Baclofen in the nasal cavity

Abstract

There are provided an intranasal baclofen preparation, an intranasal delivery device, and a method for treating dystonia and muscle hypertonia.

Description

Technical Field

[0001] Related Applications This application claims priority to U.S. Provisional Application No. 63 / 337,585, filed May 2, 2022, the entire disclosure of which is incorporated herein by reference.

[0002] This application relates, inter alia, to a formulation containing baclofen that is stable within, compatible with, and deliverable via an intranasal delivery device.

Background Art

[0003] Baclofen is a skeletal muscle relaxant and an anticonvulsant. Baclofen is a structural analog of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) and can exert its effect by stimulating GABA B receptor subtypes.

[0004] LIORESAL® Intrathecal (baclofen injection) was developed for chronic intrathecal infusion for the management of severe spasticity. Baclofen can be administered orally, but when injected directly into a patient's intrathecal space, therapeutic intrathecal concentrations are achieved, but the resulting plasma concentrations are 100-fold lower than in the case of oral administration. Thus, baclofen injections (LIORESAL® Intrathecal, Medtronic) are often administered intrathecally to manage severe spasticity of spinal origin. Preferably, baclofen is formulated without the following preservatives (LIORESAL® Intrathecal) and is commercially available as a 0.05 mg / mL solution, 0.5 mg / mL solution, or 2 mg / mL solution at pH 5 - 7 for intrathecal injection. The preservatives are baclofen (0.05 mg, 0.5 mg, or 2 mg), sodium chloride (9 mg), and water for injection (1 mL).

[0005] Concentrations of 0.5 mg / mL and 2 mg / mL have been shown to be very effective for delivery by implantable infusion devices, such as Medtronic's SYNCHROMED II® infusion device, in many patients suffering from severe spasticity. However, such devices require a surgical procedure to implant the infusion device and catheter, which is associated with significant rates of infection and complications, and also requires periodic repeat implantations due to limitations in the battery life of the implantable device.

[0006] Indeed, Haranhalli et al. reported that approximately 20 - 30% of patients using intrathecal baclofen pumps experience some complication. Generally, patients require an average of 3.5 procedures, with a total risk of infection of 14.6% and a total risk of pump and catheter problems of 19.7%.

[0007] Complications can be classified as mechanical and infection-related. Common mechanical complications include pump failure (battery failure or pump stoppage), catheter problems (twisting, breakage, rupture), CSF leakage at the catheter insertion site, and adhesion formation around the catheter insertion site. Common types of infections include wound infections, pump or catheter infections, and rarely meningitis. When using an intrathecal baclofen pump, patients need to have regular follow-up appointments where healthcare providers monitor the dosage, refill the pump, and surgically replace the pump when the battery expiration date approaches.

[0008] Despite being more effective than oral medications, many patients are unable to receive intrathecal baclofen therapy due to the risks and complications of surgery. Since only oral and intrathecal drug delivery routes are available, there are significant unmet needs for optimizing hypertonic therapy. Therefore, there is a clinical need to provide spasticity treatment with minimal side effects, non-invasiveness, and cost-effectiveness. SUMMARY OF THE INVENTION

[0009] The present teachings provide a method of treating a patient having a disorder treatable with baclofen, the method comprising administering to one or more nasal mucosae of the patient a pharmaceutically acceptable solution for nasal administration comprising baclofen in physiological saline. In various embodiments, the disorder can be one or a combination of hypertonia, spasm, and dystonia. In further embodiments, the physiological saline further comprises an additive selected from the group consisting of citric acid, cyclodextrin, and hypromellose. Further, in another embodiment, the pharmaceutical solution is in a pharmaceutically acceptable spray formulation having a volume of about 10 μL to about 200 μL. In another embodiment, administration of the pharmaceutical solution comprises spraying at least a therapeutically effective amount of baclofen into at least one nostril. In another embodiment, administration of the pharmaceutical solution comprises spraying at least a therapeutically effective amount of baclofen into each nostril. In another embodiment, administration of the pharmaceutical solution comprises spraying a first amount of the pharmaceutical solution into a first nostril, spraying a second amount of the pharmaceutical solution into a second nostril, and, optionally, after a preselected time delay, spraying a third amount of the pharmaceutical solution into the first nostril. In various aspects, administration further comprises administering at least a fourth amount of the pharmaceutical solution into the second nostril, optionally after a preselected time delay. Further, in another embodiment, nasal administration of the pharmaceutical solution is initiated at any point before or after the onset of symptoms of the disorder treatable with the pharmaceutical solution. In another embodiment, the treatment achieves a bioavailability of about 80 to 125% of the bioavailability achieved when the same baclofen is administered intrathecally.

[0010] The teachings further provide a pharmaceutical solution for nasal administration, which consists of (a) baclofen or a pharmaceutically acceptable salt thereof, and (b) one or more of citric acid, cyclodextrin, and hypromellose, or any combination thereof (in an amount of about 30% to about 95% (w / w)) in a pharmaceutically acceptable formulation for administration to one or more nasal mucosae of a patient. In various embodiments, baclofen is present in the pharmaceutical solution at a concentration of about 2.0 mg / mL to about 10.0 mg / mL.

[0011] Furthermore, the teachings provide an apparatus for delivering a medicament solution, the apparatus comprising a medicament solution (stored in a cartridge) consisting of baclofen or a pharmaceutically acceptable salt thereof, and one or more of citric acid, cyclodextrin, and hypromellose, or any combination thereof (in an amount of about 30% to about 95% (w / w)), in a pharmaceutically acceptable formulation; a nebulizer that receives the baclofen formulation from the cartridge and delivers the baclofen formulation to the nasal cavity of a patient; any dosage adjustment control that determines the amount of the baclofen formulation to be delivered; and a spray control that triggers the delivery of the baclofen formulation to the nasal cavity of the patient.

[0012] In one aspect of the invention, a method of treating a patient having a disorder treatable with baclofen comprises administering to one or more nasal mucosae of the patient a pharmaceutically acceptable solution for nasal administration consisting of baclofen in physiological saline. The disorder can be selected from the group consisting of hypertonia, spasm, and dystonia. In some embodiments, the physiological saline further comprises an additive selected from the group consisting of citric acid, cyclodextrin, and hypromellose. The medicament solution can be in a pharmaceutically acceptable spray formulation having a volume of about 10 μL to about 200 μL. Administration of the medicament solution comprises spraying at least a therapeutically effective amount of baclofen into at least one nostril, or spraying at least a therapeutically effective amount of baclofen into each nostril. Administration of the medicament solution can comprise spraying a first amount of the medicament solution into a first nostril, spraying a second amount of the medicament solution into a second nostril, and, optionally, spraying a third amount of the medicament solution into the first nostril after a preselected time delay. Optionally, at least a fourth amount of the medicament solution can be administered to the second nostril after a preselected time delay. Transnasal administration of the medicament solution can be initiated at any time before or after the onset of symptoms of the disorder treatable with the medicament solution. The treatment achieves a bioavailability of about 80 to 125% of that achieved when the same baclofen is administered intrathecally.

[0013] In another aspect of the present invention, a pharmaceutical solution for nasal administration comprises, in a pharmaceutically acceptable formulation for administration to one or more nasal mucosae of a patient, (a) baclofen or a pharmaceutically acceptable salt thereof, and (b) one or more of citric acid, cyclodextrin, and hypromellose, or any combination thereof (in an amount of about 30% to about 95% (w / w)). Baclofen can be present in the pharmaceutical solution at a concentration of about 2.0 mg / mL to about 10.0 mg / mL.

[0014] These features, aspects, advantages, and other features, aspects, and advantages of the present teachings will be better understood by reference to the following description, examples, and the appended claims.

[0015] Those skilled in the art will appreciate that the drawings described below are for illustrative purposes only. The drawings are not intended to limit the scope of the present teachings in any way.

Brief Description of the Drawings

[0016]

Figure 1

[0017] This drawing shows the delta (change) in the measured torque response from baseline in the examination of each patient. The first bar graph from left to right compares the baseline with the low dose (250 mcg) at the second visit. The second bar graph from left to right compares the baseline with the medium dose (1000 mcg) at the third visit. The third bar graph from left to right compares the baseline with the high dose (2000 mcg) at the fourth visit. The fourth bar graph from left to right compares the baseline with the fifth visit after leaving and then returning from the baseline (with residual effect). The p-values for the third panel representing the high dose are a treatment p-value of 0.004959 and a control p-value of 0.232.

[0018]

Figure 2

DETAILED DESCRIPTION OF THE INVENTION

[0019] Hypertonia is a common symptom in people with central nervous system (CNS) lesions. Hypertonia can be caused by brain or spinal cord problems and may present as spasticity, dystonia, or rigidity, often in combination. Many conditions can cause hypertonia, such as cerebral palsy, acquired brain injury, metabolic disorders, leukodystrophy, stroke, multiple sclerosis, hydrocephalus, and spinal cord injury. Patients with hypertonia cannot produce smooth and flowing limb movements due to an imbalance in signals from the brain and spinal cord, occurring with or without spasticity. Severe spasticity is associated with pain, sleep disturbances, feeding difficulties, and difficulties with activities of daily living such as position changes, movement, dressing, and hygiene management.

[0020] The treatment of hypertonia involves a comprehensive evaluation by a large, multi-disciplinary team of experts to create an individualized treatment plan for the child and overall family goals. Treatment options for hypertonia include physical therapy (e.g., constraint-induced movement therapy), enteral medications, botulinum toxin injections, intrathecal baclofen (ITB), and dorsal rhizotomy.

[0021] Gamma-aminobutyric acid receptor b (GABA B ) agonist baclofen was first reported as a treatment for spasticity by Hudgson et al. Baclofen has been widely available since its FDA approval in 1977 and is recommended for the treatment of severe spasticity and hypertonia.

[0022] Baclofen was originally administered enterally and is rapidly absorbed from the gastrointestinal tract, but only a small fraction of the dose reaches the site of action in the central nervous system by crossing the blood-brain barrier (BBB). Enteral baclofen doses in the range of 30 - 90 mg are associated with plasma concentrations of 0.05 - 0.65 mcg / mL and CSF concentrations of <0.012 - 0.096 mcg / mL.

[0023] The effects of systemic baclofen on the central nervous system (CNS) are limited by the fact that baclofen does not easily cross the blood-brain barrier. Baclofen depends on amino acid transporters to enter the cerebrospinal fluid.

[0024] Penn et al. introduced intrathecal baclofen (ITB), which directly bypasses the blood-brain barrier, as a therapeutic agent for spasticity. When directly injected into the patient's intrathecal space, a therapeutically effective intrathecal concentration of baclofen is achieved, but the resulting plasma concentration is 100-fold lower than that in the case of enteral administration. When baclofen is administered intrathecally, the concentration of baclofen present in the cerebrospinal fluid of adults increases, and at an intrathecal dose of 400 micrograms, the concentration in the cerebrospinal fluid is approximately 400 micrograms / milliliter, and the concentration in the serum is low.

[0025] In 1996, ITB administration by an implantable pump was approved by the US Food and Drug Administration as a therapeutic agent for spasticity. ITB has been clinically proven to be more effective in relieving spasticity than oral baclofen. This can be used in patients who do not show an appropriate reduction in hypertonia or who have experienced intolerable side effects with oral baclofen. Using ITB, the dose of baclofen can be maximized and its peripheral side effects can be minimized.

[0026] ITB therapy includes a surgical procedure to implant a subcutaneous pump in the patient's abdomen and a surgical procedure to insert the tip of a catheter into the cerebrospinal fluid (CSF) and implant a catheter system into the spinal canal. Direct access to the CSF increases the concentration of baclofen in the CNS and requires a lower dose than that required for systemic administration.

[0027] However, ITB therapy requires a surgical procedure to implant the infusion device and catheter, which is associated with a significant incidence of infections and complications, and due to the limited battery life of the implantable device, repeated implantations need to be performed periodically. Therefore, a more administrable form of baclofen is desired to achieve the same efficacy as intrathecal baclofen, while also requiring ease of administration like oral baclofen.

[0028] ITB therapy is the most effective treatment for severe spasticity and dystonia, but it has a relatively high complication rate and requires periodic repeat implantation due to the limited battery life of the implanted device.

[0029] Patients need to receive specialized medical care, and patients and caregivers must comply with the necessary maintenance of the pump. The negative attitude of caregivers can be an obstacle to patient care. In the case of very small or thin patients, the size of the pump may be a problem. In the case of extremely overweight patients, it may be impossible to refill the pump, which is further exacerbated by the fact that weight gain may occur after pump implantation. Despite these limitations, studies have shown that most patients using the ITB pump and their caregivers are satisfied with the results of this treatment.

[0030] Blood-brain barrier passage

[0031] The blood-brain barrier (BBB) is the main mechanism that controls drug transport to the CNS by a tightly regulated dynamic process via specific transport pathways. From a clinical perspective, there are two problems. One is that neuropharmaceuticals may not effectively penetrate the BBB, as in the case of oral baclofen, and the other is that, as in the case of oral baclofen, neuropharmaceuticals may undergo first-pass metabolism in the systemic circulation to produce active metabolites and cause side effects.

[0032] Non-invasive delivery, specifically nasal administration, has several advantages over conventional oral administration in that it aims to achieve higher absorption of the delivered dose than the oral route, resulting in lower doses and reduced susceptibility to the complications of overdosage. Furthermore, nasal delivery can avoid the complications associated with the invasive surgery required for intrathecal administration of baclofen.

[0033] In nasal administration, first-pass metabolism seen in enteral delivery is avoided, and the lungs and nasal cavity have a low drug metabolism environment. The nasal route for delivering drugs to the brain via the olfactory region is an optional solution for improving penetration through the BBB.

[0034] In contrast to invasive strategies that bypass the BBB, such as implanted pumps, the nasal route can be utilized for non-invasive drug delivery to the CNS. The nasal epithelial surface area is approximately 150 cm 2 and is small, consisting of a respiratory region and an olfactory region. The olfactory system has a delicate epithelial, endothelial, and glial barrier, but due to its special anatomical location, it can directly access the brain. Intranasal delivery combines the effectiveness of intrathecal delivery and the convenience of enteral administration without the need for surgery or implanted pumps.

[0035] The mechanism of nasal absorption of baclofen tested in animals suggests that the absorption rate in the nasal mucosa is relatively high and occurs via passive diffusion and a carrier-mediated mechanism for transporting baclofen via the BBB.

[0036] The nasal mucosa efficiently absorbs both enantiomers of baclofen non-specifically. The observed concentration-independent transport and the lack of polarized flux in excised nasal tissue suggest that baclofen is mainly absorbed by simple passive diffusion through bovine nasal tissue.

[0037] When baclofen is administered nasally, the drug may reach the brain faster because the nasal mucosa is close to the brain. Therefore, for example, in the case of spastic patients, symptom relief is seen earlier compared to oral or intrathecal administration.

[0038] Intranasal baclofen and pharmaceutical solutions for nasal administration

[0039] As used herein, baclofen refers to 4-amino-3-(p-chlorophenyl)butyric acid, its enantiomers, racemic mixtures, polymorphs, salts, solvates, esters, or hydrates. Baclofen is represented by the following structural formula.

Chemical formula

[0040] Baclofen includes R-baclofen (D-baclofen), S-baclofen (L-baclofen), or mixtures thereof including racemic compounds. The racemic compound refers to a mixture of R-baclofen and S-baclofen in equal proportions (DL-baclofen).

[0041] As used herein, the phrase "pharmaceutically acceptable salt(s)" means a salt of baclofen that is safe and effective for use in mammals and has the desired biological activity. The salts of baclofen include salts of acidic or basic groups present in the compounds of the present application. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, acid tartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate or pamoate. Certain compounds of the present invention can form pharmaceutically acceptable salts with various amino acids. Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, or diethanolamine salts. Potassium salts include potassium chloride, potassium bicarbonate, potassium phosphate, potassium gluconate, potassium citrate, etc.

[0042] Baclofen and its pharmaceutically effective salts have low solubility and can be modified in solution to be delivered into the nasal cavity at a higher concentration via the nasal route, enabling more rapid attainment of the therapeutic level of baclofen in the central nervous system, avoidance of the portal vein, and simultaneous avoidance of the first-pass effect, and / or more rapid presentation of the baclofen drug to the brain, which should be recognized by those skilled in the art. Pires et al. have described several modifications including the provision of carrier systems that can be used to increase the solubility of baclofen and provide a more concentrated baclofen formulation. See Pires, P.C., et al., Strategies to Improve Drug Strength in Nasal Preparations for Brain Delivery of Low Aqueous Solubility Drugs. Pharmaceutics 2022, 14, 588 (available at DOI handle “10.3390 / pharmaceutics14030588”), the entire text of which is incorporated herein by reference.

[0043] For example, some baclofen salts are only slightly soluble in water, so a therapeutically effective amount cannot be dissolved in an amount of aqueous solvent suitable for application to the mucosa. In the present invention, the use of a carrier system allows baclofen to be administered to one or more mucosae including the nasal mucosa. This enables the drug to be administered without hospitalization or unnecessary discomfort. Further, in some embodiments of the present invention, the gastrointestinal system can be significantly bypassed, such as by nasal administration. This latter improvement enables enhanced bioavailability, more rapid achievement of the therapeutic level of baclofen in the central nervous system and / or plasma, avoidance of the portal vein, and / or simultaneous avoidance of the first-pass effect.

[0044] As described in U.S. Patent No. 9,180,108, it has been found that the solubility of baclofen increases in a solution containing sulfate or phosphate. Baclofen at a concentration exceeding 2 mg / mL, for example, a concentration exceeding 4 mg / mL, 5 mg / mL, 6 mg / mL, or 7 mg / mL, has been described as being soluble in a solution containing phosphate, sulfate, potassium, or magnesium.

[0045] The pharmaceutical solution can have any suitable ionic strength. The pharmaceutical solution can contain salts such as NaCl or KCl to maintain the ionic strength. In various embodiments, the total ionic strength of the pharmaceutical solution resulting from various components of a formulation such as baclofen and one or more salts corresponds to an ionic strength of about 0.1 M to 0.2 M of NaCl or KCl, or about 0.15 M of NaCl or KCl.

[0046] Preferably, the pH of the pharmaceutical solution is 5.0 to 7.5, for example 5.5 to 6.5, or about 6.0. For example, the pH can be about 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4 or 7.5.

[0047] In some embodiments, the present invention describes the use of a stable aqueous solution of baclofen at a concentration exceeding 2.0 mg / mL. In particular, in some embodiments, the present invention provides for the use of a stable aqueous solution of baclofen having a concentration of about 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0 mg / mL or more.

[0048] In various embodiments, the pharmaceutical solution containing baclofen contains (i) baclofen at a concentration exceeding 2 mg / mL, and (ii) a sulfate or phosphate at a concentration of 5 mM to 25 mM, if desired. The ionic strength of this solution corresponds to 1.4 M NaCl to 1.6 M NaCl. In some embodiments, the solution consists essentially of baclofen, sulfate or phosphate, sodium ions and water. In some embodiments, the solution consists essentially of baclofen, sulfate or phosphate, sodium ions, chloride ions (e.g., from NaCl), and water.

[0049] In some embodiments, the aqueous solvent is preferably water, physiological saline (as used herein, meaning a solution consisting of water and dissolved sodium chloride or consisting essentially of water and dissolved sodium chloride), a sulfate or phosphate solution (as used herein, meaning a solution consisting of water and dissolved sulfate or phosphate or acid or consisting essentially of water and dissolved sulfate or phosphate or acid), or a sulfate or phosphate physiological saline (as used herein, meaning a solution consisting of water, dissolved sodium chloride, and dissolved sulfate or phosphate or acid or consisting essentially of water, dissolved sodium chloride, and dissolved sulfate or phosphate or acid).

[0050] The finally sterilized intranasal baclofen formulation may have any suitable concentration of baclofen, such as 0.01 mg / mL to 10 mg / mL of baclofen. In an embodiment, the finally sterilized intranasal baclofen formulation contains 0.05 mg / mL to 2 mg / mL of baclofen.

[0051] The pH can be adjusted with a suitable acid or base. In an embodiment, the pH is adjusted with HCl, H 2 SO 4 、H 3 PO 4 or NaOH.

[0052] Preferably, a therapeutically effective amount of baclofen is administered to a patient in need of treatment. As used herein, "therapeutically effective amount" means an administered amount that produces an administered effect. The exact dosage will vary depending on the purpose of the treatment and can be ascertained by one of ordinary skill in the art using known techniques. In some embodiments, a dosage of about 0.5 micrograms / kg to about 5 micrograms / kg is used. As is known in the art, adjustments for systemic and local delivery, and for the rate of new protease synthesis, as well as for age, weight, general health, gender, diet, time of administration, drug interactions, and severity of the symptoms may be required and can be confirmed by routine experimentation by one of ordinary skill in the art.

[0053] In some embodiments, baclofen is administered to a patient at a dosage of about 0.001 mg / kg / day to 100 mg / kg / day. For the purposes of the present disclosure, "patient" includes both humans and other animals, and in particular includes mammals such as mice, rats, guinea pigs, rabbits, dogs, cats, pigs, cows, monkeys, baboons, chimpanzees, and other organisms. Thus, these methods can be applied to both human therapeutic and veterinary uses. In a preferred embodiment, the patient is a mammal such as a human. A mammal "in need of treatment" includes not only mammals that are already suffering from a disease or disorder, but also mammals that need to prevent a disease or disorder, and mammals that are prone to suffering from a disease or disorder.

[0054] The baclofen formulation of the present invention can be subsequently diluted by adding other components that are administered intranasally simultaneously with baclofen. These include analgesics suitable for combination with baclofen, including morphine, clonidine, hydromorphone, hydrocodone, meperidine, celecoxib, tramadol, oxycodone, acetaminophen, ketoprofen, ketorolac, ibuprofen, naproxen, and the like. Other chemical compounds are likewise recognized in the art as being suitable for co-administration or separate administration with baclofen in the present application.

[0055] In some embodiments, the pharmaceutical solution comprises at least one additional component selected from the group consisting of an active pharmaceutical ingredient, an enhancer, an excipient, and a drug used to adjust the pH, buffer the composition, prevent degradation, and improve the appearance, odor, or taste.

[0056] Carrier system

[0057] In some embodiments, the carrier system comprises one or more alcohols or glycols, or any combination thereof, in an amount of about 10% to about 55%, about 10% to about 40%, about 10% to about 35%, about 12% to about 55%, about 12% to about 40%, about 12% to about 35%, about 15% to about 55%, about 15% to about 40%, about 15% to about 35%, about 10%, about 12.5%, about 15%, about 17.5%, about 20%, about 22.5%, about 25%, about 27.5%, about 30%, about 32.5%, about 35%, about 37.5%, about 40%, about 42.5%, about 45%, about 47.5%, about 50%, about 52.5% or about 55% (w / w). In some embodiments, the carrier system comprises one or more alcohols or glycols, or any combination thereof, in an amount of about 25% to about 40% (w / w). In some embodiments, the carrier system comprises one or more alcohols or glycols, or any combination thereof, in an amount of about 30% (w / w). In some embodiments, the alcohol is ethanol or contains ethanol. In some preferred embodiments, the glycol does not contain a glycol polymer. In some preferred embodiments, the glycol does not contain a glycol polymer having an average molecular weight greater than 200. In some preferred embodiments, the glycol does not contain polyethylene glycol having an average molecular weight greater than about 200.

[0058] A lower alkyl alcohol is an alcohol having 6 or fewer carbon atoms. Thus, any of ethanol, propyl alcohol, butyl alcohol, pentanol, benzyl alcohol, their isomers, or any combination thereof may be used.

[0059] A lower alkyl glycol is one having 6 or fewer carbon atoms. Thus, any of ethylene glycol, propylene glycol, butylene glycol, pentylene glycol, their isomers, or any combination thereof may be used.

[0060] Additional excipients

[0061] In some embodiments, the pharmaceutical solution contains at least one penetration enhancer in addition to baclofen. In some embodiments, the penetration enhancer is at least one alkyl glycoside. In some embodiments, the alkyl glycoside refers to any sugar bonded to any hydrophobic alkyl as described in U.S. Patent No. 5,661,130, the entire disclosure of which is incorporated herein by reference. The hydrophobic alkyl can be of any suitable length, for example, about 9 to about 24 carbon atoms in length, particularly about 10 to about 14 carbon atoms in length. The hydrophobic alkyl can be branched and / or partially or completely unsaturated. The alkyl can be bonded to the saccharide core via, for example, a carbonyl group, thereby forming an ester group. Suitable alkyl glycosides are non-toxic, non-ionic, and have the property of being able to increase the absorption of baclofen when administered intranasally as described herein. Exemplary saccharides that can be covalently bonded to the alkyl according to the present invention include glucose, maltose, maltotriose, maltotetrose, sucrose, and trehalose. Exemplary alkyl glycosides that can be used include octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, octadecyl α- or β-D-maltoside, -glucoside, or sucrose. In some embodiments, preferred glycosides include maltose, sucrose, or glucose bonded by a glycosidic bond to an alkyl chain of 9, 10, 12, 14, 16, 18, or 20 carbon atoms. Specific excipients that can be used in the intranasal composition according to the present invention include alkyl saccharides, dodecyl maltoside, tetradecyl maltoside, sucrose dodecanoate, sucrose monostearate, sucrose distearate, and / or combinations of two or more thereof. When present, the amount of alkyl glycoside in the composition is sufficient to enhance the absorption of baclofen administered via the intranasal route. In some embodiments, the amount of alkyl glycoside in the composition is selected so as to enhance the absorption of baclofen while not significantly irritating the nasal mucosa. In some embodiments, the amount of alkyl glycoside in the composition ranges from about 0.01% (w / v) to about 1% (w / v).In some embodiments, the amount of alkyl glycoside in the composition ranges from about 0.05% (w / v) to about 0.5% (w / v), or from about 0.125% (w / v) to about 0.5% (w / v).

[0062] The term "penetration enhancer" means a substance that functions to enhance absorption through the mucosa and / or enhance bioavailability. In some embodiments, such substances include mucolytics, protease inhibitors, and compounds that enhance the permeability of the mucosal cell membrane. Whether a particular compound is an "enhancer" can be determined by comparing two formulations containing a small polar molecule unrelated to the drug, with and without the enhancer, in an in vivo or well - characterized model study, and determining whether the absorption of the drug is enhanced to a clinically significant extent. Enhancers should not pose any problems in terms of chronic toxicity because they are non - irritating in vivo and / or are rapidly metabolized by normal cell components without significant stimulatory effects.

[0063] In some embodiments, a preferred enhancer is a lysophospholipid, such as lysophosphatidylcholine obtained from egg or soybean lecithin. Other lysophosphatidylcholines with different acyl groups, and lysocompounds formed from phosphatidylethanolamine and phosphatidic acid with similar membrane - modifying properties can also be used. Acylcarnitine (e.g., palmitoyl - dl - carnitine - chloride) is also an alternative. In some embodiments, a suitable concentration is 0.02 - 20% (w / v).

[0064] In some embodiments, suitable enhancers include chelating agents (EGTA, EDTA, alginate), surfactants (especially nonionic substances), acyl glycerols, fatty acid salts, tyloxapol, and biological detergents. Also suitable are agents that modify membrane fluidity and permeability, such as enamines (e.g., phenylalanine enamine of ethyl acetoacetate), malonates (e.g., diethyleneoxymethylene malonate), salicylates, bile salts and their analogs, and fusidinates. Suitable concentrations are up to 20% (w / v).

[0065] Mucosal preparation

[0066] Mucosal preparations are usually administered as a metered spray with a volume of less than 250 μL, preferably less than 150 μL, and ideally 25 - 100 μL. Although not prohibited in the present invention, administration in an amount exceeding about 300 μL per administration usually exceeds the absorption capacity of the membrane. As a result, most of the pharmaceutical active ingredient will be lost.

[0067] The dosage of the preparation, especially the nasal preparation, is preferably in the range of 25 - 100 μL. An amount exceeding the aforementioned range may flow past the sinuses and into the back of the throat, and the excess may be swallowed.

[0068] Administration

[0069] In some embodiments, administration of the composition comprises administering at least a portion of a therapeutically effective amount of baclofen to at least one mucosa. In some embodiments, administration of the composition comprises spraying at least a portion of a therapeutically effective amount of baclofen into at least one nostril. In some embodiments, administration of baclofen comprises spraying at least a portion of a therapeutically effective amount of baclofen into each nostril. In some embodiments, administration of baclofen comprises spraying a first amount of baclofen into a first nostril, spraying a second amount of baclofen into a second nostril, and, optionally, after a preselected time delay, spraying a third amount of baclofen into the first nostril. Some embodiments further comprise administering at least a fourth amount of baclofen into the second nostril, optionally after a preselected time delay.

[0070] Examples

[0071] Aspects of the present teachings can be further understood in light of the following examples, which should not be construed as limiting the scope of the present teachings in any way.

[0072] Example 1 - Intranasal Baclofen Study

[0073] Forty newly admitted patients with acquired brain injury receiving acute treatment in the PICU were treated with intranasal baclofen. Using the nasal route, an intranasal aqueous solution containing 250 mcg, 1000 mcg and / or 2000 mcg of baclofen per mL and 9 grams of sodium chloride delivered baclofen to the central nervous system by bypassing the BBB.

[0074] Even when the dosage of baclofen is maximized (>90 mg / day), the response to intranasal baclofen is much greater than that observed with oral baclofen. Intranasal baclofen has been used in patients with new acquired brain injury suffering from hypertonia or paroxysmal sympathetic hyperactivity (PSH), but historically, oral baclofen has been the first choice drug. The efficacy of intranasal baclofen exceeded the effects observed with oral baclofen, which has much less sedative effect.

[0075] Example 2 - Individual Intranasal Baclofen Treatment

[0076] After undergoing surgical removal of an intrathecal baclofen pump, the patient was admitted to the pediatric intensive care unit (PICU) due to increased tone. The patient had been taking several oral medications, including oral baclofen, at maximum dosages. The patient was administered a test dose of intranasal baclofen in the PICU using commercially available intrathecal baclofen for test dosages (vials of gablofen 2 - 50 mcg administered intranasally in a single dose). Despite maintaining all oral medications prior to intranasal administration, a marked improvement in tone was noted.

[0077] References All publications, patents, patent applications, and other references cited in this application are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual publication, patent, patent application, or other reference had been specifically and individually indicated to be incorporated by reference for all purposes. The citation of a reference herein is not to be construed as an admission that it is prior art to the present invention.

[0078] The following publications are specifically intended to be within the scope of the present invention and are hereby incorporated by reference in their entirety.

Prior Art Documents

Non - Patent Documents

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Non-Patent Document 1

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Non-patent Document 11

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Non-patent Document 14

Claims

1. A method for treating a patient having a disorder treatable with baclofen, said method comprising administering to one or more nasal mucosae of the patient a pharmaceutically acceptable solution for nasal administration consisting of baclofen in physiological saline.

2. The method according to claim 1, wherein said disorder is selected from the group consisting of muscle hypertonia, spasm and dystonia.

3. The method according to claim 1, wherein said physiological saline further comprises an additive selected from the group consisting of citric acid, cyclodextrin and hypromellose.

4. The method according to claim 1, wherein said pharmaceutical solution is in a pharmaceutically acceptable spray formulation having a volume of from about 10 μL to about 200 μL.

5. The method according to claim 1, wherein said administration of said pharmaceutical solution comprises spraying at least a therapeutically effective amount of said baclofen into at least one nostril.

6. The method according to claim 1, wherein said administration of said pharmaceutical solution comprises spraying at least a therapeutically effective amount of said baclofen into each nostril.

7. The method according to claim 1, wherein said administration of said pharmaceutical solution comprises spraying a first amount of said pharmaceutical solution into a first nostril, spraying a second amount of said pharmaceutical solution into a second nostril, and, optionally, after a preselected time delay, spraying a third amount of said pharmaceutical solution into said first nostril.

8. The method according to claim 7, further comprising, optionally, after a preselected time delay, administering at least a fourth amount of said pharmaceutical solution to said second nostril.

9. The method according to claim 1, wherein said nasal administration of said pharmaceutical solution is initiated at any time before or after the onset of symptoms of a disorder treatable with said pharmaceutical solution.

10. The method according to claim 1, wherein said treatment achieves a bioavailability of about 80 to 125% of the bioavailability achieved when the same baclofen is administered intrathecally.

11. A pharmaceutical solution for nasal administration, comprising (a) baclofen or a pharmaceutically acceptable salt thereof, and (b) one or more of citric acid, cyclodextrin and hypromellose, or any combination thereof (in an amount of about 30% to about 95% (w / w)), in a pharmaceutically acceptable formulation for administration to one or more nasal mucosae of a patient.

12. The baclofen is present in the pharmaceutical solution at a concentration of about 2.0 mg / mL to about 10.0 mg / mL, and the pharmaceutical solution according to claim 11.

13. An apparatus for delivering a pharmaceutical solution, the apparatus comprising: The pharmaceutical solution according to claim 11, stored in a cartridge; and An atomizer that receives the baclofen preparation from the cartridge and delivers the baclofen preparation to the nasal cavity of a patient; Any dosage adjustment control for determining the amount of the baclofen preparation to be delivered; and An apparatus comprising a spray control for triggering delivery of the baclofen preparation to the nasal cavity of the patient.

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