‘0)
`
`Europfiisches Patentamt
`
`European Patent Office
`
`Office européen des brevets .
`
`® Publication number:
`
`0 205 282
`
`A2
`
`®
`
`EUROPEAN PATENT APPLICATION
`
`@ Application number: 86304044.0
`
`int. cm A61 K 9/22 , A61 K 9/52
`
`(29 Date of filing: 28.05.86
`
`Date of publication of application:
`17.12.86 Bulletin 86/51
`
`Luxembourg(LU)
`
`
`
` @ Priority: 11.06.85 GB 8514665
`@ Applicant: Euroceitique SA
`122 Boulevard De La Petrusse
`
`
`
`
`Designated Contracting States:
`AT BE CH DE FR (33 IT LI LU NL SE
`
`
`
`
`
`® inventor: Jenkins, Anthony William
`Bridge Farm West Street
`Comberton, Cambridge(GB)
`Inventor: Leslie, Stewart Thomas
`4, Babraham Road
`Cambridge, CBZ ZRA(GB)
`inventor: Miller, Ronald Brown
`Bruderhoizallee, 191
`CH-Basel, 4059(CH)
`
`
`
`
`Cambridge CB4 4GW(GB)
`
`
`Representative: James, Stephen Richard,
`Napp Pharmaceutical Group Cambridge
`Science Park Milton Road
`
`@ Oral pharmaceutical composition.
`
`@ A sustained release, oral pharmaceutical com-
`position in solid unit dosage form, for application to
`the mucosa of the oral or nasal cavity, comprises
`compressed, mucosa adhesive cellulose, coated
`granules. the granules comprising a drug, a higher
`aliphatic
`alcohol
`and a hydrated water
`soluble
`hydroxyaikyl cellulose.
`Preferably the composition is in the form of a
`buccal
`tablet. especially a kidney shaped buccai
`Ntablet. Preferred materials are morphine as the drug,
`(hydroxypropyi cellulose as the mucosa adhesive cel-
`lulose, cetostearyi alcohol as the aliphatic alcohol
`
`wand hydroxyethyl cellulose as the water soluble cel-
`Niulose.
`The composition has enhanced adherent prop-
`(parties (to the mucosa) and prolongs the bioavailabil-
`Nity of the drug.
`
`O D
`
`.
`I.“
`
`Xerox Copy Centre
`
`

`

`O 205 282
`
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`

`1
`
`O 205 282
`
`2
`
`ORAL PHARMACEUTICAL COMPOSITION
`
`invention relates to a sustained
`The present
`release, oral pharmaceutical composition and,
`in
`particular, to an oral vehicle adapted for application
`to the mucosa of the oral or nasal cavity, especially
`within the buccal cavity.
`The administration of drugs using oral vehicles
`retained in the buccal cavity is known. Such admin-
`istration is generally effected by inserting an oral
`vehicle (eg. a tablet) containing a drug into the
`buccal cavity of
`the patient‘s mouth and then
`pressing the vehicle against
`the mucosa of
`the
`cheek or the gum until it adheres.
`Absorption of the drug in the vehicle generally
`occurs directly through the mucosa at the inner
`surface of the cheek and/or gum into the patient's
`bloodstream.
`In some cases, however,
`the drug
`may be absorbed gastrically or enterally by the
`absorption of drug contained in swallowed saliva.
`The buccal method of drug administration has
`considerable advantages over adminstration by, for
`example, swallowing a tablet or injection. One ad-
`vantage is that administration can be discontinued
`at any time (e.g. when undesired effects arising
`from the administration are identified) simply by
`removing the remainder of the vehicle. Another
`advantage, over oral administration,
`is that
`first
`pass, drug metbolism may be avoided.
`A particular problem associated with the buccal
`administration of drugs. however,
`is that the oral
`vehicle containing the drug tends, after a period, to
`become detached from the mucosa. At best this
`
`can be merely inconvenient, at worst it may lead to
`the patient swallowing the vehicle.
`it is an object of the present invention to pro-
`vide a sustained release, oral pharmaceutical oom-
`posttion having improved properties of adherence
`to the mucosa within the oral or nasal, especially
`buccal cavity.
`‘
`It is a further object of the present invention to
`provide an oral vehicle prepared from the improved
`composition and shaped to facilitate attachment
`within the bucoal cavity.
`Further objects and advantages of the present
`invention will become apparent from the following
`detailed description thereof.
`'
`According to the present invention, therefore,
`there is provided a sustained release, oral phan-
`maceutical composition in solid unit dosage form,
`for application to the mucosa of the oral or nasal
`cavity. comprising compressed. mucosa-adhesive
`cellulose coated granules, the granules comprising
`a drug, a higher aliphatic alcohol and a hydrated
`water soluble hydroxyalkyl cellulose.
`Preferably the solid unit dosage form is an oral
`vehicle for attachment within the buccal cavity.
`
`it is an important feature of the present inven-
`tion that the granules used to prepare the solid unit
`dosage form (e.g.
`tablet) comprise extragranular
`mucosa-adhesive cellulose which improves the at—
`tachment of the dosage form to the oral or nasal
`mucosa, especially within the buccal cavity.
`Preferably the extragranular, mucosa adhesive
`cellulose is applied to the granules in the form of a
`powdered solid rather than a solution. This allows
`greater control over the water content of the gran-
`ules, avoids swelling of
`the granules and also
`avoids an unnecessary drying step.
`The present inventors have surprisingly found
`that by employing extragranular cellulose adhesive,
`especially powdered adhesive, the adherent prop-
`erties of the resulting dosage form are significantly
`greater than those of a dosage form having intrag-
`ranular adhesive only.
`for
`The mucosa adhesive cellulose may be,
`example, a carboxyalkyl cellulose, such as sodium
`carboxymethyl cellulose or a hydroxyalkyl cellu-
`lose, such as hydroxypropylmethyl cellulose. Pref-
`erably, however, hydroxypropyi cellulose (HPC),
`especially that sold by the Hercules Powder Com-
`pany as Klucel HF (Trade Mark),
`is the mucosa
`adhesive material.
`
`Preferably. the mucosa adhesive cellulose is a
`high molecular weight material having a number
`average molecular weight above 200,000, espe-
`cially above 500,000.
`Surprisingly, when HPC is employed as the
`adhesive in the present forrnulat‘uan it
`is found to
`give the dosage form adhesive properties superior
`to those achieved using previously preferred adhe-
`sives, such as Karaya gum and acrylic acid poly-
`mers (eg. carbopol gel) or mixtures of these adhe-
`sives with other known binders.
`
`The concentration of extragranular adhesive
`cellulose (as a proportion of the total dosage form ‘
`weight) is preferably between 2% and 15% (w/w),
`especially between 4% and 10% (w/w). Prior to
`compression,
`the granules coated with mucosa-
`adhesive cellulose will, preferably, have a granule
`size of less than 1000th.
`
`is an aliphatic al-
`The higher aliphatic alcohol
`cohol containing from 8 to 18 carbon atoms which
`is optionally substituted by a further aliphatic group
`containing from 8 to 18 carbon atoms. Suitable
`alcohols include lauryl alcohol, myristyl alcohol,
`stearyl alcohol, or, which is preferred, cetyl alcohol
`and cetostearyl alcohol. The higher aliphatic al-
`cohol. together with the water soluble hydroxyalkyl
`cellulose, serves to control the release of the drug
`from the composition. The level of alcohol
`in the
`composition will
`therefore be determined by the
`
`10
`
`75
`
`2O
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`

`

`3
`
`"-4:
`
`G 205 282
`
`4
`
`rate of drug release required. Generally, however,
`the composition will contain between 5% and 35%
`(w/w), especially 10% and 30% (w/w), (as a propor.
`tion of the total dosage form weight) of the higher
`aliphatic alcohol.
`The hydroxyalkyl cellulose is a hydroxy lower
`alkyl ether of cellulose and is preferably selected
`from the group consisting
`of hydroxymethyl,
`hydroxyethyl, hydroxypropyl and hydroxypropyl-
`methyl cellulose, with hydroxyethyl cellulose (for
`example Natrosol 250 HX, Trade Mark, Hercules
`Powder Company) being partiCUIarly preferred. The
`hydroxyalkyl cellulose, together with the higher ai«
`iphatic alcohol, serves to control the release of the
`drug from the composition. The level of hydmxyal-
`kyl cellulose in the composition will therefore be
`determined by the rate of drug release required.
`Preferably the composition will contain between
`2% and 15% (wlw), as a proportion of the total
`dosage form weight, of the hydroxyalkyl cellulose.
`it should be noted that when the water‘soluble
`
`hydroxyalkyl cellulose used in the present com
`position is also the composition‘s mucosa adhe-
`sive,
`then the amount of hydroxyalkyl cellulose
`present in each dosage form is at least the sum of
`the hydroxyalkyl cellulose added as water—soluble
`hydroxyalkyl cellulose and the hydroxyalkyl
`cel—
`lulose added as extragranular adhesive.
`The drug employed in the present composition
`is preferably absorbable through the oral or nasal
`mucosa.
`In some instances, however, drugs that
`are absorbed gastrically and/or enterically (rather
`than via the mucosa] route) may be employed. In a
`still further instance, the drug may be one that acts
`locally in the mouth, for example in the treatment
`of mouth ulcers. Suitable medicaments will be well
`known to those skilled in the pharmaceutical art.
`Listed below are certain of the drug categories
`within which are classeda number of the drugs
`that may be employed in the present composition.
`(a) Analgesic agents; eLg. morphine. or ana~
`legues
`thereof,
`phenazocine,
`pentazocine.
`buprenorphine;
`(b) Anti-inflammatory agents; e.g. ibuprofen, in-
`domethacin, acetaminophen, phenacetin. aspirin,
`aminopyrine,
`sulpy'rine.
`phenylbutazone,
`mefenamic acid, flufenamic acid, ibutenac, colchi-
`cine,
`probenecid,
`ethenzamide,
`salicylamide,
`ketoprofen,
`tlurbiprofen, diclofenac, clidanac, al-
`clotenac, sulindac, piroxicam:
`(c) Antihistamines, e.g. clemastine fumarate,
`mepyramine, diphenylhydramine hydrochloride, de-
`xchlorpheniramine maleate;
`(d) Topical anaesthetics, e.g. benzocaine, pro-
`caine, lidocaine;
`(e) Vasodilators, e.g. nitroglycerin, nitedipine,
`papaverine,
`isosorbide dinitrate, diltiazem. nicar-
`dipine;
`
`1O
`
`15
`
`20
`
`25
`
`30
`
`35
`
`50
`
`55
`
`(f) Antitussives and expectorants, such as co~
`deine phosphate and isoproterenol hydrochloride;
`(9) Hormones; e.g.
`insulin, vasopressin and
`heparin;
`(h) Diuretics, e.g. ethacrynic acid and ben-
`drofluazide;
`(i) Anti/hypotensives,
`clonidine;
`(j) Anti-neoplastic agents, e.g. cytarabine and
`doxorubicin;
`
`propranolol
`
`and
`
`e.g.
`
`as
`
`albuterol
`
`-
`
`(k) Antidiabetic drugs. e.g. chlorpropamide and
`glibenclamide;
`such
`(l) Bronchodilators,
`(salbutamol), ipratropiumbromide;
`(m) Antiarrythmic agents, e.g. verapamil;
`(n) Anti-inflammatory steroids, e.g. hydrocor-
`tisone, prednisone, prednisolone, triamcinolone, de-
`xamethasone. betarnethasone; _
`(o) Antibiotics or Fungicides, e.g. tetracyclines,
`leucomycins.
`tradiomycins,
`penicillins,
`cephalosporins, erythromycins;
`agents.
`(p) Chemotherapeutic
`phathiazole, nitrofurazone, clotrimazole;
`(q) Cardiac tonics. e.g. digitalis. digoxin;
`(r) Oral antiseptics. e.g. chlorhexidine, hexyl-
`resorcinol, dequalinium chloride and ethacridine;
`(s) Antiasthmatics, e.g. disodium cromoglycate:
`(t) Drugs acting on the central nervous system,
`e.g. diazepam and estazolarn;
`(u)
`Anti-epileptics.
`meprobamate and nitrazepam;
`(v) Anticholinergics, e.g. scopolamine;
`(w) Muscle Relaxants e.g. baclofen, dentrolene
`sodium, cyclobenzaprine hydrochloride;
`(x) Beta-blocker, e.g. pindoiolr
`(y) Mtiarteriosclerotic agents, e.g. clofibrate,
`pentoxifylline;
`for
`(2) Drugs
`cimetidine, ranitidinej
`
`e.g.
`
`sul-
`
`e.g.
`
`phenytoin,
`
`treatment ot' ulcers,
`
`e.g.
`
`Other. e.g. nicotine.
`the dmg may be
`it will be appreciated that
`added to the present composition not only in its
`tree form, but also as a simple pharmacologically
`acceptable derivative, such as an ether, an ester,
`an amide, an acetal. a salt and the like. In some
`cases, such derivatives may actually be preferred.
`Particularly preferred drugs for use in the
`present
`composition are morphine, nitedipine,
`phenazocine, verapamil and salbutamol.
`These drugs can be used either singly or as a
`mixture of two or more. The amount of drug to be
`blended in a solid dosage unit will generally be
`enough to maintain a therapeutic level of the drug
`in the bloodstream for a predetermined period.
`
`

`

`,
`
`5
`
`0 205 282
`
`6
`
`"C
`
`in addition to the constituents discussed above,
`the present pharmaceutical composition may also
`contain certain of the known excipients, such as
`lubricants, binders, vehicles, colouring agents, taste
`controlling agents and odour controlling agents,
`that are employed to improve the appearance, od-
`our or taste of pharmaceutical preparations.
`ln a particularly preferred embodiment of the
`present composition, the granules contain between
`2% and 15% (w/w), especially between 4% and
`10% (w/w), of a binder to improve the binding and
`strength of the dosage form. Suitable binders in-
`clude starch. dextrin. tragacanth, gelatin, polyvinyl-
`pyrrolidone, polyvinylalcchol or, which is especially
`preferred. a mucosa adhesive cellulose such as a
`carboxyalkyl cellulose or a hydroxyalkyl cellulose
`especially sodium carboxymethyl cellulose, hydrox-
`ypropylmethyl
`cellulose
`or, most
`especially,
`hydroxypropyl cellulose. Compositions according to
`this invention having both extragranular adhesive
`cellulose and intragranular adhesive cellulose (as
`binder) have been found to exhibit particularly good
`qualities of adhesion and strength.
`it should be noted that when the same cel-
`lulosic material is used in the present composition
`as the water soluble hydroxyalkyl cellulose,
`the
`extragranular mucosa adhesive cellulose and the
`binder,
`then the amount of cellulosic material
`present in each dosage form is at least the sum of
`that added as water-soluble hydroxyalkyl cellulose
`and that added as binder and extragranular adhe-
`sive.
`
`The present composition is prepared by com-
`pressing mucosa—adhesive cellulose coated gran-
`ules of a mixture of«a drug. a higher aliphatic
`alcohol and a hydrated water soluble hydroxyalkyl
`cellulose.
`
`The mucosa—adhesive cellulose coated gran—
`ules may be prepared in a number of ways. For
`example, the drug may first be incorporated in the
`higher alcohol or the cellulosic material prior to
`blending‘ this with the remainder of the granules'
`constituents. Alternatively, and preferably. the drug
`may first be mixed with both the water soluble
`hydroxyalkyl cellulose and a binder before this
`' mixture is blended with the higher alcohol.
`The hydration of the water soluble hydroxyalkyl
`cellulose is effected at any convenient stage during
`the mixing of the granules’ ingredients.
`It must be
`carried out carefully since excessive hydration of
`the
`hydroxyalkyl
`cellulose
`results
`in
`an
`un-
`manageable granular mass, whilst insufficient hy-
`dration results in an erratic and inferior release rate
`
`of medicament
`
`from the final composition. The
`
`degree of hydration is in practice preferably that
`obtained by the addition of a quantity of water
`between 1 and 5, especially. 2 and 3 times, the dry
`weight of the water soluble hydroxyalkyl cellulose.
`Once the granules'
`ingredients have been
`mixed and hydrated they are then granulated and
`sieved to afford granules of a suitable granule size,
`preferably less than 1000um. Finally the granules
`are mixed with extragranular mucosa adhesive cel-
`lulose to form mucosa adhesive cellulose coated
`
`granules.
`It is important to note that the above methods
`and processes of granule formation are merely
`illustrative. Other preparations of the present mu-
`cosa adhesive coated granules will be immediately
`apparent to those skilled in this art.
`The compressed granules may be formed into
`any suitable oral dosage form by the use of. for
`example. a punch, die or press, in order to facilitate
`the use of the present composition in the mucosal,
`especially buccal, administration of drugs, however,
`there is provided, in a further aspect of the present
`invention, a kidney-shaped oral vehicle adapted to
`fit closely the shape of the buccal cavity. Such an
`oral vehicle may be prepared using kidney shaped
`punches and dies.
`Oral dosage units according to the present
`invention in the form of kidney-shaped oral vehicles
`have been found to be particularly convenient in
`the mucosal, especially buccal, administration of
`the drugs.
`it has been found that most patients
`may eat and drink freely whilst the kidney shaped
`oral vehicle is in position.
`Sustained release, oral pharmaceutical com-
`positions and oral vehicles according to this inven-
`tion, as well as processes for preparing both com-
`positions and vehicles, will now be described by
`way of example only.
`A kidney-shaped oral vehicle according to this
`invention is particularly exemplified by reference to
`Figure 1
`in which a plan, a side elevation and a
`rear elevation is shown.
`.
`
`Figure 2 shows the morphine plasma level
`achieved (as a function of time) by four patients
`using three morphine sulphate formulations.
`Figure 3 shows the morphine plasma levels
`achieved (as a function of time) by nine patients
`using a buccal morphine tablet prior to surgery.
`
`Example 1
`
`The following ingredients were used to prepare
`one thousand tablets (200 mg total weight, 10 mg
`of morphine sulphate).
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`5O
`
`55
`
`

`

`7
`
`0205282
`
`8
`
`Ingredient
`
`Height
`
`(gm)
`
`Morphine SuLphate
`
`MannitoL
`
`Lactose (Anhydrous)
`
`7.5
`
`25.0
`
`15.0
`
`Hydroxyethyt ceLLuLose
`
`13.3
`
`(NatrosoL 250 HX)
`
`Hydroxypropyt ceLLuLose
`
`12.5
`
`(KLuceL HF)
`
`CetostearyL ALcohoL
`
`Water
`
`26.?
`
`q.s.
`
`10.0
`
`50.0
`
`35.0
`
`26.6
`
`25-0
`
`53.4
`
`q.s.
`
`(approx. 65 9.)
`
`Example 3
`
`lactose,
`sulphate, mannitol,
`The morphine
`hydroxyethyl cellulose and hydroxypropyl cellulose
`(159.. added as a binder) were dry blended until
`thoroughly mixed. The mixture was then hydrated -
`(approx. 659.) until a Wet granular mass was ob-
`tained. The hydrated material was then partially
`dried in a Fluid Bed Dryer (FBD) at 6011C. granulat-
`ed and sieved through a 12 mesh screen. The
`granulated material was then completely dried in
`the FBD at BOBC, regranulated and sieved through
`a 16 mesh screen.
`
`To the warmed morphine sulphate containing
`granules was added molten cetostearyl alcohol and
`the whole was mixed thoroughly. This mixture was
`allowed to cool in the air, regranulated and sieved
`through a16 mesh screen.
`The extragranular hydroxypropyl cellulose ..
`(109.) was then added and mixed with the gran-
`, ules, until at least a substantial proportion of the
`granules had a coating of hydrcxypropyl cellulose.
`Finally the coated granules were compressed
`and formed, using a kidney-shaped punch,
`into
`kidney-shaped tablets. This process afforded one
`thousand 200 mg. tablets, each containing 10 mg.
`of morphine sulphate.
`'
`if desired the tablets could then be coated
`
`using standard procedures.
`
`Example 2
`
`The method of Example 1 was followed except
`that the amount of morphine sulphate employed
`was increased to 20 g. and the amount of lactose
`employed was reddced to 25 g.
`
`20
`
`The method of Example 1 was followed except
`that the amount of morphine sulphate employed
`was increased to 30 ’g. and the amount of lactose
`employed was decreased to 15 9.
`
`25
`
`Example 4
`
`The method of Example 1 was followed except
`sodium carboxymethyl
`cellulose
`replaced
`that
`hydroxypropyl cellulose as~the mucosa adhesive
`cellulose and binder.
`
`Example 5
`
`The method of Example 1 was followed except
`that morphine sulphate was replaced by nitroglyc-
`erin
`(5g).
`added as
`a
`1
`in
`to blend
`of
`nitroglycerine and lactose,
`the amount of anhy’
`drous lactose being reduced to zero.
`"
`
`Example 6
`
`The following ingredients were used to prepare
`one thousand tablets (200 mg. total weight. 20 mg.
`nifedipine).
`
`30
`
`35
`
`50
`
`55
`
`

`

`9
`
`D 205 282
`
`10
`
`Ingredient
`
`Nifedipine (micronised)
`
`XyLitoL
`
`Anhydrous Lactose
`
`Hydroxyethyt ceLLuLose
`
`Z
`10
`
`25
`
`42.75
`
`Weight
`20
`
`(gm)
`
`so
`
`85.5
`
`(Nat rosol. ZSOHX)
`
`3.25
`
`5.5
`
`Hydroxypropyt ceLLuLose
`
`(KLuceL HF)
`
`10
`
`‘
`
`20
`
`Sodium carboxymethyt ceLLuLose
`
`(Btanose 7MFD)
`
`Cetostearyt aLcohoL
`
`Water
`
`2.5
`
`6.5
`
`5
`
`13
`
`25
`
`lactose, hydroxyethyi
`7 The nifedipine, xylitol.
`ceHubse and hydroxypropylceflubse(15g,added
`as a binder) were dry blended until
`thoroughly
`mixed. The mixture was then hydrated (approx.
`25ml.) until a wet granular mass was obtained. The
`hydrated material was then partially dried in a Fluid
`Bed Dryer (FBD) at 6021C, granulated and sieved
`through a 12 mesh screen. The granulated material
`was then completely dried in the F80 at 60cc,
`regranulated and sieved through a 16 mesh screen.
`To the warmed nifedipine containing granules
`was added molten cetostearyl alcohol and the
`whole was mixed thoroughly. This mixture was
`allowed to cool in the air, regranulatedand sieved
`through a 16 mesh screen.
`
`20
`
`25
`
`30
`
`The extragranular hydroxypropyl cellulose (59)
`and sodium carboxymethyl cellulose (5g) was then
`added and mixed with the granules, until at least a
`substantial proportion of the granules had a coating
`of hydroxypropyl cellulose. Finally the coated gran-
`ules were compressed and formed, using a kidney-
`shaped punch, into kidney-shaped tablets.
`This process afforded one thousand 200mg.
`tablets, each containing 20mg. of nifedipine.
`
`Example 7
`
`The method of Example 6 was repeated with
`the following ingredients.
`
`% muse
`0.25
`0.5
`
`24.75
`
`49.5
`
`Ingredient
`
`Buprenorphine
`
`Anhydrous Lactose
`
`Hydroxyethyt ceLtuLose
`
`(NatrosoL 250 HX)
`
`CetostearyL aLcohoL
`
`XyLitoL
`
`Hydroxypropyt ceLLuLose
`
`(ingragranutar)
`
`(kLuceL HF)
`
`Hydroxypropyt ceLLuLose
`
`(extragranutar)
`
`Sodium carboxymethyL ceLLuLose
`
`(extragranutar)
`
`(BLanose 7MFD)
`
`12.5
`
`25
`
`25
`
`7.5
`
`2.5
`
`2.5
`
`25
`
`50
`
`50
`
`15
`
`S
`
`S
`
`60
`
`'water
`
`This process afforded one thousand 200 mg.
`tablets, each containing 0.5 mg. of buprenorphine.
`
`55
`
`ExampleB
`
`The method of Example 6 was repeated with
`the following ingredients.
`
`

`

`11
`
`O 205 282
`
`12
`
`Ingredient
`
`_Phenazocine hydrobromide
`
`Anhydrous Lactose
`
`HydroxyethyL ceLLuLose
`
`(NatrosoL 250 HX)
`
`CetostearyL atcohoL
`
`Mann‘i toL
`
`Hydroxypropyt ceLLuLcse
`
`(intragranutar)
`
`(ktucet HF)
`
`Hydroxypropyt ceLLuLose
`
`(ext ragranuLa r)
`
`Water
`
`3
`5
`
`10
`
`15
`
`30
`
`27.5
`
`7.5
`
`5
`
`Weight
`it)
`
`(g)
`
`20
`
`3o
`
`60
`
`55
`
`15
`
`10
`
`70
`
`This process afforded one thousand 200 mg.
`tablets, each containing 10 mg. of phenazocine
`hydrobromide.‘
`Referring to Figure 1, a kidney-shaped oral
`vehicle according to this invention (1) has a convex
`side (2) and a concave side (3). Both the upper
`portion (4-) and the lower portion (5) of the vehicle
`are rounded.
`
`in use the oral vehicle is placed in the buccal
`cavity of a patient, with the concave side (3) upper-
`most.
`
`CLINICAL TRIALS
`
`A comparative single dose pharmacokinetic
`study of
`three morphine sulphate preparations,
`namely morphine sulphate 10 mg. buccal tablets - .
`(prepared as described in Example 1), morphine
`sulphate liquid 10 mg, and a sustained releaSe
`morphine sulphate oral tablet 10mg (orally admin~
`istered MST CONTINUS tablet) was conducted us-
`ing four patients for each preparation. Morphine
`levels in plasma were determined using a liquid-
`solid extraction followed by radio immune-assay.
`The results are given in Figure 2.
`
`the
`From this Figure it can be seen that
`bioavailability of morphine sulphate is significantly
`prolonged using the present buccal tablets, com—
`pared with the bioavailability achieved by either a
`liquid morphine formulation or an orally admin-
`istered sustained release morphine formulation.
`A single dose pharmacokinetic study of mor-
`phine sulphate bucoai tablets, 10 mg and 20 mg.
`was conducted using nine patients. The tablet was
`placed in position in the buocal cavity four hours
`prior to laparoscopy. Morphine levels in plasma
`were determined using an VLSE/RIA method. Re-
`sults are given in Figure 3. Again the prolonged
`nature of the morphine. sulphate bioavailability is
`apparent from this Figure.
`‘
`
`PRODUCT ADHERENCE TO MUCOSA
`
`Placebo tablets. prepared as described in Ex-
`ample 1, but with morphine sulphate replaced by
`lactose (10.0gm) were used to determine the ad-
`herence of tablets, prepared according to this in-
`vention, to the oral mucosa.
`The trial was carried out using nine volunteers.
`One tablet was put in place in the buccal cavity
`twice daily (at 12 hour intervals), using both sides
`of the mouth alternatively, over a seven day period.
`Subjects were asked to record the duration of
`each tablet in the buccal cavity. Results are given
`in the Table.
`
`20
`
`25
`
`30
`
`40
`
`60
`
`55
`
`

`

`13
`
`O 205 282
`
`14
`
`Tabte
`
`TabLet: Duration (hr)
`
`Subject
`
`Night
`
`1
`
`\OOO'flO‘UI-l-‘LNN
`
`Average
`
`12
`
`12
`
`12
`
`12
`
`12
`
`12
`
`12
`
`12
`
`12
`
`12
`
`Claims
`
`1. A sustained release, oral pharmaceutical
`composition in solid unit dosage form, for applica-
`tion to the mucosa of the oral or nasal cavity,
`comprising compressed granules characterised in
`that the granules comprise a drug. a higher al-
`iphatic
`alcohol
`and a hydrated water
`soluble
`hydroxyalkyl cellulose and further in that the gran-
`ules are coated with a mucosa adhesive cellulose
`
`2. A composition according to claim 1 911.8%;
`terised Lg that the granules are coated with a pow-
`dered mucosa adhesive cellulose.
`
`3. A composition according to either claim 1 or
`claim 2 characterised Lil mat the mucosa adhesive
`cellulose comprises a carboxyalkyl cellulose or a
`hydroxyalkyl cellulose, preferably sodium carbox-
`ymethyl cellulose, hydroxypropylmethyl cellulose
`or hydroxypropyl cellulose.
`,
`4. A composition according to claim 3 charac-
`terised i_r_i_ that the mucosa adhesive cellulose com-
`prises hydroxypropyl cellulose.
`5. A composition according to any one of
`claims 1
`to 4 characterised in Lh_a_t
`the mucosa
`adhesive cellulose coating comprises between 2%
`and 15% (w/w), especially between 4% and 10% -
`(w/w), of the total dosage form weight.
`6. A composition according to any one of
`claims 1
`to 5 characterised Ln, Lila; the higher al-
`iphatic
`alcohol
`comprises
`cetyl
`alcohol
`or
`cetostearyl alcohol.
`
`Day
`
`9.?
`
`8.0
`
`7.2
`
`5.9
`
`11.0
`
`8.5
`
`10.9
`
`8.6
`
`Subject found tabLets
`
`'
`
`unacceptabLe
`
`8.4
`
`25
`
`30
`
`35
`
`4O
`
`45
`
`50
`
`55
`
`7. A composition according to any one of
`claims 1
`to 6 characterised i_n~ that the higher al-
`iphatic alcohol comprises between 5% and 35% -
`(w/w), especially between 10% and 30% (w/w), of
`the total dosage form weight.
`8. A composition according to any one of
`claims 1
`to 7 characterised 1g th_at_
`the water
`soluble hydroxyalkyl cellulose comprises hydrox-
`ymethyl cellulose, hydroxyethyl cellulose. hydrox-
`ypropyl cellulose or hydroxypropylmethyl cellulose.
`. preferably hydroxyethyl cellulose.
`9. A composition according to any one of
`claims 1 to 8 characterised i_r_l_ that the water soluble
`hydroxyalkyl cellulose comprises between 2% and
`15% (w/w), of the total dosage form weight.
`10. A composition according to any one of
`claims 1
`to 9 characterised lg that the drug com-
`prises
`morphine,
`nifedipine,
`phena‘zocine,
`verapamil or salbutamol, preferably morphine.
`11. A composition according to any one of
`claims 1
`to 10 characterised ifl mat the granules
`further comprise between 2% and 15% (w/w), es-
`pecially between 4% and 10% (w/w), of a binder
`comprising a carboxyalkyi cellulose or a hydroxyal—
`kyl cellulose. preferably sodium carboxymethyl cel-
`lulose, hydroxypropylmethyl cellulose or hydrox-
`ypropyl cellulose.
`12. A composition according to claim 11
`characterised i}; that the binder comprises hydrox-
`ypropyl cellulose.
`13. A kidney shaped oral vehicle comprising a
`sustained release. oral pharmaceutical composition
`according to any one of claims 1 to 12.
`14? A buccal
`tablet comprising a sustained
`release, oral pharmaceutical composition according
`to any one of claims 1 to 12.
`
`

`

`15
`
`O 205 282
`
`16
`
`15. A process for the preparation of a sus-
`tained release. oral pharmaceutical composition in
`solid unit dosage form,
`the composition being
`adapted for application to the mucosa of the oral or
`nasal cavity, comprising
`
`forming granules comprising a drug, a higher al-
`iphatic alcohol and a hydrated water
`soluble
`hydroxyalkyl cellulose
`
`coating the granules with a mucosa adhesive cel-
`lulose, and compressing the mucosa adhesive cel-
`lulose coated granules to give a solid unit dosage
`form.
`
`16. A process according to claim 15 charac—
`terised in M the granules are formed by a pro-
`cess comprising mixing the drug, the water soluble
`hydroxyalkyl cellulose and, preferably. a binder
`comprising a carboxyalkyl cellulose or a hydroxyal-
`kyl cellulose to form a drug containing mixture,
`
`hydrating the drug containing mixture to form a wet
`granular mass.
`
`drying the wet granular mass to form a dry granu-
`lar mass, and
`
`mixing the dry granular mass with a higher al-
`iphatic alcohol;
`Claims for contracting state AT
`
`1. A process for the preparation of a sustained
`release, oral pharmaceutical composition in solid
`unit dosage form, the composition being adapted
`for application to the mucosa of the oral or nasal
`. cavity, comprising
`
`-
`
`forming granules comprising a drug, a higher al—
`iphatic alcohol and a hydrated water soluble
`hydroxyalkyl cellulose,
`’
`
`coating the granules, with a mucosa adhesive cel-
`lulose, and
`
`compressing the mucosa adhesive cellulose, coat-
`ed granules to give a solid unit dosage form.
`2. A process according to claim 1 charac-
`terised it; M the granules are coated with a pow-
`dered mucosa adhesive cellulose.
`
`3. A process according to either claim 1 or
`claim 2 characterised in grit fiie mucosa adhesive
`cellulose comprises a carboxyalkyl cellulose or a
`hydroxyalkyl cellulose, preferably sodium carbox-
`ymethyl cellulose, hydroxypropylmethyl cellulose
`or hydroxypropyl cellulose.
`4. A process according to claim 3 charac-
`terised in mat the mucosa adhesive cellulose corn-
`prises hydroxypropyl cellulose.
`
`10
`
`15
`
`25
`
`5. A process according to any one of claims 1
`to 4 characterised in mat the mucosa adhesive
`cellulose coating comprises between 2% and 15%
`(wiw). especially between 4% and 10% (w/w), of
`the total dosage form weight.
`6. A process according to any one of claims 1
`to 5 characterised Lg th_at the higher aliphatic al-
`cohol comprises cetyl alcohol or cetostearyl
`a1»
`cohol.
`
`7. A process according to any one of claims 1
`to 6 characterised i; that the higher aliphatic al-
`cohol comprises between 5% and 35% (w/w), es-
`pecially between 10% and 30% (w/w), of the total
`dosage form weight.
`8. A process according to any one of claims 1
`to 7 characterised in m the water soluble hydrox-
`yalkyl cellulose comprises hydroxymethyl cellu-
`lose, hydroxyethyl cellulose, hydroxypropyl cellu-
`lose or hydroxypropylmethyl cellulose, preferably
`hydroxyethyl cellulose.
`9. A process according to any one of claims 1
`to 8 characterised in m the water soluble hydrox-
`yalkyl cellulose comprises between 2% and 15% -
`(w/w). of the total dosage form weight.
`10. A process according to any one of claims 1
`to 9 characterised Lg that the drug comprises mor-
`phine, nifedipine, phenazocine, verapamil or sal-
`butamol, preferably morphine.
`11. A process according to any one of claims 1
`to 10 characterised i_n m the granules further
`comprise between 2% and 15% (w/w), especially
`between 4% and 10% (w/w), of a binder compris-
`ing a carboxyalkyl cellulose or a hydroxyalkyl cel»
`lulose. preferably sodium Vcarboxymethyl cellulose,
`hydroxypropylmethyl cellulose or hydroxypropyl
`cellulose.
`-
`V
`
`12. A process according to claim 11 charac-
`terised i_n_ m the binder comprises hydroxypropyl
`cellulose;
`
`13. A process according to any one of claims 1
`to 12 characterised in m: the granules are formed
`by a process comprising
`’
`
`mixing the drug, the water soluble hydroxyalkyl
`cellulose and, preferably, a binder comprising a
`carboxyalkyl cellulose or a hydroxyalkyl cellulose
`to form a drug containing mixture,
`
`50
`
`hydrating the dmg containing mixture to form a wet
`granular mass,
`'
`
`’ drying the wet granular mass to form a dry granu-
`lar mass, and
`
`mixing the dry granular mass with a higher al-
`iphatic alcohol.
`
`

`

`17
`
`D 205 282
`
`18
`
`15. A process according to any one of claims 1
`to 13 characterised in Lila: the mucosa adhesive
`cellulose, coated granules are compressed to give
`a buccai tablet.
`
`14. A process according to any one of claims 1
`to 13 characterised lg t_l1a_t the mucosa adhesive
`cellulose. coated granules are compressed to give
`a kidney shaped oral vehicle.
`
`'0
`
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`
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`
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`
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`
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`
`30
`
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`
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`
`45
`
`50
`
`55
`
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`
`

`

`0 205 282
`
`
`
`

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