Process for preparing solid pharmaceutical dosage forms

A process for the preparation of an oral solid rapidly disintegrating dosage form of a pharmaceutically active substance which has an unacceptable taste which process comprises forming a solution or a suspension in a solvent of a form of the pharmaceutically active substance which is less soluble in water and more palatable than the form with the unacceptable taste together with a water-soluble or water-dispersible carrier material, forming discrete units of the suspension or solution and removing the solvent from the discrete units under conditions whereby a network of the carrier material carrying a dosage of the less soluble and more palatable form of the pharmaceutically active substance is formed.

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 which has an unacceptable taste to a human being or to an 
animal. 
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 geriatric 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. 
Although the solid dosage forms as described above overcome the problem of 
swallowing tablets, pills or capsules, the patient will taste the 
pharmaceutically active substrate as the dosage form disintegrates. For 
some pharmaceutically active substances the taste, if slightly unpleasant, 
can be rendered acceptable by the use of sweetening agents or flavouring 
agents which mask the taste. However, for some pharmaceutically active 
substances an unpalatable product will still be produced, despite the use 
of sweetening agents and flavouring agents, which decreases patient 
compliance. 
We have now developed a method for the preparation of an oral solid rapidly 
disintegrating dosage form of a pharmaceutically active substance which 
has an unacceptable taste which does not only depend upon trying to mask 
the unacceptable taste by the use of sweetening agents, flavouring agents 
and the like. 
Accordingly, the present invention provides a process for the preparation 
of an oral solid rapidly disintegrating dosage form of a pharmaceutically 
active substance which has an unacceptable taste, which process comprises 
forming a solution or a suspension in a solvent of a form of the 
pharmaceutically active substance which is less soluble in water than the 
form with the unacceptable taste together with a water-soluble or 
water-dispersible carrier material, forming discrete units of the solution 
or suspension and removing the solvent from the discrete units under 
conditions whereby a network of the carrier material carrying a unit 
dosage of the less soluble form of the 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 oral rapidly disintegrating solid dosage form of the present invention 
enables poorly tasting pharmaceutically active substances to be presented 
in a palatable form without changing the bioavailability of the 
pharmaceutically active substance relative to an existing marketed solid 
dosage form containing the more soluble compound. The pharmaceutically 
active substance is presented as a less soluble form rendering less of the 
drug to be tasted as the solid dosage form dissolves/disintegrates in 
saliva. 
The pharmaceutically active substance with the unacceptable taste may be 
presented in less soluble form prior to formation of the said solution or 
suspension. Alternatively, the pharmaceutically active form may be 
converted into the less soluble form during the process of the invention, 
for example during the preparation of the solution or suspension. 
The pharmaceutically active substance with the unacceptable taste may be 
rendered less soluble by conversion of a salt to a free acid or a free 
base, changing the salt form, formation of a hydrate, or changing the 
polymorphic form thereof, or by any other suitable means. 
The discrete units of the suspension or solution 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 solution or 
suspension comprising the pharmaceutically active substance in its less 
soluble form 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 solution or 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 WO94/14422. In this process the solvent is removed under conditions 
whereby the solvent is evaporated from the solid through the liquid phase 
to a gas, rather than subliming from a solid to a gas as in 
lyophilization. This is achieved by vacuum 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 solution or suspension of the 
pharmaceutically active substance is preferably water but it may be 
admixed with a co-solvent, such as alcohol, if it is desired to improve 
the solubility of the active substance. 
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, carrageenan, agar, chitosan, locust bean gum, xanthan gum, guar 
gum, acacia gum, tragacanth, konjac flour, rice flour, wheat gluten, 
sodium starch glycolate, soy fibre protein, potato protein, papain, horse 
radish peroxidase, glycine or mannitol. 
The suspension or solution 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 WO94/12142. The desired quantities of the 
suspension or solution 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 solution 
or 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 filmic 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 forms to be pushed through. 
Alternative methods of forming discrete frozen or gelled units of the 
solution or suspension include solidifying the mixtures in dropwise 
fashion. For example, the solution or 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 
solution or 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 or solution 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 process of the present invention may be used to prepare oral solid 
rapidly disintegrating dosage forms of various pharmaceutically active 
substances which have an unacceptable taste. For example, loperamide is 
incorporated into conventional tablets in the form of its hydrochloride 
which has an unacceptable taste for formulation into an oral rapidly 
disintegrating dosage form. However, the use of loperamide in the form of 
the free base enables a palatable formulation to be produced. Similarly, 
domperidone is incorporated into conventional tablets in the form of its 
maleate which has an unacceptable taste for formulation into an oral 
rapidly disintegrating dosage form. However, the use of domperidone in the 
form of the free base enables a palatable formulation to be produced. 
An advantage of the use of the less soluble forms of the pharmaceutically 
active substances in the process of the present invention is that the less 
soluble forms are generally easier to freeze dry, vacuum dry or dry 
conventionally. 
The process of the present invention for making more palatable oral rapidly 
disintegrating dosage forms obviates the need to use costly drug coating 
techniques or complexation techniques to mask the taste of the 
pharmaceutically active substance. 
The present invention also includes within its scope the oral solid rapidly 
disintegrating dosage forms prepared according to the process of the 
invention. 
Accordingly, the present invention includes within its scope an oral solid 
rapidly disintegrating dosage form of a pharmaceutically active substance 
which has been rendered more palatable by the process as described above. 
The present invention will be further described with reference to the 
following Examples.

EXAMPLE 1 
An oral solid rapidly disintegrating dosage form of loperamide was prepared 
from loperamide hydrochloride as follows: 
______________________________________ 
Quantities 
Ingredients for 400 Units 
______________________________________ 
Loperamide hydrochloride 
0.800 g 
Gelatin 2.345 g 
Mannitol 1.759 g 
Aspartame 0.300 g 
Mint flavour 0.120 g 
Sodium hydrogen carbonate 
0.150 g 
Purified water 54.526 g 
______________________________________ 
The gelatin was added to water in a mixing bowl and heated with mixing to 
approximately 40.degree. C. The mixture was mixed and homogenized under 
vacuum until dissolution of the gelatin was complete. 
The gelatin solution was added to a mixture of mannitol, sodium hydrogen 
carbonate and loperamide hydrochloride and the mixture mixed and 
homogenised until the soluble components had dissolved and the dispersion 
of the drug particles was complete. The mixture was cooled under vacuum 
and aspartame and mint flavour added thereto. 
The suspension was dosed into blister pockets, frozen and freeze dried to 
produce the final dosage form. 
During the processing the loperamide hydrochloride was converted into the 
less soluble loperamide free base form by the sodium hydrogen carbonate 
buffer. 
The product had an acceptable taste. 
EXAMPLE 2 
Domperidone maleate is a poor tasting pharmaceutical compound and when 
initially formulated as a freeze dried rapidly disintegrating oral dosage 
form, produced an unacceptable product. 
Domperidone was formulated in the form of the free base (which is less 
soluble in water or saliva than domperidone maleate) into an oral solid 
rapidly disintegrating dosage form using the following ingredients. 
______________________________________ 
Ingredients Weight per Unit 
______________________________________ 
Domperidone 10 mg 
Aspartame 0.75 mg 
Peppermint flavour 
0.15 mg 
Gelatin 5.70 mg 
Mannitol 5.20 mg 
Purified water 128.20 mg 
______________________________________ 
A solution containing the gelatin and mannitol was prepared and to this 
were added the aspartame and peppermint flavour. 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 homogeneous 
suspension obtained. The suspension was dispensed in 150 mg aliquots into 
the pockets of a blister pack, frozen and freeze dried to produce the 
final dosage form. 
The product had an acceptable taste.