CA1040533A - Controlled gastric residence medicament formulation - Google Patents

Abstract

CONTROLLED GASTRIC RESIDENCE MEDICAMENT FORMULATION
Abstract of the Disclosure The invention provides novel medicament formu-lation having prolonged gastric residence time which have a coating comprising a polymeric film which, inter alia, swells in the presence of gastric fluids.

Description

: CANADA
.
~ Case 118-3324 1~141)533 ~:
.~, . ..
CONTROLLED GASTRIC RESIDENCE MEDICAMENT FORMULATION ~ ~
, This invention relates to medicament formulatio~s,,-in particular medicament formulations having controlled residence time in the gastric region.
Nearly all drugs are best absorbed in one parti-. . . .
. 5 cular region of the gastrointestinal tract; either in ~ `
the gastric reyion and upper small intestine or in the /`~
middle or further region of the small intestine. Fol-lowing oral administration, acidic drug moieties, based on their ionisation properties, are best absorbed in the upper yastrointestinal t~act, i.e. the stomach or upper small intestine. Basic drug moieties, on the ; other hand, are best absorbed outside the gastric region and at a point in the small intestine where the ~`
pH reaches at least 3.
The absorption and availability of drugs depends `~
- (~n many factors, notably degree of solubility, rate of .. , solubility and, in particular, gastric emptying time.

o Thus, some drugs tend to be emptied from the gastric ; region before having opportunity to dissolve and be absorbed in the region of optimum availability. The ;

-O normal emptying time of the stomach is a problematical i`
.. ... .
phenomenon,varying ~7idely, from a matter of a few minutes to several hours, depending on many factors, such as the time at which the last meal was taken, the stress and anxiety of ~he individual and the position . ~:
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v CANADA

- 2 ~ 3324 , 10~)533 and level of activity of the individual. Because of these physiological factors, which influence gastric ,, .
emptying time, absorption and the subsequent availabi-lity and reliability of drug resporse varies widely.
Drugs which are absorbed in the gastric region or upper portion of the small intestine, but ~hich have ~!~ a low equilibrium solubility or slow solubility rate, are poorly available on oral administration, particu-larly because of the tendency towards premature yastric ~ 10 emptying. The oral route of administration is there-! fore unreliable for such drugs.
'rhe absorption and availability of even basic l and amphoteric drugs, wllich are best absorbed outside ¦ the gastric region, may be influenced by the gastric ¦ 15 residence time. Most basic and many amphoteric drug moieties are soluble in the gastric region where they ¦ form an acid addition salt. Further along the gastro-¦ intestinal tract, they become absorbed in their undis-sociated form. Some basic and amphoteric drugs, how-¦ 20 ever, which do not dissolve in the stomach because of premature emptying and/or low order of solubility or rate of solubility, ~ill also not dissolve in the higher '~ pH region of the lower gastrointestinal tract and are thus unavailable. Accordingly, the availability of 1 25 such drugs may also be improved by prolonglng their I gastric residence time.

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~ ~ CANADA
i~ _ 3 _ 118-33Z~

~, Many con~on drugs suffer the disadvantages, dis-: 1 cussed above, of low and variable oral availability, for example the tetracycline and cephalosporin anti-biotics and numerous other drugs, particularly aeid and amphoteric drugs. -) Most prior art drug formulations which seek to release drugs for dissolution in the stomach or gastrie regions, quickly release the drugs in an uncontrolled manner for immediate and uncontrolled availability.
;, 10 This results in blood levels and tissue concentration ~ o the drug which exceed the eoneentration necessary ., .
j to elieit the basie drug responses, with the exeess ¦ eoneentration of drug representing wasted drug or drug which may produee toxie effeets. As the blood level or tissue level falls into a sub-therapeutie range, a : subsequent dose may be adminis~ered, tending to result in an even higher peak concentration. On repetitive ~ dosing, it is not uncommon to find drug levels approach-? ing the toxic region. Most of the prior art acidie and basic drug formulations may be classiied as dump-type systems. In relatively fe~r cases can rapid release of drug in this way be }ustified and in the remaining cases sueh rapid and immediate drug delivery is both unneees-sary and undesirable from the s~and-point of theoretical ; 25 design. Despite this, it has been necessary to design '~ acidic drugs in dump systems to ensure rapid dissolution , , ' .~ , .

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CANADA
- 4 ~ 118-332 :~ ' 1()4'~S33 of the drug so that it is dissolved and available pr;i~r to or immediately after ~eing emptied from the stomach.
Such drugs tend to have a short duration of action and, based on the high concentration of drug in the stomach, may be irritating.
Prior art sustained release formulations are not particularly effective. Thus, they usually depend on -~
delaying the dissolution rate of the drug, for example ` by providing various coatings. As the dissolution of -~ 10 coated particles of drug or a coated tablet is delayed, ..
the dosage form continues to move along the gastrointes- `~
tinal tract into regions of increasingly poor absorption and availability.
- The prior art also fails-to provide controlled-and prolonged release of drugs which are intended to act locally in the stomach, e.g. antacids, acidulants ,,.. -~ .. . .~, .
and enzymes. The duration of action of such drugs has been uncontroiled and short, depending on such factors .. ~ .
as dilution with the gastric contents and gastric empty-ing, which is, as mentioned above, highly variable.

The present invention provides formulations having controlled gastric residence times.
~.,,. ~
More particularly, the present invention provides .; ~) , - a sustained release medicament formulation with prolonged gastric residence comprising:
~; ta~ a medicament core or a core comprising a diagnostic aid, and (b) a pharmaceutîcally acceptable coating on said core comprising-A' : .~

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1(i4(~533 ~1) a pharmaceutically acceptable cross-linked ~-polymeric component which comprises a prepolymer . .
cross-linked with a cross-linking agent at a ratio of 8 parts by weight of prepolymer to 0.15 to 4 parts by weight of cross-linking.agent, and .a plasticizer,in an amount o~ about 1 to 10 parts by weight per 8 parts by weight of said prepolymer, ~
the prepolymer being a copolymer of h (i) 20-90 parts by weight of a substituted or unsubstituted unsaturated dicarboxylic acid or acid anhydride having 1 to 3 carbon atoms between the two carboxylic groups, and . : .
.. . . .
, (ii) I0-80 parts by weight of an alkene of 2 to 6 i~ .
! ' . ' carbon atoms, styrene or an alkyl vinyl ether ~ ~.
in which the alkyl radical contains 1 to 16 . .
carbon atoms, said polymeric film being water~hydratable, water- ~.. .-l. permeable and swellable in the presence of gastric ~ ~ -fluids~ and, optionally, ~ ~
.
(2) a pharmaceutically acceptable, substantia}ly water~
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insoluble polymeric component, the ratio of said .
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substantlally water-lnsoluble component (2) (when ~ present) to said water-hydratable component (1) of -.
said coating ranging from about 90:10 to 10:90. .~.. -' ~:
The medicament core a) may suitably comprise any acid, ~ :
basic or amphoteric drug which is at least partially water- .
~oluble and, preferably, capable of diffusing through the .`~
coating b). Such drugs include the following:-Alkaloids Atropine sulfate . ...
~elladonna .; ~ .
Hyoscine hydrobromide .
~ ~5- .

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- 5a - CANADA
118-3324 :~:
, 4~533 Analge8ics - ~
. ~
- narcotics codeine :
dih~7drocodeinone _ ; . meperidine ~ morph~ne ' ' ''~'.'' '..: ' . , .
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-- CANADA . ::
- 6 ~ Case 118 3324 ., ,' `~
1~34~533 ':
non-narcotics ~;.
- Salicylates .~ :
"Aspirin" (trademark ~or acetylsalicylic acid~
acetaminophen d-propoxyphane : :~
Antibiotics :''',' . . ' ' Cephalosporins ;
. Penicillins : Ampicillin . ::
, Penicillin G I~ ;
! . Amoxycillin ~:
- Tetracyclines ! ;.. : :
....
Anti-can r agents :; .
~ Anti~convulsants : 15 mephenytoin - phenobarbital `.~.
trimethadione ~;;
.
Anti-Emetics .... _ ~ . ~ -Thlethylperazine Antihistamines .
Chlorophenazine :
Dimenhydrinate Diphenhydramine Perphenazine ; ;
Tripelennamine ~
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CANADA
7 - Case 118-3324 :
:. :
1C~4~S33 Anti-inflar,~atory a~ents ' hormonal hydrocortisone .. ..
prednisolone ~;
, . . .
prednisone - non-hormonal :
, .
allopuranol "Aspirin"
indomethecin Phenylbutazone Anti-malarials - :.
4-aminoquinolines 8-aminoquinolines .pyrimethamine . . : .
Anti~Migraine Agents Methyser~ide maleate :
- Antiobes ~
- Mazindole :
- ;
Phentermine .
Anti-Parkinson Levo Dopa :.
Antispasmodics .--Atropine Methscopolamine bromide .;.

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. -` ' CANADA .:.
- 8 - Case 118~3324 .~. .
; .' , .:
1046~533 :

: AntisDasmodics and Antich'oliner.~i'cs :.
.. . . .
,' Bile therapy ....
: Digestants Hydrochloric Acid :~,''' ;.. ;
Enzymes _ ,`
. Antitussives .. ' , , dextromethorphan ,~ :
.... . ~,: .
' . noscopine Bronchodilators `.. .:
. . .: . . .
,. 10 Cardiovascular A~ents ....
Anti-hypertensives ~'.
Rauwolfia alkaloids :~'."
Coronary vasodilators ,'~' nitroglycerln `.
15 ' -Organic nitrates pentaerythritol/tetr.anltrate , Electrolyte replacement ;:' ' ;,,.~ , . potassium . :
'~ - Ergot-Alkaloids .
.:. , :.
". 20 Ergotamine with and without caffeine ,,'' Hydrogenated ergot alkaloids `
.. ~ - . .
,.' - dihydroergo~istine methanesul~ate '.
. - dihydroergocornine methanesul~onate ~! dihydroergokryptine methanesulfate and ~'. 25 - combinations ''' ' . ~'~':
.'' . ~.
" .
': ,: ' CANADA
` - 9 - Case 118-3324 ,,,,~. , 1~14~533 Gastro-intestinal therapeutic a~ents j Antacids Aluminium Hydroxide ~.
Calcium carbonate - ~agnesium Carbonate Sodium Carbonate :
' Non-Steroidial Anti-fertility agents Parasymphathomimetic agents Psychotherapeutic Agents - :~
Major tran~ulllisexs chlorpromazine HCl clozapine mesoridazine metiapine - 15 reserpine thioridazine .
-` Minor tranquillisers ~
chlordiazepoxiae ~`'.
diazepam -meprobamate ' temazepam .:
i. ;
. Rhinological Decongestants ~i; . ..

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CANADA
10 - Case 11~-332~ :.
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. eda ive-hy2notics codeine phenobarbital sodium pentabarbital 5sodium secobarbital ~.
Steroids ~ : -Estrogens ~;
Diethyl stilbestrol . 17 ~-estradiol ~ ;~
Estrone Ethinyl estradiol Progestational agents , Chlormadinone Ethisterone . 15 Megestrol .
.. Melengestrol -. Noxethindrone `
.
~orethynodrel Sulfonamides fiympathomimetic agents . Vaccines :-: j . . :
Vitamins and nutrients : . essential amino acids . essential fats ; , , '. .
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:. . , CANAnA
Case 118-3324 ~04~533 The medicament core may also comprise drugs which are intended to produce local effects in the ~;
gastrie region or in the gastrointestinal tract, includ-ing antacid agents, such as ealcium earbonate, sodium carbonate, aluminium hydroxide and magnesium carbonate, enzymes, hydrochlorie acid, laY.atives and locally_ active anti-infect~ve agents, sueh as neomycin sulphate.
- The medieament core may also be replaced by diagnostic deviCes, eg devices intended to monitor tne gastric region, such as thel~idel-berg capsule.
As indicated, the medicament core has a pharma-ceutically acceptable coating. By this is meant that the coating material is not only non-toxie and other-~7ise pharmacologically acceptable, but also meets the -~
conventional standards as to coating materials for solid `
- dosage forms, for example as to rigidity and workability, `and ho~ogeneity and freedom from separation of the co~ponents of the film. ;
~ne preferred polymeric fi~s of the invention cc~prise "
a prepol~mer cross-linked with a cross-linking agent at a ratio of ~:
8 parts by ~7eight of prepolymcr to 0.15 to 4.0 parts, preferably 0.15 to 1.5 parts, more preferably 0.15 to l.0 parts of cross-linking agent. .
Naturally, ho~ver, the quantity of cross~ ing agent e~pl~ed may .. ., :
vary depending on the system.
The prepolymers and cross-linking agents used - ~
in the invention are such as will produce cross-linked .

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CANADA

1~4~533 systems ~hich hydrate and stlell in the presence of gas~
tric fluids. Suitable. prepolymers and cross-linking .`
agents are indicated in the followin~ table~
., '.: ' . Prepolymer Cross-linking Asent a) Substituted or unsub- Di- or poly-hydroxy stituted dicarboxylic acid compounds, diamines, :
polymers, or dicarboxylic polyfunctional amines, ~ acid cnhydride polymers, aromatic compounds, : . triols, aldopentoses . ketopentoses, aldo-hexoses,polysaccha-rides, as appropriate b) Acrylic polymers; ~. -c) Carboxy vinyl polymersj .
d) Polyamines; :.
e) Polyhydroxyl polymers . .
and copolymers~ . .
____________________________ _~~_________~____________.
: . f) Amylose (~rom starch);. Fatty acids ___________________________ ________________________ _ : .
g) Starch. Mixed anhydrides of : :
. acetic acid and citri :~:
acid, epichlorohydrin or phosphorus oxychlo ride ,............... _ _ ~ . .

:`
~ - CA,~A~A
; - 13 - 118-3324 ~O~)S33 , In group a) prepolyrners, suitable substituted or unsubstituted dicarbo~ylic acid anh~dride monomers are anhydrides having 1 to 3 carbon ato~s between the two carboxylic groups, in particular maleic anhydride malonic anhydride, succinic anhydride, .: ;
allylsuccinic anhydride~ phenyl maleic anhydride, mesaconic anhydride, phenylsuccinic anhydride, sulphomaleic anhydride, aconi-tic anhydride, benzylmalonic anhydride and itaconic : .
anhydride.
Preferred anhydrides are maleic anhydride, `
optional].y substituted by chlorine, 1uorine, alkyl of 1 to 16 carbon atoms, e.g. methyl, ethyl, propyl, iso-propyl, pentyl, isopentyl, octyl, dodecyl or hexadecyl, ,, .,; , .
aryl, e.g. phenyl, tolyl, xylyl or naphthyl, arylal~yl, e.g. benzyl~or S03H. Unsubstituted maleic anhydride is particularly preferred.
Sui.table substituted and unsubstituted dicar~
boxylie acids are those corresponding to the acid anhy~ ;
drides described above. ~
~ . .
Comonomers may also be copol~nerised, for exam- ~ ~
.:
ple with the dicarboxylic acid anhydrides referred to above. Suitable comonomers include alkenes of 2 to 6 carbon atoms, such as ethylene, propylene or butadiene, styrene~ or alkylvinyl ethers, in which the alkyl radi-_ cal contains 1 to 16, particularly 1 to 12, preferably ., , :, ' ' ' ., ' ,..... .
'' ' . , ' ' CANADA

~4~S33 1 to 4 carbon atoms, for example methylvinyl ether, ethylvinyl ether, isobutylvinyl ether, amylvinyl ether, hexylvinyl ether, dodecylvinyl ether, or hexadecyl vinyl ether, preferably methylvinyl ether. The preferred comonomers are ethylene, styrene and methylvinyl ether, preferably the latter.
Suitable ratios of anhydride monomer to comono-mer are Erom 90:10 to 20:80, preferably 80:20 to 40:60, ` by weiyht.
J lo The preferred prepolymers contain repeating units of formula I, (R)x - C - C ¦
O=C C=O
_ _, . ';' ~ in which one of Rl and R2 is hydrogen and the other I is chlorine, fluorine, hydroxy, alkyl of 1 to 16 carbon atoms, ~ 15 aryl, aral~.yl or -S03H, ! R is dimethylene optionally sub-stituted by alkyl of 1 to 4 carbon atoms, phenyl, or alkoxy of 1 to 12 carbon atoms, or is -Cl~2-C~=cH-~l~2 ' CANADA
- 15 ~ 3~4 : ' ~04~533 and x is 0 or 1 Preferably, Rl and R2 are each hydrogen, x is 1 and R
is dimethylene optionally substituted by phenyl or alkoxy of 1 to 4 carbon atoms.
The prepolymers preferably have average molecular ` weights of from 100,000 to 5,000,000, more preferably .:, .
250,000 to 2,000,000.
The prepolymers are known or producible in con~
ventional manner using the monomers described above.
The follo~ling commercially available polymers are suitable for use as prepolymers in the present inven-; tion [these are all polymers of methylvinyl et~ler and maleic anhydride in a one to one molar ratio~:
"Gantrez A~-ll9"1 (PVM/MA-119j Av. molecular weight 250,000, specific viscosity 0.1 - 0.5 "Gantrez AN-139"2 (P~/MA-139) Avo molecular weight - 500,000, specific viscosity 1.0 - 1.4 "Gantrez AN-149"3 (PVM/MA-149) Av. molecular weight `
750,000, specific viscosity 1.4 - 2.0 "Gantrez AN-169"4 (PVM/MA-169) Av. molecular Weight 1,250,000, specific viscosity 2.6 - 3.5 "Gantrez AN-179"5 (PVM/MA-179) Av. molecular weight l;
- - . - .
1,500,00o- -The preferred cross-linking agents for cross-linking , ) :: -~5 the prepolymers described above will naturally vary depending on the prepolymer concerned, although they .`'5, 1-5 inclusive. The terms bearing these superscript numerals axe trademarks.

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-~ CAN~

1~34~533 should be pharmaceutically acceptable. For use with the preferxed prepolymers described above, suitable cross-` linking agents include alXylene diols, such as 1,3-propylenediol, polyalXylene glycols, such as diethylene glycol cr glycerine, polyethylene glycol~e.g. of molecular `~ weight 400 to 2,000, polytetrame~hylene or methoxy-polyethylene glycol, long chain dihydric compounds, ; such as polyoxyethylene sorbitan ethers, e.g. polyoxy-ethylene sorbitan monooleate or monola~ateJ diamines, such as ethylenediamine, polyfunctional amines, such as triethylenetetramine or pentaethylene hexamine, and triols such as 1,2,3-butane tr$ol.
The prepolymer may suitably be cross-linked with the cross-linking agent in the presence of a plastici-ser, such as glycerol triacetate, ethyl acetate, diethyl -phthalate or dibutyl phthalate. The plasticiser employed will naturally depend on the prepolymer aild cross-linking agent. Ho~7ever, for the preferred systems described above, glyceryl triacetate is suitably employed. The quantity of plasticiser will also vary, but the plasticiser may suitably be present to the ;
extent of 8 parts by weight of prepolymer to 1 to 10, - preferably 1 to 7, more preferably about 4 to 5 parts by weight of plasticiser.
.; ., In the production o the formulations of the invention, the ~edicament core which~m~y ccr~rise a tablet : ' ' . . ' ... .. ...
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CANADA
r 17 - Case 118~3324 1(~;9L~533 or capsule, may be produced in conventional m~mer and is then coated with the polymeric film.
The polymeric films are produced by dissolving the prepc-lymer, cross-linking agent and any other exciplents, for example a plasticiser, eg. triacetin, in a s~itable inext solvent, eg ethyl ace-tate, methyl acetate, acetone, methyl ethyl ketone, acetic acia, Eyri-; dine or N, N-dimeth~1 formamide. The m~licam~nt core is then coated, using conventional techniques, eg. immersion coating,wi~l the solution.
The coating on the film is then suitably cross-linked in situ, using conventional methods, for example by application of heat in the presen-ce of ~Jater, eg. at a temperature of from 10 to 90, preferably 20 to 60C and at, eg. 30 to 95%, preferab.ly ~0 to 60~, relative humidity.
~he cross-linking process may suitably be carried out for a period of 4 to 200 hours, preferably 8 to 24 hours.
, .:- :' In one embodiment, the cxoss-linking process may be carried out in the shipping con~ainer. For example, tablets or capsules coated with the prepolymer solution may suitably be placed in a jar containing the determined quantity of water and stored for a period of time at a predetermined temperature to promote the cross-linking reaction.
Where the drug in the medicament core has a high molecular weight, e.g. insulin or polypeptides, it may have a low diffusion rate through the polymeric-I membrane. To overcome this problem, polymeric membrane ! 25 opening materials, which are soluble in gastric fluids~
may suitably be incorporated in the polymeric film. On ~ . .:

104~)533 contact with gastric fluid, these materials dissolve leaving openings in the membrane'through which'the drug may pass. ;' Suitable such materials include'finely divided or micronised calcium carbonate. '':' Alternatively, and in another aspect of the present ' : invention, the medicament core may be coated with a pharmaceuti- ;
cally acceptable binary polymeric film system comprising (1) a pharmaceutically acceptable, substantially water- : :
insoluble, polymeric component, and (2) a pharmaceutically acceptable cross-linked polymeric component which comprises a prepolymer cross-linked ~ with a cross-linking agent at a ratio of 8 parts by '' weight of prepolymer to 0.15 to 4 parts by weight ;'~
, of cross-linking agent, and a plasticiser,in an ' amount of about 1 to 10 parts by weight per 8 parts by weight of said prepolymer, the prepolymer being a copolymer of ;' ' (i) 20 to 90 parts by weight of a substituted or un- ;-~
. substituted unsaturated dicarboxylic acid or'acid ' 20 anhydride having 1 to 3 carbon atoms between the two carboxylic groups, and ' (ii) 10 to 80 parts by weight of an alkene of 2 to 6 ;~
carbon atoms, styrene or an alkyl vinyl ether in 1 which the alkyl radical contains 1 to 16 carbon ' atoms, ' said polymeric component being water-hydratable, water-permeable ~ and swellable in the presence of gastric fluids; ~he ratio of l said substantially water-insoluble component(l) of the coating : to said water-hydratable component(2) of the coating ranging 30 from about 90:10 to lO:gO.

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~4~533 `i:
- 18a - CANADA
8-3324 ; : :

With such a film system, upon exposure to gastric .;~ :
fluids, the water-hydratable component swells initially to provide prolonged gastric residence and may then dissolve slowly and be preferentially leached out from the coating, leaving, after a time, a p~orous but intact ;;!' network which is increasingly composed of the insoluble ~
polymer. : ~ .
Suitable insoluble polymeric components include : .
water~insoluble carboxyl contalning and carbo~ylate copolymers . , ~ .

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- 19 - 118-33Z~
~04~533 such as polyacrylates, e.g. methyl methacrylate and eth~l methacrylate.
As the hydratable, swellable polymeric component, the dicarboxylic acid and acid anhydride prepolymers described above, for example those containing units of formula I, may suitably he employed. These may be non-cross-linked or cross-linked, in the latter event, suit-able cross-linking agents being those described above.
In the binary film system, the ratio of insolu-ble component to hydratable, swellable component is ;
suitably from about 90:10 to 10:90, preferably 60:40 to , 10:90.
The average molecular weight of the insolublecomponent may, for example vary from about 25,000 to ¦ 15 about 3,000,000, preferably 50,000 to 1,000,000.
1 An advantage of the binary polymeric film system I is that its porosity increases with time, thus compensa-ting for decreasing drug concentration. In the non binary coating of the invention, the film hydrates and Il 20 swells to an equilibrium value corresponding to a maxi-¦ mum diffusional ability for the film. As drug diffuses through the film, the concentration of drug within the j core decreases and the concentration gradient across ¦ the membrane, which is the diffusional driving force, `^
¦ 25 correspondingly decreases with consequential decreasing drug release rate. In the binary systemJon the other - - CANADA
- - 20 - 118-332~ ;~
. . . .
~ g~533 hand, the increasing porosity of the polymer film com- ;~
pensates for the decreasing drug concentration gradient across the film so that a substantially constant drug release rate may be obtained or, indeed, the terminal ;
,:
release rate at the end of the diffusional process may -; actually be higher than at an earlier stage.
," -, It is also within the scope of this invention to coat half or part of the medicament core, e.g. tablet, with the films of the invention, which then act as an anchor to hold the dosage form in the stomach. In such ~ -,` cases, none o the drug, some of the drug or a second ~ ~
, . . .
.. . .
drug may be released through the film membrane, while ;;~

an insoluble drug may be released from the uncoated i: . .
portion immediately, after a delayed period,or contin-uously, depending on ~he design of the dosage form and the release profile sought. For example, a layered tablet comprising a layer of soluble drug and a layer of an insoluble drug may be partially coated. In such instances, a tablet may suitably have an intermediary, preferably central layer which is insoluble in gastric ` fluids and to which the film coating will firmly bond. -Such layers may comprise fatty or waxy materials alone , .
or ~in combination, for example with calcium sulphate di-hydrate. Suitable fatty or waxy materials include - 25 stearic acid, glyceryl monostearate, spermaceti~ cetyl alcohol and acetylated monoglycerides. In addition, to '': ' ' ' , .'~' ' ... .
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CANADA

~04~S33 .
facilitate bonding, the intermediary layer may comprise a polymeric material, for example any of the polymeric materials employed in the coating of the present inven-tion, or any other polymer which is similar in solubi~
lity properties to the coating polymer in organic solvents but which is substantially insoluble in gastric fluids.
In accordance with the present invention, theweight of the coating on the core may vary widely depending on the release pattern and gastric residence time desired. Generally, h~ever, th~
weight of the coating on a tablet-may suitably be rcm 25 to 300 mg, preferc~bly frcm 40 to 70 mg, and on a capsule from 35 to 500 mg, preferably 50 to 80 mg.
The increased gastric residence time of drug formulation of the invention is believed to be contri-buted to by the following factors:

1. Mechanical Size The polymer systems of the invention are capable of rapid swelling, to the extent of perhaps 150 to 1,000% of the original size, in the presence of gastric fluids, and the pure mechanical size effect may contri-bute to the prolonged residence time. Thus, the systems may achieve a size larger than the normal opening of the pyloric valve of the stomach and thus remain in the stomach until they rupture or are reduced in size. Even particles which are almost but not quite as large as the ' ~ ' ' ., , . ~ . .
,, ., , . . ~ . , :.

CAN~DA
- 22 ~ 332 ~ 41~S33 pyloric opening may have prolonged gastric residence.
- Film systems which s~lell rapidly or which contains tablet matrices or other contents that invite or attract water~
.. ~ .
develop the characteristics of a resilient water-filled sphere. The resiliency of such systems may be an added physical effect~together with the mechanical size~which contributes to the prolonged gastric residence.

2. Electrostatic or Charge Effects Hydrochloric acid is secreted by the cells lining ~ 10 the gastric wall. The gastric mucosa tends to have an ;~ overall positive charge. The preferred polymeric systems of the present invention possess functional groups bear-ing a negative electrostatic charge and are believed to be attracted by an electrostatic mechanism or charge effect to the gastric mucosa. Polymers containing carboxyl groups have potential negative ionogenic sites, - which will provide negative sites of attraction to the gastric mucosa, even though the magnitude of ionisation of the polymer at gastric pH may be very low.

~ .

3. Surface Effects i A. Spherical or expanded polymer systems, in particular are observed to seek a region of low surface .., tension. The mucin and contents of gastric secretion are surface active and produce a surace tension lower-. ,. .: .
ing effect at the ~all of the stomach. The surface . . .
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~ANA~A

'' ` 10~533 tension lowering effect is believed to produce a surface attraction for the film type of controlled gastric resi-dence dosage form.
B. The gastric mucosa is covered with a layer of mucus 1.0 to 1.5 mm thick. This layer is neutral or alkaline, except where it is in direct contract with pools of acid secretion of the surface cells. A gastric residence dosage form when in the stomach and contact ing the mucus layer will preferentially hydrate at the point of contact since there is a localised higher pH
at this point. This may cause adherence t.o the wall of the stomach.
The following Examples serve to illustrate the present invention. They describe the results obtained with solid cores coated with various polymeric films, which polymeric films are not necessarily the prererred I films from the standpoint of acceptability, for example f as reg~.rds workability and elegance, commercially, but which do demonstrate the advantageous effects that can be achieved by coating with polymeric films in accor-dance with the present invention.

.
. ' ' .

CANADA ,, 24 - Case 118-3324 ',.:
~040533 . . ;, . . .
EXAMPLE 1 : Mechanlsms of Control of Dru~ Release ~, ~
Stock solutions of 10~ w/v of the polymer ;~ -poly(methylvinylether-~aleic anhydride)(PVM/M~ 169) ~ere prepared by dissolving the polymer with agitation in an-hydrous ethyl acetate. When dissolution was complete, the solution w;as filtered through gauze. Film solutions were then prepared using 8 parts by vol. of the p~mer from the stock solution, 1,3,5 or 7 parts by vol. of a `
5% ~l/v solution of Triacetin ~plasticiser) in ethyl~
acetate, an~ varying parts of cross-linkin~ agents from ,' ~able I. All the film solutions were resh1y prepared because of the tendency of the ~olution to gel upon ~ ,, stan~ing.
Table I ', ; 15 Cross-lin~ing agents - - -Chemical Composition Phys cal Form,~, 6 , "~ween 20" a Polyoxyethylene sorbi~an n~nolaurate liquid "~arbowax 4U0" b Polyethylene glycol (PEG 400)av.mol.~t.400 liquid~-8 , ~0 "Carbowax 1000" b Polyethylene glyool (PEG lOOO)av. mol.wt.1000 solid , "Carbowax 1540~ b Polyethylene glycol (PEG 1540)av.~1.wt.1540 solid - ~

- , "Carbowax 2000" b Polyethylene glycol (PEG 2000~av.mol.~,~t.2000 solid "Carbowax 550'' b~tho~y Polyethylene glycol (I~EG 550)av.mol.wt.550 liquid~
; Age~,t at 6855 91~ Ethylene oxide in hydrogenated castor oil (EO) solid ~5 ''Polymeg~l d Polytetramethylene ether glycDl solid , ... ... ~
6-12 inclusive. The terms beari~g these superscript numerals , are trademarks.
' . ' ! ~ ~!
.; , . _. __ _ ____ . _ . . .! : .
'' ~

CA~lADA
- 25 - Case 118-3324 a Atlas Chemical Inc., Chicago, Ill.
b Union Carbide Corp., New York, N.Y.
; c GAF Corp., New York, N.Y.
d Qua]cer Oats Co., Chicago, Xll.
-1. Gantrez AN-169, GAF Corp., ~Tew York, N.Y~
2. Eastman Organic Chem., Rochester, N.Y.
Tahlets were prepared from the following formula in which Amaranth was used in order to evaluate film permeability because of the simple assay technique required for its detection.
Dicalcium phosphate dihydrate 750 g Starch 7S g Amaranth (F.D. and C RED ~2) 15 g Gelatin and acacia solution 225 ml Tal~ (5~ of dried granule wt.) The dicalcium phosphate dihydrate, starch and amaranth were mixed for approximately 20 minutes in a V-blender. The solution of hot gelatin, 12%, and acacia,

4~, was added slowly with continued mixing until a gra-nulation mass was obtained and the amaranth was well dispersed. The wet mass was granulated by hand through a ~ i6 mesh sieve and the granules were dried overnight in a forced hot air oven at 100F. After drying, the granules were sized through a ~16 mesh sieve and then, 2~ after weighing, 5% talc was added witn thorough mixing.
Tablets containing 650 mg of granulation ~ere '.
. . .
, ' .

CA~IAE~
- 26 - Case 118-3324 ~: - 3 04~533 ; ~

compressed on the Carver Press at 2500 and 5000 lb load for 10 seconds using 3/8 in.diameter standard concave punches. The tablets were placed in an 8 ounce ointment jar and rolled for 22 hours on a tumbler mixer to remove the sharp edges. The tablets were then dusted and dried over anhydrous calcium sulfate~ Before coating, the tablets were ~eighea on an analytical balance and their thickness was determined using an Amesb micrometer.
Tablets were coated individually ~y immersion coating by maintaining the tablet at the end of a small glass tube with suction obtained from a vacuum pump. As many as ten tubes supporting tablets could he placed on a rack or coating. A 50 or 100 ml bea~er containing an 8% polymer solution was placed inside a 250 ml beaker con- -l 15 taining 50 to 100 ml of ethyl acetate to prevent excessive I solvent loss from the polymer solution. The 250 ml beaker was kept covered as much as possible. Half of a tahlet was ! coated by immersing it into the coating solution a suffi-l cient number of times (usually 2,3, or 4 times) to obtain .1 . . .
the desired amount of polymer coat. Each coat ~las allowed to air dry for 3-5 minutes before immersing again. The tablets were then turned over on the suction tube and the opposite crowns were coated after cilowing 15 to 20 minutes for the initial coats to dry to minimise marring of the . 25 a. Fred S. Carver Inc., Summit, N.J.
b. Pmes Co., Waltham, Mass.

.
' ~NADA
- - 27 - Case 118-3324 ~041~533 intact film coat by the applied vacuum.
Each coated taklet was assigned a numbered position in order to follo~ the weight gain of polymer coat for individual tablets. Residual solvent was removed from the film coated tablets by storaye in a desiccator for 48 hours. Tablets were then re~,~eighed and their thickness redetermined so that the film weight and thickness for each tablet could be calculated. Tablets were then stored in a tight container.
The pol~meric coating on the tablets was treated l;
in order to convert the anhydride cJroup to the dicarbo-xylic acid and thus induce cross-linking. The coated tablets were placed in a desiccator containing a saturated solution of sodium hromide which provided a relative humidity of 52.5% at 41C. The coated tablets ~ere then .j . :~
placed in the h~nidity chamber on a drilled 1/4" x 4" x 5"
!'Plexiglas"* sheet, containing a "Teflon"** sheet backing, for .. .. . . . . ..
a minimum of 120 hours. The drilled "Plexiglas" sheet con-tained 24 holes to permit treatment o~ up to 24 individual 2~ tablets at a time, with each tablet separated from the others.
The apparatus used for the permeability determi-nations of free film systems consisted of a permeation ~ ~;
. - ~
cell, receiving cell, cell clamp, magnetic stirrer, and * Trademark of Rohm and Haas Co. for a poly~methylmethacrylateJ
resin in sheet form. It is a colorless, transparent thermo-plastic resin having high dielectric strength and shock resistance, and transmits white light in excess of 90~. ;~
** Trademark of duPont fox polytetrafluoroethylene. It is a white, waxy, tough thermoplastic solid highly re~istc~nt to ,~
chemicals and oxidation, thermally stable and having a low ~-coefficient of friction.
~ ~L .

~N~DA -- 28 - Case 118-3324 ~ , : ~)4~S33 ~ ::
constant-stirrer temperature bath. The permea~ion cell con-sisted of a bottomless 4 oz amber sq~e bottle containing a screw cap, polyethylene gas~.ets, and a film sample with -an exposed circular area of 1.7? sq in. The permeation ~ -~
cell was held in the receiving cell, a 600 ml beaker, in an inverted position by an adjustablel'plexiglas" clamp.
The height of the cell could be altered by changing the position of the cell within the clamp and tightening the t~lO allen screws which were recessed into the"~exiglas". - ~
The solution in the receiving cell was agitated by placing ~-a stirrer bar in-the beaker and setting the rnagnetic ;
stirrer underneath the beaker belo~r the 37C ~ater bath.
Four units were placed in the water bath and all stirrers ., .. ,:
wexe synchronised at 200 rpm.
To determlne film permeability, the coated tablets were placed on a 2 3/4 inch diameter, circular i . . .~ .
plastic or ~Jire mesh scree~, containing 20 openings per `~
inch. The screen was suspended by looping 16 gauge copper ; wire or plastic strands, obtained from the plastic mesh, over the rim of the jacketed double-walled 400 ml beaker.
The screen was suspended 2 lJ2 inches from the bottom of ., . . ~ .
- the beaker. Tablets were placed in the center of the screen.
.1~
Four units were connected in series and their temperature was maintained at 37C. The beakers were placed on magnetic stirrers and were operated at 200 rpm.
' :"' ;,. ;
.
A~

CANAD~
.
- - 29 Case 118-3324 lO~)S~3 The coated tablets were ffJaluated in a buffer solution o~ p~ 1.30 prepared from the follorJing formula HCl 7.0 ml NaCl 6.8 g Distilled H20 q.s. 1000.0 ml In the film permeability study~the film was affixed i.n the cap of the permeation cell. The receiving b~aker con-tained 550 ml of buffer solution while 25 ml of a 20 mg~
amaranth solution, in the same buffer, was pipetted into ! lo the permeation cell, after su~icient time was allowed : ~or the recelving solu~.ton to xeach 37C. The height o : the permeation cell was adjusted in order to maintain the same solution level between the permeation and receiving cells. The same buffer solution was used in the tablet ~ lS study and 350 ml were placed in the jacketed double-,, walled beakers. ~liquot samples were removed periodically and assayed spectrophotometrically for determining the degree of amaranth permeation through free ilms and film coated tablets. The same aliquot of buffer solution was pipetted back into the receiving beakers ~0110~7ing each sampling step to maintain a constant volume in the receiving cell. The amaranth concentration was determined at 520 mu on the Spectronic 20a.

a. Bausch and Lamb Incorporated, Rochester, N.Y.

.
:, :
.::

CANADA
~- - 30 - Case llff3-3324 " :
104~533 The results are sho~m in tables II-XI.
Table II
_ Comparison of Amaranth Permeation Rates and Swelling R~tios for Free Films and ~ilm Coated Tablets PVl~ 169 Cross-linked Films 1 Pf~rmeation Swelling Ratio . Cross~linking Ratio Frfi~e Film Tablet Film Free Film Tablet Film Agent '~wecn 20 8-1-5 0.0115 0.000078 1.60 .l.~9 ff3 2-5 O.OOf'3~ o,ooool~s l.Sl 1.50 ; P~G 1540 8-1-5 O.OlSO 0.00097 l.f'eO l.~'e.2 ~P~G '~f50 f'~ 5 0.0~70 0.00099 3.1f~ 2.3~ff E~ 8-o.S-5 0.0230 0.00259 2.22 2.80 1 Parts o t~e .inf~rf3dients in the polym3ric film e.g. (8-1-5) 8 parts polymer-~cfly (methylvinylether) ~alelc anhydridfn 1 part cross-linkinf3 agent-polyoxyethylene sorbitan n~nolaurate ('I~leen 20)

5 parts plasticizer - ~rriacetin 2 r.~lligrams per milliter per hour 3 ratio of s~llen to uns~llen film length q~ese results sh.f~w tha:f the perr~ation rate f~an be f~on-trolled by contxolling the ratio of cross-linking agent in the polymf~ric .

.

CANADA
- 31 - Case 118-3324 ~4~)533 film as well as by varying the cross-link~ng agent used.
The results also sho~ the relationship between the per-meation rate and the swelling ratio. These results furthèr show the correlation between the permeation rates and swelling ratios of free films and tablet coated films.
, Table III
Effect of Film Thickness on ~naranth Permeability Through PVM/I*A 169~ een-20-Triacetin (8-4-5) Free Films Thickness, mm Pe~meationSwelling . . ~
0.072l~ o.ool~6 1,28 0.1074 0.0025 1.2~ ;
0.150~ 0.0014 ~.23 0.2225 0,00072 1.20 0.2799 0,00030 1.20 l 15 The results show that the permeation rate for ,l a given system can be controlled by the film thickness.
Table IV `
Effect of Plasticiser Concentration on Amaranth Permeability Through PVM/~A 169-Tween 20-Triacetin Free Films ` ~ :

' .

.

r " '`lADA
- 32 - Case 118-3~24 04~S33 :
Ratio Film % ~ Plasticiser Permeation Thic~ness, ~m __ 8-? 7 0.0951 41 0.0040 8-2-5 0.0737 33 0~0039 8-2-3 0. o886 23 0,0051 8~2-l 0.07~2 9 0.0071 .
' . 1 All permeation values were corrected to a standard thickness of 0.10 mm.
;~ These results show that the perrneation rate is not highly sensitive to fairly major chanyes in plastici.ser concentration. The flexibility of the polymeric film can be controlled ~ithout affecting the permeat.ion rate.
Table V
~ffect of Cross-Linking Agent Concentration on Amaranth :
Per~eab lity Throu h PVM/MA-169-lween-20-TrlaGetin Free Film Ratio % w/w Cross-linking Permeation Swelling Ratio -- .
~-8-5 50 o . 00153 .l . 18 ~-4-5 33 0.00396 1.30 8-2 5 20 o.oo~6 1.51 8-~5 11 0.0115 1.60 ~-.5-5 . 6 0.0220 1,85 ;:

`

-; ; CA~`iADh -- - 33 - Case 118 3324 ~46~1533 Table V results show that the permeation cha-racteristics of the pol~neric film can be controlled by varying the concentration of the cross-linking agent.
Table VI
~, 5 Effect of Varyingi~lecular ~ieigllts of Cross-Lu~lg Agents On the Per~eation rate and ~lling Rate of ~l/2~ 169-Triacetin Free Films j Ratio Agent Average Permeation Swelling Ratio .' . , .
. 10 8-1-5 PEG l,oo 3~0-420 1 0.012 1.66 8-1~5 PEG 1000 950-1050 1 0.012 1.~0 8-1 5 PEG 15l~0 1300~1600 1 0.018 1.80 8-1-s ~EG 55~ 525~575 1 o,o67 3.18 8-2-5 PEG ~00 3~0-l~20 0.01~ 1.53 8 ~-5 PEG 1000 950-1050 O.Olg 1.69 .... ..

' "Physical Properties", Technlcal Bulletin, Union Chemi-cals Company, New York, N.Y., 1962.
These results demonstxate that the higher the molecular weight of the cross-linking agent the higher the rate of permeation.
Table VII
Effect of pH on Amaranth Permeability Through PVM/M~-169-Tween-20-~riacetin (8-1-3) Films , ' .

' . .
.
.~ .

' .:. ';

CANADA
: - 34 ~ Case 118-3324 , . . .
( ~0~533 ........

; pH Per~ation Swelling ~atio 4 1.30 0.014 1.77 3.20 0.018 2.23 These results show that a difference of several pH units in gastxic fluid has little effect on the per-; meation rate.
: Table VIII
- ''.
E~fect of Film Coat Weight and Compression Force on Amaranth Permeabllity from PVM/~~169~Tween 20-Triacetin Coated Taklets Ratio Comp. Load, lbs. Mg Coat Wt Permeation _ . _ 5) 2500 (indiYidual wtso) 8-1-5 2500 28,0 0,00101 .
8-1-5 2500 2900 0.0010 8-1-5 2500 29,5 0.00055 8-1-5 2500 30.4 0.00105 8 1-5 2500 31.3 0.00088 : :
8-1~5 . 250~ 31.~ 0.00102 .I (8-2-5) 2500 (ave, 2 to 4 coats) .1 .
8-2-5 2500 1~.3 0,00209 8~2-5 2500 28,~ o,ooo~,6f 8-2-5 2500 35.7 0.00042 8_2_5 . 5000 21~,~ 0.00~493 . , .
: .

1 .

' ' ' ' . I .

CANA~A
- 35 - Case 118-3324 ~040533 These results show that a t~o to three fold difference ln film coat ~eigh~ produced approximately a two fold difference in the permeation rate in 8-2-5 film coated tablets. Also sho~1n is that a change in compression load has little effect on permeation. ;
Table IX
Effect of Cross-Linking Agent Concentration on Amaranth Permeability Through PVM/MA 169-Tween~20-Triacetin Film Coated Tablets ~ .
RatioAve. Mg/Coat% w/w Permeation ' Cross-Linking ;' Agent ~-0.5-529.0 6 0.00101 8~1-5 30.0 11 o.ooo7~1 :
~-2 5 28~5 2~ 0.000~53 .; ... ............. .....
These results show that the permeation charac-teristics of the polymeric film coating on tablets can be contxolled by varying the concentration of the cross-linking agent.
,' 20 Table X
Effect of Varying the Molecular Weight of the Cross-Lin~ing Agent on the Permeation Rate of PV~/M~ 169-PEG-Triacetin ~8-1 5), Film Coated Tablets , .j ' , ., ~

, . ' ' .,' .` .

` ~.;

.- ~ CI~NADA
~ ~ 36 ~ Case 118-3324 : ~04~533 .
. .
Cross-Linking ~Ig Coat mm Coat Permeation Agent PEC 400 29.1 0.071 0.000409 PEG 1000 34.8 0.110 0.000781 S PEG 1540 2g.0 O,ofO 0.000973 ~EG 550 32.1 0.100 Ø00099?
~;
The results demonstrate that the higher the molecular weight of the cross-l.inking agent the higher the rate of permeation. .
Table XI
: Comparison of Permeation Rates ~or Ethylene Oxide (EO) and Tween-20-Cross-li.nked PV~ 5A-Triacetin Film Coated Tablets (8-0.5-5) . .... . ' ,, . . .. _ _ :
Cross-linking Agent Mg Coat/Tablet Permeation 15EO 22.~ 0.00432 3~,9 0.00160 ~c~ 20 2~.0 0-00153 : ~-- ..... . . ......... _ EXAMPLE 2 : Rupture Resistance of Cross-linked Polymer Films Tablets containing 270 mg of tetracycline hydro-chlorlde ~,/ere coated ~lith PVM/M~ 169-Tween 20-Triacetin . .

:' ' .

. . .

:, .. .. . .. . .

CANADA
~ 37 Case 118~3324 .. .
~0~533 ~ ~
films. The tablets were placed in simulated gastric fluid for 6 hours and then transferred to a rupture resistance ~, . .
cell. The cell comprised a water-jacketed beaker to pro-; vide constant temperature and to contain gastric fluid. -~
. ':
A"~exiglas"ring was placed in the bottom of tlle beaker ;;
to centre the tablet. A"Plexiglas~pisto~ over one inch in diameter and with a slightly concave surface, was mounted on a threaded rod and fitted to an Instron stress/strain analyser. A low range load cell was used with the tester in the compression mode, and the compression load applied to the hydratcd polymer film sac was recorded with resul-tant deformation of the sac under constant load rate con- ~`
ditions. The grams of load to produce rupture was recorded.
The results are shown in Table XII. These results show that lS the polymeric film coatings of this invention do not fatigue or lose their strength in gastric fluid for up .~ . ...
i to 6 hours.
:j . .
(Film sac was completely compressed to contact tablet residue contents without havlny ruptured.) Table XII , Ratio No. of Coats of Film Average load at ;
- rupture (~ns) `
. , ' ' -,',`'~ ...
~-0. 375~3 4 - 4~ `~
.: .-: .
~ ` 96 ,, , - , .
,''.' ' .

. .
~ ,, ~, .

~~ CANADA
` - 38 - Case 118-3324 :~C)4~533 ::
. . ~
; ~ 0.375-5 4 oYer ~00 i 5 162 over 400 8-o.S6 4 l~ .118 . .
. ~ 6 8-o.75_3 8-o . 7s-5 4 96 lol , ~XAMP~E 3 : In Vivo and In Vitro r~elea~se of~ pro nola.mine Throuah Film Coated Tablets Phenylpropanolamine tablets weré coated with ¦ 8-1 5 and 8-0.5-5 ratios of PVM/MA 169-Tween-20-Triacetin films, and were exa.mined for their in vivo 1 release patterns. Film coat weights averaging 16.1 mg ¦ and 25.2 mg for the 8-1-5 film coated tablets, and 24.8 mg ~ ::
for the 8-0.5-5 film coated tablets, ~ere evaluated as to the effect of cross-linking and film coat weight on phenylp.ropanolamine release. Including the control tablet, each of four systems were evaluated as to their effect on I - drug release in each of five human subjects. The tablets ~rere prepared as described in Example 1. The resu1ts are ' .
, ..... . . . . ;. . , ~ . , .: . ~ .
t',~,." "' '~, ' '.' . ",; '",` " ~ " ~

- CANADA
- 39 ~ Case 118~3324 . . .
s33 shotln in Table XIII.
The relative ~agnitude of difference between in vitro and in vivo results for the respective film .
coated systems is vPry similar. This indicated that the in vitro method was a good predictor OL n vivo release and that permeation rates are a valid parameter to inves-tigate when considerirg in vivo drug release.
Table XIII

. . .
Ratio Coat Wt, mg Permeation 10In Vivo Xn V~.tro In _itro In Vitro Control (no co~) 0,020 _____1 8 1-5 25.2 2~1.9 o,oo~o 0.00~7 . .
'i 8-1~5 16.1 16.3 O.OI~S ~,011 0,5_5 2l~.8 24.8 0,0~13 o~oogr 1 Tablet was in solution for less than 20 minutes.
;! 2 Calculated from the urinary drug elimination data which is quantita~ive for this drug.
. -~
1 EXAMPLE 4 : ~ Release Rate Characteristics of .
Polymeric ~ilm Coated Tetracycline Hydrochlo-`, 20 ride Tablets Commercial Tetracycline hydrochloride tablets containing:
270 mg tetracycline hydrochloride ~ ' , ' ~' .. :. .
., ~.

CANADA
~ - ~0 - Case 118-3324 :' ~0~(31533 :
.
135 m~ barium sulfate 135 mg microcrystalline cellulose were coated ~ith PV~ ~ 169~~'ween 2d!Triacetin polymer films following the procedure described in E~ample 1.
The tablets ~tere tesLed in simu~ated gastric 1uid for .; s~7elling characteristics and release rate of the tetra- .
cycline hydrochloride. The results are shown in Table XIV.
I~lithOUt varying tahlet composition a wide range of release : rates ~7ere possible by varying film composition and film thickness.
Table XIV
Nb Percent Released at Initial Media Ratio of Time Given (Hrs.) Sw~].ling Uptake and Coats 1/2 1 2 4 6 (~nutes) .Sa~ an~
:~ 15 (8-o~7S-3) 5 ~ 20 39 64 72 2 1/2-4 turgid l (8-0.56-3) 5 6 14 29 52 60 6-10 flacid (8-0.75 3) 5 . 11 . 22 40 54 72 2 1/2 3 1/2 very turgid (8-0.375-5) 5 1 11 -30 56 65 12-20 ~lacid . ~-(8-o.56-4) 5 7 21 43 70 79 2 1/2-3 1/2 very turgid (8-0.75 4) 5 5 15 33 57 66 5_7 turgid (8-0.375-5) 5 .7 12. 35 59 67 2 1/2-4 turg.i.d . (8-.o.56_5) 5 7 15 29 49 57 6-8 1/2 flacid folded ; (8~0.75-5) 5 7 29 37 62 71 3 1/2-5 flacid :-~ 0~375~3) 4 9 25 4B 75 ~2 3 4 not turgid (~-0~75 3~ 4 6 17 32 54 62 5-7 not turgid (~0.375-5) 4 17 38 46 69 76 3-5 turgid - (8-0,75_5) 4 8 19 37 52 71 4-5 flacid 3) 6 6 19 46 ~ variable turgidity.
(8-0.75-3)- 6 23 33 49 70 77 2 1l2-4 very turgid ( a o .375-5) 6 18 31 51 75 82 2-3 turgid (3-0.75-5) 6 11 20 36 58 66 4-5 turgid ~ - - - _ . - .
Avicel ~ Corp.

* ~rademark.

.,.~ .

.. ... .
'.i, . ~ '' ' ' '' ~, ' :

~A~ADA
41~. Case 118--~324 1~4~533 5 : In Vi~o Rad~ra~c Analysl6 of D.?.s nte~ration Ti~e of P~ym~ric Film Coated Tablets , .
- The effects or film coating on tablet disinte-gration and s~Jelling ~Jere investigate~ by coating barium .
sulfate tablets with PV~ ~ 169-T~een 20-Triacetin polymer films follo~ling the procedure described in Example 1. The film coated tablets ~ere then administered to male adult .' .
h~nan sub~ects. The results were compiled from radiogra-phic analysis and are sho~m in Table XV.
These results show that polymeric film coated ',............. ........ .................................................................. ...
tablets o~ this inv~ntion are cap~ble of ga,stric residence ; ~imeS greater than 7 hours.
~ Table XV

: Ratio Mg DisintegrationCoat Tim~ -No coat (Control) ~ 35min, 8-0.5-5 12.8 ~ 1 hr.
~_o,5_5 13.5 c 1 hr.
-0.5-5 l~oO c 11 8 0,5 5 15.3 ~ 1 hr.
O.S-5 23.1 c 30 ~in.
j B-o.5-5 23.8 < 30 min.
-8-0.5-5 2~.9 > :~5 c 3 hr, 8~o.5-5 31.2 > :15 ~ 2 1/2 hr.
8-o.5-5 35.1 ~ :15 ~ 2 1/2 hr, 8-1-5 9.1 > :30 < 2:40 hr.
8-1-5 9'9 < 1 hr.
8-1-5 10.5 < 1 hr.
8-1-5 15.5 > :05 ~ 2:45 hr.
8~1-5 16.7 ~ < 5 hr, 8~1-5 16.9 >2 < 3 hr.
8 l-S 28.1 >2:30 < 5:00 hr.
~1-5 36,9 >5:35 < 7:30 ~

All tablets ~ere located in the stomach at time of disintegration ' -- CANADA ..
42 - Cace 118-3324 - ~L04~533 ~:
~ - ~X~MPLE 6 : In Vivo Com~arison of D~ ease Polymer . . . ----- - - - :
Film Coated Tablets vs Co~ercial Tablets Tetracycline hydrochloride polymer film coated tablets prepared as described in Example 6 and commercial tetracycline hydrochloride t~chromycin V51 capsules ~lere administered separately to a healthy male human to deter- ~-mine the bioavailability of the polymer coated tablets of this invention as compared to a commercial product. ~,, ;
Both the coated tablets and uncoated capsules contained 250 mg of the drug. The coated tablets had a ratio of ~B-0~5-5) PV~l/MA 169-Tween 20'-Triacetin polymeric-film coating. Urine and blood samples were collected '4~
periodically and the amount of tetracycline llydrochloride in each was determined. The results are shown in qlable XVI.
These results show that the serum level of the comme.rcial product dropped to 0.54 ug/ml within 8 hours, while the coated tablets ~f this invention do not drop ;' to 0.54 ug/ml until 24 hours. This indicated that one dose ~' of-the coated tablets is equal or superior to three doses ; 20 of ~he com~ercial produc~, giv~n every 8 hours. These results further show that when the blood level concen-- tration of Table X~I is plotted vs the time curve, that the coated tablets of this invention show a phsTsiological availabllity of 266~ greater than the commercial product.

1 Lederle Laboratories * Trademark. ~;
, , ' .
.' , ' '` , ~A

~` ~
C~NADA
; ~ - 43 - Cac;e 118-3324 . 104~)533 This means that 2.6 times rore drug ~as a~sorbed from the coated controlled gastric residence product of this inver,tion than from the commcrcial product.
; , Table XVI
5oa d Tablets Urir,e mg/drug Blood, c~
Collected Volum~ ug/ml vol.Exc. cum.ug. collected ua,/ml ug/5ml.
Time ug/vol. tim~ san~le hr.lOE,itl, 37ml ~75 1,39 1.39 1 hr,0,15 0,75 2hr, 5min, 25s~15,18 6,48 7.87 2 hr~0,32 1,~0 j 3hr, Omin, 118~11.33 7,85 15,72 4 hr,0,35 1.75 4hl,15min, 232~11,00 11.60 2t.32 8 hrO0,24 1,20 6hr,20min, 148~.1 1.93 14.2a ~1.6012 hr. 0,17 0.~5 7hr,30rnin, 53r~.2,47 6.55 48,15 24 7u~. 0.10 0,50 12hr.15r,1in. 275~Ll 1.26 1'7.33 65,)la 15hr,40min- 293ml 1,1616,9982 l~rf 24hr,0r,in, 42a~1 o,7l~ 15,84 g3,3l~
25hr,15,min. 60r~1 0.87 2.61 100.9S
31hr .35,~,in,. 352~10,31 5,46 10~.4L
2 0 36hr,30~,in, 271~ 0,42 5.69 112,10 ~8hr,0"in, 333~10,29 ~ 8 116,98 -i Uncoated Capsules ~
.~ ~
, Urir,e ug drug blccd c~n.
', Collected ~olu,n3 ug/ml vol.Exc. c~m.ug. collected, ug/ml ug/5ml Time ug/vol. time sample lhr, 214Dl o.lB1.93 1.931 hr, 0,100,50 2hr, 187ml 0,444,11 6,o42 hr. 0,150,75 3hr. 55~1 o,982,70 8.744 hr. 0.12o.60 4hr. 37~ 0.203.71 12,458 hr. 0,10o.sn 6hr. 182~1 1.1510.47 22.9212 hr. 0,050 25 8hr. 57ml o.l~l~ 1,2524,17 29 hr. '5 0 25 12hr, 21l~ml 0.424,l~9 28.66 16hr. 170~1 0~433.66 32,32 j 2l~hr~ 28OD1 0.304.20 36.52 ! 35 27h-.lGmi~, ~2~10,28 1,2937,81 33nr, 20~1 0,181,82 39,63 , 38hr, 204ml o.o80,82 40,45 ; l~8nr, 390~1 0,0~o,78 41.23 :

..
' .

. CANADA
Case 118-3324 ~40533 :

E~ PLE 7 : Insoluble Antacid (u_coated) And Soluble Antacids (coated) Layered Tablet Layered tablets were prepared having the following composition :
Layer 1 (coated portion~
Calcium Carbonate100 mg/tablet Sodium Bicarbonate 100 mg ~icrocrystalline cellulosel 25 mg Layer 2 (central coat bond_ng layer) .~
Stearic Acid 150 mg PVM/MA 169 25 mg Layer 3 (u c a ed p rtion) Aluminium hydroxlde/
Magne.sium ~arbonate co-dried gel 200 mg Microcrystalline cellulosel 50 mg Each layer formula was granulated. The three .~ , . -layer tablet was prepared by conventional procedur~ on a layering press.
The layered tablet is coated by any suitable controlled gastric residence film, coating the first layer and most of the middle layer. ;
The tablets were coated with a PVM/~ 169-T~een ?O".Triacetin film (8:0.5:5 ratio) following the procedure of Example l; two of the tablets administered provides ~vicel PH 101 FMC Corp. -* Trademark.

A' ~ - , .
CANADA
- 45 - Case 118-332~ :
.
1 0 4 0 5 3 3 .-, :
neutralisatbn of the gastric acid by the uncoated fraction within the first 30 minutes wllile the coated fraction neutralise gastric acid over a 4 hour period.

., , Binary films ~7ere prepare~ containing various percentages of PVM/~A-119 and ethyl methacrylate, follo~iing the procedures of Example 1. These films were tested for s~7elling ratios and permeability follo~ling the procedures ~ . .
of Example 1. The results are shown in Tab].es XVII to XIX.
Table XVII
,; , .
Relationshlp between Swellin~ Ratio, Film ~ osltion and ~! Zero Order Permeabi ant (PV~I/MA-119-Ethyl Metha-, crylate 2042) .j Film Composition Zero Order Permeability Averase S~elling -~ 15 (~ Weight o~ Constant Ratio :' PVM/i~A) (mg. cm. l.iter/hour, mole) 35.70 x lO-l :?.29 -:.l 73,2ll% 27.50 x 10-1. 2.27 ',! 6rO24% 16.36 x lo-l 2.
63.11~ l2,l~0 x lo- 2,07 57,~% 6.50 x 10~J 1.96 ' 50.65~ 2,75 x lo-i 1.8 1lo.63,~ r 0O52 x 10 1 1,1 30.00~ o.Oa x lO- 1.22 . . . _ . . _ ~ .
,, .. 1 .
. ~ .
..j ;l ' . . .

.'. .
,, .

,, C.~NAD~

6 - Case 11~-3324 .,.,,. ~.

104~)S33 :;
..
- Table ~VIII
. . .
Amaranth Permeahilit~ throuqh PVM/MA 119 Ethyl Methacrylate 2042 Films at p~ 7 . 5 :
,:
Filrn Cc ~,ositicn Dry Fil~n LagZero Order Linear 5(% l~ight o~ qrn~c};ness Ti~r~Perrr~ation E~ate ~
p~ 5A 119) (cm) (hour) (~ ~ant;h/hcur) ~:

- 73 24~ 89 7 X 10-4 0 610 - 3 98 73.24~ 26.7 X 10_~ 0.255 7 41 -73.21~ 35.6 x 10_4 0,275 6.86 73.24% 43-35 x 10_4 0 3~9 5 55 73.2~ 62,.2 X 10 4 0.~61~ I~.64 73.21~% 71.1 X 10-4 ').50.'~ 3.62 73.21~ 88.9 X 10-4 0.61~2 3.16 67.21~ 35.6 X 10-4 0.1~ 7 67.2~ 52.~ X 10-4 0.5~0 3.25 67.21~% 53.3 x 10-4 0.605 2.7 67.21~;~ 71 1 X 10-4 0.717 2.53 67.21~ 88 9 x 10-4 0.g37 2.09 ` ~0 63 11% 53.3 x 10-4 0.702 2.28 ` 57. ~8% 35.6 X 10- 0.500 1.80 57-7~ 49. 4 x 10-4 0.~60 1.70 57.7~ 6~ .8 x 10 4 1.01~ 0.91 50 65g 20.8 x 10-4 o.6S 1.00 40.63% 20.3 x 10-44 1.565 0.25 30.Q0~ 36.1 x 10 15.200 0 02 ` .
'"-,.
. . .

i~

CA~IADA :~
47 - Casc 118-3324 ;:.
~ )40S33 ~Z`
Effect of pH on Permeability of ~axanth throush PVM/lV~-' ' ' -- :;
: 1 -Ethyl Me~hacrvlate 20~2 Films .

Eilm Ca~sition H Linear P~l~ation Lag ~. .-(~eiglt ~ Content of ~Ædi~ Rate TLme ..
S of P~ ~) ' ~ (n~/hour3 (hour~ . . . ;`:
73.24~ 7.50 5.55 0.38 -~
. 5.6~ 5.04 0,~5 : . 4.82 6.02 o,90 : . :
. 3.27 1.68 Q,go .~. ~
- 10 1.35 2.86 . 1.37 ...
67.24~ 7~5 2.7~ 0.61 :
6.61 3.45 O.t ; 5.64 . 2.53 Q.52 4.82 2.~5 0,85 ;:
. 1~ 3.27 0.73 1.50 .:.
~ .2.15 0.96 1.80 57.7~ 10.50 1.572 o.567 . :

7.50 1.01 0.92 5.6l~ .99 1.27 ~;~
2~ t,,a2 0.4~ o.9'r :~
3.27 0,03 ~.25 .
1.3S 0.31 1.95 . , .~.
.. . .. .. .....
: ,.
: EXA~LE 9 : Dru~ Release from a Blnary Film S~stems ; Tablets were prepared containing the following: ~
Dibasic Calcium Phosphate Dihydrate 1550 mg .:
; Phenylpropanolarnine HCl ~00 mg .:, 1 ' Corn Starch 750 mg ;~
Talc 300 mg ,, .:; .
3000 mg :~
The tablets were compressed in the same manner .
,; as the Amaranth tablets of Example 1 but with a 1/2 inch ;

:' 1 *, .
StaRx 1500 Staley Mfg. Co. .. :~
.'~ , .
.~ * Trademar~0 :

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' . : .:

. . :. .. . . .... .. ...

A~A
- 48 - Case 118-3324 , 104~S33 .~ , modified-ball puncl- and die set at a load of ~000 lbs. They were similarly coated by immersion technique.
Three human male subjects wexeused for the study.
Each subject ~as administered two film coated tablets alld 5 an uncoated control tablet. A minimum ~f two days~tas all~.~-ed betweenre-dosing a particular subject. Each subject in the study was re~uired to adhere to the ollowing regimen during each clinical test in order to standarise the con-; ditions of the text:
1) Upon rising in the morning,empty the bladder and drink about 200 ml of water (about one cup).
~) Wait one hour and then collect a blank urine sample.
3) A~ter collecting the blank urine sample, ingest the test tablet with the aid of 200 ml of water.
1 lS 4) Do not eat or dxink any beverages until at least 4 j hours after the tahlet had been ingested (this meant foregoing or delaying breakfast and coffee for ~ hours after administration).
5) Completely void and collect all urine possible at pre 2~ selected intervals as noted. The exact time of urine ~ collection ~as recorded on each labelled bottle ~7hich ! was providedO
~.i . .: .
j 6) At the end of 1 1/2 hours, drin~ another 100 ml of water.
ll 7) Four hours after drug administration,normal habits 1 25 could be resumed.

.~ '' ,.
t .

~- .
.

4 9 _ . ~aNsAD~ 1$ - 3 3 2 4 ,:

1040533 ~ ~
; Phenylpropanolamine hydrochloride i5 e~creted unchanged in the urine. The phenylpropanolamine excreted in the urine was oxidised to ben~dehyde using sodium ; periodate. The benzaldehyde was then extracted using a - 5 cyclohexane, wllich had previously been purified through a silica gel column to remove trace quantities of impu rities. The peak wavelength for benzaldehyde in cyclo-hexane is ~41.6 mu.
- Polyethylene lined caps and culture tubes were ~o used for the analysis. The following ingreclients were added to each tube, respectively:

Blank Tuhe Standard Tubes ~ ~e 1 ml of blank urine 1 ml blank urine 1 ml urine 3 ml water 1 ml standard 1 ml water 6 drops 1 N NaOH 6 drops 1 N NaOH 6 drops 1 NNaOH
2 ml 0.075 M NaI04 2 ml 0.075 M Na~04 j The ingredients were added in the order shown.
;I Three standards were run with each analysis. Standards, which were freshly prepared each week, contained between 30 and 50 mcg/rnl of phenylpropanolamine. Sample tubes wore prepared from the urine samples that ~ere co~ected from a particular subject at the various time intervals. The tubes were sealed and gently shaken for fifteen minutes after the ingredients were added to each tube. Ten ml of cyclo-'.

' .

, , .

" (~ANADA
- 50 - Case 118-3324 ,' ' ~L()4~533 hexane T7as tl.en added to each tube and the tubes were gently shaken in a horizontal position at lo~ speed on the Eperbach Shaker for 15 minutes. After shaling, the tubes ~Jere set aside for 5 minutes to allo~ the cyclo-hexane layer to clarify. The ~ater layer was then removed ~ and 6 ml of 0.1 N NaOH ~as adde~ to each tube. After ; gently shaking the tubes for 5 minutes in a horizontal position they were allo~ed to stand for 5 minutes before recording the absorbance of the cyclohexane layer at 241.6 mu on the Coleman-Hitachi spectrophotometex.
The three human subjects utilised in this study :i had the ollo~ing ~7elghts l Ave.Elimination Cons~ant I Keta) "';I :
Subject A 150 lbs 2.38 hr.
Subject B 180 lbs 4.18 hr.~
Subject C 120 lbs 3.05 hr.-~, jl . : .
I A control tablet and t~o film coated tablets were ;I given to each of the three subjects. Film coated tablets .. , :. .
were prepared from PVM/MA-methacrylate binary film formu-lations, and coated follo~ing the procedure of Example 1.
si Tablet 1 plain tab~ek Tahlet 2 2 coats of PV~/~ 119-65~/ polymethyl metha~
~ crylate 2041-35%
; 325 Tablet 3 2 coats of PVM/~ 139-65% Polyethyl methacry-1 late 2~42/35%
. .
", ,.
` ta)Average value obtained from results of the 3 tablets evaluated for each subject.

; .,, ' ' . . ~ .

- CANA~A
- 51 - Case 118-3324 -:

lO~S33 ~

- The follo~in~ symbols are used in the data tables:
A = mg drug in urine : u AT = mg drug absorbed ATQO=drug absorbed at infinite time , Table XX
.
Excretion of Ph~ ropanolamine from subiect A for Tablet 1 Time thour) Au AT AT

.o 2.52 I~.68 0.117 2, o 9. lo lo .62 o .266 3,0 14,10 15.61 0,390 -4,o l~.o~ 18.~2 0.1,70 6.o 2l~.00 21~.3l o.60r

8,0 27,50 27.75 o.6g lO.o 31.00 21,10 o,775 ~ 15 15.0 36.00 35.95 0,900 l l~.o 3~,70 3~.25 .9S5 Il 211.5 39.60 3g, I~l 0,93 r _ _ _ _ ¦ Drug Content of Table~ - 40.0 mg ~ . ..
Table XXI
~0 Excretion of PhenylPropanolamine from Subject A for Tablet 2 Time (hour) Au AT AT/AToo .. _ _ .. . . _ _. .
2.0 o.68 1.59 o.0lll 3.0 3.So 5.31 0.135 . o 7.61 lo .17 o.259 ` ~ 5 7.2 17.50 21. o6 o .536 ~,9 23.90 28.10 0.715 12. 5 27.70 32.20 o .819 14.5 29,80 31~, so 0.8 1~ .0 31.90 36.82 0.937 21~,0 31~ .30 32.29 l . ~oo 1:
__ Drug Content of Tab1et - 39.3 mg , , CANADA
52 - Case 118-3324 .:.
.

Table XXII
__ E~retion of Phenylprop~o]-a~rine fr~ S~ect ~ for Tablet 3 . , .- Time (hour) Au AT AT/AToo 2,0 0,00 0,11 0.003 ` 5 4,0 2.80 3,91 0,09g 6.5 g,20 12.3~ 0.316 , 9,8 17,50 23.19 0,592 15.4 23,90 31.~5 0.802 24,0 29,90 39,25 1,000 .
Drug Content of Tablet: 39 . 2 mg '; ' , :~ Table XXI:rX
1 ' . ~ Exc~,tion o:E Pl~e~n~olamin~ frc~n Subiect B for Tc~ble~ ~l , :
Time (hour) Au AT AT/AToo :.

0 2.55 4,67 0.117 i 15 2,0 9.20 10.86 0,272 3.0 14,50 15,65 0,391 4,0 18,00 18, ~2 0. ~71 5,0 21,30 21,95 0.549 I 5.8 23,30 23,78 0.595 j 20 6,8 25,40 25,'rl 0,643 ;l 8,0 27,50 2'~.75 0,694 10,0 31,1~0 31.55 0,7a~
12,5 311,20 34,14 0,853 15,0 36,10 35,96 0.~99 , 25 18,0 38,30 38,10 0,952 25.5 I~o,40 39.99 1.000 - - ''~
~ Drug Content of Tablet - 4 0 . 0 mg .~ :, ~` , :

:
. . .
.
... .

;
.

- - CANA~A
- 53 - Case 118-3324 Table XXIV
"~

Time (hour) Au AT T/ T
' - .
2,0 0,29 0,50 0,013 3.0 1,94 2,76 0.070 4,0 5.00 6.66 0.170 6.5 1l~.10 17,86 o,454

9.0 20,70 25,85 o,658 ` 11.5 25,20 31.21 0.79~
11~.0 26,10 32,22 0.820 21~.0 31.90 39.~'2 1.000 ,:, . . ..
:~ Drug Content of Tablet - 39 . 3 mg , :
TAble XXV
:, Excret.ion of Phenylpro~anolc~ne frc~n Subject B for Tc~blet 3 , 15T~ne ( hour ,) Au ~r ~r/ T
:, :
;j 2,0 1.35 1.98 0,050 l~,o 3.85 5.75 0.145 5.3 7.01~ 10.33 0,261 ! 8.o 10.84 15.68 0.397 12.0 16.92 21~.37 0,617 , 1ll.0 19.50 2~,65 0,710 2i~,0 27.60 39.55 1.000 _ Content of T~let - 39.5 mg ., ~. 1. , . . I . "

CANADA
, - 54- Case 118-332~
, ~4~S33 - Table XXVI
Excreti~n of Phenylpropanolc~Nne fr~m Subject C for Tc~blet l Time (hour) Au AT AT/ T

-~ 1,0 3.50 5.63 0.1~1 2.0 9.50 11.36 0.28l~
3.0 14.70 16.11 0.l~03 ! 4,0 18.00 19.04 o.476 '~ 6.o 23.50 24.27 o.607 l 8 0 2~.30 27.87 0.697

10 0 30.40 30.~3 0.771 ~' 12,0 32.50 32.~ , 0,822 ~,1 14.0 35.00 35.39 0.8~5 16.0 37.20 37.52 0.938 2l~,0 40.00 39.92 0.998 Drug Content o~ 'rablet - ~0.0 mg , Table XXVII
?'Excretion of Pheny~ nolamine rcm Subject C for Tciblet , Time (hour) Au AT AT/AToo -- . :
... .
i 2.0 o.85 1.70 0.043 3.0 3.60 5.52 0.140 0 7.10 9,8~ 0.250 0 17.50 21.06 0-535 12,0 26.00 30.20 o.767 1~.0 28.10 32.50 0,830 2S 17.0 31.90 36,81 0.933 2~.0 3~.20 39.10 0.990 , Drug Content of Tablet - 39.4 mg " ,:
,:' ', ' ;',~
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~ - 55 Case 11~-3324 :~
.'. , ~', . ,.
104~533 ' ;'; ~ 1 , Table XXVIII
~cretion of Ph~n~ ro~ol~E!fb~n S~iect C for Tablet 3 ~:
Time (hour) Au AT T/ T
,: :
~ 2.0 o.al 1.30 0.033 `
" 5 4,o 3.01 4.52 0.11 -6.o .9.21 12.40 0.31 8.o 10.~5 15.70 ~,397 ~
12,0 1~.50 24.00 o . 605 : .
1ll.0 19.52 2~,20 0.712 `
16,0 22.10 29.98 0.756 21~.0 2~.25 39.40 0.995 :,' ', .
- Drug Content of Tablet - 39.6 mg - .
., ~,, .
~; , .

. . ,:
, ~ In manner analogous to the pxeceding E~amples, ~ ~ .
coated formulations in ~1hich the medicament core comprises ~:
tetracycline I ampicillin j . :. . -.~ . "Aspirin"
potassium chloride phenylbutazone , 20 oxycillin - .
. i : .
or pentaerythritol tetranitrate : ~
..
may b.e produced, as may a coated formulation in which the . j . , : . r -, medicament core is replaced by a Heidelberg capsule. -'.1 ' - - ~ -,, , . i, .
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..

Claims (35)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A sustained release medicament formulation with prolonged gastric residence comprising (a) a medicament core or a core comprising a diagnostic aid and (b) a pharmaceutically acceptable coating on said core comprising (1) a pharmaceutically acceptable cross-linked polymeric component which comprises a prepolymer cross-linked with a cross-linking agent at a ratio of 8 parts by weight of prepolymer to 0.15 to 4 parts by weight of cross-linking agent, and a plasticiser, in an amount of about 1 to 10 parts by weight per 8 parts by weight of said prepolymer, the prepolymer being a copolymer of (i) 20 - 90 parts-by weight of a substituted or un-substituted unsaturated dicarboxylic acid or acid anhydride having 1 to 3 carbon atoms between the two carboxylic groups, and (ii) 10-80 parts by weight of an alkene of 2 to 6 carbon atoms, styrene or an alkyl vinyl ether in which the alkyl radical contains 1 to 16 carbon atoms, said polymeric film being water-hydratable, water-permeable, and swellable in the presence of gastric fluids, and, optionally, (2) a pharmaceutically acceptable, substantially water-insoluble polymeric component; the ratio of said substantially water-insoluble component (2) (when present) to said water-hydratable component (1) of said coating ranging from about 90:10 to 10:90.

2. A sustained release medicament formulation with prolonged gastric residence comprising a) a medicament core, and b) a pharmaceutically acceptable coating on said core compris-ing a cross-linked polymeric film which comprises a pre-polymer cross-linked with a cross-linking agent at a ratio of 8 parts by weight of prepolymer to 0.15 to 4 parts by weight of cross-linking agent, and a paasticiser, in an amount of about 1 to 10 parts per 8 parts of said prepoly-mer, the prepolymer being a copolymer of (i) 20-90 parts by weight of a substituted or unsubstituted unsaturated dicarboxylic acid or acid anhydride having 1 to 3 carbon atoms between the two carboxylic groups, and (ii) 10-80 parts by weight of an alkene of 2 to 6 carbon atoms, styrene or an alkyl vinyl ether in which the alkyl radical contains 1 to 16 carbon atoms, said polymeric film being water-hydratable, water-permeable and swellable in the presence of gastric fluids.

3. A formulation according to Claim 2, in which the polymeric film comprises a prepolymer cross-linked with a cross-linking agent at a ratio of 8 parts by weight of prepolymer to 0.15 to 1.5 parts by weight of cross-linking agent.

4. A formulation according to Claim 2, in which the prepolymer contains repeating units of formula I, I
in which one of R1 and R2 is hydrogen and the other is hydrogen, chlorine, fluorine, hydroxy, alkyl of 1 to 16 carbon atoms, aryl, aralkyl or -SO3H, and R is dimethylene, optionally sub-stituted by alkyl of 1 to 4 carbon atoms, phenyl or alkoxy of 1 to 12 carbon atoms, or is -CH2-CH=CH-CH2-.

5. A formulation according to claim 4, in which the prepolymer contains repeating units of formula I, in which each of R1 and R2 is hydrogen, and R is dimethylene optionally substituted by phenyl or methoxy.

6. A formulation according to claim 5, in which the prepolymer contains repeating units of formula I, in which each of R1 and R2 is hydrogen and R is dimethylene substituted by methoxy.

7. A formulation according to claim 6, in which the average molecular weight of the prepolymer is from 100,000 to 5,000,000.

8. A formulation according to claim 7, in which the average molecular weight is 250,000 to 2,000,000.

9. A formulation according to claim 2, in which the prepolymer is a copolymer of methyl vinyl ether and maleic anhydride in a 1:1 molar ratio.

10. A formulation according to any one of claims 7 to 9, in which the cross-linking agent is an alkylene diol, a polyalkylene glycol, a long-chain dihydric compound, a diamine, or a triol.

11. A formulation according to any one of claims 7 to 9, in which the cross-linking agent is 1,3-propylene diol, diethylene glycol, glycerine, polyethyleneglycol, poly-tetramethylene glycol, methoxypolyethylene glycol, a poly-oxyethylene sorbitan ether, ethylene diamine, triethylene tetramine, pentaethylene hexamine or 1,2,3-butane-triol.

12. A formulation according to any one of claims 7 to 9, in which the cross-linking agent is an alkylene diol or polyoxyethylene sorbitan ether.

13. A formulation according to any one of claims 7 to 9, in which the cross-linking agent is polyoxyethylene sorbitan monooleate or monolaurate.

14. A formulation according to any one of claims 7 to 9, in which the cross-linking agent is polyoxyethylene sorbitan monolaurate.

15. A formulation according to claim 2, in which the plasticiser is present to the extent of 8 parts by weight of polymer to 1 to 7 parts by weight of plasticiser.

16. A formulation according to claim 15, in which the plasticiser is present to the extent of 8 parts by weight of prepolymer to 4 to 5 parts by weight of plasticiser.

17. A formulation according to claims 15 or 16 in which the plasticiser is glyceryl triacetate, ethyl acetate, diethyl phthalate or dibutyl phthalate.

18. A formulation according to claim 15 or 16 in which the plasticiser is glycerol triacetate.

19. A formulation according to claim 2, in which the polymeric film incorporates a material which is soluble in gastric fluids to provide for film opening.

20. A formulation according to claim 19 in which the material is finely divided calcium carbonate.

21. A sustained release medicament formulation with prolonged gastric residence, comprising a) a medicament core and b) a pharmaceutically acceptable coating on said core comprising a binary polymeric film including 1) a pharmaceutically acceptable, substanti-ally water-insoluble, polymeric component and 2) a pharmaceutically acceptable cross-linked polymeric component which comprises a prepolymer cross-linked with a cross-linking agent at a ratio of 8 parts by weight of prepolymer to 0.15 to 4 parts by weight of cross-linking agent, and a plasticiser in an amount of about 1 to 10 parts by weight per 8 parts by weight of said prepoly-mer, the prepolymer being a copylymer of i) 20 to 90 parts by weight of a substituted or unsubsti-tuted unsaturated dicarboxylic acid or acid anhydride having 1 to 3 carbon atoms between the two carboxylic groups, and (ii) 10-80 parts by weight of an alkene of 2 to 6 carbon atoms, styrene or an alkyl vinyl ether in which the alkyl radical contains 1 to 16 carbon atoms, said polymeric component being water-hydratable, water-permeable and swellable in the presence of gastric fluids; the ratio of said substantially water-insoluble component(1) of the coating to said water-hydratable component (2) of the coating ranging from about 90:10 to 10:90.

22. A formulation according to claim 21, in which the substantially insoluble polymeric component is a carboxyl containing or carboxylate copolymer.

23. A formulation according to Claim 22, in which the substantially water-insoluble polymeric comp-onent is a polyacrylate.

24. A formulation according to Claim 23, in which the polyacrylate is poly(methylmethacrylate) or poly(ethylmethacrylate).

25. A formulation according to Claim 24, in which the second polymeric component is a copolymer of methyl vinyl ether and maleic anhydride in a 1:1 molar ratio.

26. A formulation according to claim 21, in which the ratio of first and second polymeric components is 60:40 to 10:90.

27. A formulation according to Claim 2 or 21 in which the medicament core is in the form of a tablet or capsule.

28. A formulation according to Claim 2 or 21 in which the medicament core is in the form of a tablet.

29. A method of producing a formulation according to Claim 2, which comprises a) coating a medicament core with a solution comprising a prepolymer and a cross-linking agent, as defined in Claim 2, and b) subjecting the resulting coated medicament core to cross-linking conditions.

30. A method according to Claim 29,in which the solution is in ethyl acetate.

31. A method according to Claim 29, in which the resulting coated medicament core is subjected to a temperature of from 10° to 90°C and a relative humidity of from 30 to 95%.

32. A method according to Claim 29 in which the resulting coated medicament core is subjected to a temperature of from 20° to 60°C and a relative humidity of from 40 to 60%.

33. A method according to Claim 22 in which the resulting coated medicament core is cross-linked in its shipping container.

34. A process for the production of a form-ulation according to Claim 21 comprising coating a medicament core with a solution of a binary polymer comprising components 1) and 2), defined in Claim 21.

35. A process according to Claim 34 in which the solution is in ethyl acetate.