Improved method for manufacturing freeze dried dosages in a multilaminate blister pack

9~O 94/12142 PCT/GI393l02459 IIVIIPit~'fllED TD<IIt~I~ FGIt 11~A,N~LdF/~C'I'IJItIING I~II~EZr~ I3RIEI) IIGS.AGE~ Il'd A 111~I1JLTILAvIVIIIVATI: ~LI~TI;It ~AC>~ ItACKGRGUNfI9 ~F TIIE IN~EImdTIG1'~ This invention relates generally to the field of manufacturing and dispensing pharmaceuticals, and snore particularly to au improved method for manufacturing freeze dried pharmaceutical tablets in disposable single dose aluminum blister packs.

In a~ecent years, pharmaceuticr.'1 producers have turned to the use off blister packs for use i~a both the forming and dispensing of pharmaceutical tablets. 'These blister packs generally consist of a blister sheet or blister film and a lidding sheet.

The blister sheet contains depressions for containing individual dosages.

In a standard process fns manufacturing freeze dried tablets, a single dosage, pn liquid form; is introduced into each depression of the blister sheet: The blister sheet, along arith the liquid dosages, is then placed into a refrigerated eawironment where the dosages are subjected to lour IS temperatures to freeze them: The blister sheets are then transferred to a freeze drier; where the ice is se~oved by sublimation.

When freeze drying is completed, the sheets ire rim~ve~ from the drying chamber s;nd covered avlth an adhesive lidding sheet; wD~ich seals the solid ddsage~ into their individeaal depressions.

~~ited Mates Patent T~lo: 4,305,502 is incorporated herein by reference as Z~ gashing, inter ells, s'&.n~a n proeess for manufacturing freeze dried tablets.

giowever, bli~3er sheets that have heretofore been used in freezing and ~ree~e drying processes have suffered from several aleficieircies: First, the blister slre~ts have typicdlly'beea~ made of a polymeric substae~ce, which, over time;

can all~w anoisture to perr~aeate the blister pack and reach the dosages stored inside.

Z5 'To salve this p~~ble~~ blister sheets have been dede0oped in which a layer of alte~sinupn is laminated between layers of polymee°While tlae presence of the alu~iuia~n layer ~arever~ts moisture from perane~atin~ 8~e blister pack, it leads to a sec~nd problem. F~la~ely; ~vleen subjected to temperature changes during the freeaing process, conv~htional aluminum/polymer laminates tend to curl up, dace 30 to the differences in the degree of thermal expansion or contraction of the opposing layers of the laminate.

This msk~s their use in f reezing processes difficult, since liquid product cas easily spell fr~m the formed depressions or can lip unevenly in the depressions during ffilling and freezing operations.

D~urthermore, the curling of the blister sheet can cause dosages to freeae or 35 subDimate unevenly, since some depressions may not be in physiedl contact with the cold surfaces of the refrigerator or freeze drier.

The only solution has been 'VV~ 94/12142 '~; ~~':~'.~!'Tj _~.,~ . ~CT/~1393I02459 -Z_ to use weights on the edges of the laminate strips to hold them sufficiently fiat.

Such ~raeasures are not practical in large scale manufacturing operations, and can interfere with ties freezing process.

A need therefore exists for a method of astilizing a high barrier aiuaninuare c ianainate in the manufacture of freeze dried dosage forms, that avoids the problem of curling of the blister sheet. a 'VVO 9x112142 : '~. ~ ~ ~ ~ hCTIG139310~4~9 _3_ ~Me~~Y 4Air TAE 11w1i~EI~'g'1f in a basic aspect, the invention is an improved method for manufacturing freeze dried dosage forms In aluminum blister packs.

The dosages are introduced as a iiduid into the depressions of a blister sheet. 'The blister sheet comprises an ~ impermeable intermediate layer positioned between first and second outer layers, with each of the outer layers having substantially the same overall coefficient of thermal exp~nsiou, as that term is defined herein.

The properties of the outer layers of the laminate are such that there are no inter-layer stresses that will cause curvature of the laminate when it is subjected to temperature changes during the freeze drying p.~ocess.

The symmetrical response of the outer layers to such temperature changes can be achieved by using the saane film mn~teriaf for both outer layers, or by using different materials which, by virtue of their intrinsic pe~perties or thickness, exhibit simslar degrees of thermal expansion Or contraction.

The cuter layers can each consist of separate subiayers, as long as 1S the subiayers in one outer layer are such that the outer layer, as a whole, exhibits the dame ov~rali degree ~f expansion or contraction as the other outer layer.

Followi~ag the intr~ciuction off the dosages into the depressions of the blister sheets the d~sages are fr~aen and freeze dried. A iidding sheet is then attached to tlee blister sheet to seal the solid doss~ges into the blister pack.

.. PCTlGB93/02459 V6'O 94/1142 ., ;. , ~.

a IIItIEF ID~~~CI~IhTICI~1 IDF TI--IE IDRAVVIN~S Fige~re 1 of the drawing is a plan view of a blister sheet, showing the configuration of the dosage depressions;

Figure Z of the drawing is a transverse cross sectio~eal view, of said blister S pack, taken generally along the line 2--2;

Figure 3 of the drawing is a cross sectional view of a blister sheet illustrating in further detail the relationship betweexa the in~ternnediate and outer Layers of the blister sheet;

Figure ~ 4 of the drawing is a cross sectional view of a blister sheet !4 illustrating in further detail the relakionship between the various layers and sublayers of the blister sheet;

Figure S of the drawing is a cr~ss sections~l view of a blister pack with the lidding sheet in peace.

WO 94112142 ~ , k'CTlC~893hD2459 ~~ ~.,~ , DETAILED DESCR1P'I'1~1V ~F 'f'H!E PREFERRED IEMl3~HDIi~E~ITS As discussed above, the invention is an improved method for manufacturing freeae dried dosage forms in aluminum buster laminates.

Turning to Figure 1 and Figaare 2, to form the blister park, depressions. l0 are formed in a strip 12 of the desired laminate through conventional cold formieog.

The slue and shape of the depressions is a matter of choice that will be dictated by the alas and nature ~f the tablet to be formed, as well as other considerations that are well known to those persons skilled in the art.

Turning to Figure 3, the laminate strip 12 comprises an, intermediate layer 14 that is substantially impermeable to moisture.

The preferred material for the intermediate layer is aluminum having a thickness of 10 to 100 dam, with the preferred thickness being approximately alS~un, although other suitable materials may be used in its place.

The intermediate aluminum layer 14 is sandwiched between a first outer layer 16 and a second outer layer 18.

The outer layers may be coated or laminated oedto the intermediate layer, but the layers do not necessar~ly heave to be bonded together.

The first and second outer layers are prefeeably made of p~lymeric substances, including polyamide, polyvinylchloride, polypropylene'or ~ther sash se~bstances: The first and second outer layers can he made of She same or different mstari~ls, end may leave different thicknesses, ~s lang as they have ubstanti~lly similar coefficients ~f thermal expansion, i.e., are made of xuch ae~ateaials and have sash thickness that the first and second outer layers exhabit substantially the same degree of expansion or contraction dyitlein the plane gf the film dvlten the lamieaate is subjected to changes in temperature, particularly within the range of te~np~ratures encountered during the freezing process, in which tem~aerata~res cs<n be as to4v as -195°C.

For instaatse, tl~e laminated filtra l2 can consist of an intermediate layer ~~ of alumia~um, positioned between first and second outer layers of pmlypropylene 16 and 18, each layer being approximately 50 ~a~s thick.

'rurni~eg to Figure 4,, it can be seen that one or both of the outer Dyers can also c~nsist of separate sublayers, with each sublayer being either polymeric or ~aonpal~meric.

For instance, the first oest~r layer 16 can consist of two or more sublayers, sued a~ a polyamide ~ublayer 20 acnd a polyvinylehl~ride sublayer 22.

The second outer layer l8 can consist of a itientic~t sublayers, or can also consist of two or more sublayers, illustrated as 24, 2fi and 28, that are different than the WO 94/12142 ~ ~,, ~, :, ; . PCT/GB93/02459 sublayers in the first outer Bayer lb. 14laterials that may be used as sublayers include the above mentioned polymers, as well ax lacquer, aluminum or paper.

A priming layer can also be included.

Again, the primary concern is that the first outer layer 16 and the second outer layer 18 exhibit, overall, substantially a the same degree of expansion or contraction in response to temperature changes, so as to prevent curling of the blister sheet.

Returning to ~°iga~re 1, a single aosage 30 of pharmaceutical, in liquid form, is Dntroduced into each depression in the blister sheet in a conventional manner. °f'he blister sheet is then placed into a refrigeration unit, foe instance . a nitrogen spray freeaing chamber, where both the sheet and the dosages are subjected to temperatures sufficient to rapidly freeze the dosages, typi~alDy as low as -19b°C. t~nee the dosages have frozen, the blister sheet is transferred to a freeae drying chamber.

Within the freeze drying chamber, the dosages are subjected to a vacuum of typically O.l to d.0 mTdar for a period of 180 to 500 x5 minutes.

At the same time, the temperature is steadily increased from typically about -30°C to about 60°C.

As shown in Figure :S, once the dosages have been freeze dried, xn adhesive lidding sheet 32 is posPtioned over the blister sheet, sealing the dosages into the individual depressions of the blister sheet.

The pr~~edeores associated'vvitDe the introduction of de~sages inter the blister sheet, the freezing and freeze drying of the dosages and the attachment off tine lidding sheet are kn~ww to persons of skill in the art, a~ad need not be treated in great depth herein.

VYhile in tiers foreg~ing there leave been described preferred embodiments of t~,e ;mention; it ~laould b~ understood to those skiDD~d in the art that various -. 25 seaodifieations end changes fan be made witD~out departing from the true spirit and scope of the ine~ehtion ,