Nasal and ocular administration of ketamine to manage pain and for detoxification.

FIELD OF THE INVENTION

The present invention relates to the management of chronic pain without requiring the administration of narcotics. The invention also relates to self-management of pain on an outpatient basis. The invention relates to methods of aiding detoxification and binding for addictive diseases, particularly smoking.

BACKGROUND OF THE INVENTION

Ketamine ((2- (2-chlorophenyl) -2- (methylamino) ~ cyclohexanone) is a general anesthetic used by physiologists, veterinarians, and researchers. Nasal administration of ketamine, in an example with rnidazolam, for achieving sedation for an ophthalmic procedure and before elective surgery in healthy children has been reported (Louon et al., 1993. Br. J. Ophthalmol. 77: 529-530; Weksler et al., 1993. Can. J. Anesthesia 40: 119-121). Ketamine is usually administered intramuscularly (i.rn.) or intravenously (iv) for induction of anesthesia.

1.1.111 i

Ketarnin has also been known to have analgesic properties (Domino et al., 1965, Clin. Pharmacol. Ther. 6: 279); analgesia can be achieved with subanesthetic doses of ketarnine (Bovill, 1971, Br. 3. Anaesth. 43: 496; Sadove et al., 1971, Anesth. Analg. 50: 452-457). The drug is administered by various routes, including iv, im, caudal, intrathecal, and subcutaneous (sc). Subcutaneous ketarnin administration has been used to treat pain after surgery and associated with terminal cancer (see, eg, Oshima et al., 1990, Can. 3. Anaesth. 37: 395-386). ®. Ketarnin hydrochloride administered via a subcutaneous cannula has been reported to successfully treat the onset of limb pain (Stannard and Porter, 1993, Pain 54: 227-230).

Pain management, and particularly chronic pain, is complex and often unsuccessful. The first line of treatment usually involves the subtraction of μ-opioid agonists, for example narcotics such as morphine (see, for example, Anderson and Brill. 1992, Semin. Anesth. 11: 158-171). However, rapid tolerance and marked resistance to narcotics frequently developed, thus rendering these agents ineffective (see, eg, Abram, 1993, Reg. Anesth. 18 (SUPPL): 406413). Antagonists N-methyl-D-aspartate receptor (NMDA), including ketarnine, have been reported to interfere with the development of tolerance to the analgesic effects of morphine, possibly by blocking the NMDA receptor and_r instead of antagonist side effects, since antagonists were not found to reverse tolerance (Trujillo and Rkil, 1994, Brain Res. 633: 178-188).

Often, pain management involves the administration of a plethora of drugs, such as narcotics, antagonist-agonists, butorphanols, benzodiazepines. GOBfl stimulators, barbiturates, barbiturate-like drugs, orally, for example in a pill or liquid formulation, or by iv or i.rn injection. Can be^,F ombinate opioid agonists and antagonists. Thus, a combination of drugs may have equivalent effects, problematic is the possibility of adverse side effects, particularly gastric distress accompanying oral administration, or the fear that injections may inspire.

Frequently, a cynic will require medication for other gastric problems such as oral medications. Oral administration for pain relievers and sedatives for the patient suffering from pain and to control the stomach and result of alternative administration for self-medication of chronic pain treatment, in addition to perioral administration are not common, they can be bulky ( for example iv or sc administration requires the use of a cannula or needles) and generally require medical training.

-4 Lilili.

United States Patent No. 4,571,953 does screen the administration of sedative, analgesic, or sedative drugs in a sweet matrix, such that the drug enters the blood stream through the oral mucosa membranes. However, this method lacks the disadvantage that a sedated patient may fall asleep with the remaining candy in his mouth, which can result in drowning. Furthermore, because the total dose of the drug in the confectionery may exceed the desired dose, the administration of the confectionery must be medically supervised. Finally, the sweet is'^KSimply unsuitable for everyday use, such as sucking on a popsicle is inappropriate practice for an employee or a business person.

Furthermore, when administration is under the control of the patient suffering from pain, i.e. on an outpatient basis, there is the potential for overdose or abuse, particularly with respect to narcotics.

Another area of ​​serious interest to medicine is the detoxification and withdrawal of dependence on addictive substances, including narcotics, cocaine, alcohol and tobacco (both from nicotine and smoking itself). In particular, medicine does not provide satisfactory mitigation to eliminate tobacco or nicotine addiction. Although general perception maintains that tobacco addiction is the least profound of these addictions, from a public health perspective, it may be the most important. In addition, current supports for the treatment of tobacco addiction or RV addiction, such as the nicotine transdermal patch or nicotine gum, treat addiction with an addictive substance supplied by tobacco use.

Tai treatment re was very much the behavior that is going to be eliminated

There is no suitable substitute, capable of reinforcing the absence of tobacco ingestion with something that is currently available.

Thus, there is a need in the art for pain management using non-opioid drugs.

Furthermore, there is a need in the art for a rapid method of reducing or eliminating the onset of pain that is refractory to standard treatment regimens.

There is another need in the art to avoid oral administration and injection of pain medication.

There is a need in the art for a convenient and socially acceptable rapid method for self-administering the patient's medication to handle or^,! The pain entered him.

There is still another need in the art to prevent overdose and abuse of the self-administered medication.

There is still a critical need in the art for an agent that can aid in the detoxification and withdrawal of substance addiction, particularly smoking or tobacco use.

These and other needs in the art have been addressed by the present invention, which is based on the inventor's discovery that ketamine can be

-6 surprisingly administered nasally to relieve pain is sworn and effective, along with or independently of other pain management regimens.

The citation or identification of any reference in this application should not be construed as an admission that such reference is available as a prior art for the present invention.

BRIEF DESCRIPTION OF THE INVENTION

The present invention is broadly directed to a method of treating pain in a patient, comprising administering a dose of ketamine effective in pain relief to a patient suffering from pain via the nasal or ocular route. In another embodiment, the present invention provides pulmonary administration of ketarnine by inhalation. Nasal administration of a dose of ketarnin analgesic advantageously allows self-administration of the drug to the patient, which provides pain management on an outpatient basis. Furthermore, the administration of ketamine in nasal sprays and inhalers is generally socially acceptable.

Pain therapy on an outpatient basis advantageously reduces the demands on hospital services, results in a substantial decrease in the cost of treatment and provides the patient with a more normal life and work environment, which can positively affect ive the treatment.

Ocular administration of ketamine is highly advantageous, for example during ophthalmic surgery. When the patient is fully covered, with the exception of the eyes, it makes access to the veins or nasal mucosa difficult. Also, if the patient is anesthetized, the nasal administration of a drug is not advisable. Because the administration of ketamine in this modality is through the eyes, the ophthalmologist who performs the surgery can ~ supplement anesthesia, avoiding the need for extra medical personnel and thus directly reducing the cost of medical care for such procedures. . Accordingly, it should be further understood that when the patient's condition avoids nasal administration of ketamine, ocular administration, for example using ketamine drops, can be substituted.

Another advantage of the invention is that it avoids the need to administer narcotic agents for the treatment of chronic pain. Although effective pain relievers, narcotics can lose their effectiveness due to tolerance or resistance. Narcotics are also highly addictive.

Outpatient pain therapy advantageously reduces the demand on hospital services, results in a substantial decrease in the cost of treatment and provides the patient with a more normal life and work environment, which can positively affect sy_> erar the treatment.

Another advantage of the invention is that it avoids and reduces the need to administer narcotic agents for the treatment of chronic pain. Although effective pain relievers, narcotics may lose effectiveness due to tolerance or resistance. Narcotics are also highly addictive.

In another aspect, the present invention is directed to a method of aiding detoxification and treatment of substance diction in a patient, comprising administering via the nasal route an effective dose of ketamine to aid in detoxification and treatment of the addiction. In another embodiment, the present invention provides pulmonary administration of ketamine by inhalation. In addition to pain management, nasal administration of an analgesic dose of ketamine has also been found to advantageously provide a powerful booster to not engage in addictive behavior, for example smoking or taking drugs. The invention allows the patient to self-administer the drug, which facilitates detoxification and addiction treatment on an outpatient basis. Furthermore, as noted above, administration of ketamine in nasal sprays and inhalers is generally socially acceptable.

In a preferred embodiment, the invention provides

-9Η 113.

a method and device for the treatment of addiction to tobacco, for example, taking turns.

Another advantage of the invention is that it avoids administration in a sweet, which requires medical supervision and is socially questionable, if not absolutely unacceptable. It also avoids the administration of the addictive substance, particularly nicotine for the treatment of addiction.

Another advantage of the invention is that ketamine is a cheap, readily available drug with minor adverse side effects. In this way, the invention

V^to,.

Consider additional savings for the overloaded health care system.

Nasal ketamine administration is rapid, allowing rapid action of the drug and easily performed by a patient without medical training.

In one aspect, the dose for addiction treatment and pain relief is approximately 0.01 to approximately 1 mg / kg of body weight. In a more preferred aspect, the ketamine dose is from about 0.05 to about 0.7 mg / kg of body weight. In another embodiment, the total dose of ketamine by nasal administration is in the range of about 1 to about 30 mg.

In a specific aspect of the invention, the ketamine dose is effective in alleviating the onset of pain in a patient suffering from a chronic pain condition.

In another aspect of the invention, the dose of ketamine

-10LUI is effective in relieving the onset of pain associated with work, particularly the work transition.

In another modality, which has been clinically proven with great success, ketamine nasal administration is effective 5 for the treatment of migraine headache.

In a particular aspect, nasal administration of ketamine may be a supplemental therapy in a pain management regimen, which includes the administration of one or more narcotics, pain relievers, and sedatives, for example as

<td> 10</td><td>described</td><td>in the above.</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td colspan="2">The present invention</td><td>behold</td><td>also</td><td>manage</td>

<td></td><td>a dose</td><td>benzodiazepine,</td><td colspan="2">effective for</td><td>inhibit</td><td>dysphoria</td>

<td></td><td>which can</td><td>be associated with</td><td>the</td><td colspan="2">administration of</td><td>high doses</td>

ketamine. In a preferred aspect, benzodiazepine is administered nasal with ketamine.

It should be noted that another advantage of the present invention is that it avoids dosing a patient with dysphoric or hallucinogenic ketamine Xities by providing a measured analgesic dose, which is well below the level associated with dysphoria or hallucination.

In yet another embodiment, the present invention contemplates administering a dose of an effective narcotic analgesic for pain relief with ketamine, - preferably the narcotic analgesic is administered via the mucosa route with ketamine.

Accordingly, the invention provides a

-11l.iu;

device for self-administration of ketamine by the · &lt;

p tooth. In its broadest aspect, the device of the invention comprises a nasal inhaler containing an aerosol formulation of ketamine and a pharmaceutically acceptable dispersant, in which the device is measured to disperse an amount of the aerosol formulation containing a dose of Ketamine effective to relieve pain or aid in detoxification and addiction treatment.

The dispersant can be a surfactant, such as, but not limited to, polyoxyethylene fatty acid esters, polyoxyethylene fatty acid alcohols, and polyoxyethylene fatty acid esters sorbitan.

In a specific embodiment, particularly for addiction treatment, the device provides a measured dose of ketamine and includes a dose limiting mechanism that limits the number of doses and preferably includes a closing time before another dose can be 'administered.

In a specific embodiment, the aerosol formulation is a dry powder aerosol formulation, in which ketamine is present as a finely divided powder. The dry powder formulation may further consist of a bulking agent, such as but not limited to, lactose, sorbitol, sucrose, and mannitol.

In another specific embodiment, the aerosol formulation is a liquid aerosol formulation that also

-12IIJII comprises a pharmaceutically acceptable diluent, such as not limited to, sterile water, saline, buffered saline, and dextrose solution.

In other embodiments, the aerosol formulation further comprises a benzodiazepine in a concentration such that the measured amount of the aerosol formulation dispersed by the device contains a dose of the benzodiazepine effective in inhibiting dysphoria, or a narcotic in a concentration such that the measured amount of the aerosol formulation dispersed by the device contains an effective dose of the narcotic to relieve pain. The present invention further contemplates including both of a benzodiazepine and a narcotic in the aerosol formulation.

Thus, it is an object of the invention to provide self-administration of a safe, non-narcotic drug for the treatment of outpatient pain and to aid in detoxification and treatment of aiction.

It is another object of the present invention to provide a method for nasal administration of a drug in a controlled amount for the treatment of pain and to aid in detoxification and addiction treatment.

A further object of the present invention is to provide a device that can be used outside a hospital or medical office by non-medical personnel for nasal self-administration of ketamine.

-131 ι: ι ιι

These and other objects of the present invention will become more readily apparent by reference to the following detailed description.

DETAILED DESCRIPTION OF La..IH «Ehl £ IQH

One aspect of the invention provides nasal administration of ketamine for pain management. In a more preferred aspect, the invention provides a method and device for patient self-administration of tamina for pain management.

The invention can alleviate pain from many causes, including but not limited to shock; limb amputation; severe thermal or chemical burn injury; strains, ligament tears, fractures, wounds and other tissue injuries; dental surgery, procedures and diseases; labor and delivery; migraine; during physical therapy; post operative pain; radiation poisoning; Cancer; acquired immunodeficiency syndrome (AIDS); epidural (or epidural) fibrosis; lower back surgery and lower laminectomy; sciatica; pain from sickle cell crisis; arthritis; autoimmune disease; intractable bladder pain; and the like. Mucosal administration of ketamine is also sensitive for use in hospice, particularly hospices that specialize in the care of patients with cancer and AIDS.

-1414

In one embodiment, the nasal administration of ketamine 1&gt;. It can mitigate or alleviate acute episodes of initial pain that can occur in a chronic pain condition. In another embodiment, nasal administration of ketamine can be used as an adjunct therapy to a conventional treatment regimen for the chronic pain condition to alleviate the onset of pain. In a specific modality, infra. Ketamine nasal administration is effective in treating intractable bladder pain.

A particular advantage of the present invention in educating labor and delivery pain is that low dose ketamine has no significant adverse effects on the fetus.

<td></td><td>can</td><td>one to be</td><td>Unaη a modality used as</td><td>relative an adjuvant</td><td>nasal administration or directly for</td>

<td> 15</td><td>try</td><td>a</td><td>asthma attack</td><td>acute. As</td><td>the conditions of the</td>

<td></td><td>pain</td><td>without</td><td colspan="2">relate can induce the</td><td>asthma, the present</td>

The invention advantageously provides pain relief, thereby reducing the cause of the attack. Also, ketamine (unlike pain medication, narcotic) is a bronchodilator.

In yet another related modality, the nasal administration of ketamine can be used in the treatment of acute nausea. Nasal ketamine is particularly attractive for this condition, as nausea prevents the use of 25 oral medications. In particular, nasal ketamine can mitigate the pain that nausea can cause and can alleviate

-1515

44.1 II:.

abdominal pain that frequently accompanies sofera nausea.

In yet another related embodiment, nasal administration of ketamine can be used to treat acute agitation, for example, agitation presented by an individual intoxicated with alcohol or drugs or by a person placed under arrest by the police.

Similarly, nasal ketamine can be useful in treating shock resulting from severe injury. Thus, even if the patient fails to feel pain due to &lt;1 severe shock, the extreme pain associated with severe injury contributes to the shock.

Still another aspect of the invention provides ocular administration of ketamine for maintenance of anesthesia and analgesia during eye surgery, or in a patient in whom the administration of ketamine is contraindicated, such as someone suffering from &lt;k syndrome &gt; Respiratory \ rés in adults, or severe injury to the nasal mucosa, for example by thermal or chemical burns. Thus, ocular administration of ketamine in doses

<td>established</td><td>in the</td><td>present they can</td><td colspan="2">replace</td><td>the</td>

<td>administration</td><td>nasal</td><td colspan="2">in disabled individuals</td><td>for</td><td>the</td>

<td>administration</td><td>nasal</td><td>ketamine.</td><td></td><td></td><td></td>

In yet another aspect, the invention provides for the nasal (or, if indicated, ocular) administration of ketamine to facilitate detoxification and aid in the treatment of

-16i .: neither.

substance addiction. In a more preferred aspect, the invention provides a method and device for patient self-administration of ketamine for pain management.

<td> 5</td><td colspan="2">In a</td><td colspan="2">preferred aspect, the</td><td colspan="2">administration</td><td>nasal</td><td>of</td>

<td></td><td>ketamine</td><td>is a</td><td>adjuvant</td><td>powerful and</td><td>cash</td><td>for</td><td>leave</td><td>of</td>

<td></td><td>smoke.</td><td>Many</td><td>individuals,</td><td>Some</td><td>of the</td><td>which</td><td colspan="2">were</td>

Strongly addicted to smoking, they have been able to break the addiction by means of the nasal administration of ketamine instead of smoking a cigarette, when urna attacks arise.

The present invention is based on the surprising and unexpected discovery that nasal administration of ketarnine can alleviate symptoms of chronic pain. Thus, in a specific example, infra. a patient suffering from intractable bladder pain and taking a variety of narcotics, pain relievers, and sedatives in an unsuccessful attempt to 4 roll pain, was able to achieve the most satisfactory pain management by nasal administration of 16-32 mg ketamine , 20 which corresponds to approximately 0.2-0.6 mg / kg of body weight. (In the specific Example, infra. A dose of 16-32 mg corresponds to 0.27-0.53 mg / kg of body weight). The dose was effective for about 15 minutes to about 1 hour in relieving pain. The patient was able to reduce the amount of pain medication, which had caused gastric distress.

-17HUI;

The invention is further based on the discovered i&gt; ¿that nasal administration of ketamine is a powerful booster to avoid addictive substances, such as tobacco smoking, narcotic smoking and others. In particular, the nasal administration of ketamine has enabled heavily addicted smokers to avoid cigarettes immediately. Although it is not intended to bind any particular theory for the mechanism by which ketamine aids in the treatment of substance addiction, the anesthetic properties are believed to offset the euphoric effects of addictive substances. For example, during smoking endorphins are secreted in response to carbon monoxide (CO) inducing hypoxia, and these endorphins provide a powerful boost to smoking behavior. Endorphins are opioid peptides that bind to the same receptors as opioids. As noted above, ketamine is capable of relieving intractable pain that is typically Hado with opioids. Thus, the observation that ketamine administration is highly effective in treating addiction to smoking is consistent with ketamine's ability to supplement or overcome opioids in pain management.

Additionally it has been found that dozens of patients suffering from intractable pain, migraine headache, chronic fatigue syndrome, or other afflictions associated with pain, have benefited from the methods and devices of the

-181.1 II.

invention. Furthermore, those of the patients who smoke have found that nasal ketamine strongly inhibits the need to smoke.

Accordingly, the present invention is directed to methods of relieving chronic pain, or aiding in detoxification and treatment of substance addiction, on an outpatient basis by nasal administration of ketamine and devices usable by non-medical personnel for nasal self-administration of ketamine.

Ketamine will preferably be prepared in a z^- . . ... . .

ormulation or pharmaceutical composition appropriate for nasal administration. Suitable formulations are discussed in detail, infra. In another embodiment, ketamine can be formulated with a mucosal penetration enhancer to facilitate drug delivery. The formulation can also be prepared with pH optimized for solubility, drug stability, absorption through the nasal mucosa

F. Hras considerations.

The invention provides the administration of an effective therapeutic dose of ketamine, that is, an effective dose to relieve pain, or to facilitate detoxification and aid in the treatment of substance addiction. The actual dose will vary, depending on the patient's body weight, the severity of pain or substance addiction, the route of administration, the nature of the drugs administered concurrently, the number of doses

-19that are to be administered per day and other factors g; orally considered by the physician skilled in the art of drug administration. In a specific embodiment, the amount of ketamine administered to a patient suffering from chronic pain is from about 10% to about 20% of the amount used to induce anesthesia. In another specific embodiment, the ketamine dose is from about 0.01 mg per kg of body weight (0.01 mg / kg) to about 1 mg / kg; preferably from about 0.05 mg / kg to about 0.7 mg / kg. In still another mode, the dose ranges from about 1 mg to about 30 mg. Preferably, the effective dose is titrated under the supervision of a physician or healthcare provider, such that the optimal dose for the particular application is accurately determined. Thus, the present invention provides a suitable dose for each individual patient.

Once the dose range is established, another advantage of the invention is that the patient can administer ketamine on a dose-to-effect basis as needed. In this way, the frequency of administration is under the control of the patient. However, the relatively low dose with each administration will reduce the chances of abuse.

Still another particular advantage of the present invention is that nasal administration of ketamine is non-invasive and provides introduction into the blood stream almost as fast as iv administration and much faster than perioral administration.

More importantly, a patient can control the administration of pain medication, since nasal administration provided for precise control over the dose and effect of the drug used to displace changes in activity and pain levels throughout the day. Nasal ketamine administration optimally provides dose-to-effect administration of the drug.

Thus, according to the invention, the

Z ''. . .

Acient can safely administer an amount of drug effective in relieving pain by controlling the amount of frequency of administration of a formulation according to the invention. Regulated patient control, safe pain medication is an important advantage, because pain is a subjective condition. The advantage here is twofold, since the patient can effectively relieve the pain 'for pain relief will have significant psychological benefits. A positive psychological attitude can significantly improve the course and overcome a treatment regimen, as well as make the entire process more durable for the patient.

Similarly, ketamine, which by itself is not addictive, is a powerful booster to avoid addictive substances. To avoid abuse by addictive personality, ketamine or administration to aid in

-2121

ΠίΙΙί detoxification or addiction treatment of the substance,

<td>p ^ cle be</td><td>provided in a metered dose device that</td>

<td>they contain</td><td>a dose limiting mechanism. The mechanism that</td>

<td>limits the</td><td>dose can provide a limited number of doses</td>

ketamine, with a closing time between doses to avoid too frequent administration.

Various terms are used throughout the specification, which are defined herein:

The term mucosal refers to a tissue comprising 10 mucous membranes, such as the nasal mucosa and the mucosa, lemon.

The term nasal administration in all its grammatical forms refers to the administration of a drug through the nasal mucosa membrane into the blood stream for systemic delivery of the drug. The advantages of nasal administration for drug delivery are that it does not require injection using a syringe and · needle, to avoid necrosis that can be accompanied by drug administration, it avoids the need to be

<td> 20</td><td>constantly sucking</td><td>a palette and</td><td colspan="2">the trans-</td>

<td></td><td>mucosa of a drug</td><td>is highly</td><td>satisfactory for</td><td>the</td>

<td></td><td>self-administration.</td><td></td><td></td><td></td>

<td></td><td>The present</td><td>invention</td><td>also contemplates</td><td>the</td>

pulmonary administration by means of an inhaler in a particular aspect.

The term mucosa penetration enhancer

-22 refers to a reagent that increases the speed or ease of penetration of the transmucosa of ketarnine, such as but not limited to, bile salts, fatty acids, surfactant, or alcohol. In specific embodiments, the permeation enhancer may be sodium cholate, sodium dodecyl sulfate, sodium deoxycholate, taurodeoxycholate, sodium glycollate, dimethyl sulfoxide, or ethanol. Suitable penetration enhancers also include glycyrrhetinic acid (US Patent No. 5,112,004 to Kowarski) and polysorbate 80, the latter preferably in combination with, jn nonionic surfactant such as nonoxynol 9, lauret-9, poloxamer-124 , octoxynol 9 or lauramide-DEñ (European Patent EP 0 242 643 B1 to Stoltz).

A therapeutically effective amount of a drug is an amount effective to demonstrate a desired activity of the drug. In accordance with the present invention, in one embodiment a therapeutically effective amount of ketarnine is an effective amount to alleviate, ie, markedly reduce pain in a patient. In another embodiment, a therapeutically effective amount is an amount effective to facilitate an individual's detoxification of an addictive substance. In yet another embodiment, a therapeutically effective amount is an effective amount to aid in the treatment of a substance addiction, ie, an effective amount as a booster to avoid the addictive substance or addictive behavior.

The term substance addiction refers to an a, ction, or habit associated with a particular addictive substance. The term addictive substance refers to a drug or agent capable of forming an addiction, including but not limited to narcotics, depressants, amphetamines, opioid pain relievers, cocaine, marijuana, tobacco (both smoked for the hypoxic dysphoria it causes and the nicotine contained in her) and alcohol.

A patient in whom the nasal or ocular administration of ketamine is an effective therapeutic regimen for pain management, maintenance of analgesia or anesthesia during eye or other surgery, or for the treatment of addiction to a substance, is preference any animal. Thus, a human but can be readily appreciated by someone of ordinary skill in the art, the methods and devices of the present invention are particularly suitable for the administration of ketamine to any animal, particularly a mammal, and which includes but does not mean that it is limited to, domestic animals such as feline or canine individuals, farm animals such as but not limited to bovine, equine, goat, sheep and pigs, wild animals (whether in the field or in a zoological garden), research animals such as mice, rats, rabbits, goats, sheep, pigs, dogs, cats, etc., that is, for veterinary medical use.

Now the invention will be described in greater detail,

-2424 i: i ii, with reference to nasal and pulmonary administration of ketamine and additional therapeutics or agents with which ketamine can be administered.

Formulations comprising ketamine for use in a wide variety of devices are contemplated by the present invention, which are designed for delivery of pharmaceutical compositions and therapeutic formulations to the respiratory tract, preferably the nasal passages. The preferred route of administration of the present invention is a .10 aerosol spray • transfer is for nasal inhalation. Ketamine combines with a dispersing agent of o

dispersant, aerosol like that can be administered in a dry powder formulation in a solution or suspension with a diluent.

.15 As used herein, the term aerosol refers to an air suspension. In particular, aerosol refers to particle formation or atomization of a formulation of the invention and its suspension in air.

In accordance with the present invention, an aerosol formulation is a formulation comprising ketamine for nasal inhalation or pulmonary administration.

As used herein, the term "inhaler" refers to both devices for nasal and pulmonary administration of the drug, for example in a solution, powder, and the like. For example, the term inhaler is intended to encompass a powered inhaler.

-25 for a propellant, as used for an ar ... ihistamine administrator for acute asthma attacks and plastic spray bottles, such as are used to administer decongestants.

As used herein, the term "dispersant" refers to an agent that aids in the formation of the ketamine aerosol or absorption of the ketamine in the mucosa tissue, or both. In a specific aspect, the dispersant can be an enhancer of mucosal penetration. Preferably, the dispersant is pharmaceutically

A? Eptable.

As used herein, the term "pharmaceutically acceptable" means approved by a government regulatory agency.

Federal or state government or listed in the United States Pharmacopeia or other generally recognized pharmacopoeias for use in animals and more particularly in humans.

Suitable dispersing agents are well known

- the art and include, but are not limited to surfactants and the like. For example, surfactants that are generally used in the art to reduce ketamine-induced surface aggregation caused by atomization of the liquid aerosol-forming solution can be used. Non-limiting examples of such surfactants are surfactants such as polyoxyethylene fatty acid esters and alcohols and polyoxyethylene sorbitan fatty acid esters. The amounts of surfactants .ί 1,112.

used will vary, generally being within the range of „01 and 4X by formulation weight. Suitable surfactants are well known in the art and can be selected based on the desired properties, depending on the specific formulation, ketamine concentration, diluent (in a liquid formulation) or in powder form (in a dry powder formulation) etc.

Liquid aerosol formulations containing ketamine and a dispersing agent in a physiologically acceptable diluent.

jlvo seco de la presente

The inventive formulations consist of aerosol in a finely divided solid dispersion form. Whether aerosol powder, ie ketamine, and with liquid or dry formulation, it must be solid to ensure that the mucous membranes of a formulation agent that of the formulation must be in broken form into liquid particles or doses Aerosol actually reaches the nasal passages or the lung. The 6th aerosol particle describes the administration of construction membranes to the nasal or pulmonary liquid particle, the mucosa. Other of the device used herein for or solid suitable for that is, it will achieve considerations such as supply, additional components in the formulation and characteristic of the particles are important. These aspects of nasal or pulmonary administration of a drug are well known in the art and manipulation of formulations, means of aerosolization, and

-2727

Lililí.

Construction of a delivery device requires routine experimentation by someone of ordinary skill in the art.

In a particular embodiment, the dynamic mean mass diameter will be 5 microns or less to ensure that the drug particles reach the pulmonary alveoli (Uearley. LL, 1991, 1991, Crit. Rev. in Ther. Drug Carrier Systems 8: 333 ).

With respect to the construction of the delivery device, any form of aerosol known in the art, including but not limited to aerosolization, nebulization, atomization or spray bottles of a liquid formulation and aerosolization of a powder formulation dry, the invention can be used in practice.

As noted above, in a preferred aspect of the invention, the device for formation of the {osol is a metered dose inhaler. A metered dose inhaler provides a specific dose when administered, 20 rather than a variable dose depending on administration. Such a metered dose inhaler can be used with either a liquid aerosol formulation or a dry powder aerosol.

Metered dose inhalers are well known in the art. In a preferred aspect, particularly for the treatment of substance addiction, the inhaler of

-2828

ILIIJ.

measurement contains a locking mechanism to limit the

<td>fj. , .Uencia</td><td>Ketamine Dose Administration. Such</td>

<td>device</td><td>is viewed as an electronic device</td>

<td>programmable</td><td>externally or switchable for</td>

different settings, or a hydraulic or pressure system that takes some time to recharge.

For nasal administration, a useful device is a small, hard bottle to which the metered dose sprayer is attached. In one embodiment, the metered dose is delivered by withdrawing the ketamine solution into a chamber of fi nite volume, which chamber has an opening dimensioned to form the aerosol of the aerosol formulation by forming a

<td>dew when</td><td>a liquid in the</td><td colspan="2">camera is compressed.</td><td>The camera</td>

<td colspan="2">it is compressed to administer</td><td>ketamine.</td><td>In a</td><td>modality</td>

<td>specific,</td><td>the camera is a</td><td>provision</td><td>pee</td><td>ton. Such</td>

<td>devices</td><td>They're available</td><td>commercially.</td><td></td><td></td>

Alternatively, a squeeze bottle of plastic with an opening or orifice sized to aerosolize an aerosol formulation to form a mist when squeezed. The opening at the top of the bottle and the top is usually found to be generally tapered to partially fit in the nasal passages for efficient delivery of the aerosol formulation. Preferably, the nasal inhaler will provide a measured amount of the aerosol formulation, for administration of a measured dose of the drug.

-29 Frequently, the aerosolization of a liquid or a dry powder formulation for inhalation in the lung will require a propellant. The propellant can be any propellant generally used in the art. Specific non-limiting examples of such propellants are a chlorofluorocarbon, a hydrofluorocarbon, a hydrochlorofluorocarbon or a hydrocarbon, including trifluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethanol and 1,1,1,2-tetrafluoroethane or combinations thereof.

Aerosol delivery systems such as the pressurized metered dose inhaler and dry powder inhaler are described in Newrnan, SP, ñerQSQiS__and the Luna. Clarke, SW and Davia, D. editors, pp. 197-22 and can be used in connection with the present invention.

In another modality, as discussed in detail below. The aerosol formulation of the present invention may include other ingredients therapeutically or pharmacologically&gt; '* ·. . . . .

, ives in addition to ketamine, such as but not limited to benzodiazepine or a narcotic pain reliever.

In general, as described in detail below. ketamine is introduced into the patient as an aerosol in an amount of between 0.01 rng per kg of mammalian body weight to about 1 mg per kg of mammalian body weight. In a specific embodiment, the dose is administered as needed. Someone with ordinary skill in the art can easily determine a volume or weight of

ι.: ιιι aerosol corresponding to this dose based on the concentration of ketamine in an aerosol formulation of the invention.

Liquid Aerosol Formulations

The present invention provides aerosol formulations and dosage forms for use in the treatment of patients suffering from pain. In general such dosage formulas contain ketamine in a pharmaceutically acceptable diluent. Pharmaceutically dilutable diluents include, but are not limited to, sterile water, saline, buffered saline, dextrose solution, and the like. In a specific embodiment, a diluent that can be used in the present invention or the .15 pharmaceutical formulation of the present invention, is phosphate buffered solution or buffered saline, generally within the pH range of 7.0-8.0, or water.

The liquid aerosol formulation of the present invention may include, as optional ingredients, pharmaceutically acceptable carriers, diluents, solubilizers or emulsifying agents, surfactants and excipients.

The formulation may include a carrier. The carrier is a macromolecule which is soluble in the circulatory system and which is physiologically acceptable, where the means of physiological acceptance are those of ability in the

-31ιι: ι ιι;

technique, they would agree to inject the carrier into a patient as a treatment regimen. The carrier of preference is relatively stable in the circulatory system with an average plasma duration acceptable for clearance. Such macromolecules include, but are not limited to soy lecithin, oleic acid, and sorbitan trioleate, with the preferred sorbitan trioleate.

The formulations of the present embodiment, too, may include agents useful for maintaining pH, stabilizing the solution, or for regulating osmotic p / ession. Examples of the agents include, but are not limited to salts, such as sodium chloride, or potassium chloride and carbohydrates, such as glucose, galactose or trickle and the like.

The present invention further contemplates liquid aerosol formulations, comprising ketamine and another therapeutically effective drug, such as a benzodiazepine or a narcotic IgE.

Dry Aerosol Powder Formulations

It is also contemplated that the present aerosol formulation can be prepared as a dry powder formulation, comprising a finely divided powder form of ketamine and a dispersant.

In another embodiment, the dry powder formulation may

-3232, 1 .iil l¡.

consist of a finely divided dry powder containing kc .amine, a dispersing agent and also a bulking agent.

Useful bulking agents in conjunction with the present formulation include agents such as lactose, sorbitol, sucrose, or mannitol, in amounts that facilitate dispersion of the powder form of the device.

The present invention further contemplates dry powder formulations comprising ketamine and another therapeutically effective drug, such as a benzodiazepine or a narcotic pain reliever.

Additional Therapeutically Active Drugs or Agents

As noted above, the invention contemplates the coordinated nasal administration of ketamine with a therapeutically effective amount of another drug, in particular a benzodiazepine or a narcotic analgesic.

Co-administration of ketamine with a benzodiazepine is indicated to counteract the potential dysphoric or hallucinogenic effects of high doses of ketamine administration. Thus, a therapeutically effective amount of a benzodiazepine is an effective amount to inhibit dysphoria. In another embodiment, an amount of a benzodiazepine is also effective to sedate the patient and can be administered.

The mild side effects of ketamine, for example

-33 dysphoria and / or hallucinations, sometimes called ketamine dreams can occur from the administration of a higher dose of 50 mg of ketamine and usually requires higher doses of 100 mg of ketamine. An advantage of the present invention is that the nasal supply of ketamine allows dose control at an effective level for analgesia, but below the level resulting in dysphoria. However, it is possible that an individual may overdose, particularly in response to an acute episode of pain. Thus, co-administration of a benzodiazepine may be indicated in certain circumstances.

Benzodiazepines that can be administered in accordance with the present invention include, but are not limited to flurazepam (Dalmane), diazepam (Valium), and preferably Versed. In another preferred aspect the formulation

<td>transmucosa of</td><td>the invention</td><td>understands</td><td>that also</td><td>there is a</td>

<td>benzodiazepine,</td><td>each</td><td>Present</td><td>in a</td><td>quantity</td>

<td>Apathetically</td><td>effective.</td><td></td><td></td><td></td>

In a preferred embodiment, a therapeutically effective amount of a narcotic pain reliever used to treat chronic pain is administered in conjunction with a ketamine. A therapeutically effective amount of a narcotic drug is an amount effective in relieving pain. Such narcotics include, but are not limited to, fentanyl, meperidine (Demoral), morphine and its narcotic analogues and derivatives such as hydromorphine (Dilaudid), and lilili.

Similar. In a preferred aspect, the transmucosal formulation of the invention comprises that there is also a narcotic, each present in a therapeutically effective amount.

The invention may be better understood by reference to the following example, which is provided by way of explanation only and is not intended to limit the invention.

EXAMPLE

A 40-year-old female patient weighing approximately 50 kg had intractable bladder pain (interstitial keptitis), which had been diagnosed 4-5 months previously. Pain management in this patient consisted of 100 mg of Demoral every 3 hours; Dilaudid 2-4 mg every 4 hours; Dalrnane 30 mg per day; Duralgesic patches (fentanyl transdermal patches); bladder washes with Pyridinium (Phenaropyridine.HC1), which is an analgesic for urinary tract infection; and suppositories of belladonna and opium. In addition to pain medication, the patient took Zanax and Tagamet to relieve gastric distress and Compagine (an antiemetic) to counteract nausea. Gastric distress and nausea in this patient resulted from pain medication.

Despite the doses and range of pain medications used by this patient, satisfactory pain management was not achieved.

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A pre-sacral or ilio-hypogastric diagnosis is

i.Iize the nerve block in this patient to relieve pain. Unfortunately, the effect of the block was temporary and the block was associated with significant motor weakness. After the block was over, the patient stated that she was unable to function, as for the most trivial activities she was exhausted.

Ketarnin (10 mg / cc) was administered drip iv over one hour, for a total dose of 40 mg of ketarnine. This resulted in reduction of pain level by a factor of (from # 20 to approximately # 10-12) as subjectively assessed by the patient. Approximately 1 hour after the ketarnine infusion was discontinued, the patient reported that the pain level had increased by approximately # 15 and then rapidly to its previous level. The patient continued to take the other pain medications without effect.

Four days after iv loading of ketarnine, a 5 ml bottle containing 100 mg / rnl of a ketarnine solution was prepared. A single spray from the bottle delivered approximately 1/5 ml of solution, ie .16 mg of ketarnine. The patient was instructed to self-administer 1-2 sprays from the bottle for severe pain. The nasal spray bottle was prepared to provide sustainable pain medication on an outpatient basis.

The patient has demonstrated extraordinary handling of the

-361-.113,.

pain with nasal ketamine administration. Ketamine n \ al has been particularly effective in controlling the onset of pain. The patient has decreased the amount of the other pain medications.

To date, dozens of patients, including patients suffering from intractable pain, severe migraine pain, chronic fatigue syndrome, and other painful afflictions, have successfully employed nasal ketamine administration to treat these problems. In addition, those patients who started treatment as smokers and who wished to quit have found that nasal ketamine strongly suppressed the need for smoking. In total, patients have taken more than 100,000 doses of nasal ketamine, without any significant problems.

The present invention is not limited in scope by the specific embodiments described herein. In fact, various modifications of the invention, in addition to those described herein, will become apparent to those skilled in the art of the foregoing description and accompanying drawings. Such modifications are intended to fall within the scope of the appended claims.

Various publications are cited herein, the descriptions of which are incorporated by reference in their entireties.

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NOVELTY OF Lft INVENTION