Patent Application
20080014152
The 622-agonists of the present invention are known and can be obtained by the skilled person by conventional methods of chemical synthesis from readily available reagents. Many of these compounds are also commercially available from chemical suppliers (see the Merck Index). For example, clenbuterol may be obtained as described in U.S. Pat. No. 3,536,712 (incorporated herein by reference). Clenbuterol is also commercially available from Boehringer Ingelheim and Sigma Chemicals. Enantiomers of β2-agonists such as clenbutarol may be obtained by methods known to the skilled chemist and are contemplated by this invention.
As discussed above, any compound having the activity of a β2 agonist is useful in this invention. Particular β2 agonists are albuterol, salmeterol, ractopamine, salbutamol, cimateril, BRL-47672, terbutaline, fenoterol, metaproterenol, isopraline, MJ-9184-1, trimetoquinol, tetrahydropapaveroline, soterenol, salmefamol, rimiterol, QH-25, isoetharine, R-804, ocripraline, quinterenol, sulfonterol, dobutamine, and isoproterenol. Preferred β2 agonists are albuterol, salmeterol, ractopamine, salbutamol, cimateril, BRL-47672, terbutaline, fenoterol, metaproterenol, and isopraline. A particularly preferred β2 agonist is clenbuterol. One or more β2 agonists may be administered together, either simultaneously or at different times as part of the same treatment regimen. In this context, doses may be provided separately or combined in a single pharmaceutical composition.
It is further believed that another β2 agonist, salmeterol, is also particularly suited for intranasal delivery across the cribriform plate and into the brain as a way of treating neurodegenerative disease. Lotvall, Respir. Med., 2001, August, 95 Suppl. B, S7-11, reports that salmeterol is highly lipophilic.
Specific dosage regimens for β2 agonists in the method of this invention are from about 0.5 to about 1000.0 μg/kg/day. A range of from about 10.0 to about 100.0 μg/day is particularly effective, and about 40 μg/day is most effective. Thus for example clenbuterol may be administered in doses of from about 0.5 to about 1000.0 μg/kg/day, and in particular from about 10.0 to about 100.0 μg/day, preferably about 40 .mu.g/day. The word “about” in this context includes a range above and below the numbers provided, as would be considered reasonable by a skilled practitioner. If more than one β2 agonist is administered in one dose, then the dosages of each should be adjusted (downward) accordingly.
Culmsee, Eur. J. Pharmacol., 1999, Aug. 20, 379(1) 33-45 reports that clenbuterol dosages greater than 1 mg/kg showed no cerebroprotective effect due to a decrease in blood pressure and an increase in plasma glucose level.
Pharmaceutical compositions containing β2 agonists such as clenbuterol administered for the method of this invention are readily prepared by the skilled practitioner. Standard pharmaceutically acceptable inactive ingredients such as stabilizers, excipients, binding agents, carriers, vehicles, preservatives may be part of the compositions. More than one β2 agonist may be used in a given composition. Other active ingredients may also be included.
The NGF inducing agent can be combined with a mucoadhesive to enhance its contact with the nasal mucosa. In some embodiments, the mucoadhesive is selected from the group consisting of a hydrophilic polymer, a hydrogel and a thermoplastic polymer. Preferred hydrophilic polymers include cellulose-based polymers (such as methylcellulose, hydroxyethyl cellulose, hydroxy propyl methyl cellulose, sodium carboxy methyl cellulose, a carbomer chitosan and plant gum.
In some embodiments, the mucoadhesive is a water-soluble high molecular weight cellulose polymer. High molecular weight cellulose polymer refers to a cellulose polymer having an average molecular weight of at least about 25,000, preferably at least about 65,000, and more preferably at least about 85,000. The exact molecular weight cellulose polymer used will generally depend upon the desired release profile. For example, polymers having an average molecular weight of about 25,000 are useful in a controlled-release composition having a time release period of up to about 8 hours, while polymers having an average molecular weight of about 85,000 are useful in a controlled-release composition having a time released period of up to about 18 hours. Even higher molecular weight cellulose polymers are contemplated for use in compositions having longer release periods. For example, polymers having an average molecular weight of 180,000 or higher are useful in a controlled-release composition having a time release period of 20 hours or longer.
The controlled-release carrier layer preferably consists of a water-soluble cellulose polymer, preferably a high molecular weight cellulose polymer, selected from the group consisting of hydroxypropyl methyl cellulose (HPMC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), carboxy methyl cellulose (CMC), and mixtures thereof. Of these, the most preferred water-soluble cellulose polymer is HPMC. Preferably the HPMC is a high molecular weight HPMC, with the specific molecular weight selected to provide the desired release profile.
The HPMC is preferably a high molecular weight HPMC, having an average molecular weight of at least about 25,000, more preferably at least about 65,000 and most preferably at least about 85,000. The HPMC preferably consists of fine particulates having a particle size such that not less than 80% of the HPMC particles pass through an 80 mesh screen. The HPMC can be included in an amount of from about 4 to about 24 wt %, preferably from about 6 to about 16 wt % and more preferably from about 8 to about 12 wt %, based upon total weight of the composition.
Hydrogels can also be used to deliver the NGF inducer to the olfactory mucosa. A “hydrogel” is a substance formed when an organic polymer (natural or synthetic) is set or solidified to create a three-dimensional open-lattice structure that entraps molecules of water or other solution to form a gel. The solidification can occur, e.g., by aggregation, coagulation, hydrophobic interactions, or cross-linking. The hydrogels employed in this invention rapidly solidify to keep the NGF inducer at the application site, thereby eliminating undesired migration from the site. The hydrogels are also biocompatible, e.g., not toxic, to cells suspended in the hydrogel. A “hydrogel-inducer composition” is a suspension of a hydrogel containing desired NGF inducer. The hydrogel-inducer composition forms a uniform distribution of inducer with a well-defined and precisely controllable density. Moreover, the hydrogel can support very large densities of inducers. In addition, the hydrogel allows diffusion of nutrients and waste products to, and away from, the inducer, which promotes tissue growth.
Hydrogels suitable for use in the present invention include water-containing gels, i.e., polymers characterized by hydrophilicity and insolubility in water. See, for instance, “Hydrogels”, pages 458-459 in Concise Encyclopedia of Polymer Science and Engineering, Eds. Mark et al., Wiley and Sons, 1990, the disclosure of which is incorporated herein by reference.
In a preferred embodiment, the hydrogel is a fine, powdery synthetic hydrogel. Suitable hydrogels exhibit an optimal combination of such properties as compatibility with the matrix polymer of choice, and biocompatibility. The hydrogel can include any of the following: polysaccharides, proteins, polyphosphazenes, poly(oxyethylene)-poly(oxypropylene) block polymers, poly(oxyethylene)-poly(oxypropylene) block polymers of ethylene diamine, poly(acrylic acids), poly(methacrylic acids), copolymers of acrylic acid and methacrylic acid, poly(vinyl acetate), and sulfonated polymers. Other preferred hydrogels include poly(acrylic acid co acrylamide) copolymer, carrageenan, sodium alginate, guar gum and modified guar gum.
In general, these polymers are at least partially soluble in aqueous solutions, e.g., water, or aqueous alcohol solutions that have charged side groups, or a monovalent ionic salt thereof. There are many examples of polymers with acidic side groups that can be reacted with cations, e.g., poly(phosphazenes), poly(acrylic acids), and poly(methacrylic acids). Examples of acidic groups include carboxylic acid groups, sulfonic acid groups, and halogenated (preferably fluorinated) alcohol groups. Examples of polymers with basic side groups that can react with anions are poly(vinyl amines), poly(vinyl pyridine), and poly(vinyl imidazole).
Preferred thermoplastic polymers include PVA, polyamide, polycarbonate, polyalkylene glycol, polyvinyl ether, polyvinyl ether, and polyvinyl halides, polymethacrylic acid, polymethylmethacrylic acid, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and sodium carboxymethylcellulose, ethylene glycol copolymers,
Other polymers that may be suitable for use as a mucoadhesive include aliphatic polyesters, poly(amino acids), copoly(ether-esters), polyalkylenes oxalates, polyamides, tyrosine derived polycarbonates, poly(iminocarbonates), polyorthoesters, polyoxaesters, polyamidoesters, polyoxaesters containing amine groups, poly(anhydrides), polyphosphazenes, biomolecules (i.e., biopolymers such as collagen, elastin, bioabsorbable starches, etc.) and blends thereof. For the purpose of this invention aliphatic polyesters include, but are not limited to, homopolymers and copolymers of lactide (which includes lactic acid, D-,L- and meso lactide), glycolide (including glycolic acid), ε-caprolactone, p-dioxanone (1,4-dioxan-2-one), trimethylene carbonate (1,3-dioxan-2-one), alkyl derivatives of trimethylene carbonate, δ-valerolactone, β-butyrolactone, χ-butyrolactone, ε-decalactone, hydroxybutyrate, hydroxyvalerate, 1,4-dioxepan-2-one (including its dimer 1,5,8,12-tetraoxacyclotetradecane-7,14-dione), 1,5-dioxepan-2-one, 6,6-dimethyl-1,4-dioxan-2-one, 2,5-diketomorpholine, pivalolactone, χ,χ-diethylpropiolactone, ethylene carbonate, ethylene oxalate, 3-methyl-1,4-dioxane-2,5-dione, 3,3-diethyl-1,4-dioxan-2,5-dione, 6,8-dioxabicycloctane-7-one and polymer blends thereof. Poly(iminocarbonates), for the purpose of this invention, are understood to include those polymers as described by Kemnitzer and Kohn, in the Handbook of Biodegradable Polymers, edited by Domb, et. al., Hardwood Academic Press, pp. 251-272 (1997). Copoly(ether-esters), for the purpose of this invention, are understood to include those copolyester-ethers as described in the Journal of Biomaterials Research, Vol. 22, pages 993-1009, 1988 by Cohn and Younes, and in Polymer Preprints (ACS Division of Polymer Chemistry), Vol. 30(1), page 498, 1989 by Cohn (e.g. PEO/PLA). Polyalkylene oxalates, for the purpose of this invention, include those described in U.S. Pat. Nos. 4,208,511; 4,141,087; 4,130,639; 4,140,678; 4,105,034; and 4,205,399. Polyphosphazenes, co-, ter- and higher order mixed monomer-based polymers made from L-lactide, D,L-lactide, lactic acid, glycolide, glycolic acid, para-dioxanone, trimethylene carbonate and ε-caprolactone such as are described by Allcock in The Encyclopedia of Polymer Science, Vol. 13, pages 31-41, Wiley Intersciences, John Wiley & Sons, 1988 and by Vandorpe, et al in the Handbook of Biodegradable Polymers, edited by Domb, et al, Hardwood Academic Press, pp. 161-182 (1997). Polyanhydrides include those derived from diacids of the form HOOC—C6H4—O—(CH2)m—O—C6H4—COOH, where m is an integer in the range of from 2 to 8, and copolymers thereof with aliphatic alpha-omega diacids of up to 12 carbons. Polyoxaesters, polyoxaamides and polyoxaesters containing amines and/or amido groups are described in one or more of the following U.S. Pat. Nos. 5,464,929; 5,595,751; 5,597,579; 5,607,687; 5,618,552; 5,620,698; 5,645,850; 5,648,088; 5,698,213; 5,700,583; and 5,859,150. Polyorthoesters such as those described by Heller in Handbook of Biodegradable Polymers, edited by Domb, et al, Hardwood Academic Press, pp. 99-118 (1997).
In some embodiments, the mucoadhseive is selected from the group consisting of poly(lactic acid) (“PLA”) and poly(glycolic acid)(“PGA”), and copolymers thereof.
In some embodiments, the mucoadhesive formulation includes a penetration enhancer such as sodium glycocholate, sodium taurocholate, L-lysophosphotidyl choline, DMSO and a protease inhibitor.
In some embodiments, the beta agonist is tagged with a molecule that binds specifically with the olfactory mucosa.
In some embodiments, the beta agonist is combined with a second lipophilic therapeutic agents. In some embodiments thereof, the second lipophilic therapeutic agent is selected from the group consisting of Vitamin A, Vitamin E, melatonin, lovastatin, and VIP analog. Vitamin A is an anti-oxidant. Vitamin E is an anti-oxidant. Melatonin is an anti-oxidant. Lovastatin decreases BAP production. VIP enhances cholinergic function.
Preferably, the intranasal procedure of the present invention can be applied to patients suffering from Alzheimer's Disease or stroke.
In some embodiments, the intranasal administration of the beta agonist across the cribriform plate is used to treat a stroke patient. Culmsee, Stroke, 2004:35:1197-1202 reports that clenbuterol has been demonstrated to show neuroprotective capacity in experimental models of stroke (citing 4 references). Zhu, J. Cereb. Blood Flow Metab., 1998 September 18(9) 1032-9 reports that stimulation of β2 agonist receptors inhibited apoptosis in the rat brain after transient forebrain ischemia. Rami, Neurosci. Res., 2003 December 47(4), 373-82 reports that clenbuterol attenuates apoptosis in the rat hippocampus after transient global ischemia. Culmsee, Eur. J. Pharmacol., 1999, Aug. 20, 379(1) 33-45 reports that 0.01-0.5 mg/kg clenbuterol reduced cortical infarct volume in rats as measured 7 days after permanent occlusion of the middle cerebral artery.
In some embodiments, the intranasal administration of the beta agonist across the cribriform plate is used to treat a patient with amyotrophic lateral sclerosis (ALS).
For delivery, there is provided a standard nose drops squeezable spray container with a long thin semi-flexible tube attached to the distal end. The outer diameter of the tube is less than a millimeter, preferably less than 0.5 mm, more preferably less than 0.25 mm. The exit hole of the tube is preferably located on the peripheral wall near the distal end of the tube so that spray exiting it can be directed upwards. There is a marker on the container that indicates when the exit hole is oriented upwards towards the cribriform plate.
Therefore, in accordance with the present invention, there is provided an intranasal spray device comprising:
The user directs the tube towards the medial wall of the nostril and points upwards so as to direct it medial to and over the middle nasal concha. The length of the tube is predetermined so that when the user has the shoulder of the container flush against the nostril the hole is adjacent the cribriform plate.
If there is concern about the safety of inserting a tube through a nasal passage, then the tube can also be balloon-like, so that it expands to full length upon being pressurized.
In some embodiments, the beta agonist is delivered iontophoretically. Preferably, the beta agonist delivered iontophoretically is clenbuterol. Jones, Brain Res., 1986, Mar. 5, 367 (1-2) 151-61 reports that the iontophoresis of clenbuterol with low currents on the order of 15 nA. In some embodiments, the iontophoresis is carried out in accordance with U.S. Ser. No. 11/200,438, entitled “Methods of Delivering Therapeutics to the Brain”, filed Aug. 8, 2005, (COD-5112), the specification of which is incorporated by reference in its entirety.
In some embodiments, the NGF inducer is combined with microparticles and the delivery of the microparticle is assisted by applying ultrasound thereto.
In some embodiments, the NGF inducer is combined with diamagnetic pyrolytic graphite microparticles and the delivery of the microparticle to the olfactory mucosa is assisted by assisted by applying a magnetic field to the pyrolytic graphite particles.
In some embodiments, the NGF inducing agent (preferably a beta agonist) is administered intrathecally through a drug pump, preferably through a lumbar puncture.
