`
`PATENT SPECIFICATION
`(21) Application No. 11319/72
`(22) Filed 10 March 19-72
`(31) Convention Application N0. 141407
`(3 3) United States of America (US)
`(44) Complete Specification published 16 April 1975
`(51) INT CL2 AGlK 31/485
`(52\ Index at acceptance
`
`(32) Filed 7'May 1971 in
`
`(11)
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`N i
`
`s
`is;
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`® 3
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`3
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`M
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`(54) ORAL NARCOTIC COMPOSITION
`
`(71) We, ENDO‘ LABORATORIES INC,
`a Corporation organised and existing under
`the Laws of the State of Delaware, located
`at 1000 Stewart Avenue, Garden City, New
`York 11530, United States of America, do
`hereby declare the invention for which we
`pray that a patent may be granted to us, and
`the method by which it is to be performed, to
`be particularly described in and by the
`following statement:-——
`This invention relates to an oral narcotic
`
`10
`
`the
`the narcotic, preventing obtainment of
`desired euphoriant effect. Thus, the combina—
`tion removes the incentive for diversion of the
`drugs into other channels and uses.
`The narcotic drug which can be used in the
`compositions of this invention is oxycodone,
`hydrocodone, codeine, propoxyphene or penta—
`zocine or a pharmaceutically acceptable salt
`thereof. Propoxyphene is not at present under
`narcotic control, but it is definitely recognised
`as a weak narcotic, and has been incriminated
`-
`__ __..‘l -113-
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`EA
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`PATENTS ACT 1949
`
`Patent No 1353815.
`
`THE
`PATENT OFFICE
`10 November 1977
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`Baa 42365/3
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`Capsule or syrup, comprising a narconc Wmcn
`has substantial activity orally as well as by
`injection,
`in combination with a narcotic
`antagonist which is much less effective orally
`than by injection,
`the ratio of antagonist to
`narcotic in the combination being such that
`the antagonist does not block the effect of the
`narcotic when the combination is administered
`orally, but does prevent the obtainment of an
`acute euphoriant effect when the combination
`is administered by injection.
`When administered orally in unit dosage
`form, the composition provides a fully effec-
`tive therapeutic dose of the narcotic, substan—
`tially
`undiminished
`by presence
`of
`the
`antagonist. However, when the combination of
`active ingredients is extracted and injected,
`the antagonist effectively blocks the effect of
`
`vention IS 0116 SUILflDIC 1U]: 01.211. aumuuauauuu
`and comprising (a) a compound having sub-
`stantial narcotic activity both orally and by
`injection,
`the compound being oxycodone,
`hydrocodone,
`codeine,
`propoxyphene
`or
`pentazocine or a pharmaceutically acceptable
`salt
`thereof, and (b) a narcotic antagonist
`which is substantially less active orally than
`by injection,
`the narcotic antagonist being
`(1) naloxone or a pharmaceutically acceptable
`salt thereof, (2) N - cyclopropylmethyl - 7,8-
`dihydro - 14 - hydroxynormorphinone or a
`pharmaceutically acceptable salt thereof, or (3)
`21 — cyclopropyl — 7.8 - (I - hydroxy — 1—
`methylethyl)
`— 6,14 - endo — ethanotetra—
`hydrooripavine or a pharmaceutically accept-
`able salt thereof,
`the weight ratio of (a) to
`(b), calculated as the free base, being
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`

`unilaoorva
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`
`
`PATENT SPECIFICATION
`(21) Application No. 113 19/72
`(22) Filed 10 March 1972
`(31) Convention Application No. 141407
`(33) United States of America (US)
`(44) Complete Specification published 16 April 1975
`(51) INT CL2 A61K 31/485
`(52) Index at acceptance
`ASB 292 294 295 29‘Y 381 382
`385 386' 387 38Y 392 39X
`401 40Y 4-23 42Y 431
`43Y 466 4'6Y 482 48Y 551
`55Y 576 57Y 586 58Y
`636 63Y r644 64Y 77Y
`
`(32) Filed '7 May 19,71 in
`
`N D b
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`e Q G
`
`?
`to
`F1
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`(54) ORAL NARCOTIC COMPOSITION
`
`10
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`30
`
`(71) We, ENDO- LABORATORIES INC,
`a Corporation organised and existing under
`the Laws of the State of Delaware,
`located
`at 1000 Stewart Avenue, Garden City, New
`York 11530, United States of America, do
`hereby declare the invention for which we
`pray that a patent may be granted to us, and
`the method by which it is to be performed, to
`be particularly described in and by the
`following statement:—
`This invention relates to an oral narcotic
`composition.
`In general, narcotic addicts do not obtain
`narcotic satisfaction or a “high” from the com-
`paratively slow, difiuse, and attenuated effect
`of narcotics taken orally. Instead they seek the
`rapid, concentrated, and undiminished effect
`of an injected narcotic, preferably intravenous
`or “mainline”,
`to achieve the desired acute
`euphoriant effect of a satisfactory “high”.
`Consequently, addicts sometimes obtain the
`more easily procurable oral narcotics such as
`analgesics and antitussives, and extract
`the
`narcotic substance so that it can be injected.
`Thus, narcotic abuse through diversion of oral
`narcotic therapeutic drugs into channels for
`injection by addicts has become a serious
`problem in medicine and public health.
`This invention provides a narcotic com-
`position for oral administration, e.g. a tablet,
`capsule or syrup, comprising a narcotic which
`has substantial activity orally as well as by
`injection,
`in combination with a narcotic
`antagonist which is much less effective orally
`than by injection, the ratio of antagonist to
`narcotic in the combination being such that
`the antagonist does not block the effect of the
`narcotic when the combination is administered
`orally, but does prevent the obtainment of an
`acute euphoriant eflect when the combination
`is administered by injection.
`When administered orally in unit dosage
`form, the composition provides a fully efiec-
`tive therapeutic dose of the narcotic, substan~
`tially
`undiminished
`by presence
`of
`the
`antagonist. However, when the combination of
`active ingredients is extracted and injected,
`
`the antagonist effectively blocks the effect of
`\
`
`35
`
`40
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`45
`
`the
`the narcotic, preventing obtainment of
`desired euphoriant elfect. Thus, the combina-
`tion removes the incentive for diversion of the
`drugs into other channels and uses.
`_
`The narcotic drug which can be used in the
`compositions of this invention is oxycodone,
`hydrocodone, codeine, propoxyphene or penta-
`zocine or a pharmaceutically acceptable salt
`thereof. Propoxyphene is not at present under
`narcotic control, but it is definitely recognised
`as a weak narcotic, and has been incriminated
`in some cases of narcotic drug abuse and addic-
`tion. Pentazocine likewise is not at present
`under narcotic control in the U.S.A.; how-
`ever, it is a mixed weak narcotic antagonist
`and borderline narcotic, from which the narco-
`tic component has emerged sufliciently to
`cause a significant'number of cases of drug
`abuse and addiction.
`The narcotic antagonist used in the inven—
`tion has
`substantially greater effectiveness
`when administered by injection than when
`administered orally; the antagonist is naloxone,
`N — cycle
`propylmethyl - 7,8 — dihydro- - 14-
`hydroxynormorphinone or 21 - cyclopropyl-
`7m: - (1 — hydroxy - 1 - methylethyl) - 6,14—
`endo — ethano - tetrahydrooripavine (or di—
`phenorphine) or a pharmaceutically acceptable
`acid addition salt thereof.
`The pharmaceutical composition of the in-
`vention is one suitable for oral administration
`and comprising (a) a compound having sub—
`stantial narcotic activity both orally and by
`injection,
`the compound being oxyeodone,
`hydrocodone,
`codeine,
`propoxyphene
`or
`pentazocine or a pharmaceutically acceptable
`salt
`thereof, and (b) a narcotic antagonist
`which is substantially less active orally than
`by injection,
`the narcotic antagonist being
`(1) naloxone or a pharmaceutically acceptable
`salt thereof, (2) N - cyclopropylmethyl - 7,8-
`dihydro — 14 — hydroxynormorphinone or a
`pharmaceutically acceptable salt thereof, or (3)
`21 - cyclopropyl — 7,8 - (1 - hydroxy - 1-
`methylethyl)
`- 6,14 - endo - ethanotetra—
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`

`1,390,772
`
`
`
`2
`
`a
`d
`oxyco age
`hydroco one
`pigggyphene
`pentazocine
`
`Ratio with
`(b) (1)
`5_() 1
`5: 0'03
`30: 0'1
`65 1 0'2
`50: 0‘2
`
`Ratio with
`(b) (2) or (3)
`15.01
`5:0'01
`90: 0‘1
`195; 0‘2
`150: 0.2
`
`10
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`15
`
`20
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`25
`
`so that (b) does not block the narcotic effect
`of (a) when the composition is administered
`orally but does prevent an acute euphoriant
`effect by (a) when the composition is injec-
`ted.
`The compositions of the invention are con-
`ventional oral narcotic compositions, except
`for the inclusion of the narcotic antagonist.
`In the case of tablets, they will generally con-
`tain 5—100 mg of the narcotic and 0.001—
`50 mg (usually 0.003—5 mg) of the antagon—
`ist. Liquid preparations will generally con-
`tain 1—20 mg/ml of the narcotic and 0.0002
`—10 mg/ml (usually 0.0006—1 mg/ml) of
`the antagonist. Additional drugs, e.g. anti-
`histamines, non—narcotic analgesics and anti—
`spasmodics may be included, along with con—
`ventional excipients in conventional amounts.
`The following are some specific Examples
`of the compositions of the invention and the
`uses to which they can be put.
`
`Example 1.
`Oxyco-dane with Naloxone — Oxycodone
`is an effective oral narcotic analgesic and is
`generally used in a dose of about 5 mg. of
`oxycodone hydrochloride per tablet, together
`with aspirin, phenacetin and caffeine (similar
`to the well known “AFC with Codeine”). The
`addict would probably have to inject
`the
`narcotic extract from 6—12 tablets to obtain
`a “high,"
`In the compositions of this invention, the
`tablet (or 5 m1 dose of liquid) should contain
`about 5 mg of oxycodone hydrochloride (or
`equivalent as the base or salt) together with
`0.01—0.3 mg. of naloxone hydrochloride (or
`equivalent as base or salts) with or without
`additional drugs such as aspirin, phenacetin
`and caffeine. The preferred tablet dose is
`oxycodone hydrochloride 5 mg. and naloxone
`hydrochloride 0.1 mg., together with aspirin
`224 mg, phenacetin 160 mg., and caffeine 32
`mg.
`
`30
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`35
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`40
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`50
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`60
`
`(or equivalent as base or, salt) together with
`0.003—0.1 mg. of naloxone hydrochloride (or
`equivalent as base or, salt) with or without
`additional drugs such as antihistamines (e.g.,
`chlorpheniramine maleate),
`vasoconstrictors
`(e.g.,
`' phenylephrine
`hydrochloride),
`non-
`narcotic analgesrcs (e.g., acetamrnophen), anti-
`spasmodics, and caffeine. The preferred tablet
`dose is hydrocodone hitartrate 5 mg. and
`naloxone hydrochloride 0.03 mg.
`
`Example 3.
`Codeine with Naloxone — Codeine phos-
`phate is an efiective oral analgesic and anti-
`tussive which is generally used in doses of
`75—60 mg.
`tablets as an analgesic and 10
`mg. tablets or liquid dosages as an antitussive
`With or without additional non-narcotic drugs
`like APC (aspirin, phenacetin, and caffeine).
`The addict would probably have to inject the
`narcotic extract from 4——8 tablets of the 60
`mg. strength to obtain a “high”.
`In the compositions of this invention, the
`tablet should contain 75—60 mg. of codeine
`phosphate or (equivalent as base, sulphate or
`other
`salt)
`together with 0.03—l mg. of
`naloxone hydrochloride (or equivalent as base
`or salts), with or without additional drugs such
`as aspirin, phenacetin, and cafieine. The pre-
`ferred tablet dosage is codeine phosphate 30
`mg. and 0.1 mg. of naloxone hydrochloride,
`together with aspirin 224 mg., phenacetin
`160 mg., and cafieine 32 mg.
`
`65
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`
`Example 4.
`Propoxyphene with Naloxone — Propoxy—
`phene hydrochloride is widely—used as an oral
`analgesic, generally in a 65 mg. dose with
`aspirin, or with aspirin, phenacetin, and cat'-
`feine. The addict would probably have to in-
`ject the narcotic extract from 4—8 tablets to
`obtain a “high”.
`In the compositions of this invention, the
`tablet should contain 30—65 mg. of propoxy-
`phene hydrochloride (or equivalent as base or
`salt) together with 0.03—1 mg. of naloxone
`hydrochloride (or equivalent as base or salt),
`with or Without aspirin or APC (aspirin,
`phenacetin, and caffeine). The preferred tablet
`dosage is propoxyphene hydrochloride 65
`mg. and naloxone hydrochloride 0.2 mg.,
`together with aspirin 224 mg., phenacetin
`160 mg, and cafieine 32 mg.
`
`95
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`100
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`120
`
`Example 2.
`Hydrocodone with Naloxone — Hydro-
`codone is an effective oral narcotic antitussive—
`analgesic and is generally used in a dose of
`about 5 mg. of hydrocodone bitartrate per
`tablet or per 5 ml. of syrup. The addict would
`probably have to inject the narcotic extract
`from 18—36 tablets to obtain a “high”.
`the
`In the components of this invention,
`tablet (or 5 ml. dose of liquid) should con-
`tain about 5 mg. of hydrocodone bitartrate
`
`Example 5.
`Pentazocine with Naloxone — Pentazocine
`is an eflective oral analgesic which is generally
`used as a tablet containing pentazocine hydro—
`chloride equivalent to 50 mg of the base. The
`addict would probably have to inject the ex—
`tract from 4—8 tablets to obtain a “high”.
`In the compositions of this invention, the
`tablet should contain 50 mg. of pentazocine
`base in the form of the hydrochloride (or
`equivalent as the base itself or other salts)
`
`

`

`3M
`
`1,390,772
`
`3
`
`together with 0.02—0.6 mg. of naloxone
`hydrochloride (or equivalent as the base or
`salt). The preferred tablet dose is pentazocine
`hydrochloride equal to 50 mg. of the base
`together with 0.2 mg. of naloxone hydro-
`chloride.
`The other antagonists mentioned herein—
`above, except for the mixed narcotic-antagon-
`ist pentazocine, can be substituted for nalox-
`one in the above Examples, at the following
`multiples or fractions of the naloxene dosages
`given: N — cyclopropylmethyl
`- 7,8 - di-
`hydro — 14 - hydroxynormorphinone - 1/3 (of
`naloxone dosage in mg.) and 21 - cyclo-
`propyl - 7.0; - (1 - hydroxy - 1 - methyl-
`ethyl)
`- 6,14 - endo — ethanotetrahydroori—
`pavine - 1/3. N — cyclopropylmethyl - 7,8-
`dihydro — 14 — hydroxynormorphinone and
`21 - cyclopropyl - 7o: — (1 - hydroxy - 1—
`methylethyl) - 6,14 - endo - ethanotetrahydro-
`oripavine are also used in combination with
`pentazocine, each antagonist being at 1/3 the
`naloxone mg. dosage. It is understood that
`pharmaceutically acceptable acid addition salts
`of the narcotic antagonist bases can also be
`used.
`
`orally than by injection, the narcotic antagon-
`ist being (1) naloxone or a pharmaceutically
`acceptable salt thereof, (2) N - cyclopropyl-
`methyl
`- 7,8 — dihydro - 14 - hydroxy—
`normorphinone or a pharmaceutically accept-
`able salt thereof, or (3) 21 — cyclopropyl - 708-
`(1 — hydroxy - 1 - methylethyl) - 6,14 - enda-
`ethanotetrahydrooripavine or a pharmaceutic-
`ally acceptable salt. thereof, the weight ratio
`of (a) to (b), calculated as the free base, being
`
`a
`oxycodone
`hydrocodone
`codeine
`propoxyphene
`pentazocine
`
`Ratio with
`(b) (1)
`5 : 0.1
`5 : 0.03
`30: 0.1
`65 : 0.2
`50: 0.2
`
`Ratio with
`(b) (2) 0r (3)
`15 : 0.1
`5 : 0.01
`90: 0.1
`195 : 0.2
`150: 0.2
`
`so that (b) does not block the narcotic eifect
`of (a) when the composition is administered
`orally but does prevent an acute euphoriant
`efiect by (a) when the composition is injec-
`ted.
`
`2. A composition according to claim 1
`wherein (b) is (2) or (3).
`3. A composition according to claim 1 sub-
`stantially as described in any one of
`the
`Examples.
`
`WHAT WE CLAIM IS:—
`1. A pharmaceutical composition suitable
`for oral administration comprising (a) a com-
`pound having substantial narcotic activity both
`orally and by injection the compound' being
`J. A. KEMP AND CO.,
`oxycodone, hydrocodone, codeine, propoxy—
`Chartered Patent Agents,
`phene or pentazocine or a pharmaceutically
`14, South Square,
`acceptable salt
`thereof, and (b)
`a narcotic
`Gray’s Inn,
`London, WC1R 5EU.
`antagonist which is substantially less active
`Printed for Her Majesty’s Stationery Oifice, by the Courier Press, Leamington Spa, 1975
`Published by The Patent Ofiice, 25 Southampton Buildings, London, WCZA lAY, from
`which copies may be obtained.
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