PCT
`
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International Bureau
`
`
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(51) International Patent Classification 7 :
`A61F 13/00
`
`(11) International Publication Number:
`
`WO 00/51539
`
`(43) International Publication Date:
`
`8 September 2000 (08.09.00)
`
`(21) International Application Number:
`
`PCT/USOO/05531
`
`(22) International Filing Date:
`
`2 March 2000 (02.03.00)
`
`(30) Priority Data:
`9904911.6
`
`3 March 1999 (03.03.99)
`
`GB
`
`R.P.
`(for all designated States except US):
`(71) Applicant
`SCHERER TECHNOLOGIES, INC. [US/US]; Suite 260,
`2030 East Flamingo Road, Paradise Valley, NV 89119
`(US).
`
`(72) Inventors; and
`JOHNSON, Edward,
`(75) Inventors/Applicants (for US only):
`Stewart [GB/GB]; Willow Vale, Castle End Road, Rus-
`combe, Berkshire RG10 9XG (GB). LACY, Jon [GB/CH];
`6, chemin Dr La Fouine, CPI—1294 Genthod (CH).
`
`(74) Agent: NICKEY, Donald, 0.; Cardinal Health,
`Cardinal Place, Dublin, OH 43017 (US).
`
`Inc., 7000
`
`(81) Designated States: AE, AL, AM, AT, AU, AZ, BA, BB, BG,
`BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB,
`GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG,
`KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK,
`MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG,
`SI, SK, SL, TJ, TM, TR, TI‘, UA, UG, US, UZ, VN, YU,
`ZA, ZW, ARIPO patent (GH, GM, KE, LS, MW, SD, SL,
`SZ, TZ, UG, ZW), Eurasian patent (AM, AZ, BY, KG, KZ,
`MD, RU, TJ, TM), European patent (AT, BE, CH, CY, DE,
`DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE),
`OAPI patent (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML,
`MR, NE, SN, TD, TG).
`
`Published
`With international search report.
`
`of anesthesia, as a sedative and/or for the treatment of anxiety are also provided.
`
`(54) Title: OPIOID AGONIST IN A FAST DISPERSING DOSAGE FORM
`
`(57) Abstract
`
`This invention relates to a pharmaceutical composition for oral administration comprising a carrier and, as active ingredient, an opioid
`(a receptor) agonist, such as fentanyl, or a salt thereof, characterized in that the composition is in the form of a fast—dispersing dosage
`form designed to release the active ingredient rapidly in the oral cavity. A process for preparing such a composition and the use of such a
`composition as an analgesic, for the treatment of chronic pain and/or breakthrough pain, as an anesthetic premedication, for the induction
`
`

`

`
`
`
`
`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT.
`SI
`Slovenia
`LS
`Lesotho
`SK
`LT
`Slovakia
`Lithuania
`LU
`SN
`Luxembourg
`Senegal
`LV
`SZ
`Swaziland
`Latvia
`TD
`MC
`Monaco
`Chad
`MD
`'I'G
`Togo
`Republic of Moldova
`MG
`TJ
`Tajikistan
`Madagascar
`MK
`TM
`Turkmenistan
`The former Yugoslav
`TR
`Republic of Macedonia
`Turkey
`TT
`Mali
`Trinidad and Tobago
`UA
`Ukraine
`Mongolia
`UG
`Mauritania
`Uganda
`US
`United States of America
`Malawi
`UZ
`Uzbekistan
`Mexico
`VN
`Viet Nam
`Niger
`YU
`Netherlands
`Yugoslavia
`ZW
`Zimbabwe
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Singapore
`
`Spain
`Finland
`France
`Gabon
`United Kingdom
`Georgia
`Ghana
`Guinea
`Greece
`Hungary
`Ireland
`Israel
`Iceland
`Italy
`Japan
`Kenya
`Kyrgyzstan
`Democratic People’s
`Republic of Korea
`Republic of Korea
`Kazakstan
`Saint Lucia
`Liechtenstein
`Sri Lanka
`Liberia
`
`ML
`MN
`MR
`MW
`MX
`NE
`NL
`NO
`NZ
`PL
`PT
`RO
`RU
`SD
`SE
`SG
`
`Albania
`Armenia
`Austria
`Australia
`Azerbaijan
`Bosnia and Herzegovina
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`Céte d’lvoire
`Cameroon
`China
`Cuba
`Czech Republic
`Germany
`Denmark
`Estonia
`
`ES
`Fl
`FR
`GA
`GB
`GE
`GH
`GN
`GR
`HU
`IE
`IL
`IS
`IT
`JP
`KE
`KG
`KP
`
`KR
`KZ
`LC
`LI
`LK
`LR
`
`
`
`
`
`

`

`WO 00/51539
`
`PCT/USOO/05531
`
`OPIOID AGONIST IN A FAST DISPERSING DOSAGE FORM
`
`Technical Field
`
`This invention relates to a pharmaceutical composition in the form of a fast
`
`dispersing dosage form and to a process for preparing such a composition. The
`
`invention also relates to the use of such a composition as an analgesic for the
`
`treatment of chronic pain and/or breakthrough pain, as an anesthetic premedication for
`
`the induction of anesthesia as a sedative and as a treatment for anxiety.
`
`10
`
`Background of the Invention
`
`Fentanyl (N—phenyl-N—[l—(2-phenylethy1)-4-piperidinyl]propanamide) is a
`
`potent synthetic opioid (u receptor) agonist, related to pethidine, which possesses a
`
`fast onset and a moderate duration of action. The agonists useful in the present
`
`invention are chemical substances capable of combining with a receptor on a cell and
`
`initiating a reaction or activity that is characteristics of opiate narcotics, but which is
`
`not derived from opium.
`
`Fentanyl, like other opioid agonists, interacts predominantly with u binding
`
`sites in the brain, spinal cord and other tissues. Its principal pharmacological actions
`
`of therapeutic value are analgesia and sedation and, in this respect, fentanyl is
`
`approximately 100 times more potent than morphine and 7,500 times more potent
`
`than pethidine. It is therefore primarily used for its analgesic properties as a
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`component of anesthesia and is normally administered by intravenous or
`
`intramuscular injection, although transdermal and transmucosal dosage forms have
`
`also been developed.
`
`When administered by the intravenous route, the onset of activity is almost
`
`immediate and the duration of analgesia is about 30 to 60 minutes after a single dose
`
`of up to 0.1 mg. Following intramuscular administration of fentanyl, the onset of
`
`activity is 7 to 8 minutes with a duration of activity of 1 to 2 hours. Intravenous
`
`fentanyl may therefore be utilized for analgesic action of short duration during the
`
`anesthetic periods of premedication, induction and maintenance and in the immediate
`
`postoperative period (recovery room) as the need arises. It may also be used as a
`
`narcotic analgesic supplement in general or regional anesthesia and, with a neuroleptic
`
`agent such as droperidol, as an anesthetic premedication for the induction of
`
`anesthesia and as an adjunct in the maintenance of general and regional anesthesia. In
`
`selected high risk patients, such as those undergoing open heart surgery or certain
`
`complicated neurological or orthopaedic procedures, it may also be used as an
`
`10
`
`15
`
`anesthetic agent with oxygen.
`
`Typical dosages for use as a premedication or postoperatively are 50 to
`
`lOOug/kg of body weight. When used as an adjunct to general anesthesia, doses may
`
`range from Zug/kg to 20—50ug/kg depending upon the complexity and duration of the
`
`20
`
`operation.
`
`Intravenously administered fentanyl tends to accumulate in skeletal muscle
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`WO 00/51539
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`PCT/USOO/0553l
`
`and fat from where it is slowly released into the blood. Repeated doses therefore lead
`
`to accumulation and prolonged activity. The plasma protein binding decreases with
`
`increasing ionization of the drug and alterations in pH may therefore affect the
`
`distribution of fentanyl between plasma and the central nervous system. Fentanyl is
`
`primarily transformed in the liver and a high first pass effect is therefore observed
`
`when the drug is administered by non—parenteral routes. However, about 75% of an
`
`intravenous dose of fentanyl is recovered in the urine with less than 10% as the
`
`unchanged drug, the main metabolites being norfentanyl and despropionylfentanyl
`
`which are both inactive.
`
`10
`
`In addition to analgesia, fentanyl may cause alterations in mood, euphoria,
`
`dysphoria and drowsiness. Moreover, therapeutic levels of fentanyl may cause nausea
`
`and vomiting directly by stimulation of the chemoreceptor trigger zone. However,
`
`nausea and vomiting are significantly more common in ambulatory than in recumbent
`
`patients.
`
`15
`
`One of the most serious adverse effects associated with use of intravenous
`
`fentanyl is hypoventilation. This is seen as a reduction in the respiratory rate (breaths
`
`per minute) and in the oxygen saturation level of the blood. Indeed, this
`
`hypoventilation may last longer than the analgesic effect. It is therefore necessary to
`
`ensure that an opioid antagonist, intubation equipment and oxygen are readily
`
`20
`
`available when fentanyl is injected.
`
`Fentanyl may also cause muscle rigidity, particularly in the muscles of
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`WO 00/51539
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`PCT/USOO/05531
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`respiration. This may occur in the postoperative period and patients should therefore
`
`be carefully monitored, especially those receiving a high dose of fentanyl. Should this
`
`effect occur, it may be reversed by administration of naloxone or overcome by
`
`neuromuscular—blocking drugs.
`
`As with other opioid agonists, fentanyl increases the tone and decreases the
`
`propulsive contractions of the gastrointestinal tract leading to constipation. However,
`
`at therapeutic dosages, fentanyl exerts minimal effects on the cardiovascular system,
`
`although orthostatic hypotension and fainting may occur in some patients and vagally—
`
`mediated bradycardia has been reported.
`
`10
`
`15
`
`20
`
`The transdermal dosage form is available as a range of patches offering a
`
`range of release rates from 25 to lOOug of fentanyl per hour over 3 days. In this
`
`dosage form, fentanyl is released as a free base. The actual amount released from the
`
`patch varies with time and also between patients. Essentially, the skin absorbs
`
`fentanyl and a depot of fentanyl concentrates in the upper skin layers. The serum
`
`fentanyl concentrations gradually increase until levelling off with peak serum
`
`concentrations being attained between 24 and 72 hours. After several sequential 72-
`
`hour applications, patients reach and maintain a steady state serum concentration.
`
`After removal of the patch, the serum fentanyl concentrations gradually decline with
`
`levels falling by 50% in about 17 hours. This slower elimination, as compared to that
`
`after intravenous administration, is due to continued absorption of drug from the depot
`
`in the skin after removal of the patch.
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`PCT/US00/05531
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`In view of the above, the transdermal patch is indicated for the management of
`
`chronic pain in patients who require continuous opioid analgesia for pain that cannot
`
`be managed by paracetamol-opioid combinations, non-steroidal analgesics or PRN
`
`dosing with short acting opioids. It is not indicated for the management of acute or
`
`postoperative pain because of the risk of hypoventilation (4% incidence) and should
`
`not be administered to children under 12 unless used in an authorized research setting.
`
`The oral transmucosal system consists of a lozenge of fentanyl citrate attached
`
`to a handle. The lozenge is sucked until complete dissolution is achieved (normally
`
`within about 12 to 15 minutes). A bioavailability study of this device in comparison
`
`10
`
`with intravenous and oral solution administration showed that the absolute
`
`bioavailability from the device was 51%, as compared to 32% from the oral solution,
`
`and that the t was also faster from the device. It is estimated that about 75% of the
`
`total dose from the device is swallowed and a third of this amount reaches the
`
`systemic circulation in addition to the 25% of the dose which is absorbed
`
`15
`
`sublingually.
`
`The oral transmucosal device has been approved for use for anesthetic
`
`premedication in children and adults and for use in anesthesia or monitored anesthesia
`
`care. The approved dose for this dosage form for premedication is between 5-15ug/kg
`
`(400 pg) for adults. However, this product is only authorized for administration in
`
`20
`
`hospital settings where there is immediate access to life support equipment, including
`
`oxygen, facilities for endotraeheal intubation, intravenous fluids and opioid
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`WO 00/51539
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`PCT/USOO/05531
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`antagonists. Also, there is a restriction on personnel authorized to administer this
`
`product.
`
`This device is clearly unsuitable for use during and after operations and can
`
`therefore only be used for some of the indications for which the intravenous injection
`
`form can be used. Also, although several clinical trials have shown that the oral
`
`transmucosal device is generally useful as a premedicant in children prior to surgery,
`
`there is a high incidence of adverse effects, some of which could complicate the
`
`induction of anesthesia.
`
`The main adverse effect is mild facial pruritus (incidence of about 50 to 60%)
`
`but the occurrence of nausea and vomiting has also been high (30 to 50%). Indeed,
`
`the high incidence of vomiting in one study in children led to the termination of the
`
`study and is probably the most troublesome side—effect. Moreover, pre—treatment with
`
`an anti-emetic has not proved to be effective in decreasing the incidence of nausea and
`
`vomiting. In addition, the device has also been shown to reduce oxygen saturation
`
`levels in blood in some children, thus necessitating constant blood oxygen monitoring
`
`in patients taking the product. There are thus significant drawbacks with respect to
`
`the adverse event profile which may limit the clinical usefulness of the oral
`
`transmucosal device form of fentanyl in some settings as a premedication before
`
`surgery.
`
`Approval has been sought for the use of the transmucosal device in the
`
`treatment of breakthrough pain in chronic pain patients already receiving opioid
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`therapy in home or hospital settings. The regulatory authorities have expressed
`
`concern regarding the incorporation of a potent and narcotic drug into a device, which
`
`looks like a child's confectionery product. It is feared that the lollipop form of the
`
`product would be attractive to a child, and result in accidental consumption of the
`
`narcotic, with potential life-threatening consequences.
`
`It is clear from the above that it would be highly desirable from a clinical point
`
`of View to find a way of administering fentanyl and other opioid (u receptor) agonists
`
`which is easy for the patient to accomplish and which bypasses first pass metabolism
`
`in the liver while still providing good bioavailability of the active ingredient and a
`
`10
`
`rapid onset of activity.
`
`According to the present invention there is therefore provided a pharmaceutical
`
`composition for oral administration comprising a carrier and, as active ingredient, an
`
`opioid (LL receptor) agonist, characterized in that the composition is in the form of a
`
`fast-dispersing dosage form designed to release the active ingredient rapidly in the
`
`15
`
`oral cavity.
`
`It has been found that such fast-dispersing dosage forms promote pre- gastric
`
`absorption of the active ingredient, that is, absorption of the active ingredient from
`
`that part of the alimentary canal prior to the stomach. The term “pre-gastrie
`
`absorption” thus includes buccal, sublingual, oropharyngeal and oesophageal
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`20
`
`absorption. An opioid (u receptor) agonist, such as fentanyl, absorbed by such pre—
`
`gastric absorption, passes straight into the systemic circulatory system thereby
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`avoiding first pass metabolism in the liver. Accordingly, bioavailability of an opioid
`
`(u receptor) agonist, such as fentanyl, absorbed in this way may also be increased.
`
`This means that the dose of fentanyl or other opioid (u receptor) agonist may be
`
`reduced while still producing the desired beneficial effects and this decrease in dose
`
`will result in a corresponding reduction of unwanted side effects.
`
`One example of a fast-dispersing dosage form is described in US. Patent No.
`
`4,855,326 in which a melt spinnable carrier agent, such as sugar, is combined with an
`
`active ingredient and the resulting mixture spun into a “candy—floss” preparation. The
`
`spun “candy-floss” product is then compressed into a rapidly dispersing, highly
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`porous solid dosage form.
`
`US. Patent No. 5,120,549 discloses a fast—dispersing matrix system which is
`
`prepared by first solidifying a matrix-forming system dispersed in a first solvent and
`
`subsequently contacting the solidified matrix with a second solvent that is
`
`substantially miscible with the first solvent at a temperature lower than the
`
`solidification point of the first solvent, the matrix—forming elements and active
`
`ingredient being substantially insoluble in the second solvent, whereby the first
`
`solvent is substantially removed resulting in a fast-dispersing matrix.
`
`US. Patent No. 5,079,018 discloses a fast-dispersing dosage form which
`
`comprises a porous skeletal structure of a water soluble, hydratable gel or foam
`
`forming material that has been hydrated with water, rigidified in the hydrated state
`
`with a rigidifying agent and dehydrated with a liquid organic solvent at a temperature
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`PCT/USDO/05531
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`of about 0°C or below to leave spaces in place of hydration liquid.
`
`Published International Application No. W0 93/ 12769 (PCT/JP93/01631)
`
`describes fast—dispersing dosage forms of very low density formed by gelling, with
`
`agar, aqueous systems containing the matrix—forming elements and active ingredient,
`
`and then removing water by forced air or vacuum drying.
`
`US. Patent No. 5,298,261 discloses fast—dispersing dosage forms which
`
`comprise a partially collapsed matrix network that has been vacuum—dried above the
`
`collapse temperature of the matrix. However, the matrix is preferably at least partially
`
`dried below the equilibrium freezing point of the matrix.
`
`Published International Application No. WO 91/04757 (PCT/US90/05206)
`
`discloses fast—dispersing dosage forms which contain an effervescent disintegration
`
`agent designed to effervesce on contact with saliva to provide rapid disintegration of
`
`the dosage form and dispersion of the active ingredient in the oral cavity.
`
`EP-A—0627218 discloses a fast-dispersing dosage form which comprises a tablet
`
`comprising a sugar alcohol or the like as principal ingredient which is prepared by the
`
`wet granulation method in which a kneaded mixture of the sugar alcohol or the like
`
`with a drug is compression molded before drying.
`
`Published International Application No. W0 94/14422 describes a process for
`
`drying frozen discrete units in which the solvent is removed under conditions whereby
`
`the solvent is evaporated from the solid through the liquid phase to a gas, rather than
`
`subliming from a solid to a gas as in lyophilization. This is achieved by vacuum
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`PCT/USOO/05531
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`drying at a temperature below the equilibrium freezing point of the composition at
`
`which point the solvent (such as water) changes phase.
`
`Summary of the Invention
`
`The term “fast-dispersing dosage form”, as used herein and in the claims, refers
`
`to compositions which disintegrate/disperse within 1 to 60 seconds, preferably 1 to 30
`
`seconds, more preferably 1 to 10 seconds and particularly 2 to 8 seconds, of being
`
`placed in the oral cavity. It therefore encompasses all the types of dosage forms
`
`described in the preceding paragraphs as well as any other equivalent dosage form
`
`However, it is particularly preferred that the fast-dispersing dosage form is of the type
`
`described in UK. Patent No. 1548022, that is, a solid fast-dispersing dosage form
`
`comprising a network of the active ingredient and a water-soluble or water-dispersible
`
`carrier which is inert towards the active ingredient, the network having been obtained
`
`by subliming solvent from a composition in the solid state, that composition
`
`comprising the active ingredient and a solution of the carrier in a solvent.
`
`In the case of the preferred type of fast—dispersing dosage form described above,
`
`the composition will preferably contain, in addition to the active ingredient, matrix
`
`forming agents and secondary components. Matrix forming agents suitable for use in
`
`the present invention include materials derived from animal or vegetable proteins,
`
`such as the gelatins, dextrins and soy, wheat and psyllium seed proteins; gums such as
`
`acacia, guar, agar, and xanthan; polysaccharides; alginates; carboxymethylcelluloses;
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`carrageenans; dextrans; pectins; synthetic polymers such as polyvinylpyrrolidone; and
`
`polypeptide/protein or polysaccharide complexes such as gelatin-acacia complexes.
`
`Other matrix formng agents suitable for use in the present invention include
`
`sugars such as mannitol, dextrose, lactose, galactose and trehalose; cyclic sugars such
`
`as cyclodextrin; inorganic salts such as sodium phosphate, sodium chloride and
`
`aluminium silicates; and amino acids having from 2 to 12 carbon atoms such as a
`
`glycine, L-alanine, L—aspartic acid, L—glutamic acid, L—hydroxyproline, L-isoleucine,
`
`L—leucine and L—phenylalanine.
`
`One or more matrix forming agents may be incorporated into the solution or
`
`10
`
`suspension prior to solidification. The matrix forming agent may be present in
`
`addition to a surfactant or to the exclusion of a surfactant. In addition to forming the
`
`matrix, the matrix forming agent may aid in maintaining the dispersion of any active
`
`ingredient within the solution or suspension. This is especially helpful in the case of
`
`active agents that are not sufficiently soluble in water and must, therefore, be
`
`15
`
`suspended rather than dissolved.
`
`Secondary components such as preservatives, antioxidants, surfactants,
`
`viscosity enhancers, coloring agents, flavoring agents, pH modifiers, sweeteners or
`
`taste-masking agents may also be incorporated into the composition. Suitable
`
`coloring agents include red, black and yellow iron oxides and FD&C dyes such as
`
`20
`
`FD&C Blue No. 2 and FD&C Red No. 40 available from Ellis & Everard. Suitable
`
`flavoring agents include mint, raspberry, licorice, orange, lemon, grapefruit, caramel,
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`vanilla, cherry and grape flavors and combinations of these. Suitable pH modifiers
`
`include citric acid, tartaric acid, phosphoric acid, hydrochloric acid, maleic acid and
`
`sodium hydroxide. Suitable sweeteners include aspartame, acesulfame K and
`
`thaumatic. Suitable taste-masking agents include sodium bicarbonate, ion—exchange
`
`resins, cyclodextrin inclusion compounds, adsorbates or microencapsulated actives.
`
`The compositions of the invention comprise an opioid (u receptor) agonist as
`
`an active ingredient. Representative drugs within this class include, but are not
`
`limited to, alfentanil, codeine, diamorphine, dihydrocodeine, fentanyl,
`
`hydromorphine, methadone, morphine, morphine—6—glucoronide, oxymorphine,
`
`pethidine, sufentanil and tramadol and salts of these compounds. Such drugs are
`
`commercially available and their routes of administration and dosage rates are
`
`reported in the literature.
`
`Thus, there is disclosed a pharmaceutical composition for oral administration
`
`comprising a carrier and, as active ingredient, an opioid agonist characterized in that
`
`the composition is in the form of a fast dispersing dosage form designed to release the
`
`active ingredient rapidly in the oral cavity.
`
`A preferred active ingredient for use in the invention is fentanyl or a salt
`
`thereof. If a salt is used, it is preferred that the salt is an acid—addition salt of fentanyl,
`
`especially the citrate salt. However, since it is known that the un-ionized form of
`
`fentanyl penetrates mucosal membranes better than the ionized form, the composition
`
`of the invention may be buffered to a suitable pH range typically 7 to 7.5 by addition
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`of an acid or alkaline substance.
`
`The active ingredient is generally present in the composition in an amount from
`
`0.2 to 95%, normally 1 to 20%, by weight of the composition of dried dosage form.
`
`Generally the active ingredient is present in an amount from 0.1 to 200 mg, normally
`
`0.2 to 20 mg per dose depending upon the particular drug.
`
`When the active ingredient is fentanyl it is preferably incorporated in the
`
`composition in an amount of from 0.5 to 10% by weight of the dried dosage form.
`
`According to another aspect of the invention there is provided a process for
`
`preparing a pharmaceutical composition as previously defined which comprises
`
`bringing a carrier into association with the active ingredient.
`
`In a further aspect, the invention provides the use of a fast-dispersing dosage
`
`form designed to release active ingredient rapidly in the oral cavity to deliver an
`
`opioid (u receptor) agonist, such as fentanyl, or a salt thereof. A method of
`
`administering an opioid (u receptor) agonist, such as fentanyl, or a salt thereof to a
`
`patient which comprises introducing into the oral cavity of the patient a composition
`
`as previously defined is also provided.
`
`The invention also provides, in another aspect, a composition as defined above
`
`for use as an analgesic. The composition is particularly useful for the treatment of
`
`chronic pain, especially in a patient already receiving opioid therapy. In this respect,
`
`it is envisaged that the composition of the invention could provide the possibility of
`
`more individual titration of dose when required when the pain is most severe,
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`especially during the night.
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`It is estimated that about 29% of patients with cancer continue to experience
`
`moderate to severe pain despite analgesic therapy and this can occur as intermittent
`
`breakthrough pain, often due to increases in a patient's activity level. Attempts to
`
`counteract this type of pain by increasing the dose of long—acting formulations of
`
`analgesics often produce slow onset of analgesia and unwanted side-effects of
`
`sedation, constipation or nausea and vomiting. However, the composition of the
`
`invention provides a rapidly acting, potent analgesic which would reduce the pain for
`
`the required time and then wear off fairly quickly thereby minimizing the side-effects
`
`of the active ingredient. Accordingly, the invention also provides a composition for
`
`use in the treatment of breakthrough pain in a patient experiencing chronic pain.
`
`The composition of the invention is easier and quicker to administer than any of
`
`the existing dosage forms of fentanyl and other opioid (u receptor) agonists. Thus, it
`
`is also suitable for administration in situations where an anesthetic, sedative or
`
`anxiolytic effect is required and the patient is conscious. The invention therefore also
`
`provides a composition for use as an anesthetic premedication, for the induction of
`
`anesthesia, for use as a sedative and/or for the treatment of anxiety.
`
`According to a further aspect of the invention there is also provided the use of a
`
`composition as defined above for the manufacture of a medicament for use as an
`
`analgesic, for the treatment of chronic pain and/or breakthrough pain, as an anesthetic
`
`premedication, for the induction of anesthesia, as a sedative and/or for the treatment of
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`anxiety.
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`PCT/U300/05531
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`A method of treating pain, especially chronic pain or breakthrough pain, or
`
`anxiety is also provided which comprises introducing into the oral cavity of a patient a
`
`therapeutically effective amount of a composition as previously defined.
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`The invention also provides a method of inducing an anesthetic effect or a
`
`sedative effect in a patient which comprises introducing into the oral cavity of the
`
`patient a pre-determined amount of a composition as previously defined calculated to
`
`induce anesthesia or sedation respectively in the patient.
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`Detailed Description of the Invention
`
`This invention is further illustrated by the following Examples.
`
`EXAMPLE 1
`
`Preparation of a fast—dispersing dosage form containing fentanyl citrate
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`(a)
`
`Preparation of fentanyl 0.126% dispersion
`
`Gelatin (765g) and mannitol (540g) were dispersed in a portion of purified
`
`water (16kg) by mixing thoroughly in the bowl of a vacuum mixer. The mix was then
`
`heated to 40°C i 2°C and homogenised for ten minutes to allow complete dissolution
`
`of the solids. The mix was cooled down to room temperature (20—24°C). When
`
`cooled, the fentanyl citrate (22.68g), the aspartame (90g), and mint flavour (90g) were
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`added sequentially to the mix. The mix was then homogenized to ensure complete
`
`dissolution of the solids. The remaining water (492g) was added to the mixer and the
`
`bulk mix homogenized to ensure dissolution was complete.
`
`(b)
`
`Preparation of fentanyl 0.2mg gas the base) units.
`
`250 mg of fentanyl 0.126% dispersion formed in (a) above was dosed into
`
`each of one of a series of pre—formed blister pockets having a pocket diameter of about
`
`12mm. The blister laminate comprised 200nm PVC (polyvinyl chloride) coated with
`
`40gsm PVdC (polyvinyl dichloride). The product was frozen immediately in a liquid
`
`nitrogen freeze tunnel. The frozen product was then stored below -20°C for a
`
`minimum of 12 hours prior to freeze-drying in a freeze drier using a drying
`
`temperature of +10°C and a chamber pressure of 0.5 mbar. The freeze dried units
`
`were then inspected for the presence of critical defects and the remainder of the batch
`
`sealed with lidding foil consisting of a paper/foil laminate (20pm aluminium).
`
`Each blister was then coded with a batch number and overwrapped in a
`
`preformed sachet by placing the blister in the sachet and sealing the open end of the
`
`sachet completely. Each sachet was then labelled with the product name, batch
`
`number, date of manufacture and suppliers name.
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`
` Ingredient Weight
`
`% by Weight of Composition
`
`
`Purified water EP/USP*
`229.061
`91.624
`
`
`
`Fentanyl citrate EP/USP
`0.126
`Gelatin EP/USNF
`10.625
`4.250
`
`Mannitol EPfUSP
`7.500
`3.000
`0.500
`
`
`
`
`
`1.250
`0.500
`000.000
`100.000
`
`
`
`
`
`
`
`Aspartame EP/USNF
`
`Mint Flavor
`
`*Ingredient removed during the 1yophilization process.
`
`EXAMPLES 2 TO 4
`
`The following formulations were prepared by analogous methods to Example 1.
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`EXAMPLE 2
`
`
`Ingredient
`Weight
`
`Purified water EP/USP*
`/ 227.497
`
`% by Weight of Composition
`90.999
`
`
`
`
`Fentanyl citrate EP/USP
`Gelatin EP/USNF
`
`Mannitol EP/USP
`
`Citric Acid EP/USP
`
`Glycine USP
`
`Cherry Flavor
`TOTAL
`
`0.628
`10.000
`
`7.500
`
`1.250
`
`1.250
`
`1.875
`250 000
`
`0.251
`4.000
`
`3.000
`
`0.500
`
`0.500
`
`0.750
`100.000
`
`*Ingredient removed during the lyophilization process.
`
`1 0
`
`EXAMPLE 3
`
`
`
`Ingredient
`|
`Weight
`% by Weight of Composition
`
`
`
`448.743
`89.749
`Purified water EP/USP*
`
`
`
`Fentanyl citrate EP/USP
`1.257
`
`4.500
`Gelatin EP/USNF
`
` Mannitol EP/USP
`
`
` Aniseed Flavor
`
`Aspartame EP/USNF
`TOTAL
`
`500.000
`100.000
`
`
`
`
`
`
`*Ingredient removed during the lyophilization process.
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`EXAMPLE 4
`
`
`
`% by Weight of Composition
`Ingredient
`'
`Weight
`
`
`Purified water EP/USP*
`457.169
`
`
`
`0.314
`
`1.571
`Fentanyl citrate EP/USP
`Gelatin EP/USNF
`20.000
`4.000
`
`Mannitol EP/USP
`15.000
`3.000
`
`
`
`2.500
`0.500
`Grape Flavor
`
`Aspartame EP/USNF
`3.750
`0.750
`
`
`FD&C Blue No. 2
`0.010
`0002
`j
`
`500.000
`100.000
`
`
`
`
`*Ingredient removed during the lyophilization process.
`
`Examples 1 to 4 using fentanyl citrate correspond to 200, 400, 800 and
`
`1000ug of fentanyl base respectively.
`
`Industrial Applicability
`
`A need exists in the medical community for improved pain management. The
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`present invention provides a dosage form that can be efficiently and economically
`
`used by patients for the management of their breakthrough pain. This is benefit tot he
`
`patients and to the caregivers.
`
`While the invention has been described through the use of specific
`
`embodiments, one skilled in the art will appreciate that various changes and
`
`modifications can be made without departing from the spirit and scope of the
`
`invention claimed herein.
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`CLAIMS
`
`PCT/USOO/05531
`
`1.
`
`A pharmaceutical composition for oral administration comprising a carrier
`
`and, as active ingredient, an opioid agonist characterized in that the composition is in
`
`the form of a fast-dispersing dosage form designed to release the active ingredient
`
`rapidly in the oral cavity.
`
`2.
`
`A composition according to claim 1 in which the opioid agonist is fentanyl or
`
`a salt thereof.
`
`3.
`
`A composition according to claim 1 in which the composition is in the form of a
`
`solid fast-dispersing dosage form comprising a network of the active ingredient and a
`
`water-soluble or water-dispersible cam'er which is inert towards the active ingredient,
`
`the network having been obtained by subliming solvent from a composition in the
`
`solid state, that composition comprising the active ingredient and a solution of the
`
`carrier in a solvent.
`
`4.
`
`A composition according to claim 1 wherein the composition disintegrates
`
`within 1 to 60 seconds of being placed in the oral cavity.
`
`5.
`
`A composition according to claim 1 in which the active ingredient is present in
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`an amount from 0.2