethanesulfonate.
  • the residue (B) of Example 3 was dissolved in boiling isopropanol and added with 1 molar equivalent of methanesulfonic acid. After cooling to room temperature, filtering and washing the cake with hot acetone, the monomethanesulfonate salt melting at 162-164°C, was obtained.
  • Example 5 Preparation of 8- ⁇ 3- .4- (2-methoxyphenyl) -1- piperazinyll -propylcarbamoyl ⁇ -3-methyl-4-oxo-2-phenyl-4H-1- benzopyran monomethanesulfonate monohydrate.
  • the monomethanesulfonate salt of Example 4 when recrystallized from water or ethanol/water gives the corresponding monohydrate salt melting in the range of 136- 141°C.
  • Example 6
  • Diethyl cyanophosphonate (0.75 mL) was added dropwise, at 0-5°C, into a stirred solution of 0.86 g of 2- cyclohexyl-3-methyl-4-oxo-4H-1-benzopyran-8-carboxylic acid and 0.85 g of 1- (3-aminopropyl) -4- (5-chloro-2- methoxyphenyUpiperazine in 6 mL of anhydrous dimethylformamide.
  • Methanesulfonic acid 0.18 g was added to a solution of the pure base in 12 L of chloroform. After solvent evaporation, the oily residue was dissolved in 10 mL of ethyl acetate and stirred at 60°C. The solvent was removed in vacuo and the solid residue was crystallizes from acetonitrile to give 1 g of the title compound as monomethanesulfonate, m.p. 200-203°C.
  • Pivaloyl chloride is added dropwise at 10-15°C to a stirred mixture of methyl 2-hydroxy-3-methylbenzoate and 4-dimethylaminopyridine in 25 ml of dichloromethane. After 2 hours at room temperature, the reaction is quenched with 200 ml of water. The organic layer is washed with 5% sodium bicarbonate, dried on anhydrous sodium sulfate and evaporated in vacuo. The product is purified by flash chromatography on silica gel. Methyl 3-bromomethyl-2- (2,2-dimethylpropanoyl)benzoate.
  • a mixture of methyl 3-methyl-2- (2,2-dimethyl- propanoyl)benzoate, N-bromosuccinimide and benzoylperoxide in of anhydrous carbon tetrachloride is stirred at reflux for about 1.5 hours. After cooling to room temperature the formed succinimide is collected by suction and washed with cold carbon tetrachloride. The mother liquors are evaporated to dryness in vacuo and the residue is rinsed with diethyl ether and collected by suction filtration to provide the title compound.
  • a mixture of methyl 3-bromomethyl-2- (2,2-dimethyl- propanoyl)benzoate and triphenylphosphine are mixed in acetonitrile and heated at reflux for about 8 hours. After cooling the product is collected by filtration and washed with cold ethyl ether. The crude product is used without purification.
  • Diethyl cyanophosphonate is added dropwise at 0/5°C into a stirred solution of 2- (1,l-dimethylethyl)benzofuran- 7-carboxylic acid and l- (3-aminopropyl) -4- (5-chloro-2- methoxyphenyl)piperazine in anhydrous dimethylformamide.
  • Triethylamine is immediately added, dropwise, at the same temperature. Stirring is continued for 30 minutes at 0/5°C and for 1 hour at room temperature.
  • the reaction mixture is poured into 2.5 % aqueous sodium carbonate solution.
  • the precipitate formed is stirred for 1 hour at room tempera ⁇ ture, collected by suction and crystallized from ethanol.
  • Example 8 In vi tro flux of Compound V free base through hairless mouse skin. The murine in vitro skin permeation rate of saturated solutions of Compound V free base in various enhancer and combination enhancer systems was tested.
  • the skin permeation rate was measured using a high- throughput screening apparatus as described in copending United States Patent Application Serial No. 08/227,964.
  • Each cell of the apparatus comprises one or more diffusion cells, each with an active area of 0.23 cm 2 and a receiving volume of 1 ml.
  • the receiver side of the micro-diffusion cells were filled with l ml receptor fluid (10 mM phosphate buffered saline, pH 5.7) by a robot after placing one ball bearing in each cell.
  • Hairless mouse skin with a thickness of between 380 and 650 ⁇ m (average thickness 540 ⁇ m) was placed and clamped on the lower half of the diffusion cell with the stratum corneum facing the donor compartment.
  • One ball bearing was placed in each donor cell and the donor vehicle solutions were loaded.
  • four donor cells were tested for each drug/enhancer formulation.
  • the donor cells were capped with rubber stoppers and the assembly was placed in a 32°C incubator and gently rocked for six hours. After six hours the units were removed from the incubator and disassembled. Excess formulation solution was removed. Each compartment was examined to ensure, undamaged skin and complete coverage of the cells with the skin. Excess formulations were blot dried and the skin was carefully removed from the receiver side of the unit. The receiver solutions were analyzed by HPLC, to determine the cumulative amount of drug permeated across the skin ( ⁇ g/cm 2 /hr) in the six hour period.
  • the enhancers tested in Table 3 include single enhancers as well as enhancer combinations.
  • the tested enhancers include solvent type enhancers and plasticizing type enhancers.
  • Enhancer combinations were prepared to achieve increased flux of Compound V.
  • Combinations comprising a plasticizer-type enhancer and a solvent-type enhancer were prepared and tested in ratios of 25:75, 50:50, and 75:25, as indicated in Table 2.
  • preferred enhancer combinations for delivery of Compound V are N-methyl-pyrrolidone:oleyl alcohol, transcutol:isopropyl myristate, and N-methyl-pyrrolidone:isopropyl myristate.
  • a particularly preferred enhancer combination is a 50:50 ratio of N-methyl-pyrrolidone and oleyl alcohol.
  • Example 9 In vi tro flux of Compound V mesylate through hairless mouse skin.
  • the murine in vitro skin permeation rate of the mesylate salt of Compound V was measured, using various enhancer systems.
  • the concentration of the drug solution was approximately 100 mg/ml for EtOH:Water:IPM and saturated in all other systems.
  • the skin permeation rates were measured as described in Example 8, and are shown in Table 4.
  • IPM indicates isopropyl myristate
  • PG indicates propylene glycol
  • EtOH:PG:IPM Labrafac 8.44 lipophile EtOH:PG:IPM: Labrafil M2125CS 17.80
  • EtOH:PG:IPM propylene glycol 19.03 laurate EtOH:PG:IPM: Labrafil M2125CS
  • the human in vi tro skin permeation rate of the mesylate salt and the free base of the drug was measured using two enhancer systems saturated with Compound V.
  • Glass diffusion cells with an area of 1 cm 2 and a receiver volume of approximately 3.3 ml were filled with a degassed phosphate buffer solution with a pH of 5.7.
  • a magnetic stirring bar provided constant mixing.
  • the temperature was kept at 32°C by a surrounding water jacket.
  • the human skin was placed on the top of the receiver cells and held in place by the donor half which was then clamped down.
  • N-methyl-pyrrolidone:Oleyl alcohol 50:50
  • Propylene glycol:Oleyl alcohol 25:75
  • N-methyl-pyrrolidone Isopropyl myristate (50:50)
  • the patch size for delivering Compound V at a minimum daily dose of, for example 0.75 mg (0.01 mg/kg body weight for an average patient weight of 75 kg) is approximately 5 - 40 cm in these enhancer systems.
  • An acrylate adhesive casting solution (Durotak 2516) was prepared containing 7% Compound V.
  • the casting solution was cast onto a silicone coated release liner (Release Technology 381B) to a thickness of 50-200 ⁇ m and dried at room temperature for 20 min. and then at 70°C for 30 min.
  • a polyester backing (3M 1220) was adhered to the dried adhesive film which was then punched into patches of the desired size.
  • the drug release from these adhesive patch systems was determined by dissolution test. Glass flow through cells with an area of 1 cm 2 and a receiver volume of approximately 3.3 ml were filled with a degassed 10 mM phosphate-buffered saline solution with a pH of 5.7. A magnetic stirring bar provided constant mixing and the temperature was kept at 32°C by a surrounding water jacket. The patches were attached to the top of the receiver cells and clamped down. The flow of the receiving solution was regulated to 3 ml/h and data points were collected every 3 hours over 24 hours. The samples were assayed for the presence of Compound V by HPLC. The results are shown in Table 6. TABLE 6
  • An acrylate adhesive casting solution (Durotak 2516) is prepared containing 10% Compound V and 20% N-methyl-2- pyrrolidone.
  • the casting solution is cast onto a silicone coated release liner (Release Technology 381B) to a thickness of 50-200 ⁇ m and dried at room temperature for 20 min. and then at 70°C for 30 min.
  • a polyester backing (3M 1220) is adhered to the dried adhesive film which is then punched into patches of the desired size.
  • An acrylate adhesive casting solution (Durotak 2516) is prepared containing 7% Compound V. Half of the casting solution is cast onto a silicone coated release liner
  • a polyester medical tape (3M Corp. or Avery Dennison) - comprising an adhesive layer with a thickness of 1-3 mm in-between a release liner and a backing layer - is affixed to a 20 cm 2 foil disk after removal of the release liner.
  • the medical tape extends the foil disk area, thereby forming a peripheral adhesive annular element.
  • a polyethylene foam coated with an adhesive on one side (Coating Sciences RX Series) is punched to an 18 cm 2 disk and adhered to the center of the foil disk.
  • the foam and exposed adhesive area are then covered by a protective release liner (Release Technology 381B) .
  • Example 15 Preparation of silicone elastomer matrix patches with peripheral adhesive.
  • Silastic MDX 4-4210 (Dow Corning Group) is mixed with 5 g of curing agent using a high shear mixer at 2000 rpm. 15 g of this solution is homogenized with 5 g of Compound V mesylate solution in Propylene glycol/propylene glycol laurate/Isopropyl myristate (2:1:1) using a high shear mixer. The prepared solution is deaerated in a vacuum (30 mmHg) for one hour and then poured between the uncoated sides of two sheets of polyester membrane (3M Scotchpak Fluoropolymer coated release liner 1022) .
  • the units are pulled through the adhesive coating units (Werner Mathis AG) to achieve a uniform thickness film, of between 0.5 and 2.0 mm.
  • the film is cured in a 100°C oven for 15 minutes.
  • the finished film is cut into disks with desired diameter and the polyester films are removed. These disks are transferred onto an adhesive film (Dow 4201 Silicone adhesive) cast on backing membrane (Scotchpak 1009) .
  • the release liner (3M 1022) is placed on top and the patches are punched out in a size larger than the silicone elastomer disks to get peripheral adhesive rim.
  • silicone elastomer containing drug and enhancer solution is in direct contact with skin and the peripheral rim of adhesive affixes the patch to the skin of the patient.
  • Two Durotak 9852 adhesive solutions were prepared, one containing 30 wt% isopropyl myristate.
  • the adhesive/ enhancer solutions were cast on the coated side of a 3M Scotchpak Fluoropolymer coated Release Liner No. 1022 or a Release Technology silicon-coated polyester membrane 381B to a thickness of 75 ⁇ m after being dried at room temperature for 30 minutes and then in a 100°C oven for fifteen minutes.
  • a 3M Cotran microporous polyethylene film membrane No. 9710 and a 3M Scotchpak polyester film laminate No. 1009 backing were laminated onto the adhesive layer.
  • the laminates were heat sealed to obtain 5 cm 2 active area circles with a narrow neck opening, and were punched out by hand by cutting along the outer edge of the heat seal.
  • These patch shells were weighed before filling.
  • the reservoir of the patch is filled with a drug solution prepared as follows.
  • Compound V fill solutions were prepared using an EtOH:water:IPM (49:49:2) enhancer mixture, with 2% hydroxypropyl cellulose as a gelling agent.
  • the concentration of Compound V mesylate was 100 mg/g of vehicle.
  • the volume of the drug fill solution for each patch was approximately 0.3 ml.
  • the fill solution was loaded with a l ml syringe through the opening of the patch, the opening of each patch was heat sealed, and the patches were re- weighed. Patches were stored at room temperature in heat- sealed Barex pouches.
  • Example 17 Hydrogel preparation.
  • Example 18 Preparation of a peripheral adhesive hvdrogel transdermal patch.
  • a polyester medical tape (3M Corporation or Avery Dennison) , comprising an adhesive layer with a thickness of between 1 and 3 millimeters, sandwiched between a release liner and a backing layer, is affixed to a 5 - 40 cm 2 foil disk after removal of the release liner from the medical tape.
  • the area of the foil disk is smaller than that of the medical tape such that the adhesive portion of the medical tape extends outwardly from the foil disk, thereby forming a peripheral adhesive annular element.
  • the disk is then filled with the hydrogel of Example 17, containing drug and optional penetration enhancers.
  • the gel and exposed adhesive surface are then covered by a protective release liner.
  • An acrylate adhesive casting solution (Durotak 2516) is prepared containing 7% Compound VI.
  • Half of the casting solution is cast onto a silicone coated release liner (Release Technology 381B) and the other half onto a backing (3M 1220) to a thickness of 50-200 ⁇ m. Both films are dried at room temperature for 20 min. and then at 70°C for 30 min.
  • Polyurethane foam (Great Western Foam Products) is punched to 20 cm 2 disks and adhered to the adhesive film on the release liner with approximately 3 cm distance in-between the disks.
  • Example 20 Preparation of peripheral adhesive monolithic foam matrix patch.
  • a polyester medical tape (3M Corp. or Avery Dennison) - comprising an adhesive layer with a thickness of 1-3 mm in-between a release liner and a backing layer - is affixed to a 20 cm 2 foil disk after removal of the release liner.
  • the medical tape extends the foil disk area, thereby forming a peripheral adhesive annular element.
  • a polyethylene foam coated with an adhesive on one side (Coating Sciences RX Series) is punched to an 18 cm 2 disk and adhered to the center of the foil disk.
  • the foam and exposed adhesive area are then covered by a protective release liner (Release Technology 381B) .
  • Example 21 Preparation of silicone elastomer matrix patches with peripheral adhesive.
  • Silastic MDX 4-4210 (Dow Corning Group) is mixed with 5 g of curing agent using a high shear mixer at 2000 rpm. 15 g of this solution is homogenized with 5 g of Compound VIII mesylate solution in Propylene glycol/ propylene glycol laurate/Isopropyl myristate (2:1:1) using a high shear mixer. The prepared solution is deaerated in a vacuum (30 mmHg) for one hour and then poured between the uncoated sides of two sheets of polyester membrane (3M Scotchpak Fluoropolymer coated release liner 1022) .
  • the units are pulled through the adhesive coating units (Werner Mathis AG) to achieve a uniform thickness film, of between 0.5 and 2.0 mm.
  • the film is cured in a 100°C oven for 15 minutes.
  • the finished film is cut into disks with desired diameter and the polyester films are removed. These disks are transferred onto an adhesive film (Dow 4201 Silicone adhesive) cast on backing membrane (Scotchpak 1009) .
  • the release liner (3M 1022) is placed on top and the patches are punched out in a size larger than the silicone elastomer disks to get peripheral adhesive rim.
  • silicone elastomer containing drug and enhancer solution is in direct contact with skin and the peripheral rim of adhesive affixes the patch to the skin of the patient.
  • Example 22 Preparation of liquid reservoir transdermal patches.
  • Two Durotak 9852 adhesive solutions are prepared, one containing 30 wt% isopropyl myristate.
  • the adhesive/ enhancer solutions are cast on the coated side of a 3M Scotchpak Fluoropolymer coated Release Liner No. 1022 or a Release Technology silicon-coated polyester membrane 381B to a thickness of 75 ⁇ m after being dried at room temperature for 30 minutes and then in a 100°C oven for fifteen minutes.
  • a 3M Cotran microporous polyethylene film membrane No. 9710 and a 3M Scotchpak polyester film laminate No. 1009 backing are laminated onto the adhesive layer.
  • the laminates are heat sealed to obtain 5 cm 2 active area circles with a narrow neck opening, and are punched out by hand by cutting along the outer edge of the heat seal.
  • These patch shells are weighed before filling.
  • the reservoir of the patch is filled with a drug solution prepared as follows.
  • Compound IX fill solutions are prepared using an EtOH:water:IPM (49:49:2) enhancer mixture, with 2% hydroxypropyl cellulose as a gelling agent.
  • the concentration of Compound IX mesylate is 100 mg/g of vehicle.
  • the volume of the drug fill solution for each patch is approximately 0.3 ml.
  • the fill solution is loaded with a 1 ml syringe through the opening of the patch, the opening of each patch is heat sealed, and the patches are re- weighed. Patches are stored at room temperature in heat- sealed Barex pouches.
  • Example 24 Preparation of a peripheral adhesive hydrogel transdermal patch.
  • a polyester medical tape (3M Corporation or Avery Dennison) , comprising an adhesive layer with a thickness of between 1 and 3 millimeters, sandwiched between a release liner and a backing layer, is affixed to a 5 - 40 cm 2 foil disk after removal of the release liner from the medical tape.
  • the area of the foil disk is smaller than that of the medical tape such that the adhesive portion of the medical tape extends outwardly from the foil disk, thereby forming a peripheral adhesive annular element.
  • the disk is then filled with a hydrogel, using compound XI as the drug, prepared according to Example 22, containing the drug and optional penetration enhancers.
  • the gel and exposed adhesive surface are then covered by a protective release liner.

Landscapes

  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne l'administration percutanée de composés inhibiteurs des récepteurs alpha-adrénergiques. L'invention concerne également des procédés d'administration de tels composés à des patients selon des posologies thérapeutiquement efficaces.
PCT/US1995/014620 1995-10-20 1995-10-20 Administration percutanee d'inhibiteurs des recepteurs alpha-adrenergiques WO1997014419A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU41534/96A AU4153496A (en) 1995-10-20 1995-10-20 Transdermal delivery of alpha adrenoceptor blocking agents
PCT/US1995/014620 WO1997014419A1 (fr) 1995-10-20 1995-10-20 Administration percutanee d'inhibiteurs des recepteurs alpha-adrenergiques

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US1995/014620 WO1997014419A1 (fr) 1995-10-20 1995-10-20 Administration percutanee d'inhibiteurs des recepteurs alpha-adrenergiques

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WO1997014419A1 true WO1997014419A1 (fr) 1997-04-24

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US6924376B2 (en) 2002-04-17 2005-08-02 Cytokinetics, Inc. Compounds, compositions and methods
US6949538B2 (en) 2002-07-17 2005-09-27 Cytokinetics, Inc. Compounds, compositions, and methods
US7160888B2 (en) 2003-08-22 2007-01-09 Warner Lambert Company Llc [1,8]naphthyridin-2-ones and related compounds for the treatment of schizophrenia
US7973069B2 (en) 2004-07-14 2011-07-05 Ptc Therapeutics, Inc. Methods for treating hepatitis C
US10588900B2 (en) 2016-02-09 2020-03-17 Pharmakea, Inc. Quinolinone lysyl oxidase-like 2 inhibitors and uses thereof
US11820747B2 (en) 2021-11-02 2023-11-21 Flare Therapeutics Inc. PPARG inverse agonists and uses thereof
US11827627B2 (en) 2021-06-04 2023-11-28 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamides as modulators of sodium channels
US11834441B2 (en) 2019-12-06 2023-12-05 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofurans as modulators of sodium channels

Citations (2)

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Publication number Priority date Publication date Assignee Title
WO1993017007A1 (fr) * 1992-02-25 1993-09-02 Recordati Industria Chimica E Farmaceutica S.P.A. Composes heterobicycliques
WO1995028932A1 (fr) * 1994-04-22 1995-11-02 Flora Inc. ADMINISTRATION TRANSDERMIQUE D'AGENTS BLOQUANTS DES RECEPTEURS ADRENERGIQUES $g(a)

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993017007A1 (fr) * 1992-02-25 1993-09-02 Recordati Industria Chimica E Farmaceutica S.P.A. Composes heterobicycliques
WO1995028932A1 (fr) * 1994-04-22 1995-11-02 Flora Inc. ADMINISTRATION TRANSDERMIQUE D'AGENTS BLOQUANTS DES RECEPTEURS ADRENERGIQUES $g(a)

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8329928B2 (en) 2002-04-17 2012-12-11 Cytokinetics, Incorporated Compounds, compositions and methods
US8633236B2 (en) 2002-04-17 2014-01-21 Cytokinetics, Inc. Compounds, compositions and methods
US7491746B2 (en) 2002-04-17 2009-02-17 Cytokinetics, Inc. Compounds, compositions and methods
US7629477B2 (en) 2002-04-17 2009-12-08 Cytokinetics, Inc. Compounds, compositions and methods
US7919524B2 (en) 2002-04-17 2011-04-05 Cytokinetics, Inc. Compounds, compositions and methods
US8119678B2 (en) 2002-04-17 2012-02-21 Cytokinetics, Incorporated Compounds, compositions and methods
US6924376B2 (en) 2002-04-17 2005-08-02 Cytokinetics, Inc. Compounds, compositions and methods
US6949538B2 (en) 2002-07-17 2005-09-27 Cytokinetics, Inc. Compounds, compositions, and methods
US7160888B2 (en) 2003-08-22 2007-01-09 Warner Lambert Company Llc [1,8]naphthyridin-2-ones and related compounds for the treatment of schizophrenia
US7973069B2 (en) 2004-07-14 2011-07-05 Ptc Therapeutics, Inc. Methods for treating hepatitis C
US10588900B2 (en) 2016-02-09 2020-03-17 Pharmakea, Inc. Quinolinone lysyl oxidase-like 2 inhibitors and uses thereof
US11058676B2 (en) 2016-02-09 2021-07-13 Pharmakea, Inc. Quinolinone lysyl oxidase-like 2 inhibitors and uses thereof
US11834441B2 (en) 2019-12-06 2023-12-05 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofurans as modulators of sodium channels
US11919887B2 (en) 2019-12-06 2024-03-05 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofurans as modulators of sodium channels
US12247021B2 (en) 2019-12-06 2025-03-11 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofurans as modulators of sodium channels
US11827627B2 (en) 2021-06-04 2023-11-28 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamides as modulators of sodium channels
US12258333B2 (en) 2021-06-04 2025-03-25 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamides as modulators of sodium channels
US11820747B2 (en) 2021-11-02 2023-11-21 Flare Therapeutics Inc. PPARG inverse agonists and uses thereof

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