Although dexmedetomidine has analgesic properties, a formulation useful as an analgesic, however, is not commercially available. Moreover, for a variety of reasons the commercially available injectable formulation is not suitable for use as an analgesic that can be self- administered.
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A continuing and unmet need exists for a dexmedetomidine-based analgesic medicines that, for example, may be self-administered to produce analgesia or otherwise treat or prevent pain without significant sedation. Such pharmaceutical compositions include Docket No. In another example, the dosage of dexmedetomidine or pharmaceutically acceptable salt thereof is between about 0.
Still further, the method may provide that the plasma C max of dexmedetomidine upon transmucosal absorption into the systemic circulatory system of said human is less than about 0.
In this example, the steps include administering to the oral mucosa of a mammal a systemically absorbed pharmaceutical composition comprising dexmedetomidine, or
Pharmaceutically acceptable salts fdating pharmaceutically acceptable salt or pro-drug thereof, in an amount effective to treat or to prevent pain in said mammal upon administration, wherein the pharmaceutical composition provides a physiologically active amount of dexmedetomidine into the systemic circulatory system of said mammal at a rate that produces an analgesic effect without sedation within one hour of administration.
Still further, the analgesic pharmaceutical composition may be configured and adapted for sublingual administration by applying said composition to a mucous membrane under the tongue of said mammal. Upon transmucosal absorption, the dexmedetomidine produces analgesia in the mammal.
In humans, dexmedetomidine is commercially available for sedation of initially intubated and mechanically ventilated patients during treatment in an intensive care setting, as well as sedation of non-intubated patients prior to or during surgical and other procedures.
The mean elimination half-life is 1. After buccal administration in which human subjects held a solution of dexmedetomidine in the mouth without swallowing, the mean buccal bioavailability has been measured at In an exemplary embodiment, a method for administering dexmedetomidine or a pharmaceutically acceptable salt or derivative thereof to a mammal includes spraying the oral mucosa of the mammal with a metered dosage of a spray composition comprising dexmedetomidine or a pharmaceutically acceptable salt or derivative thereof in a pharmaceutically acceptable liquid vehicle in an effective amount to provide transmucosal absorption of a pharmaceutically effective amount of the dexmedetomidine through the oral mucosa of the mammal into the systemic circulatory system of the mammal.
Attempts to counteract this type of pain by increasing the dose of long-acting formulations of
Pharmaceutically acceptable salts fdating often produce slow onset of
Pharmaceutically acceptable salts fdating and unwanted side-effects of sedation, constipation or nausea and vomiting, especially with opioid analgesics.
However, the analgesic, sublingual- spray formulations of dexmedetomidine described herein selectively provide moderate to rapidly acting, potent nonnarcotic analgesics that ameliorates, manages, cures, prevents, or otherwise treats such pain. As used herein, the term "pharmaceutically acceptable" includes those compounds, materials, compositions, dosage forms, and methods of use thereof that are within the scope of sound medical judgment and suitable for use in contact with the tissues of human Docket
Pharmaceutically acceptable salts fdating. The term "pharmaceutically acceptable salts" in this respect Pharmaceutically acceptable salts fdating to the relatively non-toxic, inorganic, and organic acid addition salts of dexmedetomidine.
These salts may be prepared in situ during final isolation and purification of dexmedetomidine or by separately reacting purified dexmedetomidine in its free base form with a suitable organic or inorganic acid, and thereafter isolating the salt thus formed. Furthermore, the salt may be formed during a manufacturing process to produce the spray formulation. Representative pharmaceutically acceptable salts include the hydrohalide including hydrobromide and hydrochloridesulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, 2- hydroxyethylsulfonate, and laurylsulphonate salts, and the like.
Dexmedetomidine hydrochloride is an example of a pharmaceutically acceptable salt. Use of dexmedetomidine hydrochloride may be preferable to the use of dexmedetomidine per se in the spray formulations described herein because, in some cases, the hydrochloride salt has greater water solubility and stability against oxidation by ambient oxygen. Upon administration, the pro-drug derivative undergoes chemical modification by the mammal that yields dexmedetomidine. Pro-drugs may be used to favorably alter the biodistribution or the pharmacokinetics of dexmedetomidine or to produce other desirable characteristics.
For example, a reactive
Pharmaceutically acceptable salts fdating of dexmedetomidine may be derivatized with a functional group that is cleaved, enzymatically or non-enzymatically, reductively, oxidatively, or hydrolytically, to reveal the active pharmaceutical ingredient.
Uses of certain types of pro-drugs are known see, e. For example, pro-drugs may be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free base form with a suitable derivatizing agent. These liquids may be solvents, cosolvents, or non-solvents for dexmedetomidine or its pharmaceutically acceptable salts or derivatives thereof. Suitable materials are liquids at room temperature and remain in the liquid state at room temperature, preferably at both ambient pressure as well as under elevated pressure.
Useful liquids are not particularly restricted, provided they do not interfere with the desirable medical use of the spray compositions, and they carry a therapeutically useful amount of dexmedetomidine or a pharmaceutically acceptable salt or derivative thereof e. Examples of pharmaceutically acceptable liquids include water, ethanol, dimethyl sulfoxide, propylene glycol, polyethylene glycol, propylene carbonate, pharmaceutically acceptable oils e.
The pharmaceutically acceptable liquid is selected either to dissolves the
Pharmaceutically acceptable salts fdating pharmaceutical ingredient, to produce a stable, homogenous suspension of it, or to form any combination of a suspension or solution. Examples of excipients include viscosity modulating materials e. Other examples of excipients include preservatives e.
Excipients may also be flavoring agents, sweeteners e. Still other examples of excipients include buffers and pH-adjusting agent e. Coloring agents from about 0. Such excipients may be included in the formulation to improve patient or subject acceptance or taste, to improve bioavailability, to increase shelf-life, to reduce manufacturing and packaging costs, to comply with requirements of governmental regulatory agencies, and for other purposes.
The relative amounts of each ingredient should not interfere with the desirable pharmacological and pharmacokinetic properties of the resulting formulation. Drug delivery occurs substantially via the oral transmucosal route and not via swallowing followed by gastrointestinal absorption. The term "transmucosal" refers to "Pharmaceutically acceptable salts fdating" across or through a mucosal membrane. In particular, "oral transmucosal" delivery of a drug includes delivery across any tissue of the mouth, pharynx, larynx, trachea, or upper gastrointestinal tract, particularly the sublingual, buccal, gingival and palatal mucosal tissues.
Sublingual absorption occurs through the highly vascularized sublingual mucosa, which allows a substance direct access to the blood circulation, thereby providing for direct
Pharmaceutically acceptable salts fdating administration independent of gastrointestinal influences and avoiding undesirable first-pass hepatic metabolism.
As compared to other routes of administration, transmucosal absorption of dexmedetomidine in the present formulations may have a significantly faster onset with greater bioavailability. Accordingly, the total amount of active pharmaceutical ingredient in the formulation may be reduced, thereby reducing the likelihood of deleterious side effects and providing a cost benefit to the manufacturer. One will appreciate that administering conventional dosage forms such as tablets, capsules, Docket No.
As used herein, "pain"
Pharmaceutically acceptable salts fdating a wide range of clinical manifestations, and it has a broad meaning. Pain perception is highly subjective, and different people experience pain in different ways and with greatly different intensities. The International Association for the Study of Pain defines pain as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in Pharmaceutically acceptable salts fdating of such damage.
Non-limiting types and causes of pain include neuralgia, myalgia, hyperalgesia, hyperpathia, neuritis, and neuropathy. Pain is often a symptom of an underlying physiological abnormality, such as cancer or arthritis. Some types of pain have no clearly identified causes, such as migraine headache pain. Pain may also be caused by physical trauma, such as burns or surgery. Viral infections, such as Herpes zoster chicken pox and shinglescan also cause pain.
The first issue before the...
Withdrawal from chemical dependence on alcohol or drugs of abuse is also often associated with pain symptoms. "Pharmaceutically acceptable salts fdating," "pain" is understood herein to have a very broad meaning and it's claimed uses should not be construed as being limited to any particular malady or condition. Such co-administration may be contemporaneous, wherein dexmedetomidine and another pain-treatment medicine are both administered at the same
Pharmaceutically acceptable salts fdating. Alternatively, because of the selectively moderate to rapid- acting nature of the sublingual compositions described herein, a patient may be administered a longer acting pain medicine on a regular schedule, with sublingual- spray dexmedetomidine being administered as needed throughout the day or from time to time as required.
In some cases, the dosage of the longer acting pain-treatment medicine may be reduced because of a beneficial synergistic effect produced by dexmedetomidine, which supplements the primary pharmacological therapy. In particular, dexmedetomidine may significantly potentiate the effectiveness of opioids, permitting a reduction in required opioid dosage while maintaining equivalent therapeutic usefulness.
For example, the sublingual-spray formulations may be packaged as a bulk liquid containing multiple doses in a pump spray system comprising a sealed container fitted with a metering pump. Typically, a human patient is treated by sublingual self-administration, such as by of one or more actuations from a spray pump.
An advantage of sublingual-spray delivery examples herein is the ability to titrate patients by single doses as required through single, discrete actuations. This advantage is typically absent from other forms of drug delivery e. Additional advantages of sublingual spray formulations include their ease of use, especially when self-administered absent an attending health care professional. This is in contrast to pressurized systems, e. In certain embodiments, pump sprays are preferred as the use of a pump spray with the formulations herein allows for the administration of droplets or particles having a small mean diameter and a controllable size distribution of droplets.
In other embodiments, pressurized systems containing a reservoir of pressurized propellant gas e. Liquid droplets or particles having a diameter that
Pharmaceutically acceptable salts fdating too small have the potential to enter into the lungs of a human upon administration.
In certain preferred embodiments, the droplet size of the delivered formulations further provides for an increase in surface area by being sprayed sublingually as opposed to being placed under the tongue, e.
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The size of the spray particles and shape of the spray pattern also may contribute to whether the active ingredient is absorbed into body systems other than the oral mucosa e. Premetered devices preferably contain previously measured doses or a dose fraction in some type of units e. Typical device-metered units have a reservoir containing formulation sufficient for multiple doses that are delivered as metered sprays by the device itself when activated by the patient. The device may be metered both in the amount of drug
Pharmaceutically acceptable salts fdating delivered i.
Limiting the time between each dosage can prevent
Pharmaceutically acceptable salts fdating by limiting how often a dosage can be delivered to the patient. Moreover, the device should be compatible with formulation components. Furthermore, the device should be designed to prevent partial metering, as well as over metering, of the dexmedetomidine formulation, including the dexmedetomidine, pharmaceutically acceptable salt thereof, or derivative thereof, when used according to patient instructions for use.
Preferably the reservoir is filled with the drug substance and other excipients e.
The occurrence of hydrates in...
The reservoir preferably defines a measured amount of dexmedetomidine, pharmaceutically acceptable salt thereof, or derivative thereof to be discharged upon activation. The reservoir body may be any acceptable
Pharmaceutically acceptable salts fdating, for example, formed simply by a section of a cylindrical hollow of a plastic, steel, such as stainless steel, transparent material, or the like so that its production is very simple. An actuator, Pharmaceutically acceptable salts fdating is movable relative to the orifice for activating discharge, may be provided on or with the device.
In the course of the actuating movement, the reservoir opens, e. During a part of the actuating travel following the starting position an elevated pressure is built up. In a subsequent portion of the actuating movement continuing in the same direction, the medium may be relieved of the pressure at one of the sides and communicated to an orifice. In such a manner, the medium is pushed from the reservoir and through the orifice by the action of pressure.
In certain embodiments, the orientation of the actuator, pump design, and the properties of the formulation will influence the spray symmetry and the shape. The spray pattern may also be optimized to disperse the droplets over a wider pathway thereby increasing the surface area through which the compound can be absorbed and reducing the swallowing reflex. The spray device may further be designed to facilitate ease of patient use and placement of the administered spray to specific regions of the oral mucosa.
For example, sublingual liquid provided as a liquid compatible with administration by a dropper or similar device are contemplated by the inventors. In another example, the sublingual formulation can be packaged in pharmaceutically acceptable unit dose ampules with snap-off "Pharmaceutically acceptable salts fdating" to permit the opened ampule to be tipped under a patient's tongue to dispense a single dose of the formulation. The relative amounts of each component are listed by weight.
The physical properties of the three formulations in Table 1 are described in Table 2, also below. In order to ensure proper pump priming, two actuations were performed prior to dosing. Following dose administration, serial blood samples were collected form each subject animal by venipuncture of a jugular vein as follows: All sublingual dosings showed no adverse events. Following sublingual dose administration, animals appeared normal at all times post-dose.
Blood samples were collected in vacutainer tubes containing K 2 EDTA as anticoagulant, and derived plasma samples were stored frozen until analyzed. The amounts of each component are listed by weight gand the resulting formulations were 0. By way of example, the following process was used to make Formulation Trial No. toxic pharmaceutically acceptable salts of rosuvastatin in which the . for a new drug candidate, (dating from after the priority date)) does. The first issue before the court was construction of the term “non-toxic pharmaceutically acceptable salt” as used in claim 1 of
Pharmaceutically acceptable salts fdating In one embodiment, at least one non-lactose pharmaceutically acceptable excipient an optically pure enantiomer thereof, or a pharmaceutically acceptable salt . Among the topics suggested, the...
expiration dating is defined as the time in which the pharmaceutical product.
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