WO2009100380A1 - Use of ranolazine for treating pain - Google Patents
Use of ranolazine for treating pain Download PDFInfo
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- WO2009100380A1 WO2009100380A1 PCT/US2009/033464 US2009033464W WO2009100380A1 WO 2009100380 A1 WO2009100380 A1 WO 2009100380A1 US 2009033464 W US2009033464 W US 2009033464W WO 2009100380 A1 WO2009100380 A1 WO 2009100380A1
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- ranolazine
- pain
- rnavl
- hnavl
- administered
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P23/00—Anaesthetics
- A61P23/02—Local anaesthetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Definitions
- This invention relates to methods for treating a patient suffering from neuropathic or nociceptive pain which may be mechanical, visceral, and/or inflammatory in nature, comprising administering a therapeutically effective amount of Ranolazine to a patient in need thereof
- This patent also discloses intravenous (IV) formulations of dihydrochloride Ranolazine further comprising propylene glycol, polyethylene glycol 400, Tween 80 and 0.9% saline.
- U.S. Patent No. 5,506,229 which is incorporated herein by reference in its entirety, discloses the use of Ranolazine and its pharmaceutically acceptable salts and esters for the treatment of tissues experiencing a physical or chemical insult, including cardioplegia, hypoxic or reperfusion injury to cardiac or skeletal muscle or brain tissue, and for use in transplants. Oral and parenteral formulations are disclosed, including controlled release formulations.
- Example 7D of U.S. Patent No. 5,506,229 describes a controlled release formulation in capsule form comprising microspheres of Ranolazine and microcrystalline cellulose coated with release controlling polymers.
- This patent also discloses IV Ranolazine formulations which at the low end comprise 5 mg Ranolazine per milliliter of an IV solution containing about 5% by weight dextrose. And at the high end, there is disclosed an IV solution containing 200 mg Ranolazine per milliliter of an IV solution containing about 4% by weight dextrose.
- a typical oral dosage form is a compressed tablet, a hard gelatin capsule filled with a powder mix or granulate, or a soft gelatin capsule (softgel) filled with a solution or suspension.
- a typical oral dosage form is a compressed tablet, a hard gelatin capsule filled with a powder mix or granulate, or a soft gelatin capsule (softgel) filled with a solution or suspension.
- U.S. Patent No. 5,472,707 discloses a high-dose oral formulation employing supercooled liquid Ranolazine as a fill solution for a hard gelatin capsule or softgel.
- U.S. Patent No. 6,503,911 discloses sustained release formulations that overcome the problem of affording a satisfactory plasma level of Ranolazine while the formulation travels through both an acidic environment in the stomach and a more basic environment through the intestine, and has proven to be very effective in providing the plasma levels that are necessary for the treatment of angina and other cardiovascular diseases.
- U.S. Patent No. 6,852,724 discloses methods of treating cardiovascular diseases, including arrhythmias variant and exercise-induced angina and myocardial infarction.
- U.S. Patent Application Publication Number 2006/0177502 discloses oral sustained release dosage forms in which the Ranolazine is present in 35-50%, preferably 40-45% Ranolazine.
- the Ranolazine sustained release formulations of the invention include a pH dependent binder; a pH independent binder; and one or more pharmaceutically acceptable excipients.
- Suitable pH dependent binders include, but are not limited to, a methacrylic acid copolymer, for example Eudragit ® (Eudragit® LlOO- 55, pseudolatex of Eudragit® Ll 00-55, and the like) partially neutralized with a strong base, for example, sodium hydroxide, potassium hydroxide, or ammonium hydroxide, in a quantity sufficient to neutralize the methacrylic acid copolymer to an extent of about 1-20%, for example about 3-6%.
- Suitable pH independent binders include, but are not limited to, hydroxypropylmethylcellulose (HPMC) 5 for example Methocel® ElOM Premium CR grade HPMC or Methocel® E4M Premium HPMC.
- Suitable pharmaceutically acceptable excipients include magnesium stearate and macrocrystalline cellulose (Avicel® pHlOl).
- Nociceptive pain is pain that is triggered by stimulation of sensory receptive nerve endings called nociceptors which are located through out the body in the various tissues such as skin, cornea, mucosa, muscle, and joint.
- the essential functions of nociceptors include the transduction of noxious stimuli into depolarizations that trigger action potentials, conduction of action potentials from primary sensory sites to synapses in the central nervous system, and conversion of action potentials into neurotransmitter release at presynaptic terminals.
- Nociceptive pain is typically experienced as a consequence of sprains, bone fractures, burns, bumps, bruises, and inflammation (from an infection or arthritic disorder), i.e. any damage to tissues that leads to activation of nociceptors.
- the number and type of nociceptors is highly dependent upon their location within the body. Cutaneous nociceptors located in the skin are highly concentrated and result in well-defined localized pain. Somatic nociceptors in the body's ligaments, connective tissues, and bones are much less numerous resulting in poorly-localized, aching pain which may be experienced for a longer duration. Even less numerous are visceral nociceptors located in the body's organs and viscera. Consequently, the source of visceral pain is often extremely difficult to identify.
- neuropathic pain is pain that is initiated or caused by a primary lesion or dysfunction of the nervous system itself.
- Neuropathic pain is usually perceived as a steady burning and/or "pins and needles” and/or “electric shock” sensations and/or tickling. The difference is due to the fact that "ordinary” pain stimulates only pain nerves, while a neuropathy often results in the firing of both pain and non-pain (touch, warm, cool) sensory nerves in the same area, producing signals that the spinal cord and brain do not normally expect to receive.
- Neuropathic pain may also be caused by over activity of nociceptors themselves. This over activity may be the result of an increase or decrease in the numbers, locations, or functions of cell membrane ion channels themselves.
- neuropathic pain affects at least 1.5% of the US population with neuropathic back and leg pain and diabetic neuropathy having the highest prevalence. Between 8-50% of diabetics are estimated to have symptoms of diabetic neuropathy, and 10 -19% of back pain patients are estimated to have neuropathic pain. (See, Taylor RS (2006) Pain Practice; 6: 22-26)
- neuropathic pain For a number of reasons the true prevalence of neuropathic pain is difficult to ascertain. For example it is not clear how many instances of common low back pain are neuropathic in origin. The difficulty is compounded by the fact that neuropathic pain is often a symptom or consequence of another underlying chronic disease. Typically, the physician's emphasis is on the diagnosis and treatment of the primary disease often resulting in neuropathic pain being under-diagnosed and under-treated.
- acetaminophen and antiinflammatory drugs including glucocoricoidsteroids like hydrocortisone, prednisone, and dexamethazone, and non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen, aspirin, naproxen, and celecoxib (Celebrex).
- NSAIDs non-steroidal anti-inflammatory drugs
- Stronger medications include opioids morphine, codeine, oxycodone, heroin, fentanyl, and hydrocone.
- Other treatments for neuropathic pain include tricyclic antidepressants such as amitriptyline (Elavil®), anticonvulsants like valproate, carbamazepine (Tegretol®), and capsaicin.
- the object of the invention is to provide methods for the treatment or prevention of pain comprising the step of administering to a patient in need thereof a therapeutically effective amount, or a prophylactically effective amount, of Ranolazine, or a pharmaceutically acceptable salt thereof.
- Ranolazine is administered for the treatment or prevention of neuropathic or nociceptive pain.
- nociceptive pain When nociceptive pain is to be treated it may be mechanical, chemical, and/or inflammatory in nature.
- the pain may be associated with a sodium channelopathy, polyneuropathy, autonomic neuropathy, mononeuropathy, and/or mononeuritis multiplex.
- Treatable channelopathies include, but are not limited to, erythromelalgia and paroxysmal extreme pain disorder.
- Treatable conditions associated with sodium channelopathies include, but are not limited to, myotonia and muscle paralysis.
- the pain may be the result of chronic, visceral, mechanical, inflammatory and/or neuropathic pain syndromes.
- the pain may also be resulting from, or associated with, traumatic nerve injury, nerve compression or entrapment, postherpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, cancer and chemotherapy. Additional indications for with the method of the invention is suitable include, but are not limited to, chronic lower back pain, HIV- and HIV treatment-induced neuropathy, cancer treatment-induced, i.e., chemotherapy-induced neuropathy, chronic pelvic pain, neuroma pain, complex regional pain syndrome, chronic arthritic pain, and related neuralgias.
- Figure 1 depicts the concentration-dependent block of Na ⁇ l.7 peak I Na by Ranolazine, R-Ranolazine and S-Ranolazine as described in Example 1. Data were fit with Hill equation.
- Figure 2 presents a plot of peak I NS values with repetitive pulses with duration of 2, 5, 20, and 200 msec normalized to a value recorded in response to first depolarizing step in the absence (open symbols) and presence of 100 ⁇ M Ranolazine (filled symbols) as described in Example 1.
- the block reaches the same level with pulse duration as short as 2 msec.
- Figures 3A, 3B and 3C illustrates the effect of 300 nM TTX to reduce I Na in HEK293 cells stably expressing hNavl.7+/31 subunits (A) and in untransfected ND7-23 cells (B) or ND7-23/rNavl.8 Na + channels (C), as discussed in Example 2.
- Whole-cell currents were recorded during a 50-msec test pulse to -20 (hNavl.7 or untransfected ND7-23 cells) or +20 (rNavl.8) mV at intervals of 10 sec.
- Addition of 300 nM TTX completely blocked the hNavl.7 I Na (A).
- 300 nM TTX caused minimal block of rNavl.8 l ⁇ s (C), demonstrating and confirming the reported resistance of this channel isoform to TTX.
- Figure 4A presents representative records of l ⁇ a recorded in the absence and presence of 30 ⁇ M ranolazine from HEK293 cells stably expressing hNavl.7+/31 subunits and from ND7-23 cells stably expressing rNavl.8 Na + channels as discussed in Example 2.
- Whole-cell currents were recorded during a 50-msec test pulse from - 120 to -20 (hNavl.7) or -100 mV to +20 (rNavl.8) mV in intervals of 10 sec.
- the 20-msec step was chosen to be short, to allow channel recovery from inactivation with minimal drug dissociation from blocked channels.
- Figure 5 shows the current- voltage relationships for the effects of ranolazine on activation and inactivation of hNavl.7 and rNavl .8 Na + channel currents as discussed in Example 2.
- Figure 5 A representative I Na records from HEK293 cells expressing hNavl .7+/3I subunits, and from ND7-23 cells expressing rNavl.8 Na + channels .
- Figure 5B presents activation curves for hNavl .1+ ⁇ l subunits and rNavl.8 Na + channels in the absence ( ⁇ , •) and presence (D, O) of 10 ⁇ M ranolazine.
- Figures 6A-C depicts voltage dependence of steady-state inactivation for hNavl.7 (left panels) and rNavl.8 (right panels) Na + channel currents in the absence (filled symbols) and presence of 10 ⁇ M ranolazine (open symbols) as discussed in Example 3. Conditioning prepulses of 100 msec (Figure 6A), 1 sec ( Figure 6B) and 10 sec ( Figure 6C) were used. Inset: voltage-clamp protocols.
- Figure 7C and Figure 7D are plots of recovery from inactivation in the absence and presence of 30 ⁇ M ranolazine (inset: voltage-clamp protocol). Data represent mean ⁇ SEM.
- Figure 8 plots use-dependent block of hNavl .7 ( Figure 8A), rNavl.8 ( Figure 8B) and TTX-S IN. (C) by 30 ⁇ M ranolazine as discussed in Example 2.
- Each protocol included a train of 40 pulses from -120 to -20 mV (Navl.1+ ⁇ l or endogenous TTX-S I Na ) or from -100 to +50 mV (rNavl.8) at frequencies of 1, 5 and 10 Hz in the absence (control; filled symbols) or presence of 30 ⁇ M ranolazine (open symbols).
- the amplitude of currents evoked by the n th impulse (40 th ) was normalized to that of the current evoked by the first pulse and plotted versus respective pulse number.
- Figure 9 shows the effect of increased pulse duration on the use dependence of ranolazine block of rNavl .8 I N3 as discussed in Example 2.
- Figure 9C presents plots of rNavl.8 I Na measured at +50 mV using pulses of 3 (V),5 ( ⁇ ), 20 (o) or 200 (D) msec duration in the presence of 100 ⁇ iM ranolazine. Current amplitude elicited by each pulse was normalized to the peak amplitude of current elicited by the first pulse (IP).
- Figure 10 depicts the results of ranolazine treatment of CFA-induced thermal and mechanical hyperalgesia following intraperitoneal administration as discussed in Example 3.
- Figure 1OA depicts no significant effect of treatment on paw withdrawal from thermal stimulation.
- Figure 1OB depicts a dose dependent reduction in mechanical allodynia.
- Figure 11 depicts the results of ranolazine treatment of CFA-induced thermal and mechanical hyperalgesia following oral administration.
- Figure 1OA Figure 1 IA depicts no significant effect of treatment on paw withdrawal from thermal stimulation.
- Figure 1 IB depicts a dose dependent reduction in mechanical allodynia. Optimum oral dosing was achieved at 50mg/kg. No additional benefit was observed at higher doses.
- Radexa® when referred to as Ranexa®, is the compound ( ⁇ )-N-(2,6- dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-l-piperazine-acetamide.
- Ranolazine can also exist as its enantiomers(R)-(+)-N-(2,6-dimethyIphenyl)-4-[2- hydroxy-3-(2-methoxyphenoxy)-propyl]-l-piperazineacetamide (also referred to as R- Ranolazine), and (S)-(-)-N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)- propyl]-l-piperazineacetamide (also referred to as S-Ranolazine), and their pharmaceutically acceptable salts, and mixtures thereof.
- the Ranolazine plasma concentrations used in the specification and examples refer to Ranolazine free base. At pH ⁇ 4, in an aqueous solution titrated with hydrogen chloride, Ranolazine will be present in large part as its dihydrochloride salt.
- physiologically acceptable pH refers to the pH of an intravenous solution which is compatible for delivery into a human patient.
- physiologically acceptable pH's range from about 4 to about 8.5 and preferably from about 4 to 7.
- intravenous solutions having a pH of about 4 to 6 are deemed physiologically acceptable as the large volume of blood in the body effectively buffers these intravenous solutions.
- Cardiovascular diseases or “cardiovascular symptoms” refer to diseases or symptoms exhibited by, for example, heart failure, including congestive heart failure, acute heart failure, ischemia, recurrent ischemia, myocardial infarction, STEMI and NSTEMI, and the like, arrhythmias, angina, including exercise-induced angina, variant angina, stable angina, unstable angina, acute coronary syndrome, NSTEACS, and the like, diabetes, and intermittent claudication.
- the treatment of such disease states is disclosed in various U.S. patents and patent applications, including U.S. Patent Nos. 6,503,911 and 6,528,511, U.S. Patent Application Nos. 2003/0220344 and 2004/0063717, the complete disclosures of which are hereby incorporated by reference.
- Inhibitor refers to a compound that "slows down" the metabolism of a substrate. Inhibitors may be classified into strong, moderate and weak categories. Strong inhibitors, for example including bupropion, fluoxetine, paroxetine, and quinidine, can cause a > 5-fold increase in the plasma AUC values or more than 80% decrease in clearance. Moderate inhibitors, for example including duioxetine and terbinafme, can cause a > 2-fold increase in the plasma AUC values or 50-80% decrease in clearance. Weak inhibitors, for example including amiodarone and cimetidine, can cause a >1.25-fold but ⁇ 2-fold increase in the plasma AUC values or 20-50% decrease in clearance.
- Treating” and “treatment” refer to any treatment of a disease in a patient and include: preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; inhibiting the disease, i.e., arresting its further development; inhibiting the symptoms of the disease; relieving the disease, i.e., causing regression of the disease, or relieving the symptoms of the disease.
- the "patient” is a mammal, preferably a human.
- therapeutically effective amount refers to that amount of a compound of Formula I that is sufficient to effect treatment, as defined below, when administered to a mammal in need of such treatment.
- the therapeutically effective amount will vary depending upon the specific activity of the therapeutic agent being used, and the age, physical condition, existence of other disease states, and nutritional status of the patient. Additionally, other medication the patient may be receiving will effect the determination of the therapeutically effective amount of the therapeutic agent to administer.
- pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
- the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
- Ranolazine which is named N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2- methoxyphenoxy)propyl]-l-piperazineacetamide (also known as l-[3-(2- methoxyphenoxy)-2-hydroxypropyl]-4-[(2,6-dimethylphenyl)-aminocarbonylmethyl]- piperazine ⁇ , can be present as a racemic mixture, or an enantiomer thereof, or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt thereof.
- Ranolazine can be prepared as described in U.S. Patent No. 4,567,264, the specification of which is incorporated herein by reference.
- IR immediate release
- sustained release refers to formulations or dosage units used herein that are slowly and continuously dissolved and absorbed in the stomach and gastrointestinal tract over a period of about six hours or more.
- Preferred sustained release formulations are those exhibiting plasma concentrations of Ranolazine suitable for no more than twice daily administration with two or less tablets per dosing as described below.
- Stepoisomers are isomers that differ only in the way the atoms are arranged in space.
- Enantiomers are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic” mixture. The term “( ⁇ )” is used to designate a racemic mixture where appropriate.
- Diastereoisomers are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.
- the absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When the compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S. Resolved compounds whose absolute configuration is unknown are designated (+) or (-) depending on the direction (dextro- or laevorotary) which they rotate the plane of polarized light at the wavelength of the sodium D line.
- "Polyneuropathy” is defined as a neurological disorder occurring when many peripheral nerves throughout the body malfunction simultaneously. It may be acute or chronic.
- Autonomic neuropathy refers to a group of symptoms caused by damage to nerves that regulate blood pressure, heart rate, bowel and bladder emptying, digestion, and other body functions.
- Mononeuropathy is defined as a type of neuropathy affecting only a single peripheral or cranial nerve.
- mononeuropathies include, but are not limited to, thoracic outlet syndrome, carpal tunnel syndrome, radial neuropathy, winged scapula, meralgia paraesthetica, tarsal tunnel syndrome, oculomotor nerve palsy, fourth nerve palsy, sixth nerve palsy, and Bell's palsy.
- Mononeuritis multiplex is defined a neurological disorder that involves damage to at least two separate nerve areas. It is a form of peripheral neuropathy (damage to nerves outside the brain and spinal cord). Common causes include a lack of oxygen caused by decreased blood flow or inflammation of blood vessels. No cause is identified for about a third of cases. Other common causes of mononeuritis multiplex include, but are not limited to, Diabetes mellitus, blood vessel diseases such as polyarteritis nodosa, and connective diseases such as rheumatoid arthritis or systemic lupus erythematosus.
- Channelopathy refers to a disease or condition that is associated with ion channel malformation.
- Examples of sodium channelopathies include, but are not limited to erythromelalgia and paroxysmal extreme pain disorder.
- Ranolazine is capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
- pharmaceutically acceptable salt refers to salts that retain the biological effectiveness and properties of Ranolazine and which are not biologically or otherwise undesirable.
- Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases, include by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts.
- Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines, di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines, di(substituted alkenyl) amines, tri(substituted alkenyl) amines, cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines, substituted cycloalkyl amines, di substituted cycloalkyl amine, tri substituted cycloalkyl amines, cycloalkenyl amines, di(cycloalkenyl) amines,
- Suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso -propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.
- Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
- Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like.
- pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
- the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
- the method of the invention is based on the surprising discovery that Ranolazine blocks both the Na v 1.7 and Navl.8 currents at therapeutic drug concentrations. Ranolazine inhibits both peak and "window" Nayl.7 and Navl.8 currents. On the other hand, Ranolazine selectively inhibits late relative to peak Nayl .5 current, and does not appear to block Nayl.l, 1.4 or 1.6 peak currents at therapeutic concentrations.
- DRG dorsal root ganglia
- Spinal dorsal root ganglia are not protected by a blood-brain barrier and may be accessible to systemic drug therapy.
- These cells express several isoforms of the alpha (pore- forming) subunit of the voltage-gated sodium channel (e.g., Na v 1.3, 1.6, 1.7, 1.8, 1.9).
- Na + channel isoforms are known to have different properties and roles in DRG function.
- the Na + channel isoform Nay 1.7 is highly expressed in DRG neurons and expression is further increased in DRG neurons from rats rendered diabetic by administration of streptozotocin.
- Increased expression of Na v l .7 in rat DRG neurons correlated with increased Na + current density and with the development of hyperalgesia (an increased response to a stimulus that is normally painful) and allodynia (pain elicited by a stimulus that does not normally provoke pain).
- hyperalgesia an increased response to a stimulus that is normally painful
- allodynia pain elicited by a stimulus that does not normally provoke pain.
- Navl .8 is a slowly-inactivating TTX-R Na + channel that is found in DRG cells and small nociceptive C-typepain fibers (Akopian et al, 1996;Sangameswaran et al, 1996).
- the gene SCNlOA encodes the alpha polypeptide of Navl.8 (Akopian et al, 1996;Sangameswaran et al., 1996).
- ranolazine blocked neuronal Navl.7 Na 4 current (Iw a ) in a state and use-dependent manner (Wang et al., 2008).
- Ranolazine reduces the persistent (late) Na + current (late Iw a ) in the heart (Belardinelli et al, 2006), and the drug has been approved for reduction of chronic angina, and shown to be safe (Scirica et al. , 2007).
- Several classes of drugs that act as sodium channel blockers are used to treat neuropathic pain. These include local anesthetic (e.g., lidocaine), anti-arrhythmic (e.g., mexiletine), and anti-epileptic (e.g., phenytoin, carbamazepine) drugs. None of these drugs is a selective blocker of Nay 1.7 or of any other Na + channel subtype. They may act to stabilize inactivated states of Na + channels and cause use-dependent block of channel activity, thereby reducing the maximum rate of neuronal firing. Their reported efficacy is only partial, Drenth et al.
- Na + channel subtype-selective blockers are a current focus of therapeutics.
- the method of the invention is useful for treating pain arising from a wide variety of causes. While not wishing to be bound by theory, it is believe that the ability of Ranolazine to treat pain stems is a result of its surprising capacity to act as a selective blocker of peak and window Navl.7 and Navl.8 currents.
- Ranolazine is usually administered in the form of a pharmaceutical composition.
- This invention therefore provides pharmaceutical compositions that contain, as the active ingredient, Ranolazine, or a pharmaceutically acceptable salt or ester thereof, and one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, solubilizers and adjuvants.
- Ranolazine may be administered alone or in combination with other therapeutic agents.
- Such compositions are prepared in a manner well known in the pharmaceutical art (see, e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, PA 17 th Ed. (1985) and "Modern Pharmaceutics", Marcel Dekker, Inc. 3 rd Ed. (G.S. Banker & CT. Rhodes, Eds.).
- the Ranolazine may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, for example as described in those patents and patent applications incorporated by reference, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer.
- excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose.
- the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
- Oral administration is the preferred route for administration of Ranolazine. Administration may be via capsule or enteric coated tablets, or the like.
- the active ingredient is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container.
- the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material (as above), which acts as a vehicle, carrier or medium for the active ingredient.
- compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols ⁇ as a solid or in a liquid medium), ointments containing, for example, up to 50% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.
- compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
- Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Patent Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345.
- Another formulation for use in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts.
- transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
- Ranolazine is effective over a wide dosage range and is generally administered in a pharmaceutically effective amount.
- each dosage unit contains from 1 mg to 2 g of Ranolazine, more commonly from 1 to 700 mg, and for parenteral administration, from 1 to 700 mg of Ranolazine, more commonly about 2 to 200 mg.
- the amount of Ranolazine actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
- the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
- a pharmaceutical excipient for preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
- these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
- the tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach.
- the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
- the two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
- enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
- compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
- the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra.
- the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
- Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.
- One mode for administration is parental, particularly by injection.
- the forms in which the novel compositions of the present invention may be incorporated for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.
- Aqueous solutions in saline are also conventionally used for injection, but less preferred in the context of the present invention.
- Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed.
- the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
- Sterile injectable solutions are prepared by incorporating the compound of the invention in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtration and sterilization.
- dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
- the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
- the intravenous formulation of Ranolazine is manufactured via an aseptic fill process as follows.
- WFI Water for Injection
- the required amount of Ranolazine free base is added to the dextrose solution.
- the solution pH is adjusted to a target of 3.88-3.92 with 0.1N or IN Hydrochloric Acid solution.
- 0.1N HCl or LON NaOH may be utilized to make the final adjustment of solution to the target pH of 3.88-3.92.
- the batch is adjusted to the final weight with WFI.
- the Ranolazine bulk solution is sterilized by sterile filtration through two 0.2 ⁇ ra sterile filters. Subsequently, the sterile Ranolazine bulk solution is aseptically filled into sterile glass vials and aseptically stoppered with sterile stoppers. The stoppered vials are then sealed with clean flip-top aluminum seals.
- Ranolazine may be impregnated into a stent by diffusion, for example, or coated onto the stent such as in a gel form, for example, using procedures known to one of skill in the art in light of the present disclosure.
- compositions are preferably formulated in a unit dosage form.
- unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient (e.g., a tablet, capsule, ampoule).
- Ranolazine is effective over a wide dosage range and are generally administered in a pharmaceutically effective amount.
- each dosage unit contains from 10 mg to 2 g of a compound Ranolazine, more preferably 10 to 1500 mg, more preferably from 10 to 1000 mg, more preferably from 500 to 1000 mg.
- the amount of Ranolazine actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
- the Ranolazine is formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient, especially sustained release formulations.
- the Ranolazine plasma concentrations used in the specification and examples refer to Ranolazine free base.
- the preferred sustained release formulations of this invention are preferably in the form of a compressed tablet comprising an intimate mixture of compound and a partially neutralized pH-dependent binder that controls the rate of dissolution in aqueous media across the range of pH in the stomach (typically approximately 2) and in the intestine (typically approximately about 5.5).
- An example of a sustained release formulation is disclosed in U.S. Patents 6,303,607; 6,479,496; 6,369,062; and 6,525,057, the complete disclosures of which are hereby incorporated by reference.
- one or more pH-dependent binders are chosen to control the dissolution profile of the compound so that the formulation releases the drug slowly and continuously as the formulation passed through the stomach and gastrointestinal tract.
- the dissolution control capacity of the pH-dependent binder(s) is particularly important in a sustained release formulation because a sustained release formulation that contains sufficient compound for twice daily administration may cause untoward side effects if the compound is released too rapidly ("dose-dumping").
- the pH-dependent binders suitable for use in this invention are those which inhibit rapid release of drug from a tablet during its residence in the stomach (where the pH is below about 4.5), and which promotes the release of a therapeutic amount of compound from the dosage form in the lower gastrointestinal tract (where the pH is generally greater than about 4.5).
- enteric binders and coating agents have the desired pH dissolution properties.
- phthalic acid derivatives such as the phthalic acid derivatives of vinyl polymers and copolymers, hydroxyalkylcelluloses, alkylcelluloses, cellulose acetates, hydroxyalkylcellulose acetates, cellulose ethers, alkylcellulose acetates, and the partial esters thereof, and polymers and copolymers of lower alkyl acrylic acids and lower alkyl acrylates, and the partial esters thereof.
- Preferred pH-dependent binder materials that can be used in conjunction with the compound to create a sustained release formulation are methacrylic acid copolymers.
- Methacrylic acid copolymers are copolymers of methacrylic acid with neutral acrylate or methacrylate esters such as ethyl acrylate or methyl methacrylate.
- a most preferred copolymer is methacrylic acid copolymer, Type C, USP (which is a copolymer of methacrylic acid and ethyl acrylate having between 46.0% and 50.6% methacrylic acid units).
- Such a copolymer is commercially available, from Rohm Pharma as Eudragit® L 100-55 (as a powder) or L30D-55 (as a 30% dispersion in water).
- Other pH-dependent binder materials which may be used alone or in combination in a sustained release formulation dosage form include hydroxypropyl cellulose phthalate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, polyvinylacetate phthalate, polyvinylpyrrolidone phthalate, and the like.
- pH-independent binders may be in used in sustained release formulations in oral dosage forms. It is to be noted that pH-dependent binders and viscosity enhancing agents such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, polyvinylpyrrolidone, neutral poly(meth)acrylate esters, and the like, may not themselves provide the required dissolution control provided by the identified pH-dependent binders.
- the pH-independent binders may be present in the formulation of this invention in an amount ranging from about 1 to about 10 wt%, and preferably in amount ranging from about 1 to about 3 wt% and most preferably about 2.0 wt%.
- Increasing the pH-dependent binder content in the formulation decreases the release rate of the sustained release form of the compound from the formulation at pH is below 4.5 typical of the pH found in the stomach.
- the enteric coating formed by the binder is less soluble and increases the relative release rate above pH 4.5, where the solubility of compound is lower.
- a proper selection of the pH-dependent binder allows for a quicker release rate of the compound from the formulation above pH 4.5, while greatly affecting the release rate at low pH.
- Partial neutralization of the binder facilitates the conversion of the binder into a latex like film which forms around the individual granules. Accordingly, the type and the quantity of the pH-dependent binder and amount of the partial neutralization composition are chosen to closely control the rate of dissolution of compound from the formulation.
- the dosage forms of this invention should have a quantity of pH-dependent binders sufficient to produce a sustained release formulation from which the release rate of the compound is controlled such that at low pHs (below about 4.5) the rate of dissolution is significantly slowed.
- a suitable quantity of pH-dependent binder is between 5% and 15%.
- the pH dependent binder will typically have from about 1 to about 20 % of the binder methacrylic acid carboxyl groups neutralized. However, it is preferred that the degree of neutralization ranges from about 3 to 6%.
- the sustained release formulation may also contain pharmaceutical excipients intimately admixed with the compound and the pH-dependent binder.
- Pharmaceutically acceptable excipients may include, for example, pH-independent binders or film-forming agents such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, polyvinylpyrrolidone, neutral poly(meth)acrylate esters (e.g. the methyl methacrylate/ethyl acrylate copolymers sold under the trademark Eudragit® NE by Rohm Pharma, starch, gelatin, sugars carboxymethyl cellulose, and the like.
- diluents such as lactose, mannitol, dry starch, microcrystalline cellulose and the like; surface active agents such as polyoxyethylene sorbitan esters, sorbitan esters and the like; and coloring agents and flavoring agents.
- Lubricants such as tale and magnesium stearate
- other tableting aids are also optionally present.
- the sustained release formulations of this invention have an active compound content of above about 50% by weight to about 95% or more by weight, more preferably between about 70% to about 90% by weight and most preferably from about 70 to about 80% by weight; a pH-dependent binder content of between 5% and 40%, preferably between 5% and 25%, and more preferably between 5% and 15%; with the remainder of the dosage form comprising pH-independent binders, fillers, and other optional excipients.
- the sustained release formulations of this invention are prepared as follows: compound and pH-dependent binder and any optional excipients are intimately mixed(dry-blended). The dry-blended mixture is then granulated in the presence of an aqueous solution of a strong base that is sprayed into the blended powder. The granulate is dried, screened, mixed with optional lubricants (such as talc or magnesium stearate), and compressed into tablets.
- Preferred aqueous solutions of strong bases are solutions of alkali metal hydroxides, such as sodium or potassium hydroxide, preferably sodium hydroxide, in water (optionally containing up to 25% of water-miscible solvents such as lower alcohols).
- the resulting tablets may be coated with an optional film-forming agent, for identification, taste-masking purposes and to improve ease of swallowing.
- the film forming agent will typically be present in an amount ranging from between 2% and 4% of the tablet weight.
- Suitable film-forming agents are well known to the art and include hydroxypropyl. methylcellulose, cationic methacrylate copolymers (dimethylaminoethyl methacrylate/ methyl-butyl methacrylate copolymers - Eudragit® E - Rohm. Pharma), and the like.
- These film- forming agents may optionally contain colorants, plasticizers, and other supplemental ingredients.
- the compressed tablets preferably have a hardness sufficient to withstand 8 Kp compression.
- the tablet size will depend primarily upon the amount of compound in the tablet.
- the tablets will include from 300 to 1100 mg of compound free base.
- the tablets will include amounts of compound free base ranging from 400-600 mg, 650-850 mg, and 900-1100 mg.
- the time during which the compound containing powder is wet mixed is controlled.
- the total powder mix time i.e. the time during which the powder is exposed to sodium hydroxide solution, will range from 1 to 10 minutes and preferably from 2 to 5 minutes.
- the particles are removed from the granulator and placed in a fluid bed dryer for drying at about 60 0 C.
- the oral sustained release Ranolazine dosage formulations of this invention are administered one, twice, or three times in a 24 hour period in order to maintain a plasma Ranolazine level above the threshold therapeutic level and below the maximally tolerated levels, which is preferably a plasma level of about 550 to 7500 ng base/niL in a patient.
- the plasma level of Ranolazine ranges about 1500-3500 ng base/mL.
- the oral Ranolazine dosage forms described herein are administered once or twice daily. If the dosage forms are administered twice daily, then it is preferred that the oral Ranolazine dosage forms are administered at about twelve hour intervals.
- Ranolazine may be incorporated into a pharmaceutical formulation for topical administration.
- This type of formulation typically contains a pharmaceutically acceptable carrier that is generally suited to topical drug administration and comprising any such material known in the art.
- Suitable carriers are well known to those of skill in the art and the selection of the carrier will depend upon the form of the intended pharmaceutical formulation, e.g., as an ointment, lotion, cream, foam, microemulsion, gel, oil, solution, spray, salve, or the like, and may be comprised of either naturally occurring or synthetic materials. It is understood that the selected carrier should not adversely affect Ranolazine or other components of the pharmaceutical formulation.
- Suitable carriers for these types of formulations include, but are not limited to, vehicles including Shephard'sTM Cream, Aquaphor TM , and CetaphilTM lotion.
- Other preferred carriers include ointment bases, e.g., polyethylene glycol-1000 (PEG-1000), conventional creams such as HEB cream, gels, as well as petroleum jelly and the like.
- suitable carriers for use herein include water, alcohols and other nontoxic organic solvents, glycerin, mineral oil, silicone, petroleum jelly, lanolin, fatty acids, vegetable oils, parabens, waxes, and the like.
- Particularly preferred formulations herein are colorless, odorless ointments, lotions, creams, microemulsions and gels.
- Ointments are semisolid preparations that are typically based on petrolatum or other petroleum derivatives.
- the specific ointment base to be used is one that will provide for optimum drug delivery, and, preferably, will provide for other desired characteristics as well, e.g., emolliency or the like.
- an ointment base should be inert, stable, nonirritating and nonsensitizing. As explained in Remington 's Pharmaceutical Sciences, 20 th Ed.
- ointment bases may be grouped in four classes: oleaginous bases; emulsifiable bases; emulsion bases; and water-soluble bases.
- Oleaginous ointment bases include, for example, vegetable oils, fats obtained from animals, and semisolid hydrocarbons obtained from petroleum.
- Emulsifiable ointment bases also known as absorbent ointment bases, contain little or no water and include, for example, hydroxystearin sulfate, anhydrous lanolin, and hydrophilic petrolatum.
- Emulsion ointment bases are either water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions, and include, for example, cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid.
- Preferred water-soluble ointment bases are prepared from polyethylene glycols (PEGs) of varying molecular weight; again, reference may be had to Remington's, supra, for further information.
- Lotions are preparations to be applied to the skin surface without friction, and are typically liquid or semiliquid preparations in which solid particles, including the active agent, are present in a water or alcohol base.
- Lotions are usually suspensions of solids, and preferably, for the present purpose, comprise a liquid oily emulsion of the oil-in-water type.
- Lotions are preferred formulations herein for treating large body areas, because of the ease of applying a more fluid composition. It is generally necessary that the insoluble matter in a lotion be finely divided. Lotions will typically contain suspending agents to produce better dispersions as well as compounds useful for localizing and holding the active agent in contact with the skin, e.g., methyl cellulose, sodium carboxymethylcellulose, or the like.
- a particularly preferred lotion formulation for use in conjunction with the present invention contains propylene glycol mixed with a hydrophilic petrolatum such as that which may be obtained under the trademark AquaphorTM from Beiersdorf, Inc. (Norwalk, Conn.).
- Creams containing the active agent are, as known in the art, viscous liquid or semisolid emulsions, either oil-in-water or water-in-oil.
- Cream bases are water- washable, and contain an oil phase, an emulsifier, and an aqueous phase.
- the oil phase is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant.
- the emulsifier in a cream formulation as explained in Remington's, supra, is generally a nonionic, anionic, cationic, or amphoteric surfactant.
- Micro emulsions are thermodynamically stable, isotropically clear dispersions of two immiscible liquids, such as oil and water, stabilized by an interfacial film of surfactant molecules (Encyclopedia of Pharmaceutical Technology (New York: Marcel Dekker, 1992), volume 9).
- a surfactant emulsifier
- co-surfactant co-emulsifier
- an oil phase e.g., a water phase
- Suitable surfactants include any surfactants that are useful in the preparation of emulsions, e.g., emulsifiers that are typically used in the preparation of creams.
- the co-surfactant is generally selected from the group of polyglycerol derivatives, glycerol derivatives, and fatty alcohols.
- Preferred emulsifier/co-emulsifier combinations are generally although not necessarily selected from the group consisting of: glyceryl monostearate and polyoxyethylene stearate; polyethylene glycol and ethylene glycol palmitostearate; and caprilic and capric triglycerides and oleoyl macro golglycerides.
- the water phase includes not only water but also, typically, buffers, glucose, propylene glycol, polyethylene glycols, preferably lower molecular weight polyethylene glycols (e.g., PEG 300 and PEG 400), and/or glycerol, and the like, while the oil phase will generally comprise, for example, fatty acid esters, modified vegetable oils, silicone oils, mixtures of mono- di- and triglycerides, mono- and di-esters of PEG (e.g., oleoyl macrogol glycerides), etc.
- buffers glucose, propylene glycol, polyethylene glycols, preferably lower molecular weight polyethylene glycols (e.g., PEG 300 and PEG 400), and/or glycerol, and the like
- the oil phase will generally comprise, for example, fatty acid esters, modified vegetable oils, silicone oils, mixtures of mono- di- and triglycerides, mono- and di-esters of PEG (e.g., ole
- Gel formulations are semisolid systems consisting of either small inorganic particle suspensions (two-phase systems) or large organic molecules distributed substantially uniformly throughout a carrier liquid (single phase gels).
- Single phase gels can be made, for example, by combining the active agent, a carrier liquid and a suitable gelling agent such as tragacanth (at 2 to 5%), sodium alginate (at 2-10%), gelatin (at 2-15%), methylcellulose (at 3-5%), sodium carboxymethylcellulose (at 2- 5%), carbomer (at 0.3-5%) or polyvinyl alcohol (at 10-20%) together and mixing until a characteristic semisolid product is produced.
- suitable gelling agents include methylhydroxycellulose, polyoxyethylene-polyoxypropylene, hydroxyethylcellulose and gelatin.
- additives may be included in the topical formulations of the invention.
- additives include, but are not limited to, solubilizers, skin permeation enhancers, opacifiers, preservatives (e.g., antioxidants), gelling agents, buffering agents, surfactants (particularly nonionic and amphoteric surfactants), emulsif ⁇ ers, emollients, thickening agents, stabilizers, humectants, colorants, fragrance, and the like.
- solubilizers and/or skin permeation enhancers is particularly preferred, along with emulsifiers, emollients, and preservatives.
- solubilizers include, but are not limited to, the following: hydrophilic ethers such as diethylene glycol monoethyl ether (ethoxydiglycol, available commercially as Transcutol ) and diethylene glycol monoethyl ether oleate (available commercially as SoftcutolTM); polyethylene castor oil derivatives such as polyoxy 35 castor oil, polyoxy 40 hydrogenated castor oil, etc.; polyethylene glycol, particularly lower molecular weight polyethylene glycols such as PEG 300 and PEG 400, and polyethylene glycol derivatives such as PEG-8 caprylic/capric glycerides (available commercially as LabrasolTM); alkyl methyl sulfoxides such as DMSO; pyrrolidones such as 2-pyrrolidone and N-methyl-2-pyrrolidone; and DMA. Many solubilizers can also act as absorption enhancers. A single solubilizer may be incorporated into the formulation, or a mixture of
- Suitable emulsifiers and co-emulsifiers include, without limitation, those emulsifiers and co-emulsifiers described with respect to microemulsion formulations.
- Emollients include, for example, propylene glycol, glycerol, isopropyl myristate, polypropylene glycol-2 (PPG-2) myristyl ether propionate, and the like.
- sunscreen formulations including, but not limited to, anthranilates, benzophenones (particularly benzophenone-3), camphor derivatives, cinnamates (e.g., octyl methoxycinnamate), dibenzoyl methanes (e.g., butyl methoxydibenzoyl methane), p-aminobenzoic acid (PABA) and derivatives thereof, and salicylates (e.g., octyl salicylate).
- anthranilates benzophenones (particularly benzophenone-3), camphor derivatives
- cinnamates e.g., octyl methoxycinnamate
- dibenzoyl methanes e.g., butyl methoxydibenzoyl methane
- PABA p-aminobenzoic acid
- salicylates e.g., octyl salicylate
- the Ranolazine is present in an amount in the range of approximately 0.25 wt. % to 75 wt. % of the formulation, preferably in the range of approximately 0.25 wt. % to 30 wt. % of the formulation, more preferably in the range of approximately 0.5 wt. % to 15 wt. % of the formulation, and most preferably in the range of approximately 1.0 wt. % to 10 wt. % of the formulation.
- the pharmaceutical formulation may be sterilized or mixed with auxiliary agents, e.g., preservatives, stabilizers, wetting agents, buffers, or salts for influencing osmotic pressure and the like.
- auxiliary agents e.g., preservatives, stabilizers, wetting agents, buffers, or salts for influencing osmotic pressure and the like.
- Sterile injectable solutions are prepared by incorporating Ranolazine in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization.
- dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
- the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
- HEK293 Human embryonic kidney (HEK293) cells stably transfected with cDNA encoding the ⁇ - and jSl subunits of SCN9A Na + channel were purchased from Scottish Biomedical, Glasgow, United Kingdom. HEK293 cells were cultured in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal bovine serum and 1% penicillin and 1% streptomycin.
- DMEM Dulbecco's modified Eagle's medium
- the intracellular pipette solution contents were (in mM): CsF 120, CsCl 20, EGTA 2, HEPES 5 (pH 7,4 after titration with CsOH).
- the Axopatch- 200B patch clamp amplifier (Axon Instruments Inc., Sunnyvale, CA) was used to record I N3 and to measure cellular capacitance. Data were sampled at 20 kHz and filtered (8-pole Bessel) at 5 kHz. Series resistance (R s ) compensation was 70-80% and leak subtraction was not used.
- ranolazine inhibits Navl .7 and Navl .8 Na + channels. These channels are present in peripheral pain-sensing neurons and are reported to play an important role in the etiology of neuropathic pain.
- Ranolazine inhibited hNavl .7 and rNavl.8 Na + channels in a voltage- and use (frequency) -dependent manner. Ranolazine did not alter the activation voltage range of either Navl .7 or Navl.8 Iw a , or the voltage at which half-maximal activation (Vy 3 ) of current occurred. However, ranolazine caused a concentration-dependent hyperpolarizing shift of the inactivation voltages of both currents.
- HEK293 cells stably expressing the hNavl.7 ( ⁇ -subunit) along with a human ⁇ subunit were purchased from Scottish-Biomedical, Glasgow, UK. Cells were continuously maintained using MEM (Gibco-Invitrogen, Carlsbad, CA) supplemented with 10% heat inactivated fetal bovine serum, 1% penicillin-streptomycin, 600 ⁇ g/mL geneticin (Gibco-Invitrogen), 2 ⁇ g/mL blastocydin (Calbiochem, NJ, USA), and were incubated at 37 0 C in an atmosphere of 5% CO 2 in air.
- MEM Gibco-Invitrogen, Carlsbad, CA
- penicillin-streptomycin 600 ⁇ g/mL geneticin (Gibco-Invitrogen)
- 2 ⁇ g/mL blastocydin Calbiochem, NJ, USA
- DMEM Gibco-Invitrogen
- fetal bovine serum 10% fetal bovine serum
- L-glutamine 1% L-glutamine
- non-essential amino acids 1% penicillin- streptomycin
- 400 ⁇ g/mL geneticin 400 ⁇ g/mL geneticin
- HEK293 cells were superfused with an extracellular solution containing (in mM): 140 NaCl, 3KCl, 10 HEPES, 10 glucose, 1 MgCI 2 , 1 CaCl 2 , pH 7.4 (with NaOH).
- Patch pipettes were filled with an internal solution containing (in mM): 140 CsF, 10 NaCl, 1 EGTA, 10 HEPES, pH 7.3 (with CsOH).
- pCLAMP 10.0 software (Molecular Devices) was used to generate voltage clamp protocols and acquire data.
- Cells were held at a membrane potential of -100 or -120 mV and were dialyzed with pipette solution for 5-7 minutes before current was recorded, to avoid time-dependent shifts in Na + channel gating within the first several minutes after patch rupture.
- the temperature of experimental solutions was maintained at 20 ⁇ l°C using a CL-100 bipolar temperature controller (Warner Instruments, Hamden, USA).
- Data were analyzed using CIampfit and Microcal Origin (MicroCal, Northampton, USA) software. Results are expressed as mean ⁇ S.E.M., and n refers to number of cells. All experiments were repeated on at least 2 different experimental days. Statistical significance of differences between responses of a cell in the absence and presence of drug was determined using the Student /-test, with P ⁇ 0.05 indicating statistical significance.
- WIcon t rol l/[ l+(D/IC 50 ) n HL
- Idrug/Icontroi fractional block
- D drug concentration
- IC5 0 the drug concentration that causes 50% block
- n H the Hill coefficient
- G is the measured conductance
- G max is the maximal conductance
- Vy 1 is the membrane potential at which the half-maximal channel open probability occurs
- k is the slope of the curve.
- prepulses ranging from -120 to -10 mV (for hNavl.7 I Na ) or -100 to -10 mV (for rNavl.8 I Na ) were applied for a period of 10 msec, followed by a 100-msec hyperpolarizing step to -160 (for hNavl .7) or -140 mV (for rNavl .8) and then stepped to 0 (for hNavl.7 I Na ) or +20 mV (rNavl.8 I Na ) for a period of 50-msec to measure the available current.
- ⁇ Vy is the shift in midpoint of the steady-state inactivation curve
- k is the slope factor of the steady-state inactivation curve derived from a Boltzmann fit
- [D] is the concentration of ranolazine applied
- IC 50R is the IC 50 value for resting channels
- K 1 is the dissociation constant for block of inactivated channels by ranolazine.
- the peak current elicited by the second pulse (T) was normalized relative to the current elicited by the first pulse (IQ).
- the duration of every cycle of the double pulse protocol was 20 sec.
- TZI 0 was plotted against the time delay between the two pulses and fit to a double or triple exponential function,
- I/Io [A F * exp(-t/ ⁇ yr)] + [As * exp(-t/ ⁇ s)] + A 0 ,
- t recovery time interval
- ⁇ F and ⁇ s fast and slow time constants
- a F and As relative amplitude of the fast and slow recovery component
- a 00 is the relative amplitude of the steady-state component
- IZI 0 [Ayr* exp(-t/ ⁇ >)] + [A 1 * exp(-t/ ⁇ / )] + [ A 5 * exp(-t/7 S )] + A, oo,
- t recovery time interval
- Tp, T / and Ts fast, intermediate and slow time constants, A / r ;
- As relative amplitude of the fast and slow recovery component, and Acois the relative amplitude of the steady-state component.
- Figure 3 shows the effect of 300 nM TTX on HEK293 cells stably expressing hNavl.7+ ⁇ l subunits (Figure 3A) and untransfected ND7-23 cells ( Figure 3B) or ND7- 23 cells stably expressing rNavl .8 Na + channels (ND7-23/rNavl.8; Figure 3C).
- TTX 300 nM
- 300 nM TTX caused a minimal block of rNavl .8 I Na , confirming previous reports of the resistance of rNavl.8 to the toxin.
- Ranolazine Blocks Recombinant Human and Native Rat NaL 7 and Navl.8 Currents.
- V 0 Holding potential of -120 mV (Navl .7) or -10OmV (Navl.8) V 0 5 , Holding potential of -70 mV (Navl.7) or - 4OmV (Navl .8)
- Figure 6C shows voltage-clamp protocols and summary results of experiments for steady-state slow inactivation of hNavl .7 and rNavl .8 (inactivating prepulse of 10 sec) in the absence ( ⁇ , •) and presence of 10 ⁇ M ranolazine (a, o).
- Ranolazine caused a significant (p ⁇ 0.05) leftward shift in the Vy 1 of slow inactivation without affecting the slope (k) factor of hNavl.7 and rNavl.8 I NS (see figure legends for values).
- ranolazine (30 ⁇ M) caused a significant (p ⁇ 0.05) slowing of the fast (Tp), intermediate ( ⁇ 7 ) and slow (Ts) components of rNavl.8 I Na recovery from inactivation (see Table 6, rNavl.8, Recovery from inactivation at -80 mV). Table 6. Development of slow inactivation and recovery from inactivation parameters of hNavl.7 and rNavl.8 in the absence (control) and presence of 30 ⁇ M ranolazine.
- the short depolarizing pulse duration of 10 msec was chosen to approximate the somatic action potential duration of C fibers (0.6 - 7.4 msec; (Harper and Lawson, 1985).
- Figure 9 shows representative records of rNavl.8 current elicited by 5 (Figure 9A) or 200 msec (Figure 9B) long test pulses to +50 mV at a frequency of 5 Hz in the presence of 100 ⁇ M ranolazine. Peak current elicited by each pulse was measured, normalized to the current of the first pulse, and plotted against the pulse number in Figure 9C.
- ranolazine has a selective analgesic effect on mechanical allodynia and little if any effect on thermal hyperalgesia.
- Baseline pain thresholds for thermal and mechanical stimulation were determined at 2 time points prior to the subcutaneous injection of 0.1ml of CFA (Mycobacterium tuberculosis, Sigma) suspended in oil:saline (1 :1) emulsion (0.5mg Mycobacterium/ml emulsion) into one hindpaw and an equivalent volume of sterile saline into the contralateral paw. Post-CFA withdrawal thresholds were recorded on each of the next 2 days.
- CFA Mycobacterium tuberculosis, Sigma
- ranolazine clearly reduced paw sensitivity to mechanical stimulation in a dose-dependent fashion, but no significant effect on paw sensitivity was observed with thermal stimulation.
- Adverse effects were noted following i.p. administration only when doses at or above 100mg/kg were given. The effects tended to be more pronounced at progressively higher doses.
- the adverse behavioral effects included bradykinesia, motor sluggishness manifested by slow response to stimulation and impaired performance on rotarod testing (Taylor et al., personal communication), muscle fasciculation and twitching, and convulsions. Death occurred in 50% of the rats treated with doses of 100mg/kg.
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- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Anesthesiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP09707821A EP2252294A1 (en) | 2008-02-06 | 2009-02-06 | Use of ranolazine for treating pain |
CN2009801040287A CN101977605A (en) | 2008-02-06 | 2009-02-06 | Use of ranolazine for treating pain |
CA2713521A CA2713521A1 (en) | 2008-02-06 | 2009-02-06 | Use of ranolazine for treating pain |
EA201070914A EA201070914A1 (en) | 2008-02-06 | 2009-02-06 | APPLICATION OF RANOLAZINE FOR TREATMENT OF PAIN |
AU2009212254A AU2009212254A1 (en) | 2008-02-06 | 2009-02-06 | Use of Ranolazine for treating pain |
BRPI0908428A BRPI0908428A2 (en) | 2008-02-06 | 2009-02-06 | use of ranozaline to treat pain. |
IL207292A IL207292A0 (en) | 2008-02-06 | 2010-07-29 | Use of ranolazine for treating pain |
MA33137A MA32132B1 (en) | 2008-02-06 | 2010-09-01 | The use of ranolazine for the treatment of pain |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US2669908P | 2008-02-06 | 2008-02-06 | |
US61/026,699 | 2008-02-06 | ||
US5743708P | 2008-05-30 | 2008-05-30 | |
US61/057,437 | 2008-05-30 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2009100380A1 true WO2009100380A1 (en) | 2009-08-13 |
Family
ID=40548472
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2009/033464 WO2009100380A1 (en) | 2008-02-06 | 2009-02-06 | Use of ranolazine for treating pain |
Country Status (13)
Country | Link |
---|---|
US (1) | US20090203707A1 (en) |
EP (1) | EP2252294A1 (en) |
KR (1) | KR20110013348A (en) |
CN (1) | CN101977605A (en) |
AU (1) | AU2009212254A1 (en) |
BR (1) | BRPI0908428A2 (en) |
CA (1) | CA2713521A1 (en) |
CO (1) | CO6290663A2 (en) |
EA (1) | EA201070914A1 (en) |
EC (1) | ECSP10010446A (en) |
IL (1) | IL207292A0 (en) |
MA (1) | MA32132B1 (en) |
WO (1) | WO2009100380A1 (en) |
Families Citing this family (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2486712C (en) * | 2002-05-21 | 2012-01-03 | Cv Therapeutics, Inc. | Method of treating diabetes |
US8822473B2 (en) * | 2002-05-21 | 2014-09-02 | Gilead Sciences, Inc. | Method of treating diabetes |
US20090247535A1 (en) * | 2008-03-26 | 2009-10-01 | Duke University | Use of ranolazine for non-cardiovascular disorders |
US20100292217A1 (en) * | 2009-05-14 | 2010-11-18 | Gilead Palo Alto, Inc. | Ranolazine for the treatment of cns disorders |
PT2464645T (en) * | 2009-07-27 | 2017-10-11 | Gilead Sciences Inc | Fused heterocyclic compounds as ion channel modulators |
BR112012033402A2 (en) | 2010-07-02 | 2017-01-24 | Gilead Sciences Inc | ion channel modulators according to fused heterocyclic compounds |
BR112013028886A2 (en) | 2011-05-10 | 2016-08-09 | Gilead Sciences Inc | fused heterocyclic compounds as sodium channel modulators |
UY34171A (en) | 2011-07-01 | 2013-01-31 | Gilead Sciences Inc | FUSIONED HETEROCYCLIC COMPOUNDS AS IONIC CHANNEL MODULATORS |
NO3175985T3 (en) | 2011-07-01 | 2018-04-28 | ||
SG11201604457XA (en) | 2013-12-19 | 2016-07-28 | Gilead Sciences Inc | Fused heterocyclic compounds as ion channel modulators |
EP3423057A1 (en) | 2016-03-04 | 2019-01-09 | Gilead Sciences, Inc. | Compositions and combinations of autotaxin inhibitors |
US11261188B2 (en) | 2016-11-28 | 2022-03-01 | Praxis Precision Medicines, Inc. | Fused heteroaryl compounds, and methods thereof for treating diseases, disorders, and conditions relating to aberrant function of a sodium channel |
PT3548033T (en) | 2016-11-28 | 2024-08-09 | Praxis Prec Medicines Inc | Compounds and their methods of use |
WO2018148745A1 (en) | 2017-02-13 | 2018-08-16 | Praxis Precision Medicines , Inc. | Compounds and their methods of use |
WO2018187480A1 (en) | 2017-04-04 | 2018-10-11 | Praxis Precision Medicines, Inc. | Compounds and their methods of use |
US11278535B2 (en) | 2017-08-15 | 2022-03-22 | Praxis Precision Medicines, Inc. | Compounds and their methods of use |
BR112020024379A2 (en) | 2018-05-30 | 2021-03-02 | Praxis Precision Medicines, Inc. | ion channel modulators |
US11773099B2 (en) | 2019-05-28 | 2023-10-03 | Praxis Precision Medicines, Inc. | Compounds and their methods of use |
US11505554B2 (en) | 2019-05-31 | 2022-11-22 | Praxis Precision Medicines, Inc. | Substituted pyridines as ion channel modulators |
US11279700B2 (en) | 2019-05-31 | 2022-03-22 | Praxis Precision Medicines, Inc. | Ion channel modulators |
PE20221280A1 (en) | 2019-11-27 | 2022-09-05 | Praxis Prec Medicines Inc | ION CHANNEL MODULATOR FORMULATIONS AND METHODS OF PREPARATION AND USE OF ION CHANNEL MODULATORS |
Citations (5)
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US20040063717A1 (en) * | 2002-05-21 | 2004-04-01 | Andrew Wolff | Method of treating diabetes |
US20070203079A1 (en) * | 2005-11-21 | 2007-08-30 | Caldwell Guy A | Methods of using small molecule compounds for neuroprotection |
WO2008100992A1 (en) * | 2007-02-13 | 2008-08-21 | Cv Therapeutics, Inc. | Intravenous solutions comprising ranolazine |
WO2008101008A1 (en) * | 2007-02-13 | 2008-08-21 | Cv Therapeutics, Inc. | Use of ranolazine for the treatment of coronary microvascular diseases |
WO2008128086A1 (en) * | 2007-04-12 | 2008-10-23 | Cv Therapeutics, Inc. | Ranolazine for enhancing insulin secretion |
Family Cites Families (12)
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US4657264A (en) * | 1985-11-01 | 1987-04-14 | Ingersoll-Rand Company | Fluid seal assembly with segmented sub-assembly |
DE69033967T2 (en) * | 1989-06-23 | 2002-12-19 | Syntex (U.S.A.) Llc, Palo Alto | Ranolazine and related piperazines for the treatment of shock conditions |
US5455045A (en) * | 1993-05-13 | 1995-10-03 | Syntex (U.S.A.) Inc. | High dose formulations |
US6479496B1 (en) * | 1998-09-10 | 2002-11-12 | Cv Therapeutics, Inc. | Methods for treating angina with ranolazine |
US6303607B1 (en) * | 1998-09-10 | 2001-10-16 | Cv Therapeutics, Inc. | Method for administering a sustained release ranolanolazine formulation |
EP2033633A3 (en) * | 2000-02-18 | 2009-07-08 | Cv Therapeutics, Inc. | Partial fatty acid oxidation inhibitors in the treatment of congestive heart failure |
US20030220344A1 (en) * | 2002-04-04 | 2003-11-27 | Luiz Belardinelli | Method of treating arrhythmias |
US8822473B2 (en) * | 2002-05-21 | 2014-09-02 | Gilead Sciences, Inc. | Method of treating diabetes |
AU2006203890A1 (en) * | 2005-01-06 | 2006-07-13 | Gilead Sciences, Inc. | Sustained release pharmaceutical formulations comprising ranolazine |
CA2653056A1 (en) * | 2006-07-27 | 2008-01-31 | Cv Therapeutics, Inc. | Aldh-2 inhibitors in the treatment of addiction |
CA2682207A1 (en) * | 2007-04-05 | 2008-10-16 | Cv Therapeutics, Inc. | Quinazolinone derivatives as aldh-2 inhibitors |
KR20100097675A (en) * | 2007-11-06 | 2010-09-03 | 씨브이 쎄러퓨틱스, 인코포레이티드 | Aldh-2 inhibitors in the treatment of psychiatric disorders |
-
2009
- 2009-02-06 WO PCT/US2009/033464 patent/WO2009100380A1/en active Application Filing
- 2009-02-06 US US12/367,403 patent/US20090203707A1/en not_active Abandoned
- 2009-02-06 EP EP09707821A patent/EP2252294A1/en not_active Withdrawn
- 2009-02-06 BR BRPI0908428A patent/BRPI0908428A2/en not_active Application Discontinuation
- 2009-02-06 CN CN2009801040287A patent/CN101977605A/en active Pending
- 2009-02-06 CA CA2713521A patent/CA2713521A1/en not_active Abandoned
- 2009-02-06 AU AU2009212254A patent/AU2009212254A1/en not_active Abandoned
- 2009-02-06 KR KR1020107019622A patent/KR20110013348A/en not_active Application Discontinuation
- 2009-02-06 EA EA201070914A patent/EA201070914A1/en unknown
-
2010
- 2010-07-29 IL IL207292A patent/IL207292A0/en unknown
- 2010-08-13 CO CO10099978A patent/CO6290663A2/en not_active Application Discontinuation
- 2010-09-01 MA MA33137A patent/MA32132B1/en unknown
- 2010-09-03 EC EC2010010446A patent/ECSP10010446A/en unknown
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040063717A1 (en) * | 2002-05-21 | 2004-04-01 | Andrew Wolff | Method of treating diabetes |
US20070203079A1 (en) * | 2005-11-21 | 2007-08-30 | Caldwell Guy A | Methods of using small molecule compounds for neuroprotection |
WO2008100992A1 (en) * | 2007-02-13 | 2008-08-21 | Cv Therapeutics, Inc. | Intravenous solutions comprising ranolazine |
WO2008101008A1 (en) * | 2007-02-13 | 2008-08-21 | Cv Therapeutics, Inc. | Use of ranolazine for the treatment of coronary microvascular diseases |
WO2008128086A1 (en) * | 2007-04-12 | 2008-10-23 | Cv Therapeutics, Inc. | Ranolazine for enhancing insulin secretion |
Non-Patent Citations (1)
Title |
---|
STANLEY W C: "RANOLAZINE: NEW APPROACH FOR THE TREATMENT OF STABLE ANGINA PECTORIS", 1 September 2005, EXPERT REVIEW OF CARDIOVASCULAR THERAPY, FUTURE DRUGS, LONDON, GB, PAGE(S) 821 - 829, ISSN: 1477-9072, XP009062744 * |
Also Published As
Publication number | Publication date |
---|---|
BRPI0908428A2 (en) | 2015-12-08 |
ECSP10010446A (en) | 2010-10-30 |
US20090203707A1 (en) | 2009-08-13 |
CA2713521A1 (en) | 2009-08-13 |
MA32132B1 (en) | 2011-03-01 |
EP2252294A1 (en) | 2010-11-24 |
IL207292A0 (en) | 2010-12-30 |
CN101977605A (en) | 2011-02-16 |
AU2009212254A1 (en) | 2009-08-13 |
CO6290663A2 (en) | 2011-06-20 |
EA201070914A1 (en) | 2011-04-29 |
KR20110013348A (en) | 2011-02-09 |
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