WO2009047779A2

WO2009047779A2 - Composition containing fentanyl base aromatic oils and alkyl salicylate for the delivery of fentanyl base in vapour form

Info

Publication number: WO2009047779A2
Application number: PCT/IN2008/000322
Authority: WO
Inventors: Nikki Nikhilesh Singh; Natasha Nikhilesh Singh; Umesh Shantisingh Tomar
Original assignee: Nikki Nikhilesh Singh; Natasha Nikhilesh Singh; Umesh Shantisingh Tomar
Priority date: 2007-06-20
Filing date: 2008-05-22
Publication date: 2009-04-16
Also published as: WO2009047779A3

Abstract

A method of treatment of pain in general and breakthrough cancer pain in particular by administering to a human or animal in need of the treatment a therapeutically-effective amount of fentanyl base in vapor form released from a composition comprising from about 0.005% to about 99% by weight fentanyl base and from about 1% to about 99% by weight C1-C5. alkyl salicylate.

Description

Composition containing fentanyl base aromatic oils and alkyl salicylate for the delivery of fentanyl base in vapor form

BACKGROUND OF THE INVENTION

The present invention comprises a composition containing fentanyl base and an alkyl salicylate. The invention also relates to a method of delivering fentanyl base in vapor form from the composition of the invention. The invention further comprises articles of manufacture comprising the composition of the invention. The invention also further relates to the treatment of certain nasal and upper respiratory disorders by delivery of a therapeutically-effective amount of fentanyl base in a vapor form from the composition and articles of manufacture of the invention.

In cancer patients, pain management begins with the use of appropriate therapeutic tools including comprehensive treatment approaches to address both the persistent and breakthrough pain. Breakthrough pain occurs in as much as 86% of the patients with cancer even when persistent pain is well-controlled.

Persistent pain is present to some degree throughout the day and primarily is controlled with round-the-clock medication. However it is accompanied be episodes of short, intermittent pain known as breakthrough cancer pain (Rhoiner et al Clinical Journal of Oncology Nursing 8(5), 507-512 (2004). From clinical perspective, breakthrough cancer pain can be characterized as a transitory exacerbation of pain that occurs on a background of otherwise stable pain in a patient receiving chronic opioid therapy. Breakthrough pain typically is moderate to severe in intensity and can be triggered by various activities (incidental pain), be entirely unpredicted (idiopathic pain) or occur toward the end of around-the-clock medication (such as end-of-dose failure) .

Fentanyl is a pure opioid agonist acts primarily through interaction with opioid μ receptors located in the brain, spinal cord and smooth muscle. The primary site of therapeutic action is the central nervous system. The most clinically useful pharmacologic effects of fentanyl's interaction with μ-receptors are analgesia and sedation and has an analgesic potency that is 80 times that of morphine. The analgesic effects of fentanyl are related to the blood level of the drug if proper allowance is made for delay in to and out-of-the CNS. Or put it simply - rapid absorption of fentanyl is critical for rapid relief from breakthrough cancer pain. To some degree manufacturers of Actiq® and Fentora® have overcome the issue of delay associated with gastrointestinal absorption of fentanyl by transmucosal delivery of the drug. Even though transmucosal delivery of fentanyl represents a significant improvement over either peroral or transdermal delivery systems, the formulations are not optimized to delivery the drug in its entirety in to the blood. Under normal conditions, approximately only 25% of the total fentanyl that is delivered transmucosally is rapidly absorbed through the buccal mucosa and is systemically available for rapid relief of breakthrough cancer pain.

In the treatment of breakthrough cancer pain, fentanyl has been used either in the form of a transdermal patch or a buccal transmucosal formulations respectively, lollipop/ trouche and lozenge. The transdermal patch contains up 10 mg of free-base equivalent of fentanyl, the lollipop/touche uses up to 1600 μg free-base equivalents of the drug and the lozenge contains up to 800 μg of free-base equivalent of fentanyl.

Fentanyl base has not been delivered in a vapor form at ambient conditions. Transdermal fentanyl delivery systems depend on intrinsic properties of free base form of fentanyl which tends to be inherently lipophilic and is absorbed readily through the skin and other mucosa. The transdermal adsorption of free-base form of a drug is several times faster than the corresponding corresponding salt forms (Bhalla et al., Drug Development and Industrial Pharmacy, 14 (1), 119-131 (1988). However transdermal formulations in general and the fentanyl transdermal patch particular suffer from low perfusion rates of the drug and hence are not the preferred form of delivery systems when rapid onset of action is desired.

Inhalation formulations generally tend to circumvent issues of slow rate of absorption and/ or significant pre-systemic loss of drug due to metabolism as the drug is often delivered in an absorption-facile form as tend to deliver the drug either in a nebulae of fine particles as described in US patent 6,682,716 which teaches delivery of drugs including fentanyl where in the drug is reduced to a nebula of fine particles after condensation of the vaporized drug. The drugs can also be delivered directly after vaporization at supra-ambient or higher temperatures after vaporization off heated plates such as those described in United

States Patent 7,090,890, 7,078,018 and 6,776,978, respectively or those in pending applications in United States such as 2003- 302,09240, 2004-40009128, -0096402, -0099269, -0102434, - 0202617, -0234699, -0234914, -0234916, 2005-0034723, - 0037506, -0075272, -0075273, -0079166, -0126562, -0268911, and 2006-0032496.

There are minor problems associated with the use of fentanyl base in a product composition, including its instability in light (which can be overcome by appropriate packaging of the composition, for example, in a brown-glass bottle or sealed container), its tendency to form a more stable salt form in an aqueous solution without proper buffering. Because of its narrow therapeutic index and high potency fentanyl has never been suggested or used in a composition or in a treatment where vapor phase delivery of the active is forced under positive pressure, such as metered-dose inhaler or aerosols. Rather, its use has been limited to direct application of the composition containing the fentanyl for systemic effects such as intramuscular, subcutaneous and intravenous injections, transdermal patches and sublingual tissue. Such forms either require active medical supervision when delivered via injections or tend to be less effective and efficient when delivered through the skin or transmucosal tissue. It would therefore be advantageous to deliver fentanyl base in the vapor phase in order to maximize absorption by the mucosa of the nasal and or the buccal and the upper respiratory cavity, to maximize the relative amount of surface area directly exposed to the active, and to reduce the loss of active via loss due to poor absorption.

SUMMARY OF THE INVENTION

A method has now been discovered for delivering fentanyl base in vapor form from a composition comprising fentanyl base and a

C₁ -C.5 alkyl salicylate. This composition can be formulated into a variety of articles of manufacture which can be used, without limitations, in various methods of treatment of nociceptive disorders in general and breakthrough cancer pain in particular. of the nasal mucosa and the upper respiratory tract, as well as other disorders or physiological conditions where topical or systematic delivery of fentanyl base can have a therapeutic effect.

The present invention comprises a composition comprising from about 0.005% to about 99%, preferably from about 0.05% to about 25%, most preferably from about 0.01% to about 10% by weight fentanyl base, and from about 1% to about 99%, preferably from about 5% to 75%, most preferably from about 10% to about 25% by weight C_-1 -Cs alkyl salicylate. A preferred composition comprises the fentanyl base and the alkyl salicylate in a weight ratio from about 5: 1 to about 1:20, more preferably from about 1: 1 to about 1:5, most preferably from about 1: 1 to 1:2.5. A preferred composition further comprises from about 2% to about 93%, more preferably from about 25% to about 90%, most preferably from about 65% to about 85% by weight aromatic compounds. Preferred aromatic compounds include camphor, menthol, and mixtures thereof. The types and concentrations of aromatic compounds can influence the rate of fentanyl vapor release from the composition, as well as the organoleptic properties of the composition.

Articles of manufacture can also be prepared wherein the fentanyl base and the alkyl salicylate are admixed with other optional materials, either together or separately. In the case where the fentanyl base and alkyl salicylate are separately mixed with optional ingredients, the normal use of the article will result in the two materials combining together to affect the vaporization of the fentanyl. Such an article can be, for example, a throat drop or a chewy candy gum, as described hereinafter, which is placed into and dissolved in the mouth of the user.

In another preferred embodiment, the active agent fentanyl can be either be replaced or combined with opiate analogues such as sufentanyl or sufentanil, alfentanyl or alfentanil, remifentanyl or remifentanil, carfentanyl or carfentanil, morphine, oxycodone, oxymorphone, buprenorphine, methadone and its analogues thereof. DETAILED DESCRIPTION OF THE INVENTION

Compositions

Compositions of the present invention can be prepared by simply- admixing the fentanyl base or fentanyl salt with the alkyl salicylate, and with the other optional materials including the aromatic compounds.

Fentanyl

Fentanyl is a well known is an opioid analgesic, first synthesized by Janssen Pharmaceutica (Belgium) in the late 1950s, with an analgesic potency of about 80 times that of morphine. Fentanyl was introduced into medical practice in the 1960s as an intravenous anesthetic under the trade name of Sublimaze®. The synthesis of fentanyl (N-phenyl-N-(l-phenethyl-4- piperidinyl)propanamide) by Janssen Pharmaceutica was achieved in four steps, starting from 4-piperidinone hydrochloride. The 4-piperidinone hydrochloride was first reacted with phenethyl bromide to give N-phenethyl-4- piperidinone (NPP). Treatment of the NPP intermediate with aniline followed by reduction with sodium borohydride afforded 4-anilino-N-phenethyl-piperidine (ANPP) . A final reaction between ANPP and propionic anhydride led to the fentanyl with a 47% overall yield.

In its substantially pure form, fentanyl base is a liquid (also identified by the chemical name, alpha. - [ 1 (methylamino) ethyl] benzenemethanol) is a solid, crystalline material having a melt point of about 34. degree. C. The material is highly hygroscopic, capable of forming a hydrate of up to about 5.2% water. Formation of the hydrate raises the melting point to between about 34. degree. C. -4020 C. Fentanyl base is soluble in alcohol, chloroform, ether, and oils, and is moderately and slowly soluble in water and liquid petrolatum. Solutions of fentanyl in liquid petrolatum will become turbid, however, if the fentanyl contains more than about 1% by weight of water as a hydrate. Fentanyl base has no significant vapor pressure at ambient conditions, either in its solid form or over a solution containing the fentanyl (in the absence of the alkyl salicylate).

Alkyl Salicylate

The C i -C.5 alkyl salicylate of the present invention preferably comprises methyl salicylate, ethyl salicylate, amyl salicylate, and mixtures thereof. Methyl salicylate, ethyl salicylate, amyl salicylate, and mixtures thereof each affect the vaporization of the fentanyl base when combined therewith. Methyl salicylate results in a greater and more rapid vaporization of fentanyl base relative to the other alkyl salicylates. Methyl salicylate is the preferred alkyl salicylate.

Methyl salicylate is usually prepared by the esterification of salicylic acid with methanol. Commercial grade methyl salicylate is about 99% pure, and can be obtained from Aldrich Chemical Company, Inc., Milwaukee, Wis., U.S.A. Methyl salicylate is also obtainable from natural sources such as wintergreen oil (96-99% methyl salicylate).

Ethyl salicylate can be prepared by esterification of salicylic acid with ethyl alcohol and concentrated sulfuric acid in the presence of aluminum sulfate, as described by Kotake and Fujita, Chem. Zentralbl. 2, 454 (1928), and can be obtained in relatively pure form (99%) from Aldrich Chemical Company Inc.

Amyl salicylate can be prepared by the esterification of salicylic acid with isomeric amyl alcohol.

Minor amounts of impurities found in the natural or synthetic alkyl salicylate can effect the rate of fentanyl release and the odor profile of the compositions of the invention. If removal of these minor amounts of impurities is desired, the natural or synthetic alkyl salicylate can be rectified to reduce the level of the impurities.

Aromatic Compounds

The composition can further comprise aromatic compounds. The aromatic compounds of the present invention can be naturally occurring or synthetic, and can be used in their natural form or can be rectified to a purer form. Preferred aromatic compounds of the present invention include menthol, camphor, and mixtures thereof. Menthol and camphor are well-known articles of commerce. Other aromatic compounds include, but are not limited to, lavender oil, eucalyptus oil, pine needle oil, nutmeg oil, cedar leaf oil, cedarwood oil, turpentine, isobornyl acetate, sassafras oil, thymol and various terpenes. An exhaustive list of other aromatic compounds can be found inThe Essential Oils. Gunther E., ed., R.E. Krieger Publishing Co., Vol. I-VI, 1976.

The type, relative amount, source, and purity of the aromatic material selected can affect the rate of fentanyl release and the odor and skin feel of the composition. For example, it has been found that thymol and terpenes are two materials which can reduce the rate of fentanyl release. One can choose to formulate without these materials, or to selectively incorporate them into the composition in order to regulate the amount or rate of fentanyl base released by the composition.

Aromatics from natural sources can contain low levels of terpenes and thymol. Menthol, which can be synthesized from thymol, can have trace amounts of unreacted thymol. If removal of terpenes and thymol is desired, the natural or synthetic aromatic compounds can be rectified to reduce their level, as well as the level of other inert organics.

The aromatic compounds are useful in formulating ointments, lotions, creams, gels, jellies, inhalants, nasal sprays, nasal drops, throat drops, oral medications and mouth washes.

Other Optional Ingredients

Other optional ingredients include sugars, corn syrups, plasticizers, elastomers, colorants, sweetening agents and flavorants, glycols, sorbitol, and opacifiers. These materials are useful in oral preparations such as solid, semi-solid and/ or gum candy bases.

Other optional ingredients include aqueous solvents such as water, saline solutions and buffers; non-aqueous solutions such as mineral oils, silicone oils, essential oils, alcohols such as ethyl alcohol, isopropyl alcohol and mixtures thereof, used in preparation of ointments, lotions, creams, gels, jellies, inhalants, nasal sprays, nasal drops, throat drops, oral medications and mouth washes.

Other optional ingredients include petrolatum, mineral waxes, emulsifiers such as polyethylene glycol, polyethylene glycol esters, polyethylene oxide, polyethylene oxide esters, polyethylene oxide ethers, polysorbates, carbomers, cetyl alcohol and stearyl alcohol, preservatives such as methyl paraben and propyl paraben, used in the preparation of ointments, lotions, creams, gels and jellies.

Method for Delivering Fentanyl in Vapor Form

The present invention also relates to a method of delivering a therapeutically-effective amount of fentanyl base in vapor form. This method comprises the steps of forming a composition which comprises fentanyl base or salt and alkyl salicylate, and exposing the composition to air so that the fentanyl base is vaporized from the composition into the air. By air is meant ambient atmospheric gases, but can also include any other inhalable gas. The fentanyl base can be vaporized by this method at ambient temperatures and pressures, as well as at elevated temperatures and/ or pressures. The composition which can be used in this method includes the compositions described herein before. The composition can be used as-is, or can be applied to a substrate, such as a cellulosic wick or a fabric, from where the fentanyl base, alkyl salicylate, and other volatile aromatic compounds are released.

Without being bound by any particular theory, it is believed that the fentanyl base interacts either physically or chemically with the alkyl salicylate, and is vaporized along with the alkyl salicylate. The higher relative vapor pressure of methyl salicylate relative to either ethyl or amyl salicylate may account for its greater efficacy.

The delivery of fentanyl base in vapor form enables its use in various product forms to provide a method of treatment which heretofore was impossible or impractical. Delivery of fentanyl base in vapor form is particularly useful in treatments where transdermal or transmucosal absorption or adsorption is the mechanism for delivering the active.

Articles of Manufacture

The present invention also comprises various articles of manufacture which comprise the composition of the present invention. A preferred article of manufacture is a vapor inhaler such as those used for nasal congestion. The vapor inhaler comprises of an enclosed cylindrically-shaped container having an orifice at one end of the cylinder and one or more vent holes in the other end. The cylinder could be made of polymeric or plastic material or metal such as aluminum, steel, lead, etc. The inhaler contains a wick of cellulosic material onto which has been applied a composition of the present invention. The orifice- end of the inhaler is placed into the nasal opening. Inhaling results in air being drawn into the container through the vent holes. The air picks up vaporous fentanyl base or the salt, alkyl salicylate, and other volatiles in the composition as it passes through the container, and passes through the orifice in the end of the inhaler and into the nasal cavity and respiratory tract. The composition used in the vapor inhaler comprises fentanyl base, alkyl salicylate, preferably methyl salicylate, and preferably an aromatic compound preferably selected from the group consisting of camphor, menthol, and mixtures thereof. More preferably the composition comprised within the vapor inhaler comprises:

(a) from about 0.005% to about 10%, preferably from about 5% to about 10% by weight fentanyl base;

(b) from about 5% to about 75%, preferably from about 10% to about 25% by weight alkyl salicylate selected from the group consisting of methyl salicylate, ethyl salicylate, amyl salicylate, and mixtures thereof; and (c) from about 2% to about 93%, preferably from about 25% to about 90% by weight of aromatic compounds selected from the group consisting of camphor, menthol, and mixtures thereof.

Another article of manufacture comprised in the present invention consists of a composition in a viscous, semi-solid form, comprising from about 2% to about 10% by weight fentanyl base, from about 5% to about 20% by weight alkyl salicylate, from 0% to about 30% by weight aromatic compound, and from about 40% to about 93% by weight petrolatum. The article can be topically applied to the chest and throat area, or can be used in a steam vaporizer. The article can also serve as the composition comprised in the aforementioned vapor inhaler, and can be applied onto the wick, or can be contained within the inhaler as- is, replacing the wick.

Other articles of manufacture include liquid inhalant composition comprising from about 2% to about 25% by weight fentanyl base, from about 5% to about 75% by weight alkyl salicylate, from 0% to about 93% by weight aromatic compounds, and from about 0% to about 93% by weight of a liquid vehicle such as mineral oil, or a volatile liquid vehicle such as ethanol, or an essential oil or mixture of essential oils, such as sassafras oil, pine needle oil, and others. The liquid inhalant product can be dispensed onto a fabric material by the user and held on or near the nose or mouth so that the fentanyl base can vaporize from the composition and be inhaled. Alternatively, the liquid inhalant can be delivered to the nasal cavity via a mechanical device such as a spray bottle. Another article of manufacture comprised in the present invention is a throat drop. The throat drop comprises from about

1% to about 2% by weight fentanyl base, from about 1% to about 2% by weight alkyl salicylate, from about 0% to about 5% by weight aromatic compounds, and from about 90% to about 96% by weight hard-boiled candy composition comprising one or more sugar alcohols, aromatic compounds, as well as other optional components, such as flavor oils and essences, sweeteners and others.

Another article of manufacture of the present invention is a chewy candy gum, such as that described in European Patent Publication No. 0,370,296 (May 30, 1990) and incorporated hereby reference. The chewy candy gum comprises a matrix of confectionary ingredients having distributed therein multiple discrete regions of a chewing gum composition, together with multiple discrete regions of a hard-boiled candy composition. The matrix can comprise a laminate structure comprising multiple alternate layers of the chewing gum composition and the hardboilded candy composition. Alternately, the matrix can be coated with a second hardboilded candy composition which is the same as or different than the laminated hardboiled candy composition. The fentanyl base and the alkyl salicylate can be incorporated together or separately, preferably together, into either the chewy candy gum composition or into the laminated hardboilded candy composition of the chewy candy gum. Methods of Treatment

The present invention also relates to methods of treatment of the pain and without limitations breakthrough cancer pain by administering to the person in need of such treatment a ' therapeutically-effective amount of the fentanyl base in vapor form. The treatment can be affected by delivering the fentanyl from a composition of the present invention via one or more of the aforementioned articles of manufacture.

The method of treatment of breakthrough cancer pain administering to a person in need of such treatment fentanyl base in vapor form in an amount from about 1 microgram (μg) to about 10 mg, delivered in one to four inhalations per nostril, several times per day as needed. The preferred means for delivering the fentanyl in this treatment is a vapor inhaler.

The present invention is illustrated by the following non-limiting examples. All parts and percentages herein are by weight unless otherwise stated.

EXAMPLE I

A composition of the present invention is prepared by the following procedure:

In a suitably sized steam-jacketed stainless steel mixing vessel is added 330.8 grams menthol crystals and 330.8 grams camphor crystals. The vessel is loosely covered and the contents heated to melt the crystals while maintaining a temperature of the melted liquid of about 52. degree. C. The menthol and camphor mixture is stirred occasionally while melting. When the crystals are completely melted, 223.8 grams methyl salicylate and 87.6 grams fentanyl base are added to the melted liquid. The menthol crystals, camphor crystals, methyl salicylate, and fentanyl citrate are all sourced from Aldrich Chemical Company, In., Milwaukee, Wis., U.S.A. The heat is removed and the solution is allowed to cool to ambient temperature while stirring occasionally. After the solution has cooled to ambient temperature, it is placed into a suitable brown-glass container and sealed.

The solution contains the following components by weight: Fentanyl citrate (base equivalent) 9.0% Methyl salicylate 23.0%

Menthol 34.0% Camphor 34.0%

EXAMPLE II

A method for measuring the release of fentanyl base in vapor form from the composition of Example I is as follows:

One milliliter of the solution made in Example I is drawn into a suitable glass pipet and transferred to an inhaler wick. The solution is absorbed into the wick. The wick is composed of cellulose acetate with a binder, and has dimensions of 5/ 16" (8 mm) diameter, 7/8" (22 mm) length, and a weight of about 0.24 grams. The volatile materials from the solution absorbed into the inhaler wick, including fentanyl base, are caused to vaporize from the wick, are isolated using a purge and trap technique, and are analyzed by thin layer chromatography with UV detection as defined in the following analytical method.

A. General Reagents

Reference standard of Fentanyl purchased from Aldrich, Dansyl

Chloride from Pierce Chemical Co., Menthol, Camphor, Thymol, Methyl Salicylate used for the aromatic base were purchased from local vendors. Hexane, Ether, Dichloromethane used were analytical grade solvents from Merck. Tenax GC, used as an absorbant in purge and trap method was purchased from Alltech

Associates.

B. General Apparatus

1. Wheaton purge and trap device (Alltech Associates Cat #9051)

2. Flow manometer capable of reading minimum air flow of 10 cc/sec.

3. Glass tubes with stoppers.

4. Pierce Reactitherm Heating/ Stirring module (Pierce Chemical Co. Cat #18971).

5. Reciprocal shaker mixer (laboratory fabricated).

6. Camag TLC Scanner II (Camag Sonnenmattstrasse, Switzerland) interfaced with HP 9816 computer (Hewlett Packard, PaIa Alto Calif.) and HP Thinkjet printer. 7. TLC spotter: Linomat IV (Camag).

8. TLC Plates: HPTLC Silica Gel MERCK 60 F 254 10.times.20 cm plates (Camag Cat # 034 5642).

9. Developing Chamber: Twin rough chamber (Camag Cat #022 5254).

10. Syringe: 100 μl (Camag Cat #27820).

C. TLC Conditions

a. Plate conditions - Wash plates with methanol followed by conditioning at 80. degree. C. for 1 hr. b. Sample size - Spot 5 μl of the extract @10 sec/μl c. No. of tracks - 13 d. Start position - 15 mm e. Band length - 6 mm f. Space between bands - 8 mm g. Solvent system - Cyclohexane: Benzene: Ethyl Acetate: I sopropyl Alcohol (76: 10:6:8) h. Equilibration time - 20 min. i. Development distance - 9 cm from spotting edge j. Wavelength for scanning - 366 nm

D. Purge and Trap Set Up

1. Preparation of cartridge

Standard 1 ml size disposable pipette tips are trimmed off at a distance of 25 mm from their tapered ends to give a tube of final dimensions of 45 mm length and OD of 9 mm at the uncut end and 5 mm at the cut narrower end. The narrow end is then plugged with minimum amount of glasswool and then filled with tenax GC up to 25 mm from the narrow end. The column is then plugged with non-absorbant cotton. The narrow end of this column forms the inlet and the wider end forms the outlet for vapors.

2. Wheaton Purqe and Trap Device

Wheaton Purge and Trap Device consists of a J-shaped tube connected to a larger reservoir tube by a Wheaton connector. The reservoir tube contains a sintered glass base towards the J-tube. The upper end of the reservoir tube is capped by a second Wheaton connector into which was inserted the tenax cartridge. The open end of the J-tube is connected to a regulated air source through a flow manometer and the air filter. The air flow is maintained at 22.5 cc/sec to simulate the human inhalation rate. An inhaler wick containing 1 ml of inhaler medication is transferred to the reservoir chamber. Sample is collected for period of 10 min.

E. Extractions & Derivatisation

1. After collection of the sample, transfer the tenax to a 7 ml stoppered tube.

2. Transfer 1 ml water and 100 μl 1 N HCl to acidify. Mix well. Extract with 2 ml hexane. Remove and discard hexane extract. 3. Basify with IN NaOH to ρH=9. Extract with 2.times.3 ml of ether: Dichloromethane (7:3). Pool both the extracts and evaporate solvent under nitrogen. Do not over dry.

4. Transfer 500 μl of Dansyl Chloride solution (200 mg Dansyl

Chloride/ 25 ml Acetone), 200 μl of saturated NaHCO₃ and 100 μl of Internal standard solution (2 mg ethyl ester of phenylalanine 10 ml ethanol). Mix well and seal with teflon. Heat at 45. degree. C. for one-half hour. 5. After derivatisation, extract the solution with 1 ml toluene. Transfer the toluene layer into another tube and evaporate under nitrogen to dryness. Reconstitute the sample in 75 μl toluene.

Calculations

1. The amount of fentanyl trapped is determined from a calibration plot of peak areas versus known amounts of fentanyl. For calibration, prepare a standard solution of fentanyl in methanol (5 mg/ 10 ml) and spike 0.2, 0.4, 0.6 and 0.8 BmI onto the tenax trap to deliver 10, 20, 30 and 40μl, resp., of fentanyl.

Extract and derivatize as per section (D).

2. Calibration curves are constructed by plotting the ratios of peak area to internal standard versus amount spike (μg). Subject the curve to linear regression analysis and fit straight line of the equation Y=mX+c. The sample amount (in μg) is read from the calibration curve.

3. The values thus obtained represent amounts of fentanyl released in 10 min. Thus, the rate of fentanyl release (ng/sec) can be calculated from: (Y-c)/m

EXAMPLE HI

A vapor inhaler for use in the treatment of breakthrough cancer pain is made as follows:

An inhaler wick as described in Example II, without medication, is placed into the bottom opening of an inhaler tube. The inhaler tube is cylindrically shaped, having a length of 2.44" (62 mm) and a bottom opening diameter of 0.44" (11.2 mm) bottom opening, and weighs about 1.98 grams. The inhaler tube has threads on the outside on the bottom end to accept an inhaler cover. The inhaler tube has four approximately 1.5 mm diameter vent holes along the bottom, and an approximately 3 mm inhalation opening in the top end. The vent holes allow for air to be drawn into the inhaler tube, along the length of the inhaler tube and the inhaler wick, and out the inhalation hole. An inhaler plug is press-fitted into the bottom opening of the inhaler tube, thereby enclosing the inhaler wick inside the inhaler tube. The inhaler tube and the inhaler plug are made of polypropylene, for example Eastman 4240-G or Amoco 4018.

One milliliter of the solution of Example I is drawn into a suitable glass pipet and is applied to the inhaler wick through the inhalation opening at the top end. An inhaler cover (cylindrical shape, 2.28" (58 mm) in length and 2.9 grams weight), having internal threads to mate with the inhaler tube, is screwed onto the inhaler tube. The inhaler cover is made of polypropylene, for example Amoco 4916 or 4918, or Hercules Profax 6231.

EXAMPLE IV

The treatment of breakthrough cancer by delivery of volatile fentanyl base is achieved by using the vapor inhaler of Example III in the following manner:

After removing the inhaler cover, the top end of the vapor inhaler tube is placed in one nostril. While covering the other nostril, the user takes four deep inhalations. The procedure is repeated in the other nostril. The amount of fentanyl base delivered in each nostril is approximately therapeutically equivalent to two drops of a conventional nasal decongestant solution containing 0.65%

(w/w) fentanyl HCl solution.

Claims

1. A method of treatment of pain in general and breakthrough cancer pain in particular by administering to a human or animal in need of the treatment a therapeutically-effective amount of fentanyl base in vapor form released from a composition comprising from about 0.005% to about 99% by weight fentanyl base and from about 1% to about 99% by weight C₁-Cs. alkyl salicylate.

2. A method of treatment according to claim 1 for treatment of pain in general and breakthrough cancer pain in particular.

3. A method of treatment according to claim 2 wherein the fentanyl base in vapor form is nasally or orally inhaled and is released in vapor form from a composition comprising:

(1) from about 0.005% to about 25% by weight fentanyl base, and

(2) from about 0.005% to about 75% by weight alkyl salicylate selected from the group consisting of methyl salicylate, ethyl salicylate, amyl salicylate, and mixtures thereof.

4. A method of treatment according to claim 3 comprising from about 0.005% to about 10% fentanyl base and from about 5% to about 25% alkyl salicylate.

5. A method of treatment according to claim 4 wherein the composition further comprises from about 2% to about 93% by- weight aromatic compound.

6. A method of treatment according to claim 4 or 5 wherein the amount of fentanyl base delivered by the treatment is from about 1 microgram to about 10 micrograms, delivered in from one to four inhalations per nostril, several times per day as needed.

7. A method of treatment according to claim 3 wherein the weight ratio of fentanyl base to alkyl salicylate is from about 5 to 1 about 1 to 20.

8. A method of treatment according to claim 3 wherein the alkyl salicylate is methyl salicylate.

9. A composition for use in delivering fentanyl base in vapor form for administration to a human, comprising:

(1) from about 0.01% to about 99% by weight fentanyl base, and

(2) from about 0.01% to about 99% by weight Ci -Cs alkyl salicylate.

10. A composition according to claim 9 comprising:

(1) from about 0.02% to about 25% by weight fentanyl base, and (2) from about 0.05% to about 75% by weight alkyl salicylate.

11. A composition according to claim 10 comprising: (1) from about 0.1% to about 10% by weight fentanyl base, and (2) from about 10% to about 25% by weight alkyl salicylate.

12. A composition according to claim 9, 10, or 11 wherein the alkyl salicylate is selected from the group consisting of methyl salicylate, ethyl salicylate, amyl salicylate, and mixtures thereof.

13. A composition according to claim 12 wherein the alkyl salicylate is methyl salicylate.

14. A composition according to claim 12 wherein the weight ratio of (1):(2) is about 5: 1 to about 1:20.

15. A composition according to claim 14 wherein the weight ratio of (1):(2) is about 1: 1 to about 1:5

16. A composition according to claim 9, 10, or 11 further comprising from about 2% to about 93% by weight aromatic compound.

17. A composition according to claim 13 comprising from about 25% to about 85% aromatic compound.

18. A composition according to claim 17 wherein the aromatic compound is selected from the group consisting of camphor, menthol, sassafras oil, pine needle oil, eucalyptus oil, and mixtures thereof.

19. A composition in the form of a viscous semi-solid for use in delivering fentanyl base in vapor form comprising:

(1) from about 0.02% to about 10% by weight fentanyl base; (2) from about 0.05% to about 20% by weight alkyl salicylate selected from the group consisting of methyl salicylate, ethyl salicylate, amyl salicylate, and mixtures thereof;

(3) from 0% to about 30% by weight aromatic compound; and

(4) from about 40% to about 93% by weight petrolatum.

20. A composition for use in delivering fentanyl base in vapor form comprising: (1) from about 0.02% to about 25% by weight fentanyl base;

(2) from about 0.05% to about 75% by weight Ci -C₅ alkyl salicylate selected from the group consisting of methyl salicylate, ethyl salicylate, amyl salicylate, and mixtures thereof;

(3) from 0% to about 93% by weight aromatic compound; and

(4) from 0% to about 93% by weight of liquid vehicle selected from the group consisting of: (i) mineral oil;

(ii) ethanol, isopropyl alcohol, and a mixture thereof; (iii) essential oil; and (iv) mixtures thereof.

21. A composition for use in delivering fentanyl base in vapor form comprising:

(1) from about 1% to about 2% by weight fentanyl base; (2) from about 1% to about 2% by weight alkyl salicylate selected from the group consisting of methyl salicylate, ethyl salicylate, amyl salicylate, and mixtures thereof;

(3) from 0% to about 5% by weight aromatic compound; and (4) from about 90% to about 96% by weight hardboiled candy composition.