WO2008085711A1

WO2008085711A1 - Synergy of sodium channel blockers and calcium channel blockers

Info

Publication number: WO2008085711A1
Application number: PCT/US2007/088658
Authority: WO
Inventors: Frank L. Greenway
Original assignee: Individual
Current assignee: Individual
Priority date: 2007-01-03
Filing date: 2007-12-21
Publication date: 2008-07-17
Anticipated expiration: 2009-07-03

Abstract

Methods are described for suppressing appetite through the intranasal administration of a sodium channel blocker and a calcium channel blocker. It has long been known that smell and taste are an important part of how the body prepares for a meal, for example the cephalic phase of insulin release before a meal. Depressing the sense of smell or taste in subjects prior to meals leads to decreased food intake, which ultimately leads to weight loss. The ability to deliver drugs to the CSF via intranasal application also provides anorexiant central effect.

Description

SYNERGY OF SODIUM CHANNEL BLOCKERS AND CALCIUM CHANNEL

BLOCKERS

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S. C. § 119(e) to U.S. Provisional Application Serial No. 60/883,324, filed January 3, 2007, entitled "Synergy of Sodium Channel Blockers and Calcium Channel Blockers," which is incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

Field of the Invention

[0001] The present embodiments relate to the treatment of obesity and other food intake-related diseases or conditions with administration of sodium channel blockers and calcium channel blockers.

Description of the Related Art

[0002] Obesity is a disorder characterized by the accumulation of excess fat in the body. Obesity is emerging as a global problem and is a major factor for a number of comorbidities such as coronary heart disease, hypertension, non-insulin dependent diabetes mellitus, pulmonary dysfunction, osteoarthritis and certain types of cancer.

[0003] Obesity has been defined in terms of body mass index (BMI). BMI is calculated as weight (kg)/ [height (m)]². In addition to those individuals who satisfy a strict definition of medical obesity, a significant portion of the adult population is overweight. These individuals would also benefit from the availability of an effective weight-loss composition. Current products to suppress appetite and control weight are generally drugs with undesirable side effects. The main factor causing the development of obesity is a positive energy balance through the decreased activity and increased energy intake. Weight loss and loss of body fat can thus be achieved by reducing food intake and/ or increasing energy expenditure. [0004] Studies show that weight tends to decline after a certain age. The reason for the decline in weight with aging has been attributed to the normal decline in the taste and smell senses. The smell of food alone has been demonstrated to increase pancreatic polypeptide within the first 3 minutes and to increase colonic pressure. The sight and smell of food increase insulin secretion in the first 20 minutes and this rise in insulin is blocked by atropine, suggesting that the rise is vagally mediated. Patients with anorexia have been shown to have a diminished sense of smell and in case reports, a diminished sense of taste and smell have been associated with weight loss. The smell of food also increases appetite and food intake in restrained eaters. Smell and taste are perceived by a multitude of G- protein coupled receptors expressed on specialized nerve cells in the oral and nasal epithelium.

[0005] Also, the neural connections between the nasal mucosa and the brain provide a unique pathway for noninvasive delivery of therapeutic agents to the central nervous system ("CNS").

[0006] Sodium channel blockers, like lidocaine and dyclonine have been used to decrease smell, taste and food intake. Calcium channel blocker have also been used nasally to treat obesity but such treatment may be limited by irritation at the site of administration.

SUMMARY OF THE INVENTION

Some embodiments relate to a method of treating obesity in a mammal in need of such treatment comprising applying a sodium channel blocker and a calcium channel blocker to the mammal intranasally in an amount sufficient to decrease sensation of smell.

In some embodiments, the sodium channel blocker is lidocaine.

In some embodiments, the calcium channel blocker is diltiazem.

In some embodiments, the sodium channel blocker and calcium channel blocker are applied before meals.

In some embodiments, the sodium channel blocker and calcium channel blocker are each independently in the form of a gel, powder, spray, liquid, or drop.

Some embodiments further relate to the administration of a vasoconstrictor in combination with the sodium channel blocker and calcium channel blocker. In some embodiments, the vasoconstrictor is selected from the group consisting of: epinephrine, norepinephrine, endothelin, thromboxane, naphazoline nitrate, tetrahydrozoline hydrochloride, oxymetazoline hydrochloride, phenylephrine hydrochloride and tramazoline hydrochloride.

In some embodiments, the concentration of the sodium channel blocker is from about 0.05 to about 200 mg/ml.

In some embodiments, the concentration of the calcium channel blocker is from about 0.05 to about 200 mg/ml.

In some embodiments, the sodium channel blocker is selected from the group consisting of: lidocaine, mepivacaine, bupivacaine quinidine, lorcainide, procainamide, encainide, propafenone, moricizine, mexiletine, disopyramide, aprindine, phenytoin, tocainide, flecainide, procaine, benzocaine dibucaine, tetracaine, butacaine, cyclomethycaine and tetracaine.

In some embodiments, the calcium channel blocker is selected from the group consisting of: diltiazem, verapamil, fluoxetine, nifedipine, nimodipine, amlodipine, felodipine, nicardipine, bepridil and nisoldipine.

Some embodiments further relate to the co-administration of a topical anesthetic to the oral mucosa or tongue to reduce taste sensation.

Some embodiments relate to a method of treating obesity in a mammal in need of such treatment comprising applying a sodium channel blocker, a calcium channel blocker, a humectant, a pH buffer and a thickening agent to the mammal intranasally.

In some embodiments, the humectant is selected from sorbitol, mineral oil, vegetable oil, glycerol, soothing agents, membrane conditioners, sweeteners and combinations thereof.

In some embodiments, the pH buffer is selected from acetate, citrate, prolamine, carbonate and phosphate buffers.

In some embodiments, the thickening agent is selected from xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose and carbomer.

DETAILED DESCRIPTION [0007] The effect that the smell of food has on the body and appetite is well documented. Therefore, temporarily depressing the sense of taste and smell prior to meals may be an effective strategy to decrease food intake. The present embodiments relate to methods of appetite suppression through the inhibition of olfactory neurosensory perception. In one embodiment, both a sodium channel blocker and a calcium channel blocker are applied intranasally to a mammal in need of weight loss.

[0008] In some embodiments, lidocaine, a widely used topical anesthetic which has the ability to temporarily disable nerve conduction and diltiazem, a calcium channel blocker, can be applied to the nostrils of a subject before a meal. Calcium channel blockers can inhibit the cyclic nucleotide gated channel in the olfactory epithelium, thereby targeting the biochemical entities involved in signal transduction pathways specific for the functions of smell. Thus, the administration of a calcium channel blocker reducing or eliminating olfactory sensory perception will reduce food consumption in mammals. Sodium channel blockers like lidocaine applied topically in the nose decrease the sense of smell by altering the permeability of the olfactory cells to ions and inhibiting olfactory nerve impulses. Lidocaine may also be directly taken up in the CSF and have a central effect on satiety and food consumption. Some of the weight loss effects of the sodium channel blockers may be due to regional activity in the brain. The olfactory neural pathway provides both intraneuronal and extraneuronal pathways into the brain. The intraneuronal pathway involves axonal transport and requires hours to days for drugs to reach different brain regions. The extraneuronal pathway probably relies on bulk flow transport through perineural channels, which deliver drugs directly to the parenchymal tissue of the brain, to the cerebrospinal fluid (CSF), or to both. This extraneuronal pathway allows therapeutic agents to reach the CNS within minutes. Intranasal delivery of agents to the CSF is not surprising as CSF normally drains along the olfactory axon bundles as they traverse the cribriform plate of the skull and approach the olfactory sub mucosa in the roof of the nasal cavity where the CSF is then diverted into the nasal lymphatics. With reduced olfactory perception of the food in the meal and reduced appetite caused by the administration of the sodium channel blocker and the calcium channel blocker, the subject exhibits a reduced physiological response which results in lower food intake.

[0009] Calcium channel blockers and sodium channel blockers work together synergistically in the treatment of weight loss for many reasons. Each class of compounds targets different areas of sensation pathways, resulting in a larger overall effect. By administering both sodium channel blockers and calcium channel blockers, two redundant systems for controlling the sense of smell can be targeted. Also, calcium channel blockers when administered alone can be irritating to the tissues of mammals; however, when calcium channel blockers are administered with sodium channel blockers, the irritation can be reduced. This is due at least in part to the fact that sodium channel blockers like lidocaine act as local anesthetics masking the effects of irritation. The results in calcium channel blockers being better tolerated. Also, administration of both sodium channel blockers and calcium channel blockers may allow lower concentrations of either to remain effective in treatment of obesity or food-intake related disorders.

[0010] Sodium channel blockers have very few side effects and have been used with relatively little risk for many decades. Lidocaine, for example, applied topically gives peak anesthesia in 2-5 minutes that lasts for 30-45 minutes. The maximum safe dosage for topical anesthetic in a 70 kg adult is extremely high, 500 mg, and the intravenous infusion rate following a loading bolus of 50-100 mg is 72 mg in a 24-hour period. Therefore, doses of a sodium channel blocker such as lidocaine, for example, in amounts up to 100 mg per nostril per day would be well within the safe range for topical treatment. Furthermore, sodium channel blockers are advantageous over other agents applied intranasally due to the lower incidence of nasal mucus membrane irritation.

[0011] Other sodium channel blockers that can be used in the present embodiments include, for example, dyclonine, mepivacaine, bupivacaine quinidine, lorcainide, procainamide, encainide, propafenone, moricizine, mexiletine, disopyramide, aprindine, phenytoin, tocainide flecainide, procaine, benzocaine dibucaine, tetracaine, butacaine, cyclomethycaine and tetracaine. Other calcium channel blockers that can be used in the present embodiments include, for example, diltiazem, verapamil, fluoxetine, nifedipine, nimodipine, amlodipine, felodipine, nicardipine, bepridil and nisoldipine.

[0012] In olfactory receptor neurons, much of the depolarizing current in response to odors is carried by cationic channels that are directly gated by cyclic AMP. Cyclic nucleoti de-gated (CNG) channels comprise a family of proteins, including T-type, N-type, and L-type calcium channels. The CNG channel family has been well studied and molecular modulators have been identified. Examples of known agonists for CNG channels include 8- Br-cGMP, and known antagonists include diltiazem, verapamil and fluoxetine. Diltiazem (CAS Reg. No. 42399-41-7) is a suitable calcium channel blocker for use in the treatment methods of the present embodiments. This drug belongs to a class of calcium channel blockers that are particularly effective on L-type calcium channels.

[0013] Other calcium channel blockers for use according to the methods of the invention include, but are not limited to, verapamil, fluoxetine, nifedipine, nimodipine, amlodipine, felodipine, nicardipine, bepridil and nisoldipine. Particularly preferred of these are verapamil (CAS Reg. No. 52-53-9), amlodipine (CAS Reg. No. 88150-42-9), nimodipine (CAS Reg. No. 66085-59-4), and isradipine (CAS Reg. No. 75695-93-1) which, similarly to diltiazem, target the L-type CNG channels and have a similar effect in the context of the invention.

[0014] In some embodiments, the localized effect of sodium channel blockers and calcium channel blockers is enhanced and prolonged by combining them with a vasoconstrictor in a manner known in the art. Vasoconstrictive agents are added to local anesthetics for reduction of plasma concentration of local anesthetics, reduction of minimal concentration of local anesthetic necessary for arresting the nerve impulse and prolonged effect of local anesthesia.

[0015] Suitable vasoconstrictors include, for example, epinephrine, norepinephrine, endothelin, thromboxane, naphazoline nitrate, tetrahydrozoline hydrochloride, oxymetazoline hydrochloride, phenylephrine hydrochloride, tramazoline hydrochloride, levonordefrin (Neo-Cobefrine) and nordefrin (Cobefrine).

[0016] Any therapeutic dosage, one that achieves at least a perceptible blockage of olfactory sensation, or elicits the central effects needed for appetite suppression, is appropriate and is considered to be within the scope of the present embodiments. In some embodiments, the sodium channel blocker is provided in nasal drops, gel, powder, spray, or instillation liquid in a concentration of from about 0.05 to about 200 mg/ml, preferably from about 0.5 mg/ml to about 50 mg/ml and more preferably from about 1 mg/ml to about 20 mg/ml. In some embodiments, the calcium channel blocker is provided in nasal drops, gel, powder, spray, or instillation liquid in a concentration of from about 0.05 to about 200 mg/ml, preferably from about 0.5 mg/ml to about 50 mg/ml and more preferably from about 1 mg/ml to about 20 mg/ml. The concentrations of the sodium channel blocker and the calcium channel blocker can be substantially the same or different.

[0017] In some embodiments, the sodium channel blockers and the calcium channel blockers can be delivered into the nasal passageways in any suitable manner, such as by instillation of a liquid, drops, a gel, a powder or a nasal spray. This is preferably done at least a few minutes (e.g., 1, 2, 5, 10, 15, 30, 60, 240 minutes or more) prior to a meal or other consumption of food. In some embodiments, the sodium channel blockers can be taken at a different time than the calcium channel blockers. In other embodiments, both the sodium channel blockers and the calcium channel blockers can be taken at substantially the same time. Because some of the compositions of the present embodiments are short-acting, it may be desirable to repeat the treatment after a suitable period, e.g., after 15, 30, 45, or 60 minutes. With some of the central acting effects, it may be possible to reduce frequency of administration.

[0018] The various forms of the delivery system set forth above can include a buffer to maintain the pH of the sodium channel blocker and calcium channel blocker and a pharmaceutically acceptable thickening agent and a humectant. The particular pH of the buffer can vary depending upon the particular nasal delivery formulation as well as the specific sodium channel blocker and calcium channel blocker compositions selected. Examples of buffers suitable for use in the present embodiments include acetate, citrate, prolamine, carbonate and phosphate buffers. With respect to the non-aqueous formulations set forth above, suitable forms of buffering agents can be selected such that when the formulation is delivered into the nasal cavity of a mammal, selected pH ranges are achieved therein upon contact with, e.g., a nasal mucosa.

[0019] In the some embodiments, the pH of the compositions should be maintained from about 3.0 to about 10.0. Compositions having a pH of less than about 3.0 or greater than about 10.0 can increase the risk of irritating the nasal mucosa of a recipient. Further, it is preferable that the pH of the compositions be maintained from about 3.0 to about 7.0.

[0020] Viscosity of the compositions of the present embodiments may be maintained at a selected level using a therapeutically acceptable thickening agent. In one embodiment, methyl cellulose is used because it is readily and economically available and is easy to work with. Examples of other suitable thickening agents include xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose and carbomer. The preferred concentration of the thickener will depend upon the agent selected. Viscous compositions are normally prepared from solutions by the addition of such thickening agents.

[0021] The compositions of the present embodiments can also include a humectant to reduce or prevent drying of the mucus membrane and to prevent irritation thereof. Examples of humectants that can be used in the present embodiments include sorbitol, mineral oil, vegetable oil and glycerol. The concentration of the humectant in the present compositions will vary depending upon the agent selected. Also, soothing agents, membrane conditioners, sweeteners and combinations thereof can be included in the present embodiments. [0022] In other embodiments, other optional ingredients can also be incorporated into the nasal delivery system provided that they do not interfere with the action of the sodium channel blocker or calcium channel blocker or significantly decrease the absorption of the sodium channel blocker across the nasal mucosa. Such ingredients include pharmaceutically acceptable excipients and preservatives.

[0023] In some embodiments, preservatives are also included. Examples of preservatives that can be used with the present embodiments include benzyl alcohol, parabens, thimerosal, chlorobutanol and benzalkonium chloride and preferably benzalkonium chloride. Typically, the preservative will be present in a composition in a concentration of up to about 2% by weight. The exact concentration of the preservative, however, will vary depending upon the intended use and can be ascertained by one skilled in the art.

[0024] In some embodiments, therapeutically acceptable surfactants are included. Examples of suitable surfactants include polyoxyethylene derivatives of fatty acid partial esters of sorbitol anhydrides such as Tween 80, Polyoxyl 40 Stearate, Polyoxyethylene 50 Stearate and Octoxynol. The usual concentration is from about 1% to about 10% based on the total weight.

[0025] In other embodiments, bioadhesive agents can be used to increase nasal absorption. These compounds promote binding of drugs to biological material in the nasal cavity, thereby extending residence times and allowing increased absorption. Examples of bioadhesive materials include carbopol, cellulose agents, starch, dextran, and chitosan. Those skilled in the art will recognize that the components of the compositions are advantageously selected to be chemically inert with respect to the active agent.

[0026] Other embodiments include coadministration of the nasal preparation of sodium channel blockers and calcium channel blockers with an oral preparation, in order to simultaneously decrease both smell and taste sensations. The oral preparation can advantageously utilize one of the same sodium channel anesthetics used in the nasal preparation, or a different one, and can take any suitable oral delivery form, e.g., drops, creams, powders, gels, lozenges, fast melt strips, and liquids. The concentration and dosage of the oral form is substantially similar to that of the nasal preparation, except that, if desired, the oral dosage can be greater than the nasal dosage (e.g., 1, 2, 4, 8, 10, 100 or more times the nasal dosage).

[0027] As with the nasal preparation, a vasoconstrictor can also advantageously be used with the oral form. It should be noted that various oral anesthetic preparations containing topical anesthetic are commercially available, and include gels, mouthwash, and lozenges, all of which can be used in the present embodiments.

[0028] As used herein, the term "patient" refers to the recipient of a therapeutic treatment and includes all organisms within the kingdom animalia. In preferred embodiments, the animal is within the family of mammals, such as humans, bovine, ovine, porcine, feline, buffalo, canine, goat, equine, donkey, deer and primates. The most preferred animal is human.

[0029] As used herein, the terms "treat" "treating" and "treatment" include "prevent" "preventing" and "prevention" respectively. As used herein, a "food intake-related disease or condition" includes, for example, obesity, atherosclerosis, coronary artery disease, hypertension, hypercholesterolemia, diabetes mellitus, gout, osteoarthritis, intertrigo, sleep apnea, hyperlipidemia, hypolipidemia, hypoproteinemia, Pickwickian syndrome, Cushing syndrome and asthma.

[0030] In one exemplary embodiment, a 70 kg adult patient diagnosed with obesity or a food intake-related disease or condition is given a nasal administration 20 minutes before each meal of 20 mg of lidocaine and 20 mg of diltiazem. This dosage can be adjusted based on the results of the treatment and the judgment of the attending physician. Treatment is preferably continued for at least 1 cycle of 4 weeks, preferably at least about 3 to 6 months, and may be continued on a chronic basis. EQUIVALENTS

[0031] The foregoing written specification is considered to be sufficient to enable one skilled in the art to practice the full scope of the present invention. The foregoing description details certain preferred embodiments and incorporates the best mode contemplated by the inventors. It will be appreciated, however, that no matter how detailed the foregoing may appear in text, the present invention may be practiced in many ways and the present invention should be construed to include the full scope of the appended claims and equivalents thereof.

[0032] The term "comprising" is intended herein to be open-ended, including not only the recited elements, but further encompassing any additional elements.

Claims

WHAT IS CLAIMED IS:

1. A method of treating obesity in a mammal in need of such treatment comprising applying a sodium channel blocker and a calcium channel blocker to the mammal intranasally in an amount sufficient to decrease sensation of smell.

2. The method of Claim 1, wherein the sodium channel blocker is lidocaine.

3. The method of Claim 1, wherein the sodium channel blocker is dyclonine.

4. The method of Claim 1, wherein the calcium channel blocker is diltiazem.

5. The method of Claim 1, wherein the sodium channel blocker and calcium channel blocker are applied before meals.

6. The method of Claim 1, wherein the sodium channel blocker and calcium channel blocker are each independently in the form of a gel, powder, spray, liquid, or drop.

7. The method of Claim 1, further comprising the administration of a vasoconstrictor in combination with the sodium channel blocker and calcium channel blocker.

8. The method of Claim 6, wherein the vasoconstrictor is selected from the group consisting of: epinephrine, norepinephrine, endothelin, thromboxane, naphazoline nitrate, tetrahydrozoline hydrochloride, oxymetazoline hydrochloride, phenylephrine hydrochloride and tramazoline hydrochloride.

9. The method of Claim 1, wherein the concentration of the sodium channel blocker is from about 0.05 to about 200 mg/ml.

10. The method of Claim 1, wherein the concentration of the calcium channel blocker is from about 0.05 to about 200 mg/ml.

11. The method of Claim 1, wherein the sodium channel blocker is selected from the group consisting of: lidocaine, dyclonine, mepivacaine, bupivacaine quinidine, lorcainide, procainamide, encainide, propafenone, moricizine, mexiletine, disopyramide, aprindine, phenytoin, tocainide, flecainide, procaine, benzocaine dibucaine, tetracaine, butacaine, cyclomethycaine and tetracaine.

12. The method of Claim 1, wherein the calcium channel blocker is selected from the group consisting of: diltiazem, verapamil, fluoxetine, nifedipine, nimodipine, amlodipine, felodipine, nicardipine, bepridil and nisoldipine.

13. The method of Claim 1, further comprising the co-administration of a topical anesthetic to the oral mucosa or tongue to reduce taste sensation.

14. A method of treating obesity in a mammal in need of such treatment comprising applying a sodium channel blocker, a calcium channel blocker, a humectant, a pH buffer and a thickening agent to the mammal intranasally.

15. The method of Claim 14, wherein the humectant is selected from sorbitol, mineral oil, vegetable oil, glycerol, soothing agents, membrane conditioners, sweeteners and combinations thereof.

16. The method of Claim 14, wherein the pH buffer is selected from acetate, citrate, prolamine, carbonate and phosphate buffers.

17. The method of Claim 14, wherein the thickening agent is selected from xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose and carbomer.