Intravenous administration of nimodipine

Abstract

Disclosed is a method of providing an IV nimodipine infusion regimen using a solubilized nimodipine solution suitable for IV administration. The IV nimodipine infusion regimen provides a constant infusion rate over a 24-hour period, supplemented with higher infusions of nimodipine at set intervals, to replicate the 24-hour AUC and C max of an oral dose of nimodipine.

Description

Technical Field

[0001] The present invention provides a preservative-free stable parenteral solution of nimodipine suitable for continuous intravenous (IV) administration via an IV nimodipine infusion pump. The parenteral solution composition consists of nimodipine (at a concentration in the range of about 0.01 to about 5 mg / ml), a hydrophilic surfactant, and a co-solvent, preferably ethanol. The final concentration of ethanol in the administered formulation is preferably less than about 2% w / v.

Background Art

[0002] Nimodipine is a lipophilic substituted 1,4-dihydropyridine with vasodilatatory properties and is applied to the prevention and treatment of ischemic nerve disorders due to cerebral vasospasm after subarachnoid hemorrhage (SAH). Currently, nimodipine treatment of ischemic brain injury is the primary treatment. In men, nimodipine is rapidly absorbed after oral administration, and peak concentrations are generally achieved within 1 hour. The final elimination half-life is approximately 8 - 9 hours, but with a more rapid elimination rate it becomes even more rapid, equivalent to a half-life of 1 - 2 hours; as a result, frequent (every 4 hours) dosing is required. Nimodipine is excreted almost exclusively in the form of metabolites, with less than 1% recovered in the urine as unchanged drug. Many metabolites have been identified, all of which are either inactive or significantly less active than the parent compound. Due to high first-pass metabolism, the bioavailability of nimodipine is on average 13% after oral administration. The bioavailability is significantly increased in cirrhotic patients, and C max is approximately twice the normal value, and dose reduction is required in this group of patients.

[0003] The products currently approved in the U.S. market are the solid and liquid oral dosage forms of nimodipine. Nimodipine is marketed in the United States as the oral dosage form NIMOTOP® liquid-filled capsules (Bayer Pharmaceuticals Corp.) and equivalent generics. The NIMOTOP® capsules and their generic versions each contain 30 mg of nimodipine and are generally administered in a 60 mg dose of 2 capsules, dosed every 4 hours. In the event that the patient is unconscious or unable to swallow, the contents of the nimodipine capsules are extracted with a syringe and administered via an oral or nasal (e.g., nasogastric tube) tube. The physician administering the dose may inadvertently or inappropriately withdraw a liquid dose less than the full amount from the capsule, thus creating a substantial risk of underdosing and imposing an excessive burden on healthcare professionals. Underdosing is exacerbated by the relatively low doses and high drug concentrations associated with the marketed capsules. Thus, if a physician fails to dose the full amount of the high-concentration, low-volume liquid from the marketed capsules, it can result in a significantly lower dose of nimodipine. Also, the FDA describes in a warning related to oral administration of nimodipine via a nasogastric tube that an intravenous syringe should be used to extract the formulation from the capsule because standard needles do not fit oral syringes. The use of an intravenous syringe to extract the nimodipine formulation from the capsule increases the likelihood of inadvertent intravenous administration instead of the drug being administered via the oral or nasogastric tube.

[0004] To rapidly and effectively treat or control the progression of diseases following SAH, intravenous administration of nimodipine is usually preferred. Intravenous (IV) nimodipine is approved in Europe and is sold in Europe by Bayer under the trade name Nimotop®. Currently marketed injectable nimodipine (Bayer's Nimotop®) available in Europe and other regulated markets contains a large amount of organic solvents, about 23.7% ethanol and 17% polyethylene glycol 400. The large amount of ethanol in Nimotop is harmful to people suffering from alcohol dependence or abnormal alcohol metabolism and to women during pregnancy or lactation. Also, high concentrations of ethanol can cause pain and irritation at the injection site. IV Nimotop is most often infused continuously for up to 3 weeks. Due to the high alcohol content in Bayer's IV Nimotop solution, it is diluted with saline and dextrose that are co-infused with a three-way stopcock.

[0005] Nimodipine is poorly water-soluble and thus difficult to formulate as an aqueous injectable. This is the reason why Nimotop's IV infusion utilizes up to 23.7% alcohol as a co-solvent to solubilize nimodipine.

[0006] U.S. Patent No. 5,114,956 describes a parenteral formulation containing 0.01 - 0.4% by weight of nimodipine, based on 100 parts by weight of a solvent consisting of 30 - 70% by weight, preferably 45 - 70% by weight of water, 15 - 40% by weight, preferably 15 - 30% by weight of propylene glycol and / or polyethylene glycol with average molecular weights of 200, 400 and 600, 15 - 30% by weight, preferably 15 - 25% by weight of ethanol, and appropriate and common adjuvants and / or additive substances.

[0007] Through the Adverse Event Reporting System (AERS) and other sources, including published literature, the FDA has identified 31 dosing errors with nimodipine between 1989 and 2009. According to the FDA, 25 of these involved the intravenous administration of the contents of oral capsules. According to the authorities, four patients who received nimodipine intravenously died, while another five experienced severe reactions and one patient experienced permanent damage.

[0008] The medical need to easily administer nimodipine dosage forms to patients known to have dysphagia or inability to swallow, and patients who are unconscious or receiving concomitant medications that cause drug-drug interactions, remains unmet. Additionally, the need to eliminate life-threatening dosing errors as a result of inappropriate drug administration is inevitable.

Summary of the Invention

[0009] Objectives and Summary of the Invention The object of the present invention is to provide an IV nimodipine infusion regimen that can provide a 24-hour plasma exposure of nimodipine to human patients equivalent to that of an oral regimen of 60 mg or 30 mg of nimodipine administered every 4 hours, and replace the oral nimodipine treatment regimen.

[0010] A further object of the present invention is to use an IV nimodipine infusion regimen over a 24-hour period that replicates or mimics the 24-hour area under the curve (AUC) and C max of a 60 mg oral nimodipine capsule administered at 4-hour intervals over 24 hours.

[0011] A further object of the present invention is to use an IV nimodipine infusion regimen administered over a 24-hour period that replicates or mimics the 24-hour (plasma concentration) area under the curve (AUC) and maximum plasma concentration (C max ) of a 30 mg oral nimodipine capsule administered at 4-hour intervals over 24 hours.

[0012] A further object of the present invention is to reduce the variability between subjects in nimodipine plasma concentration using this IV infusion regimen as compared to the oral route of nimodipine administration.

[0013] A further object of the present invention is to provide an IV nimodipine dosing regimen having a concentration-time profile that is more reproducible over 24 hours, has a smaller diurnal variation between morning and evening concentrations, and responds more rapidly to dose adjustments.

[0014] A further object of the present invention is to provide an IV nimodipine dosing regimen having a smaller diurnal variation between morning and evening concentrations.

[0015] A further object of the present invention is an IV nimodipine dosing regimen that responds more rapidly to dose adjustments than an oral dosing regimen that provides a similar AUC and C max A further object of the present invention is to provide an IV nimodipine dosing regimen that is less likely to be impaired by patients with reduced or absent gastrointestinal motility or in a comatose state.

[0016] A further object of the present invention is to provide an IV nimodipine dosing regimen that is less likely to be impaired by patients with reduced or absent gastrointestinal motility or in a comatose state.

[0017] According to the above and other objects, the present invention provides a substantially constant infusion rate over a 24-hour period supplemented with higher infusions of nimodipine at set intervals to replicate the 24-hour AUC and C max of the oral nimodipine dose. However, the present invention is not limited to a single 24-hour infusion. It is envisioned that the 24-hour nimodipine dosing regimen can be repeated as needed.

[0018] In a preferred embodiment, the 24-hour area under the curve and 24-hour C of 60 mg of nimodipine as an oral capsule administered at 4-hour intervals over a day maxTo replicate, nimodipine at 0.15 mg / hour is supplemented by 30-minute infusions of 4 mg of nimodipine at 4-hour intervals and infused via IV administration over the entire 24-hour period. In other words, this administration is achieved, for example, via an infusion of 8.30 mg / hour for 30 minutes followed by an infusion at 0.15 mg / hour for approximately 3.5 hours; or, in other words, via a bolus dose of 4.15 mg administered over 30 minutes followed by an infusion at 0.15 mg / hour for approximately 3.5 hours.

[0019] In certain preferred embodiments, the IV nimodipine treatment regimen is achieved by use of a programmable infusion pump or by using two infusion pumps with a controllable delivery rate (e.g., at about 0.15 mg / hour) that provide a constant infusion of nimodipine over the entire 24-hour period, supplemented by 30-minute infusions of about 4 mg of nimodipine at 4-hour intervals, and the 24-hour area under the curve and 24-hour C of the desired dose of nimodipine administered orally (e.g., as oral capsules) at 4-hour intervals over a day max is replicated.

[0020] In certain embodiments, the present invention is directed to IV nimodipine infusions where a constant infusion of nimodipine at about 0.15 mg / hour over the entire 24-hour period is supplemented by 30-minute infusions of about 4 mg of nimodipine at 4-hour intervals and replicates the 24-hour area under the curve and 24-hour C of 60 mg of nimodipine as oral capsules administered at 4-hour intervals over a day. max Thus, 27.6 mg of IV nimodipine provides equivalent 24-hour plasma nimodipine exposure to 360 mg of oral nimodipine and provides a similar pulsatile concentration-time profile. The delivery rate of the IV nimodipine infusion can vary in direct proportion to the targeted oral dose for the proposed treatment. For example, halving the infusion rate (0.075 mg / hour + 2 mg sustained over 30 minutes at 4-hour intervals) can provide plasma exposure equivalent to 30 mg oral nimodipine capsules every 4 hours.

[0021] IV nimodipine infusion of the present invention can be achieved by using two infusion pumps, one operating continuously at a low speed and the other turned on for 30 minutes at 4-hour intervals and then turned off. The two pumps deliver their infusion fluids to a common infusion line by means of a three-way valve. Alternatively, a single programmable infusion pump set at a pre-set rate can be used to deliver two infusion rates (a sequence of 30 minutes at 4.075 mg / hour followed by 3.5 hours at 0.15 mg / hour, repeated a number of times if desired). Alternatively, a single programmable infusion pump can be used to provide nimodipine continuously at a low speed and the doses administered at approximately 4-hour intervals can be administered manually.

[0022] The IV nimodipine dosing regimen of the present invention provides a nimodipine plasma profile that is more reproducible over a 24-hour period, has a smaller day-to-day variation between morning and evening concentrations, and responds more rapidly to dose adjustments if drug-related side effects (e.g., hypotension) are identified during the treatment process. In addition, IV delivery is less likely to be impaired by patients with reduced or absent gastrointestinal motility or who are in a stuporous state.

[0023] The present invention further targets a method for treating a human patient having a condition selected from aneurysms, subarachnoid hemorrhage, vasospastic angina, Prinzmetal angina, stable angina, acute myocardial infarction, cardiac arrest, arrhythmia, systemic hypertension, pulmonary hypertension, congestive heart failure, coronary artery surgery, and hypertrophic cardiomyopathy, the method comprising continuously infusing an intravenous nimodipine solution according to the present invention over a period of about 3 weeks. The nimodipine infusion regimen can be administered as an intravenous infusion, for example, via an intravenous bolus. In certain embodiments, the IV nimodipine dosing regimen can be contained within an infusion set and bag. In a further embodiment, the infusion bag is covered with an ultraviolet (UV) protective bag that further protects nimodipine from photodegradation. In other preferred embodiments, the nimodipine formulation is administered as a continuous infusion. In the method of the present invention, first-pass metabolism by the liver is minimized and bioavailability is improved. Thus, a consistent level of nimodipine is maintained in the plasma and CSF of the (e.g., human) patient.

[0024] In certain preferred embodiments, the IV nimodipine dosing regimen can be administered as a pharmaceutical composition containing a nimodipine base or any acceptable pharmaceutical salt that is active for parenteral sustained administration. The IV nimodipine dosing regimen can be an immediately injectable premix that does not require further dilution prior to administration and does not contain a bacteriostatic preservative. Alternatively, the IV nimodipine dosing regimen can be in the form of a concentrated injectable solution that can be diluted in a suitable medium (e.g., saline) for administration by infusion.

[0025] The present invention is a method of providing an IV nimodipine infusion regimen in humans, which comprises administering (i) a continuous infusion of nimodipine over a period of at least 24 hours, supplemented by (ii) higher bolus administrations of nimodipine at set intervals over a period of at least 24 hours, such that the 24-hour AUC and Cmax of nimodipine in the dosing regimen are equivalent to those of an oral dose of nimodipine. The IV nimodipine infusion regimen is administered for a period longer than 24 hours. In certain embodiments, the continuous (constant) nimodipine infusion is about 0.15 mg / hour of nimodipine infused via IV administration over a 24-hour period, supplemented by higher bolus administrations of about 4 mg of nimodipine over about 30 minutes at about 4-hour intervals, such that the IV nimodipine infusion regimen is equivalent to the 24-hour area under the curve and 24-hour Cmax of a 60 mg oral nimodipine capsule administered at about 4-hour intervals over a day. This can be achieved by supplementing with 30-minute infusions of nimodipine at about 4-hour intervals and (i) via the use of a single programmable infusion pump, or (ii) by using two infusion pumps with a controllable delivery rate that provides a constant infusion of nimodipine over the entire 24-hour period, or (iii) by using a single programmable infusion pump that provides a constant infusion of nimodipine over the entire 24-hour period, supplemented by bolus doses of nimodipine administered manually at about 4-hour intervals, such that the IV nimodipine infusion regimen is equivalent to the 24-hour area under the curve and 24-hour Cmax of the desired dose of nimodipine administered orally (e.g., as an oral capsule) at about 4-hour intervals over a day. In certain preferred embodiments, the IV nimodipine infusion regimen is one in which 27.6 mg of IV nimodipine provides a 24-hour plasma nimodipine exposure equivalent to 360 mg of oral nimodipine and provides a similar pulsatile concentration-time profile. Further, the IV nimodipine infusion regimen can vary directly proportional to the targeted oral dose for the proposed treatment.Thus, in certain embodiments, reducing the infusion rate by half to provide a sustained nimodipine dose that lasts at about 0.075 mg / hour and a bolus dose of about 2 mg of nimodipine administered over about 30 minutes at intervals of about 4 hours can result in plasma exposure equivalent to that of a 30 mg oral nimodipine capsule every 4 hours.

[0026] The IV nimodipine infusion regimen can be achieved by using two infusion pumps, one operating continuously at a low rate and one turned on for 30 minutes at 4-hour intervals and then off, with the two pumps delivering their infusates to a common infusion line via a three-way valve. Alternatively, the IV nimodipine infusion regimen can be achieved using a single programmable infusion pump set to deliver two infusion rates, a bolus dose of about 4.15 mg of nimodipine administered over about 30 minutes followed by a sustained nimodipine dose of about 0.15 mg / hour for 3.5 hours, in a sequence that can be repeated a number of times as needed (e.g., over a period of about 21 days / 3 weeks). Further, the IV nimodipine infusion regimen can be achieved via the use of a single programmable infusion pump that provides nimodipine continuously at a low rate, with the doses administered at about 4-hour intervals being administered manually. The IV nimodipine infusion regimen can provide an effect selected from the group consisting of (i) a more reproducible nimodipine plasma profile over a day; (ii) a nimodipine plasma profile with less day-to-day variation between morning and evening concentrations; (iii) a nimodipine plasma profile less likely to be compromised by patients with reduced or absent gastrointestinal motility or in a stuporous state; (iv) a nimodipine plasma profile that responds more rapidly to dose adjustments if drug-related side effects (e.g., hypotension) occur during the treatment process; and (v) any combination of the above. In certain embodiments, the human is a patient having a condition selected from aneurysms, subarachnoid hemorrhage, vasospastic angina, Prinzmetal angina, stable angina, acute myocardial infarction, cardiac arrest, arrhythmias, systemic hypertension, pulmonary hypertension, congestive heart failure, coronary artery surgery, and hypertrophic cardiomyopathy.

[0027] In certain preferred embodiments, the IV nimodipine infusion regimen provides, as the IV / oral ratio (%) and its corresponding 90% CI (range) for primary and secondary endpoints, a Day 1 Cmax of about 92% (82 - 104); an AUC on Day 3, 0 - 24 hours, and a Day 3 Cmax of about 106% (99 - 114); 92% (85 - 101) in human subjects who have completed each treatment period.

[0028] In other embodiments, the present invention is directed to providing an IV nimodipine infusion regimen in humans, which comprises administering a bolus injection of about 3.6 mg of nimodipine over about 30 minutes, followed by a continuous infusion of nimodipine at up to about 1.2 mg / hour for up to 21 days. In certain embodiments, the dosing regimen provides a PK profile (e.g., Cmax and AUC0 - 24 hours) equivalent to a 60 mg oral dose of nimodipine.

[0029] In further embodiments, the present invention is directed to providing an IV nimodipine infusion regimen in humans, wherein the human is a healthy volunteer, which comprises administering a bolus injection of about 4.5 mg of nimodipine over about 39 minutes, followed by a continuous IV infusion of nimodipine at about 1.2 mg / hour. In certain embodiments, the dosing regimen provides a PK profile (e.g., Cmax and AUC0 - 24 hours) equivalent to a 60 mg oral dose of nimodipine.

[0030] In still further embodiments, the present invention is directed to providing an IV nimodipine infusion regimen in humans, wherein (i) the continuous infusion of nimodipine is from about 0.05 mg / hour to about 1.5 mg / hour and (ii) is supplemented by higher bolus administrations of nimodipine at set intervals over a 24 - hour period, and the higher bolus administrations are about 1 mg to about 8 mg of nimodipine administered over a period of about 20 minutes to about 50 minutes.

[0031] The present invention is a method of providing an IV nimodipine infusion regimen in a human patient, comprising (i) administering a continuous infusion of nimodipine at about 0.05 mg / hour to about 1.5 mg / hour over 24 hours, supplemented by (ii) higher bolus administrations of nimodipine at set intervals over 24 hours, wherein the human is a patient having a condition selected from aneurysm, subarachnoid hemorrhage, vasospastic angina, Prinzmetal angina, stable angina, acute myocardial infarction, cardiac arrest, arrhythmia, systemic hypertension, pulmonary hypertension, congestive heart failure, coronary artery surgery, and hypertrophic cardiomyopathy. In certain embodiments, the 24-hour AUC and Cmax of nimodipine in the IV nimodipine infusion regimen are equivalent to an oral dose of nimodipine selected from 30 mg or 60 mg of nimodipine administered every 4 hours. The IV nimodipine infusion regimen in a human patient is selected from the group consisting of (i) a sequence of about 4.15 mg bolus dose of nimodipine administered over about 30 minutes, followed by a continuous nimodipine dose of about 0.15 mg / hour for 3.5 hours, repeated a number of times as necessary; (ii) a sequence of a continuous nimodipine dose lasting at about 0.075 mg / hour and a bolus dose of about 2 mg of nimodipine administered over about 30 minutes at about 4-hour intervals, repeated a number of times as necessary; and (iii) a bolus infusion of about 3.6 mg of nimodipine over about 30 minutes, followed by a continuous infusion of nimodipine at up to about 1.2 mg / hour for up to 21 days.

[0032] As used herein, the terms "replicate" or "mimic" or "equivalent" are synonymous with the term "similar" and are intended to represent the concept that the IV dosing regimen of the present invention results in a similar 24-hour plasma nimodipine exposure to an oral dosing regimen of nimodipine.

[0033] As used herein, the term "unit dose" refers to a physically discrete unit suitable as a unit dosage for a mammalian subject, each unit containing a predetermined amount of nimodipine as an active ingredient. Examples of suitable unit doses of nimodipine according to the present invention include transparent solutions, micelles or nanoemulsions in suitable containers such as ampoules or vials.

[0034] The term "comprising" is a generic term that is interpreted to mean containing, encompassing, covering, or including the elements listed in the terms that follow it, but not excluding other unrecited elements.

[0035] "Therapeutically effective amount" means an amount that is sufficient to effect treatment of a disease when administered to an animal for treating the disease.

[0036] As used herein, the terms "treating" a disease or "treatment" of a disease include preventing the disease from occurring (preventive treatment), inhibiting the disease (delaying or halting its onset), bringing about a reduction in the symptoms or side effects of the disease (including palliative treatment), and reducing the disease (causing regression of the disease) in an animal that is likely to be susceptible to the disease but has not yet experienced or manifested the symptoms of the disease.

[0037] "Stable" means that the degradation of the intravenous concentrated infusion (product) is not substantially observed after storage at 40 °C for one month. In a preferred embodiment, the term "stable" means, with respect to an intravenous concentrated infusion containing water-insoluble nimodipine and a surfactant, after storage for 48 hours, the degradation of nimodipine is less than about 5% (preferably less than 4%, or less than 3%, or less than 2%, or less than 1.5%, or less than 1% degradation), and no precipitation is observed; or, the nimodipine micelle structure is thermally stable during the final sterilization process by autoclaving at 121 °C for 30 minutes, and the average diameter of the colloidal structure does not change by more than about 50 nanometers compared to the colloidal structure before and / or after the final sterilization process.

[0038] As used herein, the term "parenteral" includes the techniques of subcutaneous injection, intravenous, intramuscular, intrasternal injection or infusion.

[0039] All numerical values expressing amounts of ingredients, reaction conditions, etc. used in this specification and the claims are to be understood as being modified in all instances by the term "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and the appended claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and without limiting the attempt to apply the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed in light of the number of significant digits and the ordinary rounding techniques.

Brief Description of the Drawings

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Mode for Carrying Out the Invention

[0041] Nimodipine is a dihydropyridine calcium antagonist. Nimodipine is isopropyl 2-methoxyethyl 1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-3,5-pyridinedicarboxylate. The molecular weight is 418.5 and the molecular formula is C21H26N2O7. Nimodipine inhibits the movement of calcium ions into these cells and thus inhibits the contraction of vascular smooth muscle. The contraction process of smooth muscle cells depends on calcium ions that enter these cells during depolarization as a slow transmembrane ionic current. In animal experiments, nimodipine probably has a high lipophilicity and can pass through the blood-brain barrier, so it has a greater effect on cerebral arteries than on other arteries of the body; a high concentration of nimodipine as high as 12.5 ng / mL has been detected in the cerebrospinal fluid of patients with subarachnoid hemorrhage (SAH) treated with nimodipine. The exact mechanism of the action of nimodipine in humans is unknown. In clinical trials, nimodipine shows a favorable effect on the severity of neurological deficits causing cerebral vasospasm following SAH, but there is no angiographic evidence that the drug either prevents or reduces the spasm of these arteries. However, whether the angiographic methodology used was appropriate to detect a clinically meaningful effect, if any, in cerebral vasospasm is unknown.

[0042] Nimodipine is a pale yellow crystalline powder that is poorly soluble in water (2.5 μg / ml, 25 °C). Therefore, its inherent solubility poses a challenge to the development of concentrated, stable, and dilutable injectable pharmaceutical formulations. The present invention aims to solve the solubility drawbacks of previously approved nimodipine dosage forms by developing a robust, stable, and easily administrable nimodipine infusion. Another object of the present invention is to provide the composition and preparation of the nimodipine infusion and its administration.

[0043] The present invention is partially directed to a protocol for replacing an oral nimodipine treatment regimen with an IV nimodipine infusion to obtain equivalent 24-hour plasma nimodipine exposure. By using a programmable infusion pump or by using two infusion pumps with controllable delivery rates, a constant infusion of nimodipine at 0.15 mg / hour over a 24-hour period is supplemented with 30-minute infusions of 4 mg of nimodipine at 4-hour intervals to replicate the 24-hour area under the curve and 24-hour C max of an oral capsule formulation of 60 mg of nimodipine administered at 4-hour intervals over a day. Thus, 27.6 mg of IV nimodipine provides equivalent 24-hour plasma nimodipine exposure to 360 mg of oral nimodipine and provides a similar pulsatile concentration-time profile. The IV concentration-time profile is more reproducible over a day, has less day-to-day variation between early morning and nighttime concentrations, and responds more rapidly to dose adjustments if drug-related side effects (e.g., hypotension) are identified during the treatment course. In addition, IV delivery is less likely to be impaired by patients with decreased or absent gastrointestinal motility or who are in a stuporous state.

[0044] The delivery rate of the IV nimodipine infusion can vary directly proportional to the targeted oral dose for the proposed treatment. For example, halving the infusion rate (0.075 mg / hour + 2 mg over 30 minutes at 4-hour intervals) can provide plasma exposure equivalent to a 30 mg oral capsule formulation of nimodipine every 4 hours.

[0045] The IV infusion can be achieved by using two infusion pumps, one operating continuously at a low rate and one turned on for 30 minutes at 4-hour intervals and then off, with the two pumps delivering their infusates to a common infusion line via a three-way valve. Alternatively, a single programmable infusion pump at a preset rate can be used to deliver two infusion rates (a sequence of 30 minutes at 4.15 mg / hour followed by 3.5 hours at 0.15 mg / hour, repeated as many times as desired).

[0046] Clinical experience with this protocol indicates that the 24-hour C max value is equivalent to the IV and oral routes of nimodipine administration, and the 24-hour AUC value is equivalent for the two routes of administration. The variability between subjects in plasma nimodipine concentration using the IV infusion approach is approximately half of the variability between subjects in plasma nimodipine concentration observed following administration of oral capsules. The degree of diurnal variation in plasma exposure over the course of a day using the IV administration protocol is approximately half of the degree of diurnal variation observed with oral nimodipine administration.

[0047] Liquid formulations For example, two important properties of pharmaceutically acceptable liquid formulations for parenteral use are the solubility of the drug in the carrier (solvent) and the stability of the final formulation (including, but not limited to, the ability of the formulation to prevent precipitation of the drug from solution). In the prior art, there are numerous examples of additives used to solubilize poorly water-soluble drugs for oral and injectable dosage forms. Such additives include organic solvents, surfactants, triglycerides, cyclodextrins, and phospholipids. Any such formulation that provides a solubilized nimodipine IV formulation is envisioned to be useful in the dosing regimen of the present invention. The IV nimodipine dosing regimen can be administered as a pharmaceutical composition containing a nimodipine base or any acceptable pharmaceutically active salt for parenteral sustained release. The IV nimodipine dosing regimen can be an immediate injectable premix that does not require further dilution prior to administration and does not contain a preservative. Alternatively, the IV nimodipine dosing regimen can be in the form of a concentrated injectable solution that can be diluted in a suitable vehicle (e.g., saline) for administration by injection.

[0048] The use of organic solvents such as ethanol is limited to parenteral formulations due to the potential for precipitation of the active (drug) upon injection, pain, inflammation, and hemolysis. Ethanol has been used in prior commercial forms of nimodipine for both solubility and stability reasons. As reported previously herein, currently marketed nimodipine formulations in Europe contain 23.7% ethanol.

[0049] In certain preferred embodiments, an IV nimodipine formulation useful in the dosing regimen of the present invention (in contrast to prior intravenous nimodipine formulations) is, for example, a solution comprising nimodipine, a hydrophilic surfactant, and a small amount of an organic solvent, wherein the nimodipine is dissolved in the small amount of the organic solvent by mixing, and further this nimodipine solution is combined with the hydrophilic surfactant to form micelles of nimodipine in a clear solution.

[0050] In a further preferred embodiment, the dosing regimen (IV nimodipine treatment regimen) is a nimodipine formulation that can be directly injected into humans (without dilution; suitable for parenteral administration, for example), comprising nimodipine at a concentration of about 0.01 mg / ml to about 1.0 mg / ml and a pharmaceutically acceptable carrier (for example, for injection) selected from the group consisting of an aqueous solution, an organic solvent, an oil, and cyclodextrin, having a volume of about 50 ml to about 1000 ml, and being contained in a pharmaceutically acceptable container (for example, a bag or a vial). When present, the organic solvent preferably constitutes less than 2% w / v or less than 1% w / v of the formulation, and nimodipine is substantially contained as micelles in the diluted injection solution, and the formulation contains an effective amount of a hydrophilic surfactant such that the formulation maintains a clear solution and does not show precipitation of nimodipine. In a preferred embodiment, the hydrophilic surfactant is from 0.01% w / v to about 2.5% w / v of the directly injectable (ready-to-use) formulation. In certain embodiments, the hydrophilic surfactant is a non-ionic hydrophilic surfactant, and in certain embodiments, most preferably, it comprises or consists of polysorbate 80. In certain embodiments, the organic solvent comprises or consists of ethanol. In certain preferred embodiments, the pharmaceutically acceptable aqueous carrier comprises water for injection. In certain preferred embodiments, the hydrophilic surfactant is included in an amount of about 0.01% to about 2.5% of the directly injectable formulation. In certain preferred embodiments, the formulation is stable when exposed to the conditions of 40°C ± 2°C / 75% RH ± 5% RH for at least 6 months; or stable when exposed to the conditions of 25°C ± 2°C / 60% RH ± 5% RH for at least 12 months. In certain preferred embodiments, nimodipine is substantially contained within micelles as a nanoemulsion.

[0051] In other embodiments, the pharmaceutically acceptable carrier is beta-cyclodextrin, and nimodipine is substantially contained within the inclusion complex. In certain embodiments, the unit dose of the concentrate is diluted to a total volume of 5 ml with water for injection and enclosed within a pharmaceutically acceptable container, such as an ampoule or a vial. In certain preferred embodiments, the organic solvent comprises ethanol.

[0052] In an embodiment of the present invention in which the organic solvent is included in a pharmaceutically acceptable carrier, the organic solvent can constitute, for example, at least 25% of the concentrate, and in certain embodiments at least 40% of the concentrate.

[0053] In certain preferred embodiments, the nimodipine concentrate has a volume of about 1 ml to about 10 ml, preferably about 5 ml, and is contained in an ampoule or vial.

[0054] In certain embodiments, the nimodipine injection concentrate is diluted with water for injection, physiological saline, dextrose or other commonly available infusions to a concentration of up to 0.01 mg / ml to maintain a clear solution and show no precipitation of nimodipine crystals. The nimodipine injection concentrate is preferably diluted with a suitable injection medium that, for example, contains less than 1% w / v alcohol mainly in an aqueous medium, for example, to enable administration in a single 100 ml or preferably 250 ml infusion bag or bottle, and the diluted injection medium maintains a clear solution showing no precipitation of nimodipine.

[0055] The present invention further partly targets a nimodipine preparation suitable for injection into humans, which comprises nimodipine at a concentration of about 0.01 mg / ml to about 1.0 mg / ml and a pharmaceutically acceptable carrier (e.g., for injection) selected from the group consisting of an aqueous solution, an organic solvent, an oil, and cyclodextrin, and has a volume of about 50 ml to about 1000 ml. When present, the organic solvent preferably constitutes less than 2% w / v of the preparation. Nimodipine is substantially contained in an injection solution, suspension, emulsion, or complex diluted as micelles or colloidal particles or inclusion compounds, and contains an effective amount of a hydrophilic surfactant such that the preparation maintains a clear solution and shows no precipitation of nimodipine. In certain embodiments, the hydrophilic surfactant is polysorbate 80. In certain embodiments, the pharmaceutically acceptable carrier is an organic solvent and further contains water for injection. In certain embodiments, the pharmaceutically acceptable carrier is an oil and further contains a pharmaceutically acceptable hydrophilic surfactant (or emulsifier) in an amount of about 0.005% to about 30%, more preferably about 0.5% to about 15%, and in certain embodiments about 0.005% to about 3.0%, and nimodipine is substantially contained within the micelles. In certain preferred embodiments, nimodipine is substantially contained within the micelles as a nanoemulsion.

[0056] In certain preferred embodiments, the emulsifier is selected from the group consisting of phospholipids and polyethylene glycol. In other embodiments, the pharmaceutically acceptable carrier is beta-cyclodextrin and nimodipine is substantially contained within the inclusion complex. In certain preferred embodiments, the nimodipine formulation is contained within a single infusion bag or bottle for continuous intravenous infusion. In certain preferred embodiments of the nimodipine formulation, the median particle size of the nimodipine micelles or nanoemulsions or complexes ranges from about 0.5 nanometers to about 350 nanometers, or from about 0.5 nm to about 200 nm, or from about 5 nm to about 50 nm. Preferably, the nimodipine formulation is transparent and does not contain crystalline precipitates of nimodipine. Preferably, the nimodipine formulation is stable. Preferably, the concentrated nimodipine formulation is stable. In certain preferred embodiments, nimodipine is substantially contained within micelles as a nanoemulsion. Administration of the nimodipine formulation via injection or infusion makes it possible to minimize the first-pass metabolism of nimodipine by the liver, and the nimodipine formulation administered via injection has significantly improved bioavailability compared to oral nimodipine formulations. With the nimodipine injection formulation of the present invention, a consistent level of nimodipine can be maintained in the plasma and CSF of a (e.g., human) patient.

[0057] In certain preferred embodiments of the above-described nimodipine concentrates and formulations, the aqueous carrier is selected from the group consisting of sodium chloride injection solution, Ringer's injection solution, isotonic dextrose injection solution, sterile water injection solution, dextrose, and lactated Ringer's injection solution.

[0058] In certain preferred embodiments of the above-described nimodipine concentrates and formulations, the oil is selected from the group consisting of fixed oils of plant origin, cottonseed oil, corn oil, sesame oil, and peanut oil.

[0059] In certain preferred embodiments, the nimodipine formulation further comprises one or more preservatives. Examples of suitable preservatives include, for example, phenol or cresol, mercury agents, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoate esters, thimerosal, benzalkonium chloride, benzethonium chloride, boric acid, p-hydroxybenzoate, phenol, chlorinated phenol compounds, alcohols, quaternary compounds, mercury agents, and mixtures of any of the foregoing.

[0060] In a further embodiment, the hydrophilic surfactant constitutes from about 0.01% to about 2.5% of the formulation, and in certain preferred embodiments, the hydrophilic surfactant constitutes at least 0.1% in the diluted nimodipine formulation.

[0061] In certain preferred embodiments, the organic solvent constitutes at least 1% of the formulation (diluted formulation).

[0062] In certain preferred embodiments, the pharmaceutically acceptable carrier constitutes from about 0.1% to about 15% of the formulation.

[0063] In certain preferred embodiments, the pH of the nimodipine formulation is from about 3 to about 9, and in certain preferred embodiments, preferably from about 4.5 to about 7.5 or 8.

[0064] Concentrate One aspect of the present invention is directed to the use of a nimodipine injection concentrate. In such embodiments, nimodipine is mixed with a pharmaceutically acceptable carrier to prepare a concentrated injection solution, suspension, emulsion or complex. Thereafter, an effective amount of a hydrophilic surfactant is added. Optionally, the pharmaceutically acceptable vehicle for injection is added in a relatively small amount (e.g., 5 ml) to prepare the final concentrated nimodipine formulation.

[0065] The concentrate can be prepared, for example, by dissolving nimodipine in a small amount of an organic solvent by mixing. Thereafter, in certain preferred embodiments, the resulting nimodipine solution is combined with an effective amount of a hydrophilic surfactant to form micelles of nimodipine in a clear solution. Thereafter, a pharmaceutical medium suitable for injection (for example, water for injection) is added to prepare the final nimodipine concentrate formulation. In certain preferred embodiments, the organic solvent can be, for example, 95% ethanol, and the hydrophilic surfactant can be polysorbate 80. The resulting formulation contains stable micelles containing nimodipine.

[0066] The concentrate can also be prepared by mixing a suitable amount of nimodipine together with an organic solvent and a hydrophilic surfactant for a period sufficient to form stable micelles. Thereafter, a pharmaceutical medium suitable for injection (for example, water for injection) is added to prepare the final nimodipine concentrate formulation. In certain preferred embodiments, the organic solvent can be, for example, polyethylene glycol, and the hydrophilic surfactant can be polysorbate 80. In certain embodiments of the invention in which an organic solvent is included, the organic solvent constitutes at least 25% (in certain embodiments at least 40%) of the formulation in the injection concentrate and at least 1% in the finally diluted injection solution. In other preferred embodiments, the solvent constitutes from about 10 to about 90%, preferably from 30% by weight to greater than about 90% by weight, of the injection concentrate and from about 0.1 to about 4% of the finally diluted injection solution.

[0067] In certain preferred embodiments, the nimodipine injection concentrate formulation comprises nimodipine at a concentration of about 0.5 mg / ml to about 5 mg / ml such that the nimodipine in the concentrate is contained in micelles; an organic solvent in an amount greater than 30% w / w and up to about 90% w / w; a hydrophilic surfactant in an amount of about 0.005 to about 30%, preferably about 0.5% or 1% to about 15%; and an injectable pharmaceutically acceptable aqueous carrier constituting about 30 to about 80% of the concentrate formulation. In preferred embodiments, the formulation is stable and transparent. In certain embodiments, the hydrophilic surfactant is polysorbate 80. In certain embodiments, the pharmaceutically acceptable carrier is water for injection and the nimodipine is substantially contained within the micelles. In certain preferred embodiments, the organic solvent comprises or consists of ethanol. In certain embodiments, the unit dose of the concentrate is diluted to a total volume of 5 ml with water for injection and enclosed within a pharmaceutically acceptable container, such as an ampoule or vial. In certain embodiments, the nimodipine injection concentrate further comprises an effective amount of a preservative. In certain preferred embodiments of the nimodipine injection concentrate, the median particle size of the micelles or nanoemulsion is in the range of about 0.5 nanometers to about 350 nanometers, or about 0.5 nm to about 200 nm, or about 5 nm to about 50 nm. Preferably, the nimodipine concentrate formulation is transparent and does not contain precipitation of nimodipine crystals. In certain preferred embodiments, the nimodipine is substantially contained within the micelles as a nanoemulsion. The nimodipine concentrate formulation (such as as described above) can be diluted with a suitable injection medium such that the diluted formulation for injection contains less than about 2% or preferably less than about 1% w / v of an organic solvent (such as alcohol). The solution is preferably a predominantly aqueous medium and the diluted injection medium maintains a clear solution that does not exhibit precipitation of nimodipine. The concentrate, when diluted with a suitable injection medium, preferably enables parenteral administration in a single 250 ml infusion bag or bottle for a human patient and the diluted formulation contains less than about 2% or preferably less than about 1% w / v of an organic solvent (such as alcohol). In certain embodiments, the concentrate and the diluted solution further comprise an effective amount of a pharmaceutically acceptable preservative.In certain preferred embodiments, substantially all or all of the nimodipine contained in the formulation is contained in micelles.

[0068] In other embodiments, nimodipine is at a concentration of about 0.5 mg / ml to about 5 mg / ml, about 1% to about 15% of a hydrophilic surfactant, and the pharmaceutically acceptable carrier for injection constitutes about 10% to about 90% of the formulation injection concentrate. The pharmaceutically acceptable carrier for injection is selected from the group consisting of aqueous solutions, organic solvents, oils, and cyclodextrins, and the injection solution, suspension, emulsion, or complex in which nimodipine is concentrated as micelles or colloidal particles or inclusion complexes is substantially contained therein, and the formulation is stable and transparent. In certain embodiments, the hydrophilic surfactant is polysorbate 80. In certain embodiments, the pharmaceutically acceptable carrier is water for injection, further comprising about 0.5% to about 30% of a pharmaceutically acceptable hydrophilic surfactant (or referred to herein as an emulsifier), and nimodipine is substantially contained within the micelles. In other embodiments, the pharmaceutically acceptable carrier is an organic solvent, and the concentrate further comprises water for injection. In other embodiments, the pharmaceutically acceptable carrier is an oil, further comprising about 0.005% to about 30%, more preferably about 0.5 to about 15% of a pharmaceutically acceptable hydrophilic surfactant, and nimodipine is substantially contained within the micelles. In certain preferred embodiments, the hydrophilic surfactant (emulsifier) is selected from the group consisting of phospholipids and polyethylene glycol. In certain embodiments, the unit dose concentrate is diluted to a total volume of 5 ml with water for injection and enclosed within a pharmaceutically acceptable container, such as an ampoule or vial. In certain embodiments, the nimodipine injection concentrate further comprises an effective amount of a preservative. In certain preferred embodiments of the nimodipine injection concentrate, the median particle size of the micelles or nanoemulsion is in the range of about 0.5 nanometers to about 350 nanometers, or about 0.5 nm to about 200 nm, or about 5 nm to about 50 nm. Preferably, the nimodipine concentrated formulation is transparent and does not contain crystal precipitation of nimodipine. Preferably, the nimodipine concentrated formulation is stable. In certain preferred embodiments, nimodipine is substantially contained within the micelles as a nanoemulsion.

[0069] The concentrate can be prepared by mixing a suitable amount of nimodipine with a pharmaceutically acceptable oily carrier and a hydrophilic surfactant until a clear solution is obtained, adding at least one pharmaceutically acceptable emulsifier to produce a nanoemulsion and / or a self-emulsifying concentrate formulation. The self-emulsifying formulation forms a nanoemulsion when diluted with water for injection or any commonly available intravenous infusion. In such embodiments, nimodipine is preferably present in an oil phase, preferably soybean oil, medium-chain triglycerides, oleic acid, ethyl oleate, which contains other pharmaceutically acceptable additives either alone or in combination with an emulsifier and water for injection. In certain embodiments, the emulsifier can be, for example, phospholipid lipoid 80 and / or PEG400. The median particle size of the micelles or nanoemulsion ranges from about 0.5 nanometers to about 350 nanometers. In certain embodiments of the invention containing an oily carrier, the oily carrier constitutes about 1% to about 30% of the formulation in the injection concentrate and about 0.005% to about 3% of the ultimately diluted injection solution. In other preferred embodiments, the oil constitutes about 5% to about 20% by weight of the formulation in the injection concentrate and about 0.025% to about 2% in the ultimately diluted injection solution. The amount of emulsifier can constitute about 1% to about 30% of the formulation in the injection concentrate and about 0.005% to about 3% of the ultimately diluted injection solution.

[0070] In a further embodiment, the present invention is a method for preparing a nimodipine preparation (concentrate) for intravenous administration, comprising mixing nimodipine with a pharmaceutically acceptable carrier for injection at a concentration of about 0.5 mg / ml to about 5 mg / ml such that the pharmaceutically acceptable carrier for injection constitutes about 10% to about 90% of the concentrate; then adding about 1% to about 15% of a hydrophilic surfactant to prepare a concentrated injection solution, suspension, emulsion or complex; and optionally adding about 0.5 ml to about 4.0 ml of a pharmaceutically acceptable medium for injection to prepare a nimodipine concentrate preparation. Preferably, the nimodipine concentrate preparation is transparent and does not contain precipitation of nimodipine crystals. The method further comprises diluting the nimodipine concentrate to a volume of about 50 ml to about 1000 ml in a pharmaceutically acceptable carrier for injection selected from the group consisting of aqueous solutions, organic solvents, oils and cyclodextrins, and wherein, if present, the organic solvent constitutes less than 2% w / v of the formulation, and the formulation maintains a transparent solution and does not show precipitation of nimodipine crystals. In certain preferred embodiments of the nimodipine concentrate or diluted formulation, the median particle size of the nimodipine micelles or nanoemulsions or complexes is in the range of about 0.5 nanometers to about 350 nanometers, or about 0.5 nm to about 200 nm, or about 5 nm to about 50 nm.

[0071] The nimodipine infusion rate can be, for example, from about 0.05 mg of nimodipine per hour to about 5 mg of nimodipine per hour. In certain embodiments, the intravenous nimodipine dose is about 2 to 10 mg administered every 5 hours. In certain embodiments, the nimodipine preparation is administered via intravenous bolus, intravenous infusion, intra-arterial, oral, or intranasal via a nasogastric tube. In certain embodiments, the method further comprises diluting with a 2.5×10 -5 molar solution of nimodipine and flushing the exposed artery after clipping the aneurysm and before intravenous injection of the administered nimodipine to improve patient outcome.

[0072] In yet another embodiment of the present invention, a suitable amount of nimodipine is mixed with a hydrophilic surfactant together with a suitable amount of cyclodextrin (e.g., beta-cyclodextrin) in water for a period sufficient to form a stable nimodipine inclusion complex. In such an embodiment, the cyclodextrin preferably constitutes about 5% to about 45% of the formulation in the injection concentrate and about 0.025% to about 4.5% of the finally diluted injection solution.

[0073] In certain embodiments of the present invention, the hydrophilic surfactant constitutes at least about 8% of the formulation in the injection concentrate and at least 0.1% of the formulation in the finally diluted injection solution. In other preferred embodiments, the hydrophilic surfactant constitutes about 1 wt% to about 15 wt% of the formulation of the injection concentrate and about 0.01% to about 2.5% of the finally diluted injection solution.

[0074] In certain preferred embodiments, the hydrophilic surfactant comprises a pharmaceutically acceptable nonionic surfactant. The nonionic surfactant is preferably included in an amount sufficient to inhibit precipitation of the active pharmaceutical ingredient from a pharmaceutically acceptable medium for injection (e.g., an aqueous solution) after dilution. The nonionic surfactant can form stable micelles with the active pharmaceutical ingredient, solubilize the drug, and can further impart photo-stability to the drug.

[0075] Using the HLB value as a rough guide, the hydrophilic surfactant is considered to be these compounds having an HLB value greater than 10, particularly 12 to 17. Aqueous nonionic surfactants are more soluble in water than in oil (which has an HLB greater than 10).

[0076] Pharmaceutically acceptable nonionic surfactants useful in the formulations of the present invention include, for example, polyoxyethylene compounds, ethoxylated alcohols, ethoxylated esters, ethoxylated amides, polyoxypropylene compounds, propoxylated alcohols, ethoxylated / propoxylated block polymers, and propoxylated esters, alkanolamides, amine oxides, fatty acid esters of polyhydric alcohols, ethylene glycol esters, diethylene glycol esters, propylene glycol esters, glyceryl esters, polyglyceryl fatty acid esters, sorbitan esters, sucrose esters, and glucose (dextrose) esters, but are not limited thereto. Further examples are reaction products of natural or polyethoxylated castor oil and ethylene oxide. Ethoxylated castor oil can have an ethylene oxide content of 25 to 100 moles per molecule, preferably 35 to 60 moles per molecule. Natural or polyethoxylated castor oil can react with ethylene oxide in a molar ratio of about 1:35 to about 1:60, and the polyethoxylated component can be optionally removed from the product. Nonionic hydrophilic surfactants useful in the present invention include alkylgluceoside; alkyl maltoside; alkyl thioglucoside; lauryl macrogolglycenides; polyoxyethylene alkyl ether; polyoxyethylene alkyl phenol; polyethylene glycol fatty (mono and di) acid esters; polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; polyglyceryl fatty acid esters; polyoxyethylene glycerides; polyoxyethylene sterols and their analogs; polyoxyethylene vegetable oils, polyoxyethylene hydrogenated vegetable oils; polyols, and reaction mixtures in sterols of at least one member selected from the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils; sugar esters, sugar ethers; scroglycerides; fatty acid salts, bile acid salts, phospholipids, phosphate esters, carboxylates, sulfates, sulfonates.More specifically, the nonionic surfactant may include, for example, polyoxyethylene fatty acid alcohol esters, sorbitan fatty acid esters (Span), polyoxyethylene sorbitan fatty acid esters (e.g., polyoxyethylene (20) sorbitan monooleate (Tween80), polyoxyethylene (20) sorbitan monostearate (Tween60), polyoxyethylene (20) sorbitan monolaurate (Tween20) and other Tweens, sorbitan esters, glycerol esters, e.g., Myrj and glycerol triacetate (triacetin), polyethylene glycol, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, polysorbate 80, poloxamer, poloxamine, polyoxyethylene castor oil derivatives (e.g., Cremophor® RH40, Cremphor A25, Cremphor A20, Cremophor® EL) and other Cremophor, sulfosuccinates, alkyl sulfates (SLS); PEG glyceryl fatty acid esters, e.g., PEG-8 caprylic / capric glyceryl (Labrasol), PEG-4 caprylic / capric glyceryl (Labrafac Hydro WL 1219), PEG-32 lauryl glyceryl (Gelucire 444 / 14), PEG-6 monooleyl glyceryl (Labrafil M 1944 CS), PEG-6 linoleyl glyceryl (Labrafil M 2125 CS); propylene glycol mono- and di-fatty acid esters, e.g., propylene glycol laurate, propylene glycol caprylate / caprate; Brij® 700, ascorbyl-6-palmitate, stearylamine, sodium lauryl sulfate, polyoxyethylene glycerol triiricinoleate, and any combination or mixture thereof. Polyethylene glycol (PEG) itself does not function as a surfactant, but various PEG-fatty acid esters have useful surfactant properties. Among the PEG-fatty acid monoesters, esters of lauric acid, oleic acid, and stearic acid are the most useful.

[0077] Examples include PEG-8 laurate, PEG-8 oleate, PEG-8 stearate, PEG-9 oleate, PEG-10 laurate, PEG-10 oleate, PEG-12 laurate, PEG-12 oleate, PEG-15 oleate, PEG-20 laurate, and PEG-20 oleate. Polyethylene glycol fatty acid esters are also suitable for use as surfactants in the compositions of the present invention, for example PEG-20 dilaurate, PEG-20 dioleate, PEG-20 distearate, PEG-32 dilaurate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-20 glyceryl oleate, and PEG-30 glyceryl oleate. The hydrophilic surfactant may further comprise any of the foregoing mixtures.

[0078] Polysorbate 80 is a particularly preferred hydrophilic nonionic surfactant in the formulations of the present invention and is a surfactant commonly used in protein parenteral formulations to minimize denaturation at the air-water interface. Polysorbate 80 may also be used in injectable solution formulations of small molecules for the purpose of improving solubility by micelle formation. Polysorbates are nonionic surfactants of sorbitan esters. Polysorbates useful in the present invention include, but are not limited to, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80 (Tween80), and any combination or mixture thereof. Other suitable preferred surfactants include poloxamer, poloxamer 407, and transcutol. The surfactant can be any surfactant suitable for use in pharmaceutical compositions. Suitable surfactants can also be ionic hydrophilic surfactants or hydrophobic surfactants. Suitable hydrophilic surfactants can be anionic, cationic, zwitterionic, or nonionic, with nonionic hydrophilic surfactants being preferred at present. Preferably, the nimodipine formulation of the present invention comprises at least one nonionic hydrophilic surfactant.

[0079] However, in other embodiments, the nimodipine formulation may include a mixture of two or more nonionic hydrophilic surfactants, as well as a mixture containing at least one nonionic hydrophilic surfactant and at least one hydrophobic surfactant.

[0080] In certain embodiments, the surfactant(s) can be one or more of the surfactants described in U.S. Patent No. 6,363,471.

[0081] In certain embodiments of the present invention, the organic solvent is an alcohol (e.g., ethanol) and the solubilizer is a polysorbate.

[0082] In the above embodiments, nimodipine is solubilized through the formation of colloidal particles called micelles using a surfactant as a solubilizer and stabilized by using a co-solvent and / or a suitable substrate in an aqueous formulation. This results in the formation of micelles, or minute colloidal particles around the nimodipine molecules, which are isolated from the surrounding water molecules but form a clear aqueous solution. The liquid formulation is suitable for use as parenteral, nasal or oral administration.

[0083] Water-miscible surfactant molecules such as polysorbates consist of both hydrophobic and hydrophilic moieties that can solubilize selected water-insoluble drugs. Surfactants are also self-assembling and can form micelles when the surfactant monomer concentration reaches the critical micelle concentration. Thus, surfactants can solubilize drug molecules either by a direct co-solvent effect or by incorporation into micelles. Nonionic surfactants in commercially available solubilized oral and injectable formulations include polyoxyl 35 castor oil (Cremophor EL), polyoxyl 40 hydrogenated castor oil (Cremophor RH40), polysorbate 20 (Tween20), polysorbate 80 (Tween80), d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), Solutol HS-15, sorbitan monooleate (Span80), polyoxyl 40 stearate, and various polyglycolized glycerides, including Labrafil M-1944CS, Labrafil M-2125CS, Labrasol, Gellucire 44 / 14, and Softigen767.

[0084] In the present invention, the nimodipine formulation preferably forms a colloidal structure (micelle) with a diameter of about 10 nm. In other preferred embodiments, the average diameter of the colloidal structure varies from about 0.5 nm to about 200 nm, more preferably from about 5 nm to about 50 nm. In the present invention, the nimodipine micelle structure is thermally stable during the final sterilization process by autoclaving at 121 °C for 30 minutes.

[0085] In embodiments utilizing an oily carrier, the formulation may include an oily carrier in the form of a commercially available emulsion, such as Intralipid (10 - 20% soybean oil), Liposyn (10 - 20% safflower oil), and Lipofundid MCT / TCL (5 - 10% soybean oil and medium-chain triglycerides). Nimodipine is lipophilic and can be formulated for intravenous administration in an oil-in-water emulsion since nimodipine partitions into the oil phase.

[0086] In certain preferred embodiments, the nimodipine injection formulation is a cyclodextrin inclusion complex. Suitable cyclodextrins include, but are not limited to, beta-cyclodextrins such as hydroxy-propyl-beta-cyclodextrin and beta-cyclodextrins containing one or more hydroxybutylsulfonate moieties such as sulfobutyl-ether-beta-cyclodextrin, alpha-cyclodextrin, gamma-cyclodextrin, and cyclodextrins as described in U.S. Patent No. 6,610,671 or U.S. Patent No. 6,566,347. In one embodiment, the nimodipine injection formulation comprises a beta-cyclodextrin inclusion complex formed by continuously mixing nimodipine, a hydrophilic surfactant, and beta-cyclodextrin in a water bath at about 60 degrees Celsius with occasional heating for 48 to 78 hours to increase the formation of the complex.

[0087] Any suitable pharmaceutically acceptable water-miscible organic solvent can be used in the present invention. The selection of a suitable organic solvent depends in part on the solubility of the active substance (nimodipine) in the solvent, the degree to which the solvent is water-miscible, and the durability of the solvent. The solvent should be physiologically acceptable. Examples of solvents that can be used in the present invention include, but are not limited to, ethanol, glycol, glycerin, propylene glycol, and various alcohols such as various polyethylene glycols and dimethyl isosorbide (DMI).Further useful alcohols include, but are not limited to, methanol (methyl alcohol), ethanol (ethyl alcohol), 1-propanol (n-propyl alcohol), 2-propanol (isopropyl alcohol), 1-butanol (n-butyl alcohol), 2-butanol (sec-butyl alcohol), 2-methyl-1-propanol (isobutyl alcohol), 2-methyl-2-propanol (t-butyl alcohol), 1-pentanol (n-pentyl alcohol), 3-methyl-1-butanol (isopentyl alcohol), 2,2-dimethyl-1-propanol (neopentyl alcohol), cyclopentanol (cyclopentyl alcohol), 1-hexanol (n-hexanol), cyclohexanol (cyclohexyl alcohol), 1-heptanol (n-heptyl alcohol), 1-octanol (n-octyl alcohol), 1-nonanol (n-nonyl alcohol), 1-decanol (n-decyl alcohol), 2-propen-1-ol (allyl alcohol), phenylmethanol (benzyl alcohol), diphenylmethanol (diphenylcarbinol), triphenylmethanol (triphenylcarbinol), glycerin, phenol, 2-methoxyethanol, 2-ethoxyethanol, 3-ethoxy-1,2-propanediol, di(ethylene glycol) methyl ether, 1,2-propanediol, 1,3-propanediol, 1,3-butanediol, 2,3-butanediol, 1,4-butanediol, 1,2-pentanediol, 1,3-pentanediol, 1,4-pentanediol, 1,5-pentanediol, 2,3-pentanediol, 2,4-pentanediol, 2,5-pentanediol, 3,4-pentanediol, and 3,5-pentanediol.

[0088] In embodiments where the emulsifier is incorporated into the concentrate, the emulsifier can be a pharmaceutically acceptable polyethylene glycol. Polyethylene glycol is available in many different grades with various molecular weights. For example, polyethylene glycol is available as PEG200; PEG300; PEG400; PEG540 (blend); PEG600; PEG900; PEG1000; PEG1450; PEG1540; PEG2000; PEG3000; PEG3350; PEG4000; PEG4600 and PEG8000. In certain embodiments, the polyethylene glycol used to prepare the nimodipine concentrate is preferably PEG400.

[0089] The nimodipine concentrate of the present invention can be contained in any pharmaceutically acceptable container (e.g., ampoule, vial) in unit doses for subsequent dilution (e.g., at the site and time of administration to a human patient).

[0090] Dilution The injectable nimodipine formulation of the present invention is preferably clear, contains nimodipine as micelles or inclusion complexes, etc., and is diluted with an injectable pharmaceutically acceptable carrier (e.g., water for injection) as described and disclosed herein to produce a thermodynamically stable dispersion of nonionic surfactant nanoparticles that are micelles, inclusion complexes, etc. The diluted nimodipine formulation is stable, i.e., nimodipine does not phase separate over a wide range of temperatures, over a wide range of water hardness and over a wide range of pH. Thus, when diluted with water for injection, physiological saline, dextrose or commonly available infusions, the nimodipine injection concentrate disclosed herein. In certain embodiments, the concentration of the diluted nimodipine formulation is from about 0.05 mg / ml to about 0.2 mg / ml. For example, the concentration of the diluted nimodipine formulation can be 0.08 mg / ml, 0.12 mg / ml, 0.16 mg / ml or 0.2 mg / ml. In certain preferred embodiments, the concentrate of the diluted nimodipine formulation maintains a clear solution and does not show precipitation of nimodipine.

[0091] According to the present invention, the nimodipine formulation enables a clear improvement over IV Nimotop by mainly administering IV nimodipine in a single 250 ml infusion bag or bottle containing an aqueous medium. In certain embodiments, the solution may contain a low alcohol content. For example, the alcohol content of the nimodipine formulation can be, for example, from about 0% to about 5%. In certain preferred embodiments, the nimodipine formulation may contain less than 2% w / v or less than 1% w / v alcohol. This low alcohol content in the formulation provides many advantages known to those skilled in the art, for example, to produce the nimodipine formulation of the present invention applicable to the administration to patients suffering from alcohol dependence, alcohol metabolism disorders and patients during pregnancy or lactation.

[0092] The present invention is a micellar formulation of nimodipine that provides improved aqueous solubility and stability including photostability. Nimodipine does not precipitate from this formulation even when diluted with water up to 250 times its original concentration.

[0093] In certain embodiments of the present invention, the nimodipine injection concentrate is diluted in an infusion bag containing water for injection or any commonly available intravenous infusion. The infusion volume can range from about 50 ml to about 1000 ml. The present invention provides for the dilution of the formulation in a single infusion bag that is infused over a specific period of time, different from Bayer's Nimotop intravenous injection which requires the assistance of a three-way stopcock to inject the Nimotop solution together with two other co-infusions to prevent precipitation of any drug. The present invention provides a single infusion that does not precipitate upon dilution and / or administration and thus improves safety and efficacy.

[0094] In certain preferred embodiments, the nimodipine injection is further diluted to a 2.5×10 -5 molar solution of nimodipine and can be used to irrigate the exposed artery to improve the patient's outcome before intravenous injection of nimodipine administered after clipping an aneurysm.

[0095] In certain preferred embodiments, nimodipine formulations that do not contain a novel solvent (e.g., less than 1% w / v of an organic solvent, such as ethanol) can be administered intravenously as a bolus, by intravenous infusion, intraarterially, orally, or intranasally using a nasogastric tube.

[0096] In certain preferred embodiments, which are nimodipine injections after dilution in commonly available infusions, the infusion set and bag can be covered with an ultraviolet (UV) protective bag that further protects from photodegradation.

[0097] The compounds of the present invention can be administered parenterally, if desired, as a formulation that ultimately contains conventional non-toxic pharmaceutically acceptable carriers, adjuvants, and vehicles.

[0098] Injectable preparations, such as sterile aqueous or oily suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions or suspensions in a non-toxic parenterally acceptable diluent or solvent. Acceptable vehicles and solvents are water, Ringer's solution, and isotonic sodium chloride. In addition, sterile fixed oils are conventionally utilized as a solvent or suspending medium. For this purpose, any bland fixed oil containing synthetic mono- or diglycerides can be used, and in addition, fatty acids such as oleic acid are utilized in the preparation of injectables. Carriers suitable for intravenous administration include physiological saline or phosphate buffered saline (PBS), as well as solutions containing solubilizing agents, such as glucose, polyethylene glycol, and polypropylene glycol and mixtures thereof.

[0099] The formulation can contain an aqueous vehicle. Aqueous vehicles include, by way of example and not limitation, sodium chloride injection solution, Ringer's injection solution, isotonic dextrose injection solution, sterile water injection solution, dextrose, and lactated Ringer's injection solution. Non-aqueous parenteral vehicles include, by way of example and not limitation, fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil, and peanut oil.

[0100] The antibacterial agents in the bacteriostatic or fungistatic concentrate include phenol or cresol, mercury agents, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride, benzethonium chloride, boric acid, p-hydroxybenzoate, phenol, chlorinated phenol compounds, alcohols, quaternary compounds, mercury agents, mixtures of the foregoing, etc., and must be added to parenteral preparations in multi-dose containers. The isotonic agents include, but are not limited to, sodium chloride and dextrose. The buffering agents include phosphate buffers and citrate buffers. The antioxidant includes sodium bisulfate. The local anesthetic includes procaine hydrochloride. The suspending and dispersing agents include sodium carboxymethylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone. The emulsifying agent includes polysorbate 80 (TWEEN® 80) [The sequestering or chelating agent for metal ions includes EDTA]. The pharmaceutically acceptable pH adjusters include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid or lactic acid. The nimodipine preparation of the present invention may further include physiologically acceptable components, such as sodium chloride and similar substances conventionally used to achieve the isotonicity of body fluids typically, pH buffers, preservatives, stabilizers and antioxidants that establish a physiologically compatible pH range and improve the solubility of nimodipine.

[0101] In certain preferred embodiments, which are injectable preparations after dilution in water for injection and other commonly available intravenous infusions, the pH of the finally diluted solution is from about 3 to about 9, and in certain preferred embodiments is from about 4.5 to about 8. In some embodiments of the present invention, the pH is adjusted using pharmaceutically acceptable buffers or alkylating agents, and suitable alkalizing agents and buffers include, but are not limited to, NaOH, KOH, triethylamine, meglumine, L-arginine, sodium phosphate buffers (any of tribasic sodium phosphate, dibasic sodium phosphate, monobasic sodium phosphate, or o-phosphoric acid), sodium bicarbonate, and mixtures of any of the foregoing.

[0102] In certain other embodiments, the formulation can be made isotonic by the addition of an isotonicity agent, such as, but not limited to, any pharmaceutically acceptable sugar, salt, or any combination or mixture thereof, such as, but not limited to, dextrose and sodium chloride. The isotonicity agent can be present in an amount of from about 100 mOsm / kg to about 500 mOsm / kg, or from about 200 mOsm / kg to about 400 mOsm / kg, or from about 280 mOsm / kg to about 320 mOsm / kg.

[0103] Stability of Nimodipine Drug stability is the ability of the IV nimodipine formulations useful in the present invention to maintain the physical, chemical, therapeutic, and microbiological properties of nimodipine over the period of storage and use by the patient. Drug stability is measured by the rate of change that occurs in the pharmaceutical dosage form. The drug dosage cannot be used after the levels of known and unknown impurities exceed the limits as per the guidelines set by ICH. In addition, some of the products of drug degradation are toxic and harmful to the patient. Several factors affect the stability of the drug; oxidative degradation being one of the major factors. The rate of this oxidative degradation is directly proportional to the amount of oxygen available to the drug in the formulation. Temperature increases oxidative degradation. Applicants' experimental studies clearly show that overhead oxygen and dissolved oxygen play important roles in the stability of the nimodipine IV formulation. Degassed water for injection for formulation preparation and blanketing (purging with an inert gas) during processing and the filling process provide a robust and stable nimodipine IV drug formulation. To achieve a more stable drug formulation, the dissolved oxygen content should be about 2.0 ppm in the nimodipine formulation and the overhead oxygen content should be less than 5%. After dilution as described above, the nimodipine formulation of the present invention is preferably chemically stable for at least 48 hours at most for continuous infusion.

[0104] Treatment with Nimodipine According to the present invention, intravenous nimodipine solutions can be used to treat conditions such as, but not limited to, aneurysms, subarachnoid hemorrhage, vasospastic angina, Prinzmetal's angina, stable angina, acute myocardial infarction, cardiac arrest, arrhythmias, systemic hypertension, pulmonary hypertension, congestive heart failure, coronary artery surgery, and hypertrophic cardiomyopathy.

[0105] Nimodipine is applied to the treatment of ischemic neurological disorders following aneurysmal subarachnoid hemorrhage. For the injectable Nimotop® 0.02% solution (Bayer plc), the encouraged treatment is as follows: in the first 2 hours of treatment, 1 mg of nimodipine, i.e., 5 ml of Nimotop solution (about 15 μg / kg bw / h), should be injected per hour via a central catheter. If well tolerated, the dose should be increased to 2 mg of nimodipine per hour, i.e., 10 ml of Nimotop solution (about 30 μg / kg bw / h), after 2 hours if no severe drop in blood pressure is observed. Patients with a body weight of less than 70 kg or with unstable blood pressure should start at 0.5 mg of nimodipine per hour (2.5 ml of Nimotop solution), or a lower dose if necessary. Nimotop capsules are also available in the United States for oral administration, each containing 30 mg of nimodipine in a vehicle of glycerin, peppermint oil, purified water, and polyethylene glycol 400. The oral dose is 60 mg (two 30 mg capsules each) every 4 hours for 21 consecutive days, preferably more than 1 hour before or more than 2 hours after a meal.

[0106] In certain embodiments of the present invention, the IV nimodipine solution can be continuously infused over a period of about 3 weeks. The infusion rate is set based on the patient's tolerance and can avoid a drop in blood pressure. Preferred infusion rates are from about 0.05 mg of nimodipine per hour to about 5 mg of nimodipine per hour. Dose setting is not possible with currently FDA-approved oral dosage forms in the United States.

[0107] In certain embodiments of the present invention, the IV nimodipine dosage is reduced to about 2 - 10 mg every 5 hours without a decrease in the efficacy and safety of the pharmaceutical, as compared to the currently approved oral dosage of 60 mg every 4 hours. Currently approved oral nimodipine pharmaceuticals in the United States have high first-pass metabolism that results in many metabolites, all of which are either inactive or significantly less active than the parent compound. The bioavailability of nimodipine is on average 13% after oral administration. First-pass metabolism is avoided via intravenous administration, and the variability within the subject (patient) associated with currently approved oral dosage forms is reduced. Also, continuous intravenous infusion of the nimodipine formulation of the present invention via a single bag and / or bottle is a convenient way to administer effective concentrations of nimodipine to unconscious patients and patients who have difficulty swallowing oral dosage forms.

[0108] Detailed Description of Preferred Embodiments The following examples of formulations useful in the present invention should not be construed as limiting the invention in any way, but are merely examples of the various formulations described herein.

[0109] [Examples 1 - 4] The formulations of Examples 1 - 4 were prepared as follows: Nimodipine was added to ethanol with stirring and mixed until a clear solution was observed. Next, polysorbate 80 was added as a surfactant with stirring and mixed for 30 minutes to form stable micelles. Then, the volume was increased to 5 ml with water for injection to prepare a concentrated nimodipine injection formulation. The concentrated nimodipine injection can be diluted with any amount of commonly used intravenous infusion. The components of Examples 1 - 4 are listed in Table 1 below:

[0110]

Table 1

[0111] [Example 5] The nimodipine formulation of Example 3 was tested in the examination of dilution carried out with different commonly used intravenous infusions (0.9% sodium chloride, 5% dextrose, and lactated Ringer's solution) to understand the chemical interactions and observe whether nimodipine crystals precipitate after dilution. Crystallization of nimodipine was not observed after dilution of this formulation with these three different IV infusions, as shown in Table 2 below.

[0112]

Table 2

[0113] Figure 1 is a graphical representation of the nimodipine concentration of the formulation of Example 3 at the concentrations (0.2 mg / ml, 0.02 mg / ml, and 0.01 mg / ml) tested in 0.9% sodium chloride solution.

[0114] Figure 2 is a graphical representation of the nimodipine concentration of the formulation of Example 3 at the concentrations (0.2 mg / ml, 0.02 mg / ml, and 0.01 mg / ml) tested in 5% dextrose solution.

[0115] Figure 3 is a graphical representation of the nimodipine concentration of the formulation of Example 3 at the concentrations (0.2 mg / ml, 0.02 mg / ml, and 0.01 mg / ml) tested in lactated Ringer's solution.

[0116] Also, the concentrated formulation of Example 3 was exposed to UV light in a controlled UV chamber for 48 hours to understand the photodegradation of this novel nimodipine formulation. The nimodipine formulation was maintained in amber and clear glass vials under the same conditions. As shown in Table 3, photodegradation was not observed in either amber or clear glass vials. This result supports the conclusion that the concentrated (micellar) formulation of Example 3 provides photostability to nimodipine.

[0117]

Table 3

[0118] Figure 4 is a graphical representation of the period of UV light exposure of the nimodipine formulation of Example 3, which had a nimodipine concentration of 2 mg / ml and was contained in amber vials and clear glass vials. The plot shows the nimodipine concentration over time.

[0119] [Examples 6 - 8] In Examples 6 - 8, a nimodipine concentrate was prepared as follows: Nimodipine was added to polysorbate 80 and polyethylene glycol 400 while stirring, mixed for 30 minutes to form stable micelles, and the volume was adjusted to 5 ml with water for injection. Benzyl alcohol was added as a preservative. This nimodipine injection concentrate can be diluted with any amount of commonly used intravenous infusions. The formulations of Examples 6 - 8 are described in more detail in Table 4 below:

[0120]

Table 4

[0121] [Examples 9 - 11] In Examples 9 - 11, a nimodipine concentrate was prepared as follows: Nimodipine was added to polysorbate 80 and soybean oil while stirring, mixed until a clear solution was observed, and phospholipid lipoid 80 and PEG400 were added as emulsifiers to prepare a nanoemulsion and / or self - emulsifying formulation. This nimodipine injection concentrate can be diluted with any amount of commonly used intravenous infusions to form a nanoemulsion. The formulations of Examples 9 - 11 are described in more detail in Table 5 below:

[0122]

Table 5

[0123] [Example 12] In Example 12, a nimodipine concentrate was prepared as follows: While stirring, beta-cyclodextrin was added to water for injection and mixed for 15 minutes. While stirring, nimodipine and polysorbate 80 were added to the above dispersion and mixed for 48 hours to obtain a clear solution. Heating was applied using a water bath heated to 60 degrees to increase the proportion of the inclusion complex.

[0124] Regarding the formulation of Example 12, it is described in more detail in Table 6 below:

[0125]

Table 6

[0126] [Example 13] In Example 13, the nimodipine concentrate of Example 3 was subjected to a final sterilization process by autoclaving at 121°C for 30 minutes. Figure 5 is a graph showing the micelle particle size distribution of Example 3 before final sterilization, with a peak at a particle size of approximately 10 nm. The particle size distribution was measured using a Malvern Zetasizer Nano ZS at a temperature of 25°C. Figure 6 is a graph showing the micelle particle size distribution of Example 3 after final sterilization (autoclaving at 121°C for 30 minutes), with a peak at a particle size of approximately 10 nm. The particle size distribution was measured using a Malvern Zetasizer Nano ZS at a temperature of 25°C. Based on these results, the formulation of Example 3 is considered to be stable.

[0127] [Example 14] The formulation of Example 14 was prepared as follows: While stirring, nimodipine was added to ethanol and mixed until a clear solution was observed. Then, while stirring, polysorbate 80 was added as a surfactant and mixed for 30 minutes to form stable micelles. Then, sufficient water for injection was added to the solution to produce 5 ml of a nimodipine injection concentrate. The nimodipine injection concentrate can be further diluted with any amount of commonly used intravenous infusions. Regarding the components of Example 14, they are described in Table 7 below:

[0128]

Table 7

[0129] [Example 15 (Stability)] Amber glass bottles were filled with the formulations of Example 3 (5 mL concentrate), Example 3 (100 mL ready-to-inject), and Example 14 (5 mL concentrate), fitted with rubber stoppers and flip-off seals, and subjected to stability testing under the following conditions: - ICH accelerated conditions at 40°C ± 2°C / 75% RH ± 5%; and - ICH room temperature conditions at 25°C ± 2°C / 60% RH ± 5%.

[0130] Samples were analyzed to measure the nimodipine assay and impurities. Also, the physical stability of the formulations of the invention, such as physical appearance and pH drift, was recorded. The stability of the concentrate of Example 3 is provided in Table 8 below.

[0131]

Table 8

[0132] The stability of the ready-to-inject embodiment of Example 3 is provided in Table 9 below.

[0133]

Table 9

[0134] The stability of the concentrate of Example 14 is provided in Table 10 below:

[0135]

Table 10

[0136] [Example 16 (in vivo test)] An in-vivo test was conducted in healthy Wistar rats to evaluate the drug release from the continuous intravenous infusion of nimodipine prepared according to Example 14. A single-dose parallel test was performed to evaluate the pharmacokinetics and relative bioavailability of plasma and CSF (cerebrospinal fluid) following a single intravenous infusion (4 hours) of 0.73 mg of nimodipine against an oral solution of 5.5 mg of nimodipine (Nymalize). The pharmacokinetic study was carried out in 6 healthy rats (3 males and 3 females). The test formulation was a single dose of 0.73 mg of nimodipine administered as a controlled-rate continuous intravenous infusion over a 4-hour period (after dilution in 5% dextrose in water (D5W) infusion to a concentration of 0.182 mg / ml). The reference was an oral solution of Nymalize containing 5.5 mg of nimodipine administered orally using an orogastric tube (the oral bioavailability of nimodipine was on average 13%, and hence the oral dose was adjusted accordingly). Blood samples were collected at 15 minutes, 30 minutes, and 1, 2, 4, 6, 8, 12, and 24 hours after dosing. CSF samples were collected at 1, 2, 4, and 24 hours after dosing. All samples were analyzed using a validated LC-MS analytical method.

[0137]

Table 11

[0138] After administration of a single dose of 0.73 mg over 4 hours by continuous infusion, the mean C max was at a median T max of 1.92 hours and was 249 ng / mL. The mean AUC 0-t and AUC 0-無限 were 1081 and 1084 ng*h / mL, respectively. The mean elimination half-life was 3.68 hours. The clearance and volume of distribution were 11.4 mL / min and 3.66 L, respectively.

[0139] After administration of a single dose of the 5.5 mg oral solution dose, the mean C max was at a median T maxIt was 479 ng / mL. AUC 0-t and AUC 0-無限 were 1850 and 1850 ng*h / mL, respectively. The mean elimination half-life was 2.6 h. The relative bioavailability was 22.6% relative to the test article of intravenous continuous infusion.

[0140] The pharmacokinetic results are reported in Tables 12, 13 and Figure 7 [Mean plasma concentration-time profile of nimodipine according to reference (oral solution) and intravenous continuous infusion test article (Example 14) in rats].

[0141]

Table 12

[0142]

Table 13

[0143]

Table 14

[0144] Consistent levels of nimodipine were observed in the CSF over the period of a single dose infusion of 0.73 mg administered over 4 h. The range of nimodipine CSF levels was measured at 1.26 - 1.56 ng / ml. Consistent nimodipine CSF concentrations were achieved within 1 h of infusion. The CSF / plasma ratio was consistent up to 4 h of infusion in the range of 0.0064 - 0.0075. The plasma and CSF concentrations of nimodipine in rats treated with the nimodipine intravenous continuous infusion formulation are reported in Table 14 and Figure 8.

[0145] Due to high first-pass metabolism, the oral bioavailability of nimodipine averaged 22% in this study. During the oral treatment period, plasma concentrations and the shape of the concentration curve varied considerably among rats, probably reflecting variability in first-pass elimination, which also reflects the low mean oral bioavailability of nimodipine.

[0146] The absolute bioavailability of continuous intravenous infusion of nimodipine is 100%. The high bioavailability of the IV infusion formulation also results in a reduction in pharmacokinetic variability. In addition, avoidance of the first-pass effect following intravenous infusion has the potential to reduce the impact of drug-drug interactions associated with the induction or inhibition of CYP3A4. The standard deviation (SD) of the plasma concentration of nimodipine in rats when treated with continuous intravenous infusion of nimodipine and the reference oral solution is reported in Table 15 and Figure 9.

[0147]

Table 15

[0148] It can be concluded that when the stable micellar nimodipine formulation of the present invention is administered as a continuous intravenous infusion, first-pass metabolism by the liver is minimized, resulting in improved bioavailability. Thus, a consistent level of nimodipine is maintained in plasma and CSF.

[0149] [Example 17 (Stability)] The degradation of nimodipine in the formulations of Examples 3 and 14 was tested while varying the dissolved oxygen level, and the nimodipine formulations were autoclaved with / without degassing and replacement of the headspace with an inert gas to understand the effects in the manufacturing and filling processes.

[0150] A series of experiments were conducted to evaluate the role of headspace oxygen and dissolved oxygen in oxidative drug degradation in the formulation of nimodipine.

[0151] In the first experiment, 95% ethanol was utilized without inert gas blanketing, and the WFI in the formulation of Example 3 was not degassed during formulation preparation (the process of removing dissolved oxygen from water via the passage of an inert gas). The results are provided in Table 16.

[0152] In the second experiment, 95% ethanol was used in the formulation preparation of Example 3 along with inert gas blanketing and degassed WFI. Samples were analyzed by HPLC before and after the autoclave treatment process. The samples were analyzed using the HPLC method to observe oxidative drug degradation that resulted in the formation of pyridine analog impurities before and after autoclave treatment. The results are provided in Table 16.

[0153] In the third experiment conducted, 100% ethanol was utilized in the formulation of Example 14. The preparation and all other conditions withstood the same as those in Experiment 2. The formulation solution was filtered through a 0.22u PVDF filter and the samples were analyzed before and after the autoclave treatment process. The results are provided in Table 16.

[0154]

Table 16

[0155] As can be seen from the results provided in Table 16, in the first experiment, the formation of pyridine impurities of 0.06% and 0.15% respectively was observed under both conditions. When blanketing with an inert gas prior to sealing the vial and then autoclaving the sealed vial, a decrease in pyridine analog impurities from 0.15% to 0.08% was observed.

[0156] As can be seen from the results provided in Table 16, in the second experiment, no oxidative drug degradation was observed and no pyridine analog impurities were detected.

[0157] As can be seen from the results provided in Table 16, in the third experiment, as evidenced by the absence of pyridine analog impurities, the nimodipine formulation did not experience oxidative degradation.

[0158] These experimental tests clearly show that the levels of overhead oxygen and dissolved oxygen play an important role in the oxidative drug degradation of nimodipine formulations. Degassed WFI for formulation preparation as well as inert gas blanketing during processing and during the filling process provide a robust and stable nimodipine IV drug formulation.

[0159] [Example 18] The PK study was completed at a single site in Canada and followed a Phase 2 crossover design where each subject received either IV GTX-104 first followed by oral nimodipine or oral nimodipine first followed by IV GTX-104. Fifty-eight healthy subjects were randomized in a 1:1 ratio between an IV nimodipine infusion formulation (Treatment A: nimodipine IV infusion over 72 hours, a continuous infusion of nimodipine at 0.15 mg / hour over 72 hours in addition to 30-minute infusions of 4 mg of nimodipine every 4 hours) prepared according to the applicant's previous patent application US SN15 / 485,813 (now US Patent No. 10,092,557) and Treatment B (Nimotop: oral nimodipine capsules, 60 mg (two 30 mg capsules administered every 4 hours over 72 hours with 240 mL of water). A total of 56 and 55 subjects were included in the Phase 1 and Phase 2 PK analyses, respectively, but 2 subjects did not complete one of the Phase 2 and 1 subject was excluded due to protocol deviations predefined in the Statistical Analysis Plan (SAP). At 8:00 am on Day 4, for example, is the end point of the continuous infusion of 0.15 mg / h and no 4 mg dose is administered.

[0160] The composition of the IV nimodipine injection formulation used in Example 18 is as follows:

[0161]

Table 17

[0162] This composition is similar to that described in Table 7, Example 14.

[0163] Blood samples were obtained at a pre-determined time point and measured using an assay method with a confirmed nimodipine concentration to characterize and compare the PK profiles for both IV and oral administrations. The primary PK endpoints were the maximum concentration (C max , expressed as such) during the first 4 hours on Day 1, and the total amount of nimodipine in blood on Day 3 (expressed as the area under the curve (AUC) (AUC 3日目、0~24時間 ). The secondary endpoint was C max on Day 3. As defined in the SAP, the log-transformed PK parameters of these three endpoints were statistically analyzed using an analysis of variance (ANOVA) model. For each endpoint, the IV / oral ratio was presented along with the corresponding 90% confidence interval (CI). A ratio of 1 indicates no absolute difference between the IV nimodipine injection and oral nimodipine. The 90% CI is the range within which the IV / oral ratio is predicted to fall (9 out of 10 times) if the study is repeated.

[0164] The IV / oral ratios (%) and their corresponding 90% CIs (ranges) for the primary and secondary endpoints in 56 subjects who completed each treatment period were as follows: C max on Day 1: 92% (82 - 104); AUC 3日目、0~24時間 : 106% (99 - 114); C max on Day 3: 92% (85 - 101). More specifically, the pharmacokinetic results were as follows: C max 1日目0~4時間 for IV injection was 63.086 vs 68.595, with a ratio of 91.968 (81.663 - 103.574) * ; AUC 3日目0~24時間 for oral nimodipine was 491.630 vs 462.116, with a ratio of 106.387 (99.246 - 114.041); C max 3日目0~24時間 was 77.5 ng / ml for the IV nimodipine injection formulation, compared to 85 ng / ml for oral nimodipine, with a ratio of 92.118 (84.721 - 100.16). * Geometric least squares mean (ng / mL for C max or h*ng / mL for AUC). **Geometric mean IV / oral: %(90% CI). Note: There was no statistical difference for the three parameters (p > 0.107). The results are illustrated in Figure 10 (Pharmacokinetics - Day 1) and Figure 11 (Pharmacokinetics - Day 3).

[0165] All three endpoints showed that there was no statistically significant difference in exposure between IV nimodipine and oral nimodipine over the defined periods for both maximum and total exposure. Plasma concentrations obtained after IV administration showed significantly less variability between subjects compared to oral administration of the capsule formulation, which is because IV administration is not sensitive to some of the physiological processes that affect oral administration, such as taking the drug with or without food, various GI transit times, drug uptake from various parts of the gastrointestinal tract into the systemic circulation, and various hepatic blood flows and first-pass metabolism in the liver. Previous studies have shown that these processes significantly affect the oral bioavailability of nimodipine and thus result in oral administration having a greater tendency for variability within and between subjects. The bioavailability of IV nimodipine was comparable to that of oral nimodipine based on two major PK endpoints (C max 1日目0~4時間 , AUC 3日目0~24時間 ) and one secondary endpoint (C max 3日目0~24時間 ). The day-to-day variation associated with IV nimodipine was approximately half of that seen with oral nimodipine. There were no serious AEs (adverse events) or AEs resulting in discontinuation after administration of the IV nimodipine formulation.

[0166] The bioavailability of the oral nimodipine capsule formulation was observed to be only 7.2% compared to the IV nimodipine infusion formulation. In addition, the day-to-day variation associated with IV nimodipine was approximately half of that seen with the oral nimodipine capsule formulation. The day-to-day variation takes into account changes in body functions (blood flow, renal function, and hepatic metabolism) over a day. The oral nimodipine administered was 60 mg × 18 doses = 1080 mg; the IV dose of the IV nimodipine solution formulation was 4 mg × 18 doses + 0.15 mg / hour × 72 hours = 82.8 mg.

[0167] Neither serious adverse events nor adverse events (AEs) leading to discontinuation were reported during the trial. As predicted for a Phase I trial in healthy volunteers, more administration / sampling site-related events were reported with IV GTX-104 (41% vs. 11% oral). Oral nimodipine was associated with more gastrointestinal disorders (16% vs. 7% IV). The other most frequently reported AEs (IV / oral) were headache (36% / 36%), somnolence (9% / 13%) and hot flush / flushing (10% / 11%).

[0168] [Example 19] An alternative biologically equivalent dosing regimen consisting of a single bolus followed by a continuous infusion was simulated using a validated population PK (“popPK”) model. After confirmation of the simulation in healthy volunteers at several dose ranges, a dosing regimen of a 4.5 mg single bolus infused over 30 minutes followed by a continuous infusion of 1.2 mg / hour was found to be biologically equivalent to oral nimodipine every 4 hours. The population use of this bridging strategy was derived from the weight and age distributions in the PK study described in Example 18. The predicted AUC and C max are shown in Table 18. Plots of the Day 1 profile and Day 3 profile in healthy volunteers are shown in Figures 12 and 13, respectively. This popPK modeling data was used to inform the dosing regimen used in patients with subarachnoid hemorrhage. In Figures 12 and 13, the solid line is the median profile and the shaded area is the 95% prediction interval. Abbreviations: IV = intravenous; PO = oral.

[0169]

Table 18

[0170] [Example 20] In accordance with the good modeling practices recently outlined in the FDA guidance on population PK modeling, a population PK analysis of nimodipine was conducted following oral and IV infusion to identify the IV dosing regimen that would match the day 1 C max and day 3 AUC 24h of 60 mg oral nimodipine in patients with subarachnoid hemorrhage (SAH).

[0171] To achieve this, clinical data from available PK studies were used to develop an initial population PK model refined with covariates in healthy volunteers, and data from the literature (covariates in aSAH patients) were used to create a more robust and predictive model of the PK profile predicted in aSAH patients.

[0172] Using this population PK model, one initial single IV bolus infused over 30 minutes followed by a continuous infusion dose was simulated for a virtual population of patients. These IV doses were compared to the oral exposures available in healthy volunteers and simulated for patients considering potential inter-individual variability in covariates and other factors. A sensitivity analysis at the value of the EBE (empirical Bayes estimate) of the model for both routes of administration was investigated.

[0173] The simulation results suggested that an IV dose of 3.6 mg over 30 minutes followed by an infusion of 1.2 mg / hour was biologically equivalent to the reference (60 mg PO q4h). Plots of the day 1 profile and day 3 profile are shown in Figures 14 and 15, respectively. The results of the simulation are shown in Tables 19 and 20. The steady-state concentration is predicted to be 20.7 ng / mL for PO and 23.2 ng / mL for IV. Abbreviations: IV = intravenous; PO = oral. The lines are median values and the shaded areas are 95% prediction intervals.

[0174]

Table 19

[0175]

Table 20

[0176] Conclusion It will be apparent to those skilled in the art that nimodipine concentrates and diluted formulations can be prepared using different but equivalent methods, and that these formulations can use other surfactants, carriers and emulsifiers other than those specifically described herein. Such solubilized formulations are considered to be within the scope of the appended claims.

Claims

1. A method of providing an IV nimodipine infusion regimen in a human, comprising measuring the 24-hour AUC and C of nimodipine at the administration regimen. ｍａｘ 1. A pharmaceutical composition comprising nimodipine for use in a method comprising administering (i) a continuous infusion of nimodipine over a period of at least 24 hours, supplemented with (ii) higher bolus doses of nimodipine at set intervals over said at least 24 hour period, such that a dose equivalent to an oral dose of nimodipine is administered.

2. The constant nimodipine infusion was 0.15 mg / hour nimodipine infused via IV administration over a 24-hour period, supplemented with higher bolus doses of nimodipine at 4-hour intervals by infusion of 4 mg nimodipine over 30 minutes, such that the IV nimodipine infusion regimen was 0.15 mg / hour nimodipine infused over a 24-hour period, and the 24-hour C ｍａｘ The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is equivalent to

3. The method is accomplished (i) through the use of a single programmable infusion pump, or (ii) by using two infusion pumps with controllable delivery rates that result in a constant infusion of nimodipine over an entire 24 hour period, or (iii) by using a single programmable infusion pump that results in a constant infusion of nimodipine over an entire 24 hour period, supplemented with bolus doses of nimodipine administered manually at 4 hour intervals, supplemented with 30 minute infusions of nimodipine at 4 hour intervals, wherein the IV nimodipine infusion regimen results in a 24 hour area under the curve and 24 hour C of a desired dose of nimodipine administered orally at 4 hour intervals over the course of a day. ｍａｘ The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is equivalent to

4. 4. The pharmaceutical composition of claim 3, wherein 27.6 mg of IV nimodipine provides equivalent 24-hour plasma nimodipine exposure to 360 mg of oral nimodipine and provides a similar pulsatile concentration-time profile.

5. 5. The pharmaceutical composition of claim 4, wherein the infusion rate can be halved to provide a continuous nimodipine dose sustained at 0.075 mg / hour and a 2 mg nimodipine bolus dose administered over 30 minutes at 4 hourly intervals, resulting in a plasma exposure equivalent to a 30 mg nimodipine oral capsule every 4 hours.

6. The pharmaceutical composition of claim 1, wherein the method provides an effect selected from the group consisting of: (i) a nimodipine plasma profile that is more reproducible throughout the day; (ii) a nimodipine plasma profile that has less diurnal variation between early morning and nighttime concentrations; (iii) a nimodipine plasma profile that is less likely to be compromised by reduced or lost gastrointestinal motility or by the patient being comatose; (iv) a nimodipine plasma profile that responds more quickly to dose adjustments if drug-related side effects occur during the course of treatment; and (v) any combination of the above.

7. 10. The pharmaceutical composition of claim 1, wherein the human is a patient with a condition selected from aneurysm, subarachnoid hemorrhage, vasospastic angina, Prinzmetal angina, stable angina, acute myocardial infarction, myocardial arrest, arrhythmia, systemic hypertension, pulmonary hypertension, congestive heart failure, coronary artery surgery, and hypertrophic cardiomyopathy.

8. The pharmaceutical composition of claim 1, wherein the method comprises continuously infusing an intravenous nimodipine solution according to the present invention over a period of three weeks.

9. The method of claim 8, wherein the IV / oral ratio (%) and corresponding 90% CI (range) for the primary and secondary endpoints are 92% (82-104) of Day 1 C in human subjects who completed each treatment period. ｍａｘ AUC of 106% (99-114) ３日目、０～２４時間 , and Day 3 C ｍａｘ : 92% (85-101).

10. The pharmaceutical composition of claim 1, wherein the method comprises administering a bolus injection of 3.6 mg of nimodipine over 30 minutes followed by a continuous infusion of 1.2 mg / hour of nimodipine for up to 21 days for the treatment of subarachnoid hemorrhage.

11. The pharmaceutical composition of claim 1, wherein the method comprises administering a bolus infusion of 4.5 mg of nimodipine over 39 minutes followed by a continuous IV infusion of 1.2 mg / hour of nimodipine, and the human is a healthy volunteer.

12. 2. The pharmaceutical composition of claim 1, wherein the nimodipine continuous infusion is 0.05 mg / hour to 1.5 mg / hour and (ii) is supplemented with higher bolus doses of nimodipine at set intervals over the 24 hour period, the higher bolus doses being 1 mg to 8 mg of nimodipine administered over a period of 20 minutes to 50 minutes.

13. The pharmaceutical composition of claim 1, wherein the method comprises (i) administering a continuous infusion of 0.05 mg / hour to 1.5 mg / hour of nimodipine for 24 hours, supplemented with (ii) higher bolus doses of nimodipine at set intervals over the 24 hour period, and wherein the human is a patient with a condition selected from aneurysm, subarachnoid hemorrhage, vasospastic angina, Prinzmetal angina, stable angina, acute myocardial infarction, myocardial arrest, arrhythmia, systemic hypertension, pulmonary hypertension, congestive heart failure, coronary artery surgery, and hypertrophic cardiomyopathy.

14. 24-hour AUC and C of nimodipine with IV nimodipine infusion regimen ｍａｘ is equivalent to an oral dose of nimodipine selected from 30 mg or 60 mg nimodipine administered every 4 hours.

15. 14. The pharmaceutical composition of claim 13, wherein the IV nimodipine infusion regimen in a human patient is selected from the group consisting of: (i) a 4.15 mg nimodipine bolus dose administered over 30 minutes, followed by a 3.5 hour continuous nimodipine dose at 0.15 mg / hour, repeated as many times as needed; (ii) a 0.075 mg / hour continuous nimodipine dose and a 2 mg nimodipine bolus dose administered over 30 minutes at 4 hour intervals, repeated as many times as needed; and (iii) a 3.6 mg nimodipine bolus infusion over 30 minutes, followed by a 1.2 mg / hour nimodipine continuous infusion for up to 21 days.

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