Process for preparing solid pharmaceutical dosage forms of hydrophobic substances

Process for preparing an oral rapidly disintegrating dosage form of a hydrophobic pharmaceutically active substance comprising forming a suspension of the hydrophobic pharmaceutically active substance in a solvent containing a pharmaceutically acceptable surfactant together with a water-soluble or water-dispersible carrier material, forming discrete units of the suspension and removing solvent from the discrete units under conditions whereby a network of the carrier material carrying a dosage of the hydrophobic pharmaceutically active substance is formed.

This application is a 371 of PCT/GB95/02485 filed Oct. 20, 1995 published 
as WO96/13251 May 9, 1996. 
The present invention relates to a process for preparing solid 
pharmaceutical dosage forms and, in particular, to a process for preparing 
an oral solid rapidly disintegrating dosage form of a pharmaceutically 
active substance. 
Many pharmaceutically active substances are presented for oral 
administration in the form of tablets, pills or capsules. The tablet, pill 
or capsule generally has to be swallowed with water so that the 
pharmaceutically active substance can be absorbed via the 
gastro-intestinal tract. For some patients swallowing the tablet, pill or 
capsule is difficult or impossible and this is particularly the case for 
paediatric patients and geriatic patients. A similar difficulty is often 
encountered when trying to administer tablets to non-human animals which 
may be uncooperative in taking tablets, pills or capsules. 
Oral solid pharmaceutical dosage forms which rapidly disintegrate in the 
mouth and methods for their preparation have been proposed in GB-A-1548022 
and GB-A-2111423. The solid dosage forms as disclosed comprise an open 
matrix network carrying the pharmaceutically active substance, the open 
matrix comprising a water-soluble or water-dispersible carrier material 
which is inert towards the pharmaceutically active substance. The solid 
dosage forms are prepared by the sublimation or removal of solvent from a 
solution or suspension comprising the pharmaceutically active substance 
and the carrier material. Sublimation or removal of solvent is preferably 
carried out by freeze drying. 
Other methods for the preparation of oral solid pharmaceutical dosage forms 
which rapidly disintegrate in the mouth are disclosed in U.S. Pat. No. 
5,039,540, U.S. Pat. No. 5,120,549, U.S. Pat. No. 5,330,763, 
PCT/JP93/01631 and PCT/US93/12566. 
The solid dosage forms which are produced by these various methods rapidly 
disintegrate on being placed in the mouth of the patient, thereby 
delivering the desired dose of the pharmaceutically active substance. 
The preparation of oral solid rapidly dispersing dosage forms generally 
involves the formation of a suspension of the drug in water, optionally 
together with a co-solvent such as alcohol, together with the matrix 
forming components. For many drugs a homogeneous suspension cannot be 
prepared due to the hydrophobicity of the drug which causes a stable foam 
to form during the mixing process which results in a lack of uniformity of 
content of the drug in the final product. This problem is exacerbated for 
very fine particles where air entrapment during mixing becomes greater. 
We have now developed a process for the preparation of oral solid rapidly 
disintegrating dosage forms of hydrophobic drugs in which the foregoing 
problem is overcome. 
Accordingly, the present invention provides a process for the preparation 
of an oral rapidly disintegrating dosage form of a hydrophobic 
pharmaceutically active substance which process comprises forming a 
suspension of the hydrophobic pharmaceutically active substance in a 
solvent containing a pharmaceutically acceptable surfactant together with 
a water-soluble or water-dispersible carrier material, forming discrete 
units of the suspension and removing solvent from the discrete units under 
conditions whereby a network of the carrier material carrying a dosage of 
the hydrophobic pharmaceutically active substance is formed. 
By the term "rapidly disintegrating" as used herein is meant that the solid 
dosage form will disintegrate in water at 37.degree. C. in 60 seconds or 
less, preferably 5 to 10 seconds or less when tested by the following 
procedure which is analogous to the Disintegration Test for Tablets, B.P. 
1973 and which is described in British Patent No. 1548022: 
Apparatus 
A glass or suitable plastic tube 80 to 100 mm long, with an internal 
diameter of about 28 mm and an external diameter of 30 to 31 mm, and 
fitted at the lower end, so as to form a basket, with a disc of rustproof 
wire gauze complying with the requirements for a No. 1.70 sieve (B.P. 1973 
page A136). 
A glass cylinder with a flat base and an internal diameter of about 45 mm 
containing water and not less than 15 cm deep at a temperature between 
36.degree. and 38.degree. C. 
The basket is suspended centrally in the cylinder in such a way that it can 
be raised and lowered repeatedly in a uniform manner so that at the 
highest position the gauze just breaks the surface of the water and at the 
lowest position the upper rim of the basket just remains clear of the 
water. 
Method 
Place one shaped article in the basket and raise and lower it in such a 
manner that the complete up and down movement is repeated at a rate 
equivalent to thirty times a minute. The shaped articles are disintegrated 
when no particle remains above the gauze which would not readily pass 
through it. 
On oral administration of the solid dosage form of the invention to a 
patient the pharmaceutical dosage form rapidly disintegrates in the mouth. 
The process for the preparation of oral rapidly disintegrating solid dosage 
forms in accordance with the present invention enables hydrophobic 
pharmaceutically active substances to be presented for administration in 
this form. 
The incorporation of the surfactant into the solvent used during the 
preparation of the suspension of the drug prevents the formation of a foam 
on mixing and ensures uniformity of the content of the drug in the dosage 
units and thus overcomes problems associated with air entrapment. 
Furthermore, hydrophobic pharmaceutically active substances do not 
generally disperse easily and rapidly in the mouth and the addition of the 
surfactant during the processing of the drug improves the dispersion of 
the dosage units formed in the process of the invention within the mouth. 
Furthermore, for some hydrophobic pharmaceutically active substances the 
addition of the surfactant during processing improves the bioavailability 
of the product due to improved wetting of the pharmaceutically active 
substance leading to further dissolution and absorption. 
Any surfactant which fulfils the requirement of pharmaceutical 
acceptability may be used in the invention. Particularly suitable 
surfactants for use in the present invention are the Poloxamers which are 
.alpha.-hydro-co-hydroxypoly(oxyethylene)-poly(oxyethylene)block 
copolymers and polysorbates which are polyoxyethylene derivatives of 
sorbitan esters. Since the surfactant will remain in the finished dosage 
form of the product it is important that it has an acceptable taste. 
The process of the present invention is of particular use for the 
preparation of oral solid rapidly disintegrating dosage forms of 
hydrophobic pharmaceutically active agents which have a very small 
particle size since the ease of wetting becomes more difficult in the 
absence of a surfactant as the particle size decreases and the air 
entrapment during mixing in the absence of a surfactant becomes greater. 
The present invention is thus of particular utility in preparing solid 
rapidly disintegrating dosage forms of hydrophobic pharmaceutically active 
agents having an average particle size of less than less than 50 .mu.m, 
generally of less than 20 .mu.m, more preferably less than 10 .mu.m. 
Hydrophobic pharmaceutically active agents which may be processed according 
to the present invention include domperidone and bromocriptine mesylate. 
The discrete units of the suspension may be in the form of liquid units, 
for example contained within the pockets of a suitable mould, solid units, 
for example frozen units, or gelled units where the carrier material 
readily forms a gel. 
The removal of solvent from the discrete units of the suspension comprising 
the hydrophobic pharmaceutically active substance and a water-soluble or 
water-dispersible carrier material is carried out by techniques well known 
to those skilled in the art. 
When the discrete units are in liquid form they will generally be frozen or 
gelled prior to drying. 
The liquid suspension which may be contained within the pockets of a 
suitable mould is frozen, for example by passing a gaseous cooling medium, 
such as liquid nitrogen over the mould, or by inserting the mould into a 
nitrogen spray freezing chamber, or cooling by passing the mould over a 
cold surface. Once the dosage forms have been frozen, the mould may be 
stored in a cold store, prior to drying. Frozen discrete units may be 
dried by freeze drying according to techniques which are well known in the 
art. The solvent is sublimed in a freeze drying process under a reduced 
pressure which transforms the solid solvent directly into a vapour. The 
freeze drying process will generally be carried out in a freeze drying 
chamber typically operating under a vacuum of 0.1 to 1.0 mBar for a period 
of time of from 180 to 500 minutes. 
Alternatively, frozen discrete units may be dried by a process as described 
in U.S. Pat. Nos. 5,120,549 and 5,330,763. In this method the 
pharmaceutically active substance and carrier material dispersed in a 
first solvent is solidified and the solidified matrix is subsequently 
contacted with a second solvent that is substantially miscible with the 
first solvent at a temperature lower than the solidification point of the 
first solvent, the matrix component being substantially insoluble in the 
second solvent, the first solvent thereby being removed from the matrix. 
Another alternative process for drying frozen discrete units is described 
in W094/14422. In this process the solvent is removed under conditions 
whereby the solvent is evaporatated from the solid through the liquid 
phase to a gas, rather than subliming from a solid to a gas as in 
lyophilization. This is achieved by vacuum drying at a temperature below 
the equilibrium freezing point of the composition at which point the 
solvent (such as water) changes phase. 
When the discrete units are gelled units, any drying methods can be used 
which do not affect the properties of the preparations. For example, 
drying may be carried out at decreased pressure, or by forced-air drying. 
Drying at decreased pressure is preferably carried out at a temperature of 
from 25.degree. to 35.degree. C. under a vacuum of -750 mm Hg or less, for 
2 to 5 hours, whilst drying using forced-air drying is preferably carried 
out at a temperature of from 3.degree. to 15.degree. C. for 1 to 6 days. 
The solvent used in forming the suspension of the pharmaceutically active 
substance is preferably water but it may be admixed with a co-solvent, 
such as alcohol, if desired. 
The carrier material which is used to form the network containing the 
pharmaceutically active substance may be any water-soluble or 
water-dispersible material that is pharmaceutically acceptable, inert to 
the pharmaceutically active substance and which is capable of forming a 
rapidly disintegrating network. The preferred carrier material for use in 
the present invention is gelatin, preferably pharmaceutical grade gelatin. 
Other materials may also be used, for example hydrolysed dextrose, dextran, 
dextrin, maltodextrin, alginates, hydroxyethylcellulose, sodium 
carboxymethylcellulose, microcrystalline cellulose, corn-syrup solids, 
pectin, carrogeenan, agar, chitosan, locust bean gum, xanthan gum, guar 
gum, acacia gum, tragacanth, konjac fluor, rice flour, wheat gluten, 
sodium starch glycolate, soy fibre protein, potato protein, papain, horse 
radish peroxidase, glycine or mannitol. 
The suspension prepared according to the process of the present invention 
is preferably formed into discrete units by introduction into a mould 
which preferably comprises a plurality of depressions, each depression 
being of the desired shape and size for the oral dosage form product. The 
mould preferably comprises a plurality of depressions formed in a sheet of 
a filmic material which may be similar to the material employed 
conventionally in the blister packaging of pharmaceuticals. A particularly 
preferred filmic material for use as a mould in the present invention is 
described in W094/12142. The desired quantities of the suspension may be 
filled into the mould using an automatic filling means which delivers a 
predetermined dose into each of the depressions in the mould. 
A covering material may be adhered to the filmic material in the area 
surrounding the depressions after the removal of solvent from the 
suspension filling the depressions. The covering sheet is preferably an 
aluminium foil or aluminium foil laminate which may be adhered to the 
filmic material around the depressions by, for example a heat sensitive 
material. The cover sheet may be adhered to the filnic material in a 
manner such that it can be peeled away by the user to uncover the oral 
dosage form in the depression in the mould or, alternatively, it may be 
adapted for the oral dosage formed to be pushed through. 
Alternative methods of forming discrete frozen or gelled units of the 
suspension include solidifying the mixtures in dropwise fashion. For 
example, the suspension may be passed through one or more holes to form 
drops, spheres or a spray of small particles which can be solidified by 
passage through a cold gas or liquid, for example liquid nitrogen. 
Alternatively, the drops, spheres or spray may be solidified by contact 
with a chilled liquid which is immiscible with the suspension and which 
has a density such that the drops either fall through the immiscible 
liquid as they solidify, or float on the surface of the immiscible liquid. 
The suspension prepared in accordance with the process of the present 
invention may also contain other additional ingredients such as colouring 
agents, flavouring agents, sweetening agents or preservatives, or fillers 
such as mannitol or sorbitol which improve the physical properties of the 
oral dosage form. 
The present invention also includes within its scope the oral solid rapidly 
disintegrating dosage forms prepared according to the process of the 
invention. 
The present invention will be further described with reference to the 
following non-limiting Example.

EXAMPLE 
Domperidone was formulated in the form of the free base into an oral 
rapidly disintegrating dosage form using the following ingredients. 
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Domperidone microfine 
10.000 mg 
average particle size less than 50 .mu.m 
Gelatin 5.513 mg 
Mannitol 4.136 mg 
Aspartame 0.75 mg 
Mint flavour 0.30 mg 
Poloxamer 188 1.125 mg 
Purified water 
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A solution containing the gelatin, mannitol and Poloxamer 188 was prepared 
and to this were added the aspartame and mint flavouring. Aliquots of the 
resulting solution were added to the domperidone powder and a paste formed 
on stirring. The remainder of the solution was added and a homogeneous 
suspension was obtained. The suspension was dispensed in 150 mg aliquots 
into the pockets of a blister pack, frozen and dried to produce the final 
dosage form. 
The bioavailability of the domperidone final dosage form finished product 
was equivalent to that of a compressed tablet form containing the same 
quantity of domperidone. The bioavalability of a similar oral rapidly 
disintegrated product prepared without the Poloxamer surfactant was not, 
however, equivalent to that of the compressed tablet.