Intranasal opioid compositions   

Abstract: The present invention relates to pharmaceutical compositions for intranasal administration to a mammal that contain an effective amount of an opioid, a liquid nasal carrier for the opioid, and optionally a sweetener, flavoring agent or masking agent. In some embodiments of the present invention, the pharmaceutical compositions have improved bioavailability. In other embodiments of the present invention, the opioid compositions improve patient compliance.

This application is a continuation of pending U.S. application Ser. No. 11/674,803, filed Feb. 14, 2007, which is a continuation of U.S. application Ser. No. 10/647,789, filed Aug. 23, 2003, which is a continuation-in-part of U.S. application Ser. No. 09/790,199 filed Feb. 20, 2001, which is a continuation-in-part of U.S. application Ser. No. 09/569,125 filed May 10, 2000, now abandoned. The entire disclosure of these applications is herein incorporated by reference.

BACKGROUND OF THE INVENTION

Pain is a major symptom of many diseases, (e.g., cancer, arthritis, neurological diseases, heart attacks, etc.). Inadequate treatment of pain can lead to depression, anger, fear of disease progression and in some extreme cases, suicide.

Unfortunately, a patient\'s non-compliance or failure to take medication as prescribed, has been linked to inadequate treatment of pain. This is not surprising, since many pain treatment regimens involve administering pain medications by injection route (e.g., intravenous (IV), intramuscular (IM) or subcutaneous injection). The intravenous route is normally regarded as one of the most in-convenient routes to administer pain medication to achieve rapid pain relief. Intravenous administration may cause non-compliance, because not only do patients fear getting the injection, but unpleasant experiences such as pain, irritation and infection resulting at the injection site may also lead to non-compliance.

The intranasal route is currently receiving special interest, especially in the area of pain management. When medication is administered via the intranasal route, the medication is applied to the nasal mucosa where it is absorbed. The extensive network of blood capillaries under the nasal mucosa is particularly suited to provide rapid and effective systemic absorption of drugs. The intranasal route of administration should achieve similar dose to plasma concentration (bioavailability) and efficacy to that of the intravenous route.

Intranasal administration of medication provides numerous advantages over the intravenous route. The principal advantages of intranasal route are non-invasive delivery, rapid drug absorption, and convenience. The intravenous route, unlike the intranasal route, requires sterilization of hypodermic syringes and, in the institutional setting, leads to concerns among medical personnel about the risk of contracting disease if they are accidentally stuck by a contaminated needle. Strict requirements for the safe disposal of needles and syringes have also been imposed.

In contrast, intranasal administration requires little time on the part of the patient and attending medical personnel, and is far less burdensome on the institution than injectable routes. There is no significant risk of infection of the patient or medical personnel in the institutional setting when dealing with the intranasal delivery of medication.

A second important advantage of intranasal administration over intravenous is patient acceptance of the intranasal delivery route. In some cases, the injections cause burning edema, swelling, turgidity, hardness and soreness. In contrast, intranasal administration is perceived as non-invasive, is not accompanied by pain, has no after-effects and produces prompt relief in the patient exhibiting pain symptoms. This is of particular advantage when the patient is a child. Many, if not most, patients experience anxiety and exhibit symptoms of stress when faced with hypodermic injections via the IM or IV routes. Further, most people have some familiarity with nasal sprays in the form of over-the-counter decongestants for alleviating the symptoms of colds and allergies that they or a family member have used routinely. Another important consideration is that the patient can self-administer the prescribed dosage(s) of nasal spray without the need for trained medical personnel.

Among the many medications available to treat pain, opioids (e.g., morphine, methadone, hydromorphone, butorphanol, etc.) play one of the most important roles. The major advantage of the opioids is that they have an extensive history of use and are much more effective in treating severe pain than other classes of medications e.g. aspirin, acetaminophen, ibuprofen, etc. Another major advantage is that opioids exhibit few adverse effects on organs such as the stomach, liver, or kidney, other than very minor problems such as nausea or constipation. This is a major benefit over other medications such as aspirin or anti-inflammatory drugs that may cause ulcers, kidney problems, high blood pressure, or liver inflammation. In addition to relieving pain, opioids have other beneficial effects, such as, for example, peripheral arterial vasodilation, when treating heart attacks, provides the benefit of reducing oxygen demand on the heart.

There are different intranasal opioid formulations known in the pharmaceutical arts. However, some intranasal opioid formulations have reduced bioavailability at conventional doses. These formulations require more pain medication to be administered to the patient or else the pain will be inadequately treated.

Given the problems associated with inadequate treatment of pain and patient noncompliance, there is a need for intranasal opioid compositions that have improved bioavailability. There is also a need for intranasal compositions that improve patient compliance.

SUMMARY

In various embodiments, the present invention provides intranasal opioid compositions that have improved bioavailability when compared to intranasal prior art opioid compositions. In other embodiments, the present invention provides intranasal opioid compositions that improve patient compliance.

In one embodiment, the present invention provides a pharmaceutical composition for intranasal administration to a mammal; comprising: an effective amount of an opioid; a liquid nasal carrier for the opioid; and one or more sweeteners, flavoring agents, or masking agents or combinations thereof.

In another embodiment, the present invention provides a pharmaceutical composition having improved bioavailability for intranasal administration to a mammal; comprising: an effective amount of butorphanol; a preservative-free liquid nasal carrier.

In still another embodiment, the present invention provides a pharmaceutical composition having improved bioavailability for intranasal administration to a mammal; comprising: an effective amount of hydromorphone; a liquid nasal carrier having the essential absence of a preservative and the composition containing at least one sweetener, flavoring agent or masking agent.

In one preferred embodiment, the present invention provides a pharmaceutical composition for intranasal administration to a mammal; comprising: an effective amount of hydromorphone; a preservative-free liquid nasal carrier comprising sodium chloride, citric acid, water and at least one sweetener, flavoring agent or masking agent.

In still another preferred embodiment, the present invention provides a method of treating a mammal suffering from pain comprising intranasally administering to the mammal an effective amount of butorphanol or hydromorphone; a preservative-free liquid nasal carrier comprising sodium chloride, citric acid, water and at least one sweetener, flavoring agent or masking agent.

For a better understanding of the present invention together with other and further advantages and embodiments, reference is made to the following description taken in conjunction with the examples, the scope of which is set forth in the appended claims.

Preferred embodiments of the invention have been chosen for purposes of illustration and description, but are not intended in any way to restrict the scope of the invention. The preferred embodiments of certain aspects of the invention are shown in the accompanying figures, wherein:

FIG. 1 is a graphic representation of the concentration of butorphanol in blood plasma versus time after administration of the test formulation from a unit-dose spray device (Invention)) and the administration of the test formulation in a multi-dose spray device (Prior Art).

FIG. 2 is a graphic representation of the data of FIG. 1 over a longer time period.

FIG. 3 is a graphic representation of the concentration of hydromorphone in blood plasma versus time for IV, IM and intranasal (IN) doses (mean (n=9) Hydromorphone concentration versus time graphs following IV, IM, and IN doses of 2 mg Hydromorphone HCI (6 hrs after dose).

FIG. 4 is a graphic representation of the data of FIG. 3 over a longer period of time (mean (n=9) Hydromorphone concentration versus time graphs following IV, IM, and IN doses of 2 mg Hydromorphone HCI (16 hrs after dose).

FIG. 5 is a graphic representation of the concentration of hydromorphone in blood plasma versus time for a group of subjects (graph of Hydromorphone concentrations versus time following IN doses of 2 mg Hydromorphone HCI to 9 subjects).

DETAILED DESCRIPTION

The invention will now be described in connection with preferred embodiments. These embodiments are presented to aid in an understanding of the present invention and are not intended to, and should not be construed to, limit the invention in any way. All alternatives, modifications and equivalents that may become obvious to those of ordinary skill on reading the disclosure are included within the spirit and scope of the present invention.

In accordance with one embodiment of the present invention, it has now been surprisingly found that intranasal pharmaceutical compositions can be made having improved bioavailability in terms of plasma opioid levels. These intranasal compositions contain an opioid; and a liquid nasal carrier for the opioid. For example, it has been unexpectedly discovered, among other things, that at least about 10 to about 20% higher plasma levels of butorphanol can be achieved by administering an intranasal formulation from a unit-dose spray device. Improved bioavailability includes increases in plasma or serum opioid concentration when compared to prior art opioid formulations. Preferred increases include, but are not limited to, increases of more than 5% to 40% in bioavailability of the opioid.

Opioids as herein include any substance naturally or synthetically derived from opium. Suitable opioids for use in the present invention include, but are not limited to, morphine, apomorphine, hydromorphone, oxymorphone, dihydromorphine, levorphanol, levallorphan, levophenacylmorphan, norlevorphanol, nalorphine, nalbuphine, buprenorphine, butorphanol, naloxone, naltrexone, nalmexone, oxilorphan, cyclorphan, ketobemidone, fentanyl, sufentanil, alfentanyl, or combinations thereof. The most preferred opioids for use in the present invention include butorphanol and/or hydromorphone.

The opioid may be in free form or in pharmaceutically acceptable salt or complex form. Some examples of pharmaceutically acceptable salts of opioids include those salt-forming acids and bases that do not substantially increase the toxicity of the compound. Some examples of suitable salts include salts of alkali metals such as magnesium, potassium and ammonium. Salts of mineral acids such as hydrochloric, hydriodic, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids, as well as salts of organic acids such as tartaric, acetic, citric, malic, benzoic, glycollic, gluconic, gulonic, succinic, arylsulfonic, e.g. p-toluenesulfonic acids, and the like.

Intranasal opioid compositions of the present invention include a liquid nasal carrier. As used herein, “liquid nasal carrier” includes a solution, emulsion, or suspension designed for delivery of the opioid to the nasal mucosa. The liquid nasal carrier includes a diluent suitable for application to the nasal mucosa. Suitable diluents include aqueous or non-aqueous diluents or combination thereof. Examples of aqueous diluents include, but are not limited to, saline, water, dextrose or combinations thereof. Non-aqueous diluents include, but are not limited to, alcohols, particularly polyhydroxy alcohols such as propylene glycol, polyethylene glycol, glycerol, and vegetable and mineral oils. These aqueous and/or non-aqueous diluents can be added in various concentrations and combinations to form solutions, suspensions, oil-in-water emulsions or water-in-oil emulsions. In the preferred butorphanol or hydromorphone compositions, the diluent is saline or water.

The nasal carrier of the present invention may also contain excipients such as antioxidants, chemical preservatives, buffering agents, surfactants and/or agents that increase viscosity. Antioxidants are substances that prevent oxidation of the formulations. Suitable antioxidants for use in the present invention include, but are not limited to, butylated hydroxytoluene, butylated hydroxyanisole, potassium metabisulfite, and the like.

In some embodiments of the present invention, the composition contains a preservative that is chosen in quantities that preserve the composition, but do not cause irritation of the nasal mucosa. Suitable preservatives for use in some embodiments of the present invention include, but are not limited to, benzalkonium chloride, methyl, ethyl, propyl or butylparaben, benzyl alcohol, phenylethyl alcohol, benzethonium, or combination thereof. Typically, the preservative is added to the compositions of the present invention in quantities of from about 0.01% to about 0.5% by weight.

In some embodiments of the present invention, the formulation is preservative-free. As used herein, preservative-free includes compositions that do not contain any preservative. Thus, the composition does not contain, for example, benzalkonium chloride, methyl, ethyl, propyl or butylparaben, benzyl alcohol, phenylethyl alcohol, or benzethonium.

If a buffering agent is employed in the composition, it is chosen in quantities that preferably do not irritate the nasal mucosa. Buffering agents include agents that reduce pH changes. Preferred buffering agents for use in the present invention include, but are not limited to, salts of citrate, acetate, or phosphate. The most preferred buffers include sodium citrate, sodium acetate, sodium phosphate, and/or combinations thereof. Typically, the buffer is added to the compositions of the present invention in quantities of from about 0.01% to about 3% by weight.

When one or more surfactants is employed, the amount present in the compositions of the invention will vary depending on the particular surfactant chosen, the particular mode of administration (e.g. drop or spray) and the effect desired. In general, however, the amount present will be of the order of from about 0.1 mg/ml to about 10 mg/ml, preferably about 0.5 mg/ml to 5 mg/ml and most preferably about 1 mg/ml.

The pharmaceutical compositions of the present invention may include one or more agents that increase viscosity chosen in quantities that preferably do not irritate the nasal mucosa and increase nasal retention time. Preferred agents that increase viscosity include, but are not limited to, methylcellulose, carboxymethylcellulose sodium, ethylcellulose, carrageenan, carbopol, and/or combinations thereof. The most preferred agents used to increase viscosity and increase nasal retention time is methylcellulose or carbopol. Typically, the agent that increases viscosity is added to the compositions of the present invention in quantities of from about 0.1% to about 10% by weight.

In some embodiments of the present invention, one or more sweetener or flavoring agents are employed. The sweetener or flavoring agent includes any agent that sweetens or provides flavor to the pharmaceutical composition: The sweetener or flavoring agent will mask any bitter or bad taste that may occur if the pharmaceutical composition drips back into the mouth after intranasal administration. By addition of a sweetener or flavoring agent to the intranasal composition, any barrier that a patient may have to taking the intranasal composition because of unpleasant taste is reduced. By adding a sweetener, flavoring agent or masking agent to the intranasal pharmaceutical composition of the present invention, patient compliance is enhanced or improved.

Preferred sweeteners or flavoring agents or masking agents to use in some embodiments of the present invention include, but are not limited to, acacia syrup, anethole, anise oil, aromatic elixir, benzaldehyde, benzaldehyde elixir, cyclodextrins, compound, caraway, caraway oil, cardamom oil, cardamom seed, cardamom spirit, compound, cardamom tincture, compound, cherry juice, cherry syrup, cinnamon, cinnamon oil, cinnamon water, citric acid, citric acid syrup, clove oil, cocoa, cocoa syrup, coriander oil, dextrose, eriodictyon, eriodictyon fluidextract, eriodictyon syrup, aromatic, ethylacetate, ethyl vanillin, fennel oil, ginger, ginger fluidextract, ginger oleoresin, dextrose, glucose, sugar, maltodextrin, glycerin, glycyrrhiza, glycyrrhiza elixir, glycyrrhiza extract, glycyrrhiza extract pure, glycyrrhiza fluidextract, glycyrrhiza syrup, honey, iso-alcoholic elixir, lavender oil, lemon oil, lemon tincture, mannitol, methyl salicylate, nutmeg oil, orange bitter, elixir, orange bitter, oil, orange flower oil, orange flower water, orange oil, orange peel, bitter, orange peel sweet, tincture, orange spirit, compound, orange syrup, peppermint, peppermint oil, peppermint spirit, peppermint water, phenylethyl alcohol, raspberry juice, raspberry syrup, rosemary oil, rose oil, rose water, rose water, stronger, saccharin, saccharin calcium, saccharin sodium, sarsaparilla syrup, sarsaparilla compound, sorbitol solution, spearmint, spearmint oil, sucrose, sucralose, syrup, thyme oil, tolu balsam, tolu balsam syrup, vanilla, vanilla tincture, vanillin, wild cherry syrup, or combinations thereof.

Most preferred sweeteners to use in some embodiments of the present invention include, but are not limited to, saccharin, sodium saccharin, xylitol, mannitol, sorbitol, sucralose, maltodextrin, sucrose, aspartame, acesulfame potassium, dextrose, glycosides, maltose, sweet orange oil, dextrose, glucose, honey or combinations thereof. Most preferred flavoring agents to use in some embodiments of the present invention include, but are not limited to, glycerin, wintergreen oil, peppermint oil, peppermint water, peppermint spirit, menthol, syrup, or combinations thereof. Most preferred masking agents do not make contact with the taste buds. The preferred masking agent for use in the present invention includes, but is not limited to, cyclodextrins, cyclodextrins emulsions, cyclodextrins particles, cyclodextrins complexes, or combinations thereof.

The pharmaceutical compositions of different embodiments of the present invention may of course also include additional ingredients, such as pharmaceutically acceptable surfactants, co-solvents, adhesives, agents to adjust the pH and osmolarity.

The pharmaceutical compositions of the present invention are not limited to any particular pH. However, generally for nasal administration a mildly acid pH will be preferred. The pH ranges from about 3 to 6 are preferred, more preferred pH ranges are from about 3 to about 5, and most preferred pH ranges are from about 4 to about 5. If the adjustment of the pH is needed, it can be achieved by the addition of an appropriate acid, such as hydrochloric acid, or base, such as for example, sodium hydroxide. In the preferred embodiments of the present invention, butorphanol or hydromorphone formulations, have a pH of about 5.0 and a pH of about 4, respectively.

The pharmaceutical composition in some embodiments of the present invention can be made, for example, by mixing the opioid with a liquid nasal carrier and/or a sweetener, flavoring agent, or masking agent or combinations thereof at room temperature under aseptic conditions to form a mixture. In other embodiments of the present invention, the mixture is filtered. It will be understood by those of ordinary skill in the art that the order of mixing is not critical, and the present invention includes without limitation mixing of the formulation in any order.

Pharmaceutical compositions of the present invention can be administered intranasally by nasal spray, drop, solution, suspension, gel, and the like. In one preferred embodiment, the pharmaceutical composition of the present invention is a sterile solution or suspension.

When the pharmaceutical composition is a liquid, preferred volumes of the liquid are absorbed through the nasal mucosa. The preferred volume of the liquid includes volumes of from about 0.025 ml to about 2 ml, more preferably, from about 0.25 ml to 1 ml, and most preferably from about 0.05 ml to about 15 ml in an adult and smaller for children. However, the pharmaceutical compositions of the present invention are not limited to one particular volume.

Preferred devices for intranasal delivery of pharmaceutical compositions of the present invention are available from, for example, Pfeiffer of America of Princeton, N.J. and Valois of America, Inc. of Greenwich, Conn. These devices are preferred because they have the capability of consistently delivering the pharmaceutical composition. These devices are easily operable by the patient, leave virtually no opioid remaining in the device after use and can thereafter be discarded without concern that others may abuse the opioid or other controlled substance.

The device can be filled with single or multidose amounts of opioids. Preferably, the device is filled with one single dose of opioid. In a preferred embodiment, the container holding the pharmaceutical composition and its sealing means are sterilizable, most preferably, at least parts of the device that are in contact with the pharmaceutical composition is constructed and assembled in a configuration that can be sterilized. Devices with one or more unit-dose(s) can be sterilized either before or after packaging, employing methods and technology that are well known in the art. Individual devices can be packaged, sterilized and shipped; alternatively, entire shipping and storage packages can be sterilized at once, and the devices removed individually for dispensing, without affecting the sterility of the remaining units.

The amount of opioid that can be intranasally administered in accordance with the composition and methods of the present invention will depend on the particular opioid chosen, the condition to be treated, the desired frequency of administration and the effect desired. As used herein, an effective amount of opioid includes that amount effective to achieve the relief or palliation of symptoms, condition and/or diseases associated with pain. Some diseases and/or conditions that cause pain include, but are not limited to, cancer, arthritis, neurological diseases, heart attacks, trauma, childbirth, migraines, or surgery.

Maximal dosage of the pharmaceutical composition of the present invention for a mammal is the highest dosage that elicits analgesia or anesthesia, which does not cause undesirable or intolerable side effects such as respiratory depression. The minimal dose of the opioid is the lowest dose that achieves the desired result. In any event, the practitioner is guided by skill and knowledge in the field, and the present invention includes without limitation dosages that are effective to achieve the pain relieving effect in the mammal. Preferred doses of opioids for intranasal administration include, but are not limited to, hydromorphone HCL from about 0.1 mg to about 30 mg; butorphanol tartrate from about 0.1 to about 10.0 mg; fentanyl citrate from about 5 mcg to about 500 mcg; methadone HCl from about 0.5 to about 50 mg; oxymorphone HCL from about 0.1 mg to about 30 mg; and morphine HCL from about 1 mg to about 40 mg.

The intranasal opioids of the present invention can be used, for example, to elicit analgesia or an analgesic response to relieve or alleviate pain. The opioids of the present invention may also be used to produce anesthesia or an anesthetic response where the mammal experiences loss of feeling or sensation, especially loss in pain sensation, to permit the performance of surgery or other painful procedures. The opioid is administered to a mammal suffering from a condition and/or disease that require opioid treatment. Mammals include, for example, humans, as well as pet animals such as dogs and cats, laboratory animals, such as rats and mice, and farm animals, such as horses and cows.

The examples below demonstrate improved bioavailability of illustrative compositions of the present invention when delivered from a unit-dose spray device compared to the same compositions when delivered from a multi-dose spray device. The examples also show pharmaceutical compositions that include sweeteners, flavoring agents, or masking agents or combinations thereof, which can improve patient compliance.

This example compares bioavailability of a butorphanol formulation when administered using a unit-dose or multi-dose delivery device. The formulation contains 10 mg butorphanol tartrate, 6.5 mg sodium chloride, 1.0 mg citric acid, 0.20 mg benzethonium chloride in purified water with 1.2 mg sodium hydroxide and hydrochloric acid added to adjust the pH to 5.0. The multi-dose sprayer purports by its label to administer 0.1 ml of liquid composition by metering upon activation by the user. The formulation had the following function and properties when administered to human subjects via the Pfeiffer Unitdose Second Generation spray device. Administration of a 2 mg dose of butorphanol tartrate produced a Tmax (hr) of about 0.234 (range about 0.083 to about 0.333); a Cmax (pg/ml) of about 5230 (range of about 2393 to about 8478); an AUC(0-t) of about 10661 pg*hr/ml (range of about 5351 to about 17722). Administration using the multi-dose spray pump produced a Tmax of 0.245 hr, a Cmax of 4072 pg/ml and an AUC(0-t) of 9329 pg*hr/ml.

The second delivery system employed to administer the butorphanol compositions was a unit-dose disposable intranasal applicator that is commercially available from Pfeiffer of America under the designation “Unitdose Second Generation.” Each of the Pfeiffer spray applicators was charged with sufficient liquid to deliver a 0.1 mL dose of the butorphanol test formulation. The glass containers were filled using a pipette under clean conditions, sealed and assembled to the applicator. Each of the applicators was weighed prior to use and after use. Qualified medical personnel administered, one dose into each nostril, after which the applicator was recovered for weighing. In the case of the unit-dose applicators (test formulation), two devices were used for each patient, both of which were discarded following the post-use weighing. The results of these studies of the method and system of the invention and the comparative prior art method follow.

TABLE I Sample Characteristics of Dose Weight Delivery. Delivery mean wt. std. std. System N gms dev. error minimum maximum Unit-Dose 23 0.206 0.00660 0.00138 0.193 0.223 Multi-Dose 24 0.180 0.0285 0.00582 0.114 0.220

The statistical comparison of dose 1 and dose 2 for the test formulation unit dose delivery system was done using a paired t-test. Analysis of the data indicated that the difference between the mean, sprays of the two applications using the Pfeiffer device was not statistically significant (t=1.0; p=0.3). The sample of 23 sprayers (actually 23 sets of 2 sprayers, since they were single-dose) had a mean total dose for two sprays of 0.206 grams with a standard deviation of 0.00660 grams.

The total dose dispensed by two sprays was recorded. The sample of 24 multi-dose sprayers had a mean total dose for two sprays of 0.180 grams with a standard deviation of 0.0285 grams.

The two-sample t-test for the comparison of the unit-dose and multi-dose sprayers indicated a statistically significant difference between the mean total doses taking into account the size of the sample. The unit-dose mean total dose was significantly closer to the prescribed target and dose than the multi-dose mean total dose (t=4.3; p<0.001). A 95% confidence interval for the difference in means is (0.0140, 0.0380).

The F test for the comparison of variances revealed that the variability in the total doses dispensed by the multi-dose sprayer was significantly higher than the variability in weights dispensed by the unit-dose sprayer (F=18.7; p<0.001). The variability in the multi-dose sprayer is 18.6 times that of the unit-dose sprayer. High variability in dose delivery leads to higher rates of adverse drug effects at excessive dose and inadequate treatment if the dose is low. Both consequences harm the patient hence the goal is to precisely deliver the prescribed dose.

A t-test was used in each case to compare the observed sample mean to the desired weight of 0.2 grams. The unit-dose sprayer dispensed a mean total weight that was significantly higher than the goal of 0.2 grams (t=4.4; p<0.001). A 95% confidence interval for the mean total weight dispensed by the unit-dose sprayer is (0.203, 0.209). The multi-dose sprayer dispensed a mean total weight that was significantly lower than the goal of 0.2 grams (t=3.4; p<0.003). A 95% confidence interval for the mean total weight dispensed by the multi-dose sprayer is (0.168, 0.192). Based on the above, the unit-dose delivery system of the test formulation exhibits a much higher degree of accuracy in intranasally administering the volume of liquid composition corresponding to 0.1 gm: +3% vs-10%.

This example assesses the bioequivalence of a butorphanol formulation administered from the unit-dose or multi-dose sprayers described above. The test formulation comprises 1 ml of STADOL[[®NS]] NS containing 10 mg butorphanol tartrate, 6.5 mg sodium chloride, 1.0 mg citric acid, 0.20 mg benzethonium chloride in purified water with 1.2 mg sodium hydroxide and hydrochloric acid added to adjust the pH to 5.0. The multi-dose sprayer accompanying STADOL[[®NS]] NS purports, by its label, to administer 0.1 ml of liquid. The unit-dose delivery device delivers 0.1 ml of liquid.

The second analysis was to determine whether the intrasubject variabilities of the two spray devices are equal. The study was initiated with 16 subjects, 15 of which completed the study to provide data for this analysis; one subject dropped out after the second period. The following analysis considers both raw and normalized data, with the latter standardized with respect to the dose dispensed.

For both the raw and normalized data, log transformations are applied to the pharmacokinetic endpoints Cmax, AUC (00891 ast), and AUC(inf.). A mixed effects model was considered for each parameter. Fixed effects for the factors sequence (4 levels), period 3 levels) and formulation (2 levels) were included in the model. Additionally, gender, as well as the interactions between gender and each of sequence, period and formulation was included as a factor in each model to determine whether separate analyses would be necessary for males and females. A total of seven models were considered: Tmax, log of raw Cmax values, log of normalized Cmax values, log transformed values for raw and normalized AUC(last), and log values for raw and normalized AUC(inf.). In all cases, the interaction between gender and formulation was not significant, indicating that separate models for males and females were not warranted. In addition, the lack of significance of the effects included in each model indicate that there was no evidence of unequal carryover between the delivery system of the prior art and that in one embodiment of the present invention.

The mean levels of butorphanol from analysis of the subject\'s blood plasma reported in pg/ml are plotted against time in FIGS. 1 and 2. The concentration of drug for the unit-dose was unexpectedly higher than that of the multi-dose system. The testing for bioequivalence was done using the method of two one-sided t-test (as described by Bolton, S., Pharmaceutical Statistics. Marcel Dekker, Inc., New York, 1997, pages 415 ff.). For each parameter, the 90% confidence interval for the ratio of the test unit-dose to reference multi-dose devices appear in Table 2 below.

TABLE 2 Summary of the two one-sided hypothesis tests for PK parameters Lower Conf Limit for Upper Conf Limit for Parameter Ratio of Test/Reference Ratio of Test/Reference Tmax 0.749 1.132 log (Cmax)* 1.031 1.855 log (AUClast)* 1.037 1.540 log (AUCinf)* 1.050 1.461 log (normCmax)* 0.897 1.589 log (AUClast)* 0.921 1.290 log (normAUCinf)* 0.937 1.220 *Note: The actual confidence limits obtained for these parameters have been exponentiated since the data were log-transformed originally.