United States Patent [191
`Hussain
`
`[11] Patent Number:
`[45] Date of Patent:
`
`4,464,378
`Aug. 7, 1984
`
`[54] METHOD OF ADMINISTERING NARCOTIC
`ANTAGONISTS AND ANALGESICS AND
`NOVEL DOSAGE FORMS CONTAINING
`SAME
`[75] Inventor:
`[73] Assignee:
`
`Anwar A. Hussain, Lexington, Ky.
`University of Kentucky Research
`Foundation, Lexington, Ky.
`[21] Appl. No.1 258,308
`[22] Filed:
`Apr. 28, 1981
`
`[51] Int. 01.3 .......................................... .. A61K 31/405
`[52] US. 01. ........................... .. 424/260; 260/239 BB;
`546/44; 546/45; 546/46; 546/61
`[58] Field Of Search ................ .. 424/260; 260/239 BB
`[56]
`References Cited
`U.S. PATENT DOCUMENTS
`
`4,275,059 6/1981 Flora et a1. ....................... .. 424/230
`
`Primary Examiner-Stanley J. Friedman
`Attorney, Agent, or Firm-Burns, Doane, Swecker &
`Mathis
`
`ABSTRACT
`[57]
`The invention provides a novel method of administer
`ing narcotic antagonists, narcotic analgesics and related
`compounds, and novel dosage forms containing those
`compounds which are adapted for nasal administration.
`The nasal dosage forms disclosed include solutions,
`suspensions, gels and ointments. Especially preferred
`compounds which can be advantageously administered
`in accordance with the invention include naloxone,
`naltrexone, nalbuphine, levorphanol, buprenorphine,
`butorphanol, A9-tetrahydrocannabin0l (THC), can
`nabidiol (CBD) and levonantradol.
`
`51 Claims, 1 Drawing Figure
`
`Page 1
`
`RB Ex. 2008
`BDSI v. RB PHARMACEUTICALS LTD
`IPR2014-00325
`
`

`

`US. Patent
`U S Patent
`
`Aug. 7, 1984 '
`Aug. 7, 1984
`,
`
`4,464,378
`4,464,378
`
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`Page 2
`
`Page 2
`
`
`

`

`1
`
`4,464,378
`
`METHOD OF ADMINISTERING NARCOTIC
`ANTAGONISTS AND ANALGESICS AND NOVEL
`DOSAGE FORMS CONTAINING SAME
`
`BACKGROUND OF THE INVENTION
`1. Field of the Invention
`The present invention relates to a novel method of
`administering narcotic antagonists, narcotic analgesics
`and related compounds, and to novel dosage forms
`containing such compounds adapted for nasal adminis
`tration.
`‘
`2. Background Art
`Morphine, which has the structural formula
`
`N-Cl-Ig
`
`>
`
`' HO
`
`O
`
`on
`
`20
`
`25
`
`30
`
`2
`pendence potential, as well as its potent narcotic .antag
`onist and analgesic activity. See Cowan et al, Br. J.
`Pharmac. (1977), 60, 537-545; Jasinski et al, Arch. Gen.
`Psychiatry, Vol. 35, April 1978, 501-516; Mello et al,
`Science, Vol. 207, Feb. 8, 1980, 657-659.
`Virtually all of the members of the groups of mor
`phine analogues discussed supra are well-absorbed by
`injection, but are rarely used orally because of inef?
`cient and variable absorption by that route. The low
`effectiveness of naloxone when taken orally has been
`attributed to the rapid and almost total formation of a
`less activemetabolite in the ?rst hepatic transit. See
`Fishman et al, J. Pharmacol. Exp. T her. 187, 575-580
`(1973). Also Berkowitz et al, J. Pharmacol. Exp. Ther.
`195, 499-504, and the references cited therein.
`Yet other structural modi?cations of the morphine
`molecule have resulted in codeine and its analogues;
`methadone and related compounds; and meperidine and
`related compounds such as profadol. Also see, gener
`ally, Pharmacological Basis of Therapeutics, ed. Good
`man and Gilman, sixth edition, Chapter 22, “Opioid
`Analgesics and Antagonists”, by Jaffe and Martin, pp.
`494-534 (MACMILLAN PUBLISHING CO., INC.,
`New York, 1980); Cutting’s Handbook of Pharmacology,
`sixth edition, ed. T. Z. Czaky, M.D., Appleton-Cen
`tury-Crofts/New York, Chapter 50, pp. 551-571.
`Recent studies of THC, or A9-tetrahydrocannabinol,
`which is the active ingredient in marijuana, or its deriv
`atives (e.g. CBD or cannabidiol, and levonantradol)
`suggest that these compounds are potentially useful in a
`wide varietyvof therapeutic areas, such as in the preven
`tion of narcotic withdrawal symptoms and as antiemet
`ics, particularly in the treatment of cancer patients un
`dergoing chemotherapy. Unfortunately, oral adminis
`tration has been found to be much less effective than
`intramuscular injection. See, Medical News, Monday,
`Jan. 19, 1981, page 3, for a more detailed discussion of
`the various therapeutic uses of THC and its derivatives.
`
`is a potent narcotic analgesic which is principally used
`to relieve pain; it is also used in the dyspnea of heart
`failure, in pulmonary edema and cough, as a sedative
`and in the control of diarrhea (chiefly in the form of
`paragoric). Morphine causes both depression and stimu
`lation in the central nervous system and the gut, its most
`signi?cant actions being analgesia, hypnosis, respiratory
`depression, smooth muscle spasm, nausea, vomiting and
`circulatory and other effects (especially miosis). The
`35
`drug is well-absorbed by injection, but absorption via
`the oral route is inefficient and variable, probably be
`cause of metabolismiinthe liver, chie?y by conjugation
`with glucuronic acid. Abuse leads to habituation or
`addiction.
`The morphine molecule has been subjected to a vari
`ety of structural modi?cations in efforts to enhance
`selected properties and/or to deemphasize others, as
`well as to produce-drugs which actually antagonize the
`effects of morphine and other opioid analgesics. Such
`efforts have led to the development of a variety of
`45
`classes of chemical compounds, such as the class of
`morphine analogues whose structures are very closely
`allied to that of morphine, retaining both the phenolic
`OH and the N-methyl substituent of morphine, such as
`apomorphine, levorphanol and oxymorphone, and
`which as a group have strong analgesic, respiratory
`depressant and smooth muscle stimulant activity but
`which also are highly addicting. Retention of the phe
`nolic hydroxyl while replacing the methyl on the nitro
`gen atom with a larger alkyl or similar side-chain has
`afforded both morphine analogues which are relatively
`pure opioid antagonists (e.g. naloxone and naltrexone)
`and‘are used in the treatment of narcotic-induced respi
`ratory depression (overdose), in the diagnosis of nar
`cotic addiction and in the prophylaxis of narcotic abuse;
`and morphine analogues which are agonist-antagonists
`(e.g. buprenorphine, pentazocine, nalorphine and cy
`clazocine), which display varying degrees of morphine
`like activity as well as of morphine-antagonist behavior,
`and which can therefore be used as analgesics as well as
`for the purposes for which the relatively pure antago
`nists are used. Buprenorphine appears to be a particu
`larly valuable analogue because of its low physical de
`
`SUMMARY OF THE INVENTION
`‘In view of the foregoing, it is apparent that a serious
`need exists for the improved delivery of narcotic antag
`onists‘, narcotic analgesics and related compounds
`which are not well-absorbed orally. Thus, it is an object
`of the present invention to provide novel dosage forms
`and a novel method of administering morphine or an
`analogue thereof bearing at least one phenolic hydroxyl
`substituent and having narcotic analgesic, antagonist or
`agonist-antagonist activity, or A9-tetrahydrocannabino1
`or a pharmacologically active analogue thereof bearing
`at least one phenolic hydroxyl substituent, which will
`provide greatly enhanced bioavailability as compared
`to oral administration, while at the same time providing
`- relative ease of administration when compared to intra
`muscular, subcutaneous or intravenous injection. This
`object is achieved by nasal administration of morphine,
`A9-tetrahydrocannabinol, or one of their aforesaid phe
`nolic, pharmacologically active analogues, advanta
`geously formulated into a solution, suspension, ointment
`or gel adapted for nasal administration.
`'
`
`50
`
`60
`
`65
`
`BRIEF DESCRIPTION OF THE DRAWING
`The FIGURE of the drawing is a semi-logarithmic
`plot of mean plasma levels of naloxone after intrave
`nous, nasal and oral administration of a dose of 30 pg of
`naloxone per rat.
`
`Page 3
`
`

`

`4,464,378
`
`oxymorphone
`
`5
`
`4
`
`-continued
`
`CH3
`/
`N
`
`HO
`
`O
`
`15
`
`buprenorphine
`
`20
`
`3
`DETAILED DESCRIPTION OF THE
`INVENTION
`The narcotic analgesics, narcotic antagonists and
`narcotic agonist-antagonists intended for use in the
`compositions and method of the present invention in
`clude morphine and pharmacologically active ana
`logues thereof having at least one aromatic ring, said
`ring bearing at least one free OH group. Particularly
`signi?cant morphine analogues contemplated by the
`present invention include morphine-like analgesics such
`as apomorphine, hydromorphone, levorphanol, meto
`pon and oxymorphone; and narcotic antagonists and
`agonist-antagonists such as buprenorphine, diprenor
`phine, butorphanol, cyclazocine, pentazocine, phenazo
`cine, levallorphan, nalorphine, naloxone, alazocine,
`nalbuphine, oxilorphan, nalmexone and naltrexone.
`Other analogues contemplated by the invention in
`cluded ketobemidone, apocodeine, profadol, cyclor
`phan, cyprenorphine, desomorphine, dihydromorphine,
`3-hydroxy-N-methylmorphinan,
`levophenacylmor
`phan, metazocine, norlevorphanol, oxymorphone,
`phenomorphan, pholcodine and hydroxypethidine. Es
`pecially preferred morphine analogues are those having
`antagonist or agonist-antagonist properties, especially
`naloxone, nalbuphine, naltrexone, buprenorphine and
`butorphanol. Any pharmaceutically acceptable form of
`morphine or of its phenolic analogues can be used, i.e.
`the free base or a pharmaceutically acceptable acid
`addition salt thereof (e. g. naloxone hydrochloride, nal
`buphine hydrochloride, nalorphine hydrochloride, na
`lorphine hydrobromide, levallorphan tartrate, mor
`phinc sulfate, levorphanol tartrate, buprenorphine hy
`drochloride, butorphanol tartrate, pentazocine lactate,
`pentazocine hydrochloride, phenazocine hydrobro
`mide, morphine hydrochloride, profadol hydrochlo
`ride, etc.); generally, the selected compound is em
`ployed in the instant compositions and method in the
`pharmaceutically acceptable form which has previously
`been found most advantageous for use by injection or
`orally. The structural formulae for representative free
`bases encompassed by the present invention are set
`forth below:
`
`25
`
`30
`
`35
`
`45
`
`butorphanol
`
`HO
`
`cyclazocine
`
`N/CHz-Q
`
`— CH3
`
`CH3
`
`HO
`
`55
`
`pentazocine
`
`60
`
`CH3
`
`CH3
`
`—CH3
`
`apomorphine
`
`HO
`
`OH
`
`levorphano]
`
`HO
`
`CH3
`
`HO
`
`Page 4
`
`

`

`5
`-continued
`
`phenazocine
`
`CHZCHZ
`/
`N
`
`—CH3
`
`CH3
`
`N
`
`CH2CH=CH2
`
`HO
`
`nalorphine
`
`HO
`
`~ O
`
`Q“
`
`levallorphan
`
`CH;CH=CH2
`
`‘ / .
`
`N
`
`-
`
`naloxone
`
`CH2CH=CH2
`
`.
`
`/ ‘
`N .
`
`H0
`
`0 .
`
`\\
`O
`
`nalbuphine
`
`N-CH2—<>
`
`HQ
`
`0
`
`’ ‘DH
`
`naltrexone
`
`4,464,378
`
`profadol
`
`6
`-continued
`
`OH
`
`10
`
`N
`
`These morphine analogues and their salts can be pre
`pared by well-known methods. Morphine itself can of
`course be isolated from natural ‘sources and then con
`verted, if desired, into a pharmaceutically acceptable
`acid addition salt. »
`The cannabinoids intended for use in the method and
`compositions of the present invention include A9-tet
`rahydrocannabinol (THC) and pharmacologically ac
`tivederivatives thereof having at least one free OH
`group on an aromatic ring thereof. .A9-Tetrahydrocan
`nabinol has the structural formula
`
`20
`
`25
`
`30
`
`35
`
`Preferred derivatives thereof for use in the present in
`vention include‘cannabidiol (CBD) and levonantradol.
`These compounds can be prepared by known methods
`or, in the case of THC and CBD, isolated from natural
`
`sources.
`
`'
`
`'
`
`'
`
`45
`
`In accord with the present invention, morphine, THC
`and‘ their pharmacologically active phenolic analogues
`can be administered nasally with results considerably
`superior to those obtained with oral administration in
`terms of enhanced drug bioavailability and minimiza
`tion of blood level variations, thus enabling 'use of these
`drugs at the dosage levels previously possible only by ‘
`injection without the disadvantages inherent in subcuta- “
`neous, intrasmuscular or intravenous administration. It
`would appear that‘ these drugs are rapidly absorbed
`from the nasal mucosa into systemic blood without
`extensive metabolism in the gastrointestinal tract and
`./or extensive ?rst-pass metabolism.
`The following study was undertaken to examine the
`bioavailability of a representative drug employed in the
`method and compositions of the invention, namely nal
`oxone, administered nasally, in comparison with the
`55
`‘bioavailability of that drug when administered orally
`and intraveneously.
`Sprague-Dawley male rats, each weighing about 270
`grams, were used in the study. Three groups of three,
`rats each were employed, one group for each route of
`administration. The rats were anesthetized with pento
`barbital (50 mg/kg) prior to administration of the drug.
`Naloxone was administered at a dose of 30 lag/rat (~40
`pCi/rat) as 3H-naloxone in 0.1 m1 of isotonic saline. For
`intravenous administration, the drug was injected
`65
`' through the femoral vein. For oral (intraduodenal) ad
`ministration, the abdomen of ‘ each rat was opened
`through a midline incision and the drug was injected
`
`Page 5
`
`

`

`5
`
`10
`
`8
`TABLE I '
`(PART C)
`PLASMA LEVELS OF NALOXONE AFTER ORAL
`ADMINISTRATION OF 30 pg/RAT (40 uCi/RAT) OF 3H
`NALOXONE IN INDIVIDUAL RATS
`Plasma Level (ng/ml)
`II
`III
`Mean
`0.10
`1.43
`0.25
`0.15
`0.74
`0.44
`0.30
`0.64
`0.37
`0.15
`0.64
`0.34
`0.03
`0.25
`0.16
`0.10
`0.17 '
`0.18
`0.05
`0.16
`0.11
`0.02
`0.14
`0.09
`0.03
`0. 12
`0.06
`0.06
`0.10
`0.06
`0.02
`0.07
`0.04
`
`1
`0.22
`0.44
`0.18
`0.22
`0.19
`0.28
`0.13
`0.10
`0.04
`0.03
`0.03
`
`SE
`0.10
`0.30
`0.24
`0.15
`0.11
`0.09
`0.06
`0.06
`0.05
`0.04
`0.03
`
`Time
`(Min.)
`1
`3
`5
`10
`20
`30
`45
`60
`90
`120 ‘
`180
`
`4,464,378
`7
`directly through the duodenum. For nasal administra
`tion, an incision was made in the neck of each rat and
`the trachea was cannulated with a polyethylene tube.
`Another tube was inserted from the esophagus to the
`posterior part of the nasal cavity, and the nasoplantine
`was closed with an adhesive agent to prevent drainage
`of the drug from the nasal cavity to the mouth. The
`drug was then administered to the nasal cavity through
`the tube by means of a syringe. Blood was sampled
`periodically from the femoral aorta. Unchanged radi
`olabelled naloxone was analyzed according to the pro
`cedure described by Fishman et al, J. Pharmacol. Exp.
`Ther. 187, 575-580 (1973). The method involved cen
`trifugation of the blood and spiking the plasma samples
`with cold naloxone. The drug was then extracted from
`the plasma with ethyl acetate. The ethyl acetate extract
`was then spotted onto thin layer chromatographic
`plates and the plates were developed in a 100:60:2 chlo
`roform-methanol-acetic acid system (parts by volume).
`The zone corresponding to free naloxone visualized by
`ultraviolet absorption was removed and the radioactiv
`ity counted.
`TABLE I below shows the individual plasma level
`data of naloxone from intravenous (PART A), nasal
`(PART B) and oral (PART C) routes, while the ?gure
`of drawing shows the mean plasma levels of naloxone
`for the different routes of administration. TABLE II
`below shows the area under the curve values (AUC 0)
`for the individual rats for each of the three routes of
`administration, the bioavailability calculated for the
`nasal and oral routes, and the half-lives of elimination of
`35
`the drug after intravenous and nasal administration.
`TABLE I
`Plasma Level (nglml!
`
`TABLE 11
`AREA UNDER THE BLOOD LEVEL CURVE VALUES
`(AUC ‘0) FOR INDIVIDUAL RATS FROM THE THREE
`ROUTES OF ADMINISTRATION OF NALOXONE AND
`HALF-LIVES 0F ELIMINATION OF NALOXONE
`FOLLOWING INTRAVENOUS AND NASAL
`ADMINISTRATION
`11
`111
`Mean SE
`1
`1540.5
`1685.8
`1498.7 121.9
`1269.7
`IV
`1336.2
`1312.0
`1517.5 193.5
`1904.2
`Nasal
`11.3
`35.5
`22.0
`7.1
`19.1
`Oral
`BIOAVAILABILITY CALCULATIONS:
`AUC nasal
`W x 100 = 1.013 X 100 = 101.3%
`AM
`>< 100 = 0.015 x 100 = 1.5%
`AUC iv
`
`11
`59.2 min.
`52.1 min.
`-
`
`25
`
`30
`
`It can be seen from TABLE II that the areas undei
`the curve following intravenous and nasal administra‘
`tion were not signi?cantly different, i.e. absorption 01
`naloxone via the nasal route of administration was as
`effective as via the intravenous route. On the othe1
`hand, oral administration of 30 pg of naloxone resulted
`in bioavailability equal to only 1.5% that of the same
`dose given intravenously. Also from TABLE II, it can
`be seen that the nasal bioavailability of naloxone was
`nearly 70 times greater than the oral bioavailability.
`It also can be seen from TABLE I and the FIGURE
`of drawing that naloxone was very rapidly absorbed
`from the nasal mucosa; thus, at the 30 1.1g dosage level,
`the peak plasma level was attained in about 5 minutes
`after instillation of the nose drops. Further, the half-life
`of elimination of the drug after nasal administration was
`found to be comparable to its half-life following intrave
`nous nasal administration.
`The study described above indicates that naloxone is
`rapidly absorbed from the nasal mucosa into the sys
`temic circulation without extensive intestinal or ?rst
`pass metabolism. It is further apparent from this study
`that the bioavailability of naloxone when administered
`nasally is equivalent to the bioavailability of the drug
`when administered intravenously and vastly superior to
`its bioavailability by the oral route. As the phenolic
`hydroxyl group in naloxone is believed to be responsi
`ble for the extensive metabolism seen when the drug is
`administered orally and, consequently, for the drug’s
`poor oral bioavailability, it follows that similar im
`provement in bioavailability for nasal versus oral ad
`ministration will be observed in the case of the other
`phenolic drugs intended for use in the method and com
`positions of the present invention.
`
`45
`
`50
`
`55
`
`65
`
`Time
`(Min.)
`
`1
`
`II
`
`III
`
`Mean
`
`SE
`
`PLASMA LEVELS OF NALOXONE AFTER INTRA
`VENOUS ADMINISTRATION OF 30 lag/RAT (4O “Ci/RAT)
`OF 3I*I—NALOXONE IN INDIVIDUAL RATS
`101.65
`91.45
`138.57
`110.56
`14.31
`52.28
`44.00
`77.77
`58.02
`10.16
`31.38
`33.03
`47.93
`37.45
`5.26
`15.60
`16.92
`26.34
`19.62
`3.38
`10.27
`11.44
`13.01
`11.57
`0.79
`7.28
`9.16
`8.59
`8.34
`0.56
`5.47
`7.98
`6.77
`6.74
`0.72
`4.87
`5.82
`5.54
`5.41
`0.28
`3.01
`4.63
`4.23
`3.96
`0.49
`2.15
`3.87
`2.57
`2.86
`0.52
`1.25
`1.77
`1.40
`1.47
`0.15
`
`1
`3
`5
`10
`20
`30
`45
`60
`90
`120
`180
`
`PLASMA LEVELS OF NALOXONE AFTER NASAL
`ADMINISTRATION OF 30 ug/RAT (40 pCi/RAT) OF
`3I-I—NALOXONI£ IN INDIVIDUAL RATS
`36.20
`12.71
`20.97
`23.29
`41.21
`30.85
`42.80
`38.29
`54.45
`33.41
`44.15
`44.00
`45.30
`31.53
`31.02
`35.95
`22.73
`17.68
`17.99
`19.47
`13.46
`11.83
`10.79
`12.03
`9.36
`7.95
`6.56
`7.96
`8.26
`5.98
`4.98
`6.41
`4.79
`3.16
`2.80
`3.58
`3.65
`2.29
`1.84
`2.59
`1.95
`1.22
`1.10
`1.42
`
`6.88
`3.75
`6.07
`4.68
`1.63
`0.78
`0.81
`0.97
`0.61
`0.54 '
`0.27
`
`1
`3
`5
`10
`20
`30
`45
`60
`90
`120
`180
`
`Page 6
`
`

`

`15
`
`10
`EXAMPLE 1
`l Gram of naloxone hydrochloride is dissolved in 80
`ml of distilled water and the pH of the resultant solution
`is adjusted to 7.4 with dilute sodium hydroxide solution.
`A quantity of water sufficient to bring the total volume
`to 100 ml is then added and suf?cient sodium chloride
`(or other appropriate salt) is added to adjust the solution
`to isotonicity. The solution is then sterilized by being
`passed through a 0.2 micron Millipore ?lter. The ?nal
`composition contains 1 mg of naloxone hydrochloride
`per 0.1 mlof solution.
`.
`The above procedure is repeated using 1 gram of
`levallorphan tartrate in place of the naloxone hydro
`chloride. The resultant composition contains 1 mg of
`lavallorphan tartrate per 0.1 ml of solution.
`Repetition of the procedure of the ?rst paragraph of
`this example using 5 grams of apomorphine hydrochlo
`ride, 3 grams of hydromorphone hydrochloride, 4
`grams of metopon hydrochloride, 1.5 grams of oxymor
`phone hydrochloride, 0.6 grams of buprenorphine hy
`drochloride, 2 grams of butorphanol tartrate, 3 grams of
`pentazocine hydrochloride, 3 grams of phenazocine
`hydrobromide or 5 grams of nalorphine hydrochloride
`in place of the naloxone hydrochloride affords a nasal
`composition containing, respectively, 5 mg of apomor
`phine hydrochloride, 3 mg of hydromorphone hydro
`chloride, 4 -mg of metopon hydrochloride, 1.5 mg of
`oxymorphone hydrochloride, 0.6 mg of buprenorphine
`hydrochloride, 2 mg of butorphanol tartrate, 3 mg of
`pentazocine hydrochloride, 3 mg of phenazocine hy
`drobromide, or 5 mg of nalorphine hydrochloride, per
`0.1- ml of solution.
`
`EXAMPLE 2
`l5 Grams of nalbuphine hydrochloride are combined
`with 80 ml of distilled water and the pH is adjusted to
`4.5 with dilute sodium hydroxide solution. A quantity of
`water suf?cient to bring the total volume to 100 ml is
`then added and suf?cient sodium chloride is added to
`adjust the solution to isotonicity. The solution is then
`sterilized by being passed through a 0.2 micron Mil
`lipore ?lter. The resultant composition contains 15 mg
`of nalbuphine hydrochloride per 0.1 ml.
`The procedure described above is substantially re
`peated, except that 15 grams of morphine sulfate are
`used in place of the nalbuphine hydrochloride, afford
`ing a nasal composition containing 15 mg of morphine
`sulfate per 0.1 ml. '
`Repetitionv of the procedure of the ?rst paragraph of
`this example using 20 grams of pentazocine lactate in
`place of the nalbuphine hydrochloride affords a nasal
`composition containing 20 mg of pentazocine lactate
`per ‘0.1 ml.
`
`4,464,378
`9
`Any of the selected drugs intended for use in the
`present invention, i.e. morphine, THC or one of their
`pharmacologically active phenolic analogues, can be
`administered nasally to warm-blooded animals, conve
`niently by formulation into a nasal dosage form com
`prising the desired drug, in a therapeutically effective
`amount (i.e., depending on the selected drug, an anal
`gesically effective amount, an antiemetic effective
`amount, an amount effective to antagonize the effects of
`a narcotic agent, etc.), together with a nontoxic phar
`maceutically acceptable nasal carrier therefor. This
`type of composition can be used in the treatment of any
`of the variety of conditions which are responsive to
`treatment with the selected drug itself by other routes
`of administration.
`As indicated earlier, in the compositions of the inven
`tion, the drug can be employed in the form of the free
`base or, in the case of morphine and its analogues, in the
`form of a pharmaceutically acceptable salt thereof.
`Suitable nontoxic pharmaceutically acceptable nasal
`20
`carriers will be apparent to those skilled in the‘ art of
`nasal pharmaceutical formulations. For those not skilled
`in the art, reference is made to the text entitled “REM
`INGTON’s PHARMACEUTICAL SCIENCES”,
`14th, edition, 1970. Obviously, the choice of suitable
`carriers will depend on the exact nature of the particu
`lar nasal dosage ‘form desired, e.g., whether the drug is
`to be formulated into a nasal solution (for use as drops
`or as a spray), a nasal suspension, a nasal ointment or a
`nasal gel. Preferred nasal dosage forms are solutions,
`30
`suspensions and gels, which contain a major amount of
`water (preferably puri?ed water) in addition to the
`active ingredient. Minor amounts of other ingredients
`such'as pH adjusters (e.g., a base such as NaOH), emul
`si?ers or dispersing agents, buffering agents, preserva
`tives, wetting agents and jelling agents (e.g., methylcel
`lulose) may also be present. Most preferably, the nasal
`composition is isotonic,’ is. it has the same osmotic
`pressure as blood serum. If desired, sustained release
`nasal compositions, e.g. sustained release gels, can be
`readily prepared, preferably by employing the desired
`drug in oneof itsi ‘relatively insoluble forms, such as the
`free base or anfinsoluble 'salt. In the case of morphine
`and its analogues§‘when the free base is not suf?ciently
`insoluble for sustained release compositions, or when a
`more highly insoluble form is desired, a long chain
`carboxylic acid salt of the desired drug can be'conve
`niently employed. The carboxylic acid portion of the
`salt preferably contains 10 to 20 carbon atoms. Such
`“salts (e.g. stearates, palmitates etc.) can be readily syn
`thesized, for example, by dissolving the hydrochloride
`salt of the drug in water, then adding the alkali metal
`salt of the desired long chain carboxylic acid (e.g. so
`dium stearate). The corresponding long chain carbox
`ylic acid salt of the drug which precipitates out of the
`solution is removed by ?ltration. Alternatively, equimo
`lar amounts of the free base of the drug and the long
`chain carboxylic acid are combined in methanol. That
`mixture is then added to a small volume of water, caus
`ing the desired salt (e.g. stearate) of the drug to precipi
`tate out.
`Examples of the preparation of typical nasal composi
`tions containing selected drugs are set forth below.
`However, it is to be understood that these examples are
`given by way of illustration only and are not to be con
`strued as limiting the invention either in spirit or in
`scope as many modi?cations both in materials and in
`methods will be apparent to those skilled in the art.
`
`60
`
`35
`
`40
`
`45
`
`50
`
`EXAMPLE 3
`l Gram of naltrexone is dissolved in 80 ml of isotonic
`saline solution and the pH of the resultant solution is
`adjusted to 7.0-7.2 with dilute hydrochloric acid. A
`quantity of isotonic saline suf?cient to bring the total
`volume to 100 ml is then added, and the solution, is
`sterilized by being passed through a 0.2 micron Mil
`lipore ?lter. The resultant composition contains 1 mg of
`naltrexone per 0.1 ml.
`Repetition of the foregoing procedure utilizing 0.5
`65
`gram of levonantradol in place of the naltrexone affords
`a nasal composition containing 0.5 mg of levonantradol
`per 0.1 ml.
`
`Page 7
`
`

`

`4,464,378
`11
`The procedure of the ?rst paragraph of this example
`is substantially repeated, save that 4 grams of butor
`phanol are employed in place of the naltrexone, to af
`ford a nasal composition containing 4 mg of butor
`phanol per 0.1 ml.
`Substitution of 2 grams of cyclazocine for the naltrex
`one used in the ?rst paragraph of this example and
`substantial repetition of the procedure there detailed
`afford a nasal composition containing 2 mg of cyclazo
`cine per 0.1 ml.
`
`10
`
`COMPOSITION B
`
`Ingredient
`nalorphine hydrobromide
`Tween 80
`methylcellulose
`water, puri?ed
`
`COMPOSITION C
`
`Ingredient
`buprenorphine hydrochloride
`Tween 80
`methylcellulose
`water, puri?ed
`
`Amount
`500 mg
`3 m8
`30 mg
`10 ml
`
`Amount
`100 mg
`2 mg
`20 mg
`10 ml
`
`20
`
`35
`
`EXAMPLE 4
`80 Grams of water are heated to 80° C. and 3.0 grams
`of Methocel are added, with stirring. The resultant
`mixture is allowed to stand at room temperature for 3
`hours. Then, 1.5 grams of naloxone stearate are sus
`pended in 20 grams of water, that suspension is added to
`the gel and thoroughly mixed, and the resultant viscous
`solution or gel is adjusted to isotonicity with sodium
`chloride. The sustained release composition thus ob
`tained contains 1.5 mg of naloxone stearate per 0.1 ml.
`The above procedure is substantially repeated, except
`that 2.0 rather than 3.0 grams of Methocel are em
`ployed, and 1.5 grams of naltrexone myristate are substi
`tuted for the naloxone stearate. The sustained release
`composition prepared in this manner contains 1.5 mg of
`naltrexone myristate per 0.1 ml.
`Repetition of the procedure of the ?rst paragraph of
`this example, but using 20 grams of nalbuphine palmi
`tate in place of the naloxone stearate, affords a sustained
`release composition containing 20 mg of nalbuphine
`palmitate per 0.1 ml.
`The procedure of the ?rst paragraph of this example
`is substantially repeated, except that 3 grams of levor
`phanol stearate are employed in place of the naloxone
`stearate. The resultant sustained release composition
`contains 3 mg of levorphanol stearate per 0.1 ml.
`Substitution of 4 grams of buprenorphine stearate for
`the naloxone stearate used in the ?rst paragraph of this
`example and substantial repetition of the procedure
`there detailed afford a sustained release composition
`containing 4 mg of buprenorphine stearate per 0.1 ml.
`In a similar manner, repetition of the procedure of the
`?rst paragraph of this example, but using 2.5 grams of
`45
`butorphanol palmitate, 3.5 grams of pentazocine myris
`tate, 10 grams of THC, 20 grams of GED or 1 gram of
`levonantradol in place of the naloxone stearate affords a
`sustained release composition containing, respectively,
`2.5 mg of butorphanol palmitate, 3.5 mg of pentazocine
`myristate, 10 mg of THC, 20 mg of CBD or 1 mg of
`levonantradol, per 0.1 ml.
`EXAMPLE 5
`55
`The following are illustrative aqueous solutions of
`selected drugs suitable for use as nasal drops or nasal
`spray. In each case, the pH of the ?nal composition is
`adjusted to 7.4. If desired, the solutions are adjusted to
`isotonicity.
`
`Naturally, the therapeutic dosage range for nasal
`administration of the drugs according to the present
`invention will vary with the size of the patient, the
`condition for which the drug is administered and the
`particular drug employed. Generally, the daily dosage
`will approximate the amounts previously employed for
`IV, IM or SC administration of the particular drug
`involved. Thus, a typical dose of buprenorphine would
`be 4-8 mg per day as a maintenance dose in the treat
`ment of narcotic addicts. The quantity of nasal dosage
`form needed to deliver the desired dose will of course
`depend on the concentration of drug in the composi
`tion. The volume of solution or gel which would be
`needed to deliver the daily dose of buprenorphine speci
`?ed above would be 0.1 to 0.2 ml of 4% solution or gel.
`While the invention has been described in terms of
`various preferred embodiments, the skilled artisan will
`appreciate that various modi?cations, substitutions,
`omissions and additions may be made without departing
`from the spirit thereof. Accordingly, it is intended that
`the scope of the present invention be limited solely by
`the scope of the following claims.
`What is claimed is:
`1. A method for eliciting an analgesic or narcotic
`antagonist response in a warm-blooded animal, which
`comprises nasally administering to said animal:
`(a) to elicit an analgesic response, an analgesically
`effective amount of morphine, hydromorphone,
`metopon, oxymorphone, desomorphine, dihydro
`morphine, levorphanol, cyclazocine, phenazocine,
`levallorphan,
`3-hydroxy-N-methylmorphinan,
`levophenacylmorphan, metazocine,
`norlevor
`phanol, phenomorphan, nalorphine, nalbuphine,
`buprenorphine, butorphanol or pentazocine, or a
`nontoxic pharmaceutically acceptable acid addi
`tion salt thereof; or
`.
`(b) to elicit a narcotic antagonist response, a narcotic
`antagonist effective amount of naloxone, naltrex
`one, diprenorphine, nalmexone, cyprenorphine,
`levallorphan, alazocine, oxilorphan, cyclorphan,
`nalorphine, nalbuphine, buprenorphine, butor
`phanol, cyclazocine or pentazocine, or a nontoxic
`pharmaceutically acceptable acid addition salt
`thereof.
`2. A method according to claim 1 for eliciting a nar
`cotic antagonist response in a warm-blooded animal,
`which comprises nasally administering to said animal a
`narcotic antagonist effective amount of naxolone, nal
`trexone, diprenorphine, nalmexone, cyprenorphine,
`levallorphan, alazocine, oxilorphan, cyclorphan, nalor
`
`40
`
`COMPOSITION A
`
`Ingredient
`nalbuphine hydrochloride
`Tween 80
`methylcellulose
`water, puri?ed
`
`Amount
`1000 mg
`4 mg
`40 mg
`10 ml
`
`65
`
`Page 8
`
`

`

`myristate.
`
`4,464,378
`13
`14
`phine, nalbuphine, buprenorphine, butorphanol, cyclaz
`18. The method according to claim. 17 wherein the
`compound administered is hydromorphone, metopon or
`ocine or pentazocine, or a nontoxic pharmaceutically
`acceptable acid addition salt thereof.
`oxymorphone, or a nontoxic pharmaceutically accept
`3. The method according to claim 2 wherein the
`able acid addition salt thereof. ‘
`compound administered is naloxone, naltrexone, nalor
`19. The method according to claim 15 wherein the
`phine, nalbuphine, buprenorphine, diprenorphine, nal
`compound administered is in the form of a long chain
`carboxylic acid salt, the carboxylic acid portion of the
`mexone or cyprenorphine, or a nontoxic pharmaceuti
`cally acceptable acid addition salt thereof.
`salt containing from 10 to 20 carbon atoms.
`20. A method according to claim 2 wherein the com
`4. The method according to claim 2 wherein the
`pound administered is butorphanol, pentazo