Use of perillyl alcohol to enhance levodopa delivery

Abstract

The present application provides compositions and methods for intranasal administration of perillyl alcohol and L-dopa to patients in need of treatment for Parkinson's disease. The compositions and methods of the present application enhance the entry of L-dopa into the brain of patients suffering from Parkinson's disease.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Patent Application No. 63 / 180,936, filed April 28, 2021, which is incorporated by reference in its entirety.

[0002] The present invention relates to the use of perillyl alcohol (POH) to enhance levodopa (L-dopa) delivery to a mammal. Specifically, POH is used in patients in need of treatment for the management of Parkinson's disease (PD). [Background technology]

[0003] Parkinson's disease ("PD") is a long-term degenerative disorder of the central nervous system that primarily affects the motor system. Symptoms usually appear slowly, and as the disease worsens, non-motor symptoms become more common. The most obvious early symptoms are tremor, rigidity, slowness of movement, and difficulty walking. Cognitive and behavioral problems can also occur, with depression, anxiety, and apathy occurring in many people with PD. Parkinson's dementia is commonly seen in advanced stages of the disease. Parkinson's patients can also have problems with sleep and the sensory system. The motor symptoms of the disease result from the death of cells in the substantia nigra, an area of ​​the midbrain, which leads to dopamine deficiency. The cause of this cell death is poorly understood, but involves the accumulation of misfolded proteins in Lewy bodies in neurons.

[0004] Managing Parkinson's disease is a challenge that requires a tailored approach for each individual. In advanced stages of the disease, patients may experience motor complications despite optimized pharmacological treatment. Apomorphine, a short-acting D1 and D2-like receptor agonist, has been shown to provide rapid and effective relief of unpredictable "off" periods. Apomorphine is an aporphine alkaloid derived from the acidification of morphine. Its molecular formula is C 17 H 17 It is NO2.

[0005] Perillyl alcohol (POH), a naturally occurring monoterpene, has been suggested to be an effective agent against a variety of cancers, including CNS, breast, pancreatic, lung, melanoma, and colon cancer. Gould, M. Cancer chemoprevention and therapy by monoterpenes. Environ Health Perspect. 1997, 105(Suppl. 4):977-979. Intranasal delivery of drugs provides a non-invasive treatment that bypasses the blood-brain barrier and rapidly delivers pharmaceutical agents directly to the CNS. Drugs administered intranasally reach the parenchymal tissues of the brain, spinal cord and / or cerebrospinal fluid (CSF) within minutes. In addition to delivery via the olfactory tract and trigeminal nerve, animal studies have also shown that therapeutic agents can be delivered systemically via the nasal vasculature. Hashizume et al.New therapeutic approach for brain tumors: intranasal delivery of telomerase inhibitor GRN 163.Neuro-oncology 10:112-120,2008.Thorne et al.Delivery of insulin-like growth factor-1 to the rat brain and spinal cord along olfactory and trigeminal pathways following intranasal administration.Neuroscience 127:481-496,2004.Intranasal delivery of therapeutic agents may provide a systemic method for treating other types of cancer, such as lung cancer, prostate cancer, breast cancer, hematopoietic cancer and ovarian cancer.Wang et al. demonstrated that intranasal delivery can deliver blood-brain barrier (BBB) ​​impermeable drugs such as bortezomib to the brain (Wang-Journal of Neurosurgery). [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Gould, M. Cancer chemoprevention and therapy by monoterpenes.Environ Health Perspect.1997,105(Appendix 4):977-979 [Non-Patent Document 2] Hashizume et al.New therapeutic approach for brain tumors:intranasal delivery of telomerase inhibitor GRN 163.Neuro-oncology 10:112-120,2008 [Non-Patent Document 3] Thorne et al.Delivery of insulin-like growth factor-1 to the rat brain and spinal cord along olfactory and trigeminal pathways following intranasal administration.Neuroscience 127:481-496,2004 [Non-Patent Document 4] Wang - Journal of Neurosurgery Summary of the Invention [Means for solving the problem]

[0007] In some embodiments, the present invention provides a method of administering L-dopa (L-3,4-dihydrophenylalanine) to the central nervous system of a mammal (e.g., a human), the method comprising administering a medicament comprising a monoterpene simultaneously with L-dopa.

[0008] In some embodiments, the central nervous system is the brain.

[0009] In some embodiments, the present invention provides a method of administering L-dopa to a mammal (eg, a human), the method comprising administering a monoterpene simultaneously with L-dopa.

[0010] In some embodiments, the present invention provides a method of administering a pharmaceutical composition comprising a monoterpene and L-dopa to a mammal (e.g., a human). In these embodiments, the monoterpene and L-dopa are mixed to form a mixture. In some embodiments, the administration is intranasal administration.

[0011] In some embodiments, the monoterpene can be perillyl alcohol.

[0012] In some embodiments, the present application provides pharmaceutical compositions comprising perillyl alcohol that can be administered by intranasal application to enhance L-dopa entry into the brain of a patient, in some embodiments, a patient in need of treatment for the management of PD.

[0013] In some embodiments, the present application provides a pharmaceutical composition comprising perillyl alcohol and a pharma- ceutically acceptable carrier or diluent that can be administered by intranasal application to enhance L-dopa entry into the brain of a patient, in some embodiments, a patient in need of treatment for the management of PD.

[0014] In some embodiments, the present application provides pharmaceutical compositions comprising POH and L-dopa that can be administered by intranasal application to enhance entry of L-dopa into the brain of a patient, in some embodiments, a patient in need of treatment for the management of PD.

[0015] Perillyl alcohol has the following structure:

[0016] [ka]

[0017] In some embodiments, the pharma- ceutically acceptable carrier or diluent may be ethanol, glycerol, or a combination thereof.

[0018] In some embodiments, the present invention further provides a method for treating a disease in a mammal, the method comprising delivering a therapeutically effective amount of POH and a pharma- ceutically acceptable carrier or diluent to the mammal simultaneously with administration of L-dopa to the mammal. In some embodiments, the disease to be treated can be PD. The route of administration of perillyl alcohol includes intranasal delivery.

[0019] In some embodiments, the present invention further provides a method for treating a disease in a mammal, the method comprising delivering a therapeutically effective amount of a pharmaceutical composition comprising POH and L-dopa to the mammal. The disease to be treated can be PD. The route of administration of the pharmaceutical composition comprising POH and L-dopa includes intranasal. In some embodiments, the pharmaceutical composition also comprises a pharmaceutically acceptable carrier or diluent.

[0020] In some embodiments, the monoterpene can be a purified version of POH. This purified version of POH is sometimes referred to as NEO100. NEO100 is a highly purified (greater than about 99% pure) POH. NEO100 can be manufactured under current good manufacturing practice (GMP) conditions. In some embodiments, the monoterpene is provided in an amount ranging from about 0.01% (w / v) to about 5% (w / v), 0.01% (w / v) to about 1% (w / v), or 0.3 (w / v) of NEO100 in 50:50 ethanol:glycerol.

[0021] NEO100 has been used in a Phase I / IIa trial in patients with recurrent malignant glioma without toxic side effects (Schonthal AH, et al. Phase I trial of intranasal NEO100, highly purified perillyl alcohol, in adult patients with recurrent glioblastoma. Neurooncol Adv. 2021 Feb 12).

[0022] In some embodiments, NEO100 can be used with any drug that can be dissolved in NEO100. [Brief description of the drawings]

[0023] [Figure 1] 1 shows the results of the rotation test after treatment of mice with various compounds. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] The present invention provides a method for enhancing L-dopa delivery to the mammalian central nervous system using monoterpenes.

[0025] The monoterpenes may have a purity of greater than about 98.5% (v / v), greater than about 99.0% (v / v), or greater than about 99.5% (v / v).

[0026] The monoterpene can be formulated into a pharmaceutical composition with or without a carrier or diluent, wherein the monoterpene is present in an amount ranging from about 0.01% (w / v) to about 100% (w / v), about 0.1% (w / v) to about 80% (w / v), about 1% (w / v) to about 70% (w / v), about 10% (w / v) to about 60% (w / v), about 1% (w / v) to about 10% (w / v), about 1% (w / v) to about 5% (w / v), about 1% (w / v) to about 3% (w / v), about 3% (w / v) to about 10% (w / v), or about 0.1% (w / v) to about 20% (w / v). In some embodiments, the monoterpene is present in an amount ranging from about 0.01% (w / v) to about 5% (w / v), from about 0.01% (w / v) to about 1% (w / v), or in an amount of 0.3% (w / v).

[0027] Monoterpenes and L-dopa can be administered simultaneously. In some embodiments, monoterpenes and L-dopa are mixed to form a mixture before administration. They can exert advantageous combined effects (e.g., additive or synergistic effects).

[0028] The route of administration can be varied and can include intranasal.

[0029] The invention also provides a method of treating a disease, eg, treating one or more symptoms of PD, comprising delivering the composition to a patient.

[0030] A specific example of a monoterpene that may be used in the present invention is perillyl alcohol (commonly abbreviated as POH). The perillyl alcohol composition of the present invention may contain (S)-perillyl alcohol, (R)-perillyl alcohol, or a mixture of (S)-perillyl alcohol and (R)-perillyl alcohol.

[0031] In some embodiments, the monoterpene can be a purified version of POH, called NEO100. NEO100 is a highly purified (>99%) POH. In some embodiments, the monoterpene is provided in an amount ranging from about 0.01% (w / v) to about 5% (w / v), or 0.01% (w / v) to about 1% (w / v) of NEO100 in 50:50 ethanol:glycerol. In some embodiments, the monoterpene is provided in an amount of 0.3% (w / v) of NEO100 in 50:50 ethanol:glycerol.

[0032] In the context of this disclosure, the terms "treat", "treatment" and the like, in relation to any of the disease conditions listed herein, refer to reducing or alleviating at least one symptom associated with such a condition, or slowing or reversing the progression of such a condition. Within the meaning of this disclosure, the term "treat" also refers to halting a disease, delaying its onset (i.e., the period before clinical manifestations of the disease), and / or reducing the risk of developing or worsening a disease.

[0033] The phrase "pharmacologically acceptable" when used in connection with compositions and / or cells of the present disclosure refers to molecular entities and other components of such compositions that are physiologically tolerable and typically do not produce adverse reactions when administered to a mammal (e.g., human). Preferably, as used herein, the term "pharmacologically acceptable" means approved by a federal or state regulatory agency or listed in the United States Pharmacopeia or other generally recognized pharmacopoeias for use in mammals, more specifically humans. "Acceptable" means that the carrier is compatible with the active ingredients of the composition (e.g., nucleic acid, vector, cell, or therapeutic antibody) and does not adversely affect the subject to which the composition is administered. Any of the pharmaceutical compositions and / or cells used in the present methods may include pharmaceutically acceptable carriers, excipients, or stabilizers in the form of lyophilized formulations or aqueous solutions.

[0034] Pharmaceutically acceptable carriers, including buffers, are well known in the art and may include phosphates, citrates, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives; low molecular weight polypeptides; proteins such as serum albumin, gelatin, or immunoglobulins; amino acids; hydrophobic polymers; monosaccharides; disaccharides; and other carbohydrates; metal complexes; and / or non-ionic surfactants.In some embodiments, the pharma-ceutically acceptable carrier may include ethanol, glycerol, or a combination thereof.See, for example, Remington: The Science and Practice of Pharmacy 20th Ed. (2000) Lippincott Williams and Wilkins, Ed. KE Hoover.

[0035] To prepare such pharmaceutical compositions, one or more monoterpenes and / or at least one therapeutic agent can be mixed with pharma- ceutically acceptable carriers, adjuvants and / or excipients according to conventional pharmaceutical compounding techniques. The therapeutic agent can be L-dopa. Pharmaceutically acceptable carriers that can be used in the compositions of the present invention include standard pharmaceutical carriers, such as phosphate buffered saline, water, and emulsions, such as oil / water emulsions or water / oil emulsions, and any of a variety of wetting agents. The compositions can further contain solid pharmaceutical excipients, such as starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, and the like. Liquid and semi-solid excipients can be selected from glycerol, propylene glycol, water, ethanol, and a variety of oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Liquid carriers, particularly for injections, include water, saline, aqueous dextrose, and glycols.For examples of carriers, stabilizers, and adjuvants, see Remington's Pharmaceutical Sciences, edited by EW Martin (Mack Publishing Company, 18th Edition, 1990).The composition can also include stabilizers and preservatives.

[0036] In some embodiments, L-dopa can be administered at a dose ranging from about 0.050 mg / kg to about 500 mg / kg of body weight. Other ranges include about 0.1 mg / kg to about 100 mg / kg, about 1 mg / kg to about 50 mg / kg, about 5 mg / kg to about 35 mg / kg, and about 10 mg / kg to about 30 mg / kg. In some embodiments, L-dopa can be administered at a dose of 30 mg / kg.

[0037] As used herein, the term "therapeutically effective amount" is an amount sufficient to treat a particular disorder or disease or to obtain a pharmacological response that treats a disorder or disease. The method of determining the most effective administration means and dosage may vary depending on the composition used in the therapy, the purpose of the therapy, the target cell being treated, and the subject being treated. Therapeutic dosages can generally be titrated to optimize safety and efficacy. Single or multiple administrations can be performed, with the dosage level and pattern selected by the treating physician. The appropriate dosage formulation and method of administering the agent can be easily determined by those skilled in the art.

[0038] The present disclosure also provides the above composition for intranasal administration. Thus, the composition can further include a permeation enhancer. Southall et al.Developments in Nasal Drug Delivery, 2000. The composition can be administered intranasally in liquid form, such as solution, emulsion, suspension, drops, or in solid form, such as powder, gel, or ointment. Devices for delivering intranasal drugs are well known in the art. Nasal drug delivery can be performed using devices including, but not limited to, intranasal inhalers, intranasal spray devices, atomizers, nasal spray bottles, unit dose containers, pumps, droppers, squeeze bottles, nebulizers, metered dose inhalers (MDIs), pressurized inhalers, insufflators, and bidirectional devices. The nasal delivery device can be metered to administer an accurate effective dose to the nasal cavity. The nasal delivery device can be for single unit delivery or multiple unit delivery. In a particular example, the ViaNase Electronic Atomizer from Kurve Technology (Bethell, Washington) can be used in the present invention (http: / / www.kurvetech.com). The compounds of the present invention can also be delivered by tube, catheter, syringe, packtail, cotton ball, nasal tampon or submucosal injection. US Patent Publication Nos. 20090326275, 20090291894, 20090281522 and 20090317377.

[0039] The compositions of the present invention can be formulated as aerosols using standard procedures. The monoterpene and / or at least one therapeutic agent can be formulated with or without a solvent and with or without a carrier. The formulation can be a solution or an aqueous emulsion containing one or more surfactants. For example, an aerosol spray can be produced from a pressurized container containing a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrocarbon, compressed air, nitrogen, carbon dioxide, or other suitable gas. The dosage unit can be determined by providing a valve to deliver a metered amount. A pump spray dispenser can dispense a metered dose or a dose having a specific particle or droplet size. As used herein, the term "aerosol" refers to a suspension of fine solid particles or droplets of a liquid solution in a gas. Specifically, an aerosol includes a gas-borne suspension of droplets of a monoterpene, such as may be produced in any suitable device, such as an MDI, a nebulizer, or a mist sprayer. An aerosol also includes a dry powder composition of the composition of the present invention suspended in air or other carrier gas. Gonda (1990) Critical Reviews in Therapeutic Drug Carrier Systems 6:273-313. Raeburn et al., (1992) Pharmacol. Toxicol. Methods 27:143-159.

[0040] The composition can be delivered to the nasal cavity as a powder in the form of microspheres delivered by a nasal insufflator. The composition of the present invention can be absorbed on a solid surface, such as a carrier. The powder or microsphere can be administered in a dry, airless form. The powder or microsphere can be stored in the container of an insufflator. Alternatively, the powder or microsphere can be filled into a capsule, such as a gelatin capsule, or other single-dose unit adapted for nasal administration.

[0041] The pharmaceutical composition can be delivered to the nasal cavity by placing the composition directly in the nasal cavity, for example, in the form of a gel, ointment, nasal emulsion, lotion, cream, nasal tampon, dropper, or bioadhesive strip. In certain embodiments, it may be desirable to extend the residence time of the pharmaceutical composition in the nasal cavity, for example, to promote absorption. Thus, the pharmaceutical composition can be optionally formulated with bioadhesive polymers, gums (e.g., xanthan gum), chitosan (e.g., highly purified cationic polysaccharides), pectin (or any carbohydrate that thickens like a gel or emulsifies when applied to the nasal mucosa), microspheres (e.g., starch, albumin, dextran, cyclodextrin), gelatin, liposomes, carbamers, polyvinyl alcohol, alginates, acacia, chitosan, and / or cellulose (e.g., methyl or propyl; hydroxyl or carboxy; carboxymethyl or hydroxypropyl).

[0042] Nebulizer devices generate a high velocity air stream that causes the therapeutic agent in liquid form to spray as a mist. The therapeutic agent is formulated in liquid form, such as a solution or suspension of particles of appropriate size. In one embodiment, the particles are micronized. The term "micronized" is defined as about 90% or more of the particles have a diameter of less than about 10 μm. Suitable nebulizer devices are commercially available, for example, from PARI GmbH (Starnberg, Germany). Other nebulizer devices include Respimat (Boehringer Ingelheim) and those disclosed, for example, in U.S. Patent Nos. 7,568,480 and 6,123,068, and WO 97 / 12687. Monoterpenes can be formulated as aqueous solutions or liquid suspensions for use in nebulizer devices.

[0043] The device for intranasal administration can be an intranasal spray device, an atomizer, a nebulizer, a metered dose inhaler (MDI), a pressurized inhaler, an insufflator, an intranasal inhaler, a nasal spray bottle, a unit dose container, a pump, a dropper, a squeeze bottle, or a two-way device.

[0044] In some embodiments, the compositions of the present invention can be delivered via a nasal spray applicator. If intranasal application is desired, the composition can be placed in an intranasal spray administration device or atomizer and then applied by spraying into the patient's nostrils for delivery to the mucous membranes of the nostrils. A sufficient amount is applied to achieve the desired systemic or local drug level. An intranasal spray delivers about 5 cc microliters, with 1 cc to 10 cc microliters typically applied. In some embodiments, about 5 cc microliters per dose. It may be administered to one or both nostrils and may be applied as frequently as desired or required.

[0045] In some embodiments, the spray composition of the present invention is generally used in a dosage regimen according to the patient being treated.The frequency of use and dosage may vary from patient to patient.A patient may receive multiple doses during the day.A person skilled in the art, such as a physician, may select the dosage regimen and dosage for a particular patient or patients.

[0046] The dosage is independent of how deeply the intranasal spray device is inserted into the nostril, whether the patient is inhaling, or the angle of insertion of the device.

[0047] PD impairs body motor control and is the result of selective death of dopaminergic (DA) neurons in the substantia nigra of the midbrain. The disease is characterized by the aggregation of α-synuclein forming Lewy bodies in neurons. Many reports have shown an association between toxin exposure and increased risk of PD. 6-hydroxydopamine (6-OHDA) is a specific neurotoxin that targets catecholamine neurons via the dopamine-activated transporter (DAT). Injection of 6-OHDA into the medial forebrain bundle or neostriatum of the brain causes irreversible loss of DA neurons in the ventral midbrain. The consistent loss of dopamine innervation in the target regions is associated with a series of long-term behavioral disorders. Thus, 6-OHDA-induced lesions are the most widely used animal model of PD.

[0048] The following examples are offered for illustrative purposes only and are not intended to limit the invention.

[0049] [Example]

[0050] Induction of unilateral lesions of PD in C57BL / 6 mice by injection of 2,4,5-trihydrophenethylamine ("6-OHDA") C57BL / 6 mice were sedated and placed in a stereotaxic frame. 12ug of 6-OHDA was injected into the right substantia nigra pars reticulata (SNpc) of the DA pathway to generate hemiparkinsonian mice. 6-OHDA was injected into the mouse brain according to the following coordinates: 3mm caudal to bregma; 1.2mm lateral to midline; 4.8mm ventral to the dura surface. The tooth-bar was set 1.0mm below the interaural line. The rate of 6-OHDA injection was 1.0ul / min, and the cannula was left in situ for an additional 4 minutes after completion of the injection before being removed.

[0051] Confirmation of PD in mice by the apomorphine rotation test To verify successful lesion formation, an apomorphine rotation test was performed 3 weeks after 12 μg 6-OHDA injection.

[0052] Rotational behavior was first tested without apomorphine. Mice were placed in the testing apparatus and, after a short habituation period, whole-body ipsilateral (towards the lesion) and contralateral (away from the lesion) rotations were manually counted for 5 min. All mice were hemiplegic.

[0053] Rotational behavior was then tested using apomorphine. Mice were injected subcutaneously into the nape of the neck with apomorphine. Apomorphine was injected subcutaneously at 0.5 mg / kg body weight with 0.2% ascorbic acid and 0.9% saline. Mice were placed back into the testing apparatus. After 10 min, rotational behavior was assessed for 60 min. Whole-body ipsilateral and contralateral rotations were manually counted.

[0054] Rotations away from the lesion were counted and >50 rotations per minute were considered to demonstrate a positive effect after PD was induced.

[0055] Intranasal NEO100 enhanced L-dopa delivery.

[0056] Figure 1 shows data from seven experimental mice (mouse #376, mouse #377, mouse #378, mouse #380, mouse #381, mouse #812, mouse #819) that were confirmed to have positive PD after challenge with subcutaneous apomorphine, as described above.

[0057] Seven mice were then tested using different treatment regimens on different days as previously described. The different treatment methods included: (1) oral L-dopa, (2) intranasal ("IN") NEO100 (0.3% w / v) and oral L-dopa, (3) IN L-dopa, (4) IN NEO100 (0.3% w / v) mixed with L-dopa, (5) IN NEO100 (0.3% w / v), (6) NEO100 (0.05% w / v) mixed with L-dopa, and (7) NEO100 (0.1% w / v) mixed with L-dopa. In each of these different treatment methods, the oral L-dopa dose was fixed at 30 mg / kg.

[0058] The results show that IN NEO100 (0.3% w / v) and oral L-dopa induce mice to make contralateral rotations away from the lesion caused by 6-OHDA injection in the medial forebrain bundle, MFB.

[0059] Rotation Station Setup Plastic Cylinder: The cylinder was 12.5 inches in diameter and was placed on a flat surface on a piece of construction paper. The sides of the cylinder were covered with construction paper.

[0060] Red light: A red light is attached to the top of the cylinder to allow the mouse to be visualized in the dark, which is the mouse's activity cycle. However, since the mouse itself cannot detect red light sufficiently, the mouse perceives its environment as dark and remains active.

[0061] Video camera: A video camera was mounted above the cylinder. The rotating platform mouse was in full view and well lit. The camera used must have a rotating screen. This screen was used to visualize and count the mouse rotations. Rotations were also recorded.

[0062] Counting method and rest period: Mice were monitored for 60 min and net contralesional rotations were counted. Net contralateral rotations were calculated and counted by subtracting (total 360° right rotations - total 360° left rotations) every minute. After each apomorphine administration, mice were given at least 4 days to ensure the drug was cleared from the system before behavioral testing.

[0063] statistical analysis A two-tailed Student's t-test was used. Additionally, the log-rank test was used to assess the significance of L-dopa-induced ipsilateral rotation towards the lesion side. P<0.05 was considered significant. The calculated p-values ​​for individual test mice #376, #377, #378, #380, #381, #812 and #819 are **0.0058 vs. **0.0049; **0.0033 vs. **0.003; **0.0035 vs. **0.0044; *0.035 vs. *0.027; ***0.00067 vs. ***0.00011; **0.008 vs. **0.0011; and **0.0026 vs. **0.0024, respectively.

[0064] Thus, because intranasal delivery of a mixture of NEO100 and L-dopa induces contralateral rotations, the mixture may be suitable for treatment to provide relief from unpredictable "off" periods in PD patients.

[0065] The scope of the present invention is not limited by what has been specifically shown and described above. Those skilled in the art will recognize that there are suitable alternatives to the illustrated examples of materials, configurations, structures and dimensions. Numerous references, including patents and various publications, are cited and discussed in the description of the present invention. Citation and discussion of such references is provided merely to clarify the description of the present invention and is not an admission that any reference is prior art to the invention described herein. All references cited and discussed herein are incorporated herein by reference in their entirety. Variations, modifications, and other implementations of what is described herein will occur to those skilled in the art without departing from the spirit and scope of the present invention. While specific embodiments of the present invention have been shown and described, it will be apparent to those skilled in the art that changes and modifications can be made without departing from the spirit and scope of the present invention. The matter set forth in the foregoing description and accompanying drawings is offered by way of illustration only and not by way of limitation.

Claims

1. A pharmaceutical composition comprising perillyl alcohol (POH) and L-dopa, A pharmaceutical composition formulated for intranasal delivery to a mammal.

2. 2. The pharmaceutical composition of claim 1, comprising perillyl alcohol in an amount ranging from 0.01% (w / v) to 5% (w / v).

3. 10. The pharmaceutical composition of claim 1, comprising L-dopa in an amount ranging from 5 mg / kg to 35 mg / kg of a subject's body weight.

4. The pharmaceutical composition according to any one of claims 1 to 3, further comprising one or more pharma- ceutically acceptable carriers or diluents.

5. 5. The pharmaceutical composition of claim 4, wherein the one or more pharma- ceutically acceptable carriers or diluents is an ethanol / glycerol mixture, the mixture having a ratio of ethanol to glycerol of 1:

1.

6. 1. A method of treating one or more symptoms in a patient having Parkinson's disease, comprising: administering to said patient a pharmaceutical composition comprising POH; and administering to said patient L-dopa; The method wherein the POH is administered simultaneously with the L-dopa.

7. 1. A method of treating one or more symptoms in a patient having Parkinson's disease, comprising: A method comprising administering to a patient a pharmaceutical composition, said pharmaceutical composition comprising POH and L-dopa.

8. A method for administering L-dopa to the central nervous system of a mammal, comprising: The method comprises administering to said mammal a pharmaceutical composition, said pharmaceutical composition comprising POH and L-dopa.

9. The method of any of claims 6 to 8, wherein the pharmaceutical composition further comprises one or more pharma- ceutically acceptable carriers or diluents.

10. The method according to any one of claims 6 to 8, wherein the pharmaceutical composition is administered intranasally.

11. 9. The method of any of claims 6 to 8, wherein the one or more pharma- ceutically acceptable carriers or diluents is an ethanol / glycerol mixture, said mixture having a ratio of ethanol to glycerol of 1:

1.

12. The method of claim 10, wherein the intranasal administration is performed using a device selected from the group consisting of an intranasal inhaler, an intranasal spray device, an atomizer, a nasal spray bottle, a unit dose container, a pump, a dropper, a squeeze bottle, a nebulizer, a metered dose inhaler (MDI), a pressurized inhaler, and an insufflator.

13. The method of claim 10, wherein the pharmaceutical composition is administered intranasally in a liquid form selected from the group consisting of a solution, an emulsion, a suspension, and drops, or in a solid form selected from the group consisting of a powder, a gel, and an ointment.

14. The method of claim 13, wherein the pharmaceutical composition further comprises a bioadhesive polymer, gum, chitosan, pectin, microsphere, gelatin, liposome, carbamer, polyvinyl alcohol, alginate, acacia, chitosan, or cellulose.

15. The method of claim 8, wherein the central nervous system is the brain.

16. The method of claim 6, wherein the pharmaceutical composition comprises perillyl alcohol in an amount ranging from 0.01% (w / v) to 5% (w / v).

17. The method of claim 6, wherein the POH has a purity of greater than 98.5% (v / v).

18. The method of claim 8, wherein the mammal has Parkinson's disease.

19. The pharmaceutical composition of claim 1, wherein the POH has a purity of greater than 98.5% (v / v).

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