United States Patent:   5,976,577

Assignee:  RP Scherer Corporation (Troy, MI)

Filed:  July 11, 1997

Process is provided for preparing an oral solid rapidly disintegrating freeze-dried dosage form of a pharmaceutically active substance having an unacceptable taste, wherein prior to freeze drying, a suspension of uncoated or coated coarse particles of a pharmaceutically active substance in a carrier material is cooled to reduce the viscosity and minimize release of the active substance during processing, as well as beyond the point of disintegration of the form in the mouth, to minimize bad taste from the drug.

DESCRIPTION OF THE INVENTION

It has now been found, in accordance with the present invention, that it is possible to produce fast dispersing dosage forms which disintegrate rapidly in the mouth and which do not depend on the use of sweetening or flavoring agents to mask the taste. The dosage forms have good mouth feel and do not exhibit premature release of the drug in the mouth. The invention is based on the discovery that it is possible to produce a fast dispersing freeze-dried dosage form containing drug particles which may be uncoated or coated with a polymer or lipid material which exhibit minimal release of the drug in the mouth. This is achieved by using coarse coated drug particles and controlling the viscosity of the suspension by reducing the temperature during the holding time in suspension to minimize sedimentation of the particles without altering the physical properties of the dried units. The resulting dosage form exhibits delayed release of the drug for a time at least sufficient to mask the taste in the mouth before swallowing, and typically for a longer period of time to provide controlled or sustained release of the drug after swallowing.

In accordance with one aspect, the present invention provides a rocess for preparing an oral solid rapidly disintegrating dosage form of pharmaceutically active substance, comprising forming a suspension n a continuous phase of coarse particles of the pharmaceutically active substance in a carrier material, reducing the temperature of the suspension to increase the viscosity of the suspension and minimize sedimentation of the particles, forming discrete units of the cooled suspension, and removing the continuous phase to produce the rapidly disintegrating form.

The term "coarse particles" as used herein means drug particles having a size such that coatings can be formed thereon which are sufficiently intact and continuous to prevent or minimize loss of the drug during processing to form the dosage forms or during disintegration of the dosage form in the mouth prior to swallowing. Size of the particles has an important effect on the rate of release of drug when coated. A smaller particle has a much larger overall surface area for diffusion. As a result, the rate of release of drug is greater the smaller the particle. Current coating techniques are able to effectively coat particles greater than 100 .mu.m, whereas particles less than 100 .mu.m may not have an intact coat, which will result in rapid release of the drug once in suspension. Coating of larger particles therefore decreases the rate of release of drug. Typically, according to the present invention, the coarse particles may have a size of up to 1 millimeter, although the average size is generally up to about 500 .mu.m, for example 75 to 400 .mu.m, more usually in the region of about 100-300 .mu.m. In this size range, it is possible to apply a uniform intact coating on the particle in order to achieve efficient freeze-dried dosage forms with slow drug release rate.

Increasing the particle size gives rise to increased sedimentation rate of the particles in suspension. This causes difficulties in obtaining uniformity of dose in each dosage form and can also cause splitting of the units if the drug particle sediments in the individual blister pockets before being frozen. The present invention overcomes this problem by adjusting the viscosity by reducing the temperature of the fluid suspension by an amount such as to increase the viscosity to a level sufficient to prevent or substantially eliminate settling out of the drug particles, preferably over a period of about 5 minutes. The temperature of the suspension is generally reduced from about 23-25^oC. to about 14-20^oC., typically to about 15-19^oC.

According to the present invention, adjustment of the temperature of the suspension can alter the viscosity of the mix without effecting the properties of the dried units. This prevents rapid sedimentation of the drug particles, which is necessary to prevent rapid release of active agent while at the same time maintaining rapid disintegration times without gummy or gritty sensation.

The carrier material which forms a network or matrix containing the pharmaceutically active substance after removal of the continuous phase 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, i.e. disintegrates within 10 seconds or less in the mouth. The preferred carrier material for use in the present invention is gelatin, usually pharmaceutical grade gelatin. Other substances may be used as the carrier material are, for example, hydrolyzed dextrose, dextran, dextrin, maltodextrin, alginates, hydroxyethyl cellulose, sodium carboxymethyl cellulose, microcrystalline cellulose, corn-syrup solids, pectin, carrageenan, agar, chitosan, locust bean gum, xanthan gum, guar gum, acacia gum, tragacanth, conjac flower, rice flower, wheat gluten, sodium starch glycolate, soy fiber protein, potato protein, papain, horseradish peroxidase, glycine and mannitol.

It is possible to adjust the viscosity of the suspension sufficiently to prevent rapid sedimentation of drug particles up to 400 .mu.m. The use of particles in this size range can prevent release of drug during the mixing stage. As demonstrated in the working examples, when gelatin is used, it has been found that reducing the holding temperature of the suspension from about 23^oC. to about 15^oC., the viscosity of the suspension is increased sufficiently to prevent any sedimentation over a five-minute period. For a placebo formulation, the viscosity at 25^o would be approximately 1.5-4.0 mPa.s, which would be expected to increase to between 20-50 mPa.s at 15^oC., when measured at 500 s^-1 using a Haake VT550 viscometer with an NV sensor. The viscosity of a particular formulation will vary greatly, however, depending on the drug concentration and properties. The data in Example 2 shows a viscosity at 23^oC. of 36 mPa.s which increases to 73 mPa.s upon cooling to 15^oC. The higher values in this example are due to the presence of an additional 19.5% drug material but a significant increase in viscosity is again observed.

The ideal properties of the dried units can be maintained by a slight alteration in the polymeric carrier material or the temperature used. By varying the polymer level, a slightly different temperature will be required to maintain unit properties of hardness and disintegration, whilst preventing sedimentation. The polymer level used must therefore be optimized with the holding temperature, as alterations in either will affect the sedimentation rate, unit hardness and disintegration time.

A further advantage realized in the use of temperature modification of the suspension is the consequent decrease in the rate of release of drug from particles which have been coated. Diffusion processes are temperature dependent. By holding the suspension at a lower temperature and at higher viscosity, the rate of release of drug from the coated particles is reduced. This allows longer available mixing times before release of drug has reached a point where the bitter or unpleasant taste is no longer masked. This is useful for the production process where dosing of large batches takes a number of hours. Drug release from the coated particles does occur gradually, but the process of the invention decreases this rate substantially allowing longer production run times.

The term "rapidly disintegrating" as used herein means that the solid dosage form will disintegrate in water at 37^oC. in 60 seconds or less. The forms usually disintegrate in about 5-20 seconds, more usually 5 to 10 seconds or less, when tested by the following procedure which is analogous to the Disintegration Test for Tablets, B.P. 1973 which is described in British patent number 1548022:

Apparatus: this comprises 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 disk of rust-proof wire gauze complying with the requirements for a No. 1.70 sieve (B.P. 1973, page A136).

A glass cylinder is provided with a flat base and an internal diameter of about 45 mm containing water not less than 15 cm deep at a temperature between 36^o and 38^oC.

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: one shaped article is placed in the basket and raised and lowered in such a manner that the complete up and down movement is repeated at a rate equivalent to 30 times a minute. The shaped article is disintegrated when no particle remains above the gauze which would not readily pass through it.

In accordance with another aspect of the invention, there is provided an oral solid rapidly disintegrating dosage form of a pharmaceutically active substance when prepared by the process of the invention.

In yet a further aspect, the invention provides an oral solid rapidly disintegrating dosage form of a pharmaceutically active substance comprising coarse particles of the active substance having an intact coating of a polymer or lipid material homogeneously dispersed in a matrix of a water soluble or water dispersible carrier material. The optimum size of the coated particles is in the region of about 50 .mu.m to 400 .mu.m, preferably about 100-300 .mu.m.

The present invention solves a number of problems associated with rapidly disintegrating dosage forms. In particular, the larger sized particles employed allows for the formation of a continuous intact coating on the drug particles which prevents or minimizes early release of the drug during processing, and also prevents early release during rapid disintegration of the dosage form in the mouth. The coating also can be such as to provide controlled or sustained release of the drug so that drug release begins at a particular time after administration or when the drug has reached a particular location within the body.

The coated particles may be produced using any of the coating techniques capable of producing particles in the size range of interest. Examples are solvent evaporation, solvent extraction, coarcevation, spray congealing, spray drying, pan coating, air suspension techniques, spheronization, lyposomes, complex formation, hot-melt encapsulation, interfacial polymerization, electrostatic encapsulation, ion-exchange resins, centrifugal processes, or combinations thereof.

The coated particles can contain up to about 98% by weight of the pharmaceutically active substance. More usually this amount is 10% to 95% by weight.

Generally, the coating on the particles is a polymer or lipid material and serves to prevent loss of the pharmaceutical agent during processing, as well as delaying release of the pharmaceutically active substance beyond the point of disintegration of the form in the mouth. Any suitable polymer or lipid or combination can be used as the coating material. Examples of suitable polymers include cellulose and derivatives such as ethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, cellulose acetate, cellulose acetate phthalate, hydroxypropylmethylcellulosephthalate, acrylic derivatives, such as polymethacrylates, polyglycolic--polylactic acid, polyvinylalcohol, gelatin, collagen and polyethyleneglycol. Examples of suitable lipid materials include waxes such as beeswax and lanolin, stearic acid and derivatives such as glycerol esters, fixed oils, fats, phospholipids, and glycolipids.

Such coatings are well known to persons skilled in this art. Persons skilled in the art could also readily provide coatings having a particular dissolution time so as to ensure that drug release is prevented until required.

The continuous phase used for forming the suspension of the pharmaceutically active substance is preferably water. The water may be admixed, if desired, with a co-solvent such as an alcohol, e.g. ethanol.

The free-flowing fluid suspension generally has a solids content of 50% by weight or less, more usually 5-25% by weight. A solids content of higher than 50% by weight results in the mixture becoming more akin to a paste rather than a fluid suspension.

Dosing from a fluid suspension rather than a paste offers advantages by facilitating the dosing and freeze-drying processes and producing product with a very rapid disintegration time. If dosed from a paste the disintegration time is generally much greater due to the overall higher content of solids.

According to the process of the invention, sedimentation in the drug suspension in the carrier material is controlled by manipulation of the matrix temperature to create a more viscous solution. By cooling a 3% gelatin solution from about 25^oC. to about 15^oC., the viscosity increases from about 2.0 mPa.s to 50.0 mPa.s. By following this approach, it is possible to sufficiently delay the rate of sedimentation of coated particles without significantly altering the physical properties of the finished units.

Other methods exist that could be used to increase the viscosity of the mix to prevent sedimentation such as the inclusion of polymers or viscosity modifying agents. Due to the nature of the dosage form however, the use of these compounds will tend to alter the finished properties of the units if included at a sufficient level to prevent sedimentation of the coarse particles. Such viscosity modifying agents include cellulose or cellulose derivatives such as ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, caboxymethylcellulose, sodium hydroxypropylmethylcellulose, carbomer, xanthan gum, maltodextrin, acacia, tragacanth, povidone and polyvinyl alcohol. The presence of these polymers at the levels required to increase the viscosity causes an increase in the disintegration times of the dried units. When taken, the units disperse to form a gummy mass rather than the melting sensation obtained with ideal freeze-dried dosage forms.

It is also possible to adjust the density of the coated drug particles by selection of suitable lipids/polymers or combinations thereof and manipulation of the coat/drug ratio. By applying a sufficient coat to the drug particle of a lipid or waxy material that has a density lower than that of the drug particle or of the solution, the rate of sedimentation of the coated particle can be decreased.

In accordance with another aspect of the invention, an agent may be added to the suspension which gives increased structural integrity to the matrix. The structure-forming agent is typically a polyhydric alcohol, for example mannitol or sorbitol. The structure-forming agent is normally added to the suspension in an amount of about 1-5% by weight, for example about 2-4% by weight.

The suspension may also contain other additional ingredients such as, for example, flavoring agents and sweetening agents. Preservatives and coloring agents may also be added,

The discrete units into which the suspension is formed may be liquid units, for example contained within the pockets of a suitable mold. Alternatively, the suspension may be in the form of solid units, for example frozen units or gelled units where the carrier material readily forms a gel. Typically each unit will contain up to 250 mg of the drug, for example 10-100 mg. Unit dosage forms of the drug in rapidly disintegrating form are encompassed by the present invention.

The suspension of the particles in the carrier material is preferably formed into discrete units by introduction into a mold which preferably comprises a plurality of depressions, each of the depressions being of the desired shape and size for the oral dosage form product. The mold preferably comprises a plurality of depressions formed in sheet of a filmic material which may be similar to the material employed conventionally in the blister packaging of pharmaceuticals. A preferred filmic material for use as a mold in the present invention is described in WO94/12142. The desired quantities of the suspension may be filled into the mold using an automatic filling means which delivers a predetermined dose into each of the depressions in the mold.

A covering material may be adhered to the film material in the areas surrounding the depressions after removal of solvent from the suspension filling the depressions. The covering sheet is preferably an aluminum foil or aluminum foil laminate which may be adhered to the film material around the depressions by, for example, a heat sensitive material. The cover sheet may be adhered to the film material in a manner such that it can peeled away by the user to uncover the oral dosage form in the depressions in the mold. Alternatively, it may be adapted to the oral dosage forms being 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 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.

Removal of the continuous phase from the discrete units of the suspension comprising the pharmaceutically active substance is carried out by techniques well known to those skilled in the art. For example, when the discrete units are in a liquid form, they will generally be frozen or gelled prior to drying. The suspension contained within the pockets of a suitable mold is frozen, for example by passing a gaseous cooling medium such as liquid nitrogen over the mold or by inserting the mold into a nitrogen spray freezing chamber. Alternatively, the mold may be cooled by passing the mold over a cold surface. Once the dosage forms have been frozen, the mold 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 continuous phase, for example water, is sublimed in a freeze drying process under a reduced pressure which transforms the solid phase solvent (ice) directly into a vapor. 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. According to that process, the pharmaceutically active substance and carrier material dispersed in a solvent is solidified and the solidified matrix is subsequently contacted with a second solvent that is substantially miscible with the first at a temperature lower than the solidification point of the first solvent. The matrix component is substantially insoluble in the second solvent and the first solvent is thereby removed from the matrix.

An 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 a 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 may 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 preferable, and is typically carried out at a temperature of from 25^oC. to 35^oC. under a vacuum of -750 mmHg or less, for 2 to 5 hours. Drying using forced-air is preferably carried out at a temperature from 3^o to 15^oC. for 1 to 6 days.

The process of the invention is advantageously used to prepare oral solid rapidly disintegrating dosage forms of various pharmaceutically active substances. The invention is particularly adapted to the formation of oral solid rapidly disintegrating dosage forms of drugs having an unacceptable taste. For example, paracetamol, which is routinely incorporated into conventional tablets has a bitter taste, can be formulated according to the present invention into an oral rapidly disintegrating dosage form which does not have an unacceptable taste. By coating paracetamol with a polymer or lipid material to provide coated microparticles of paracetamol, and incorporating the microparticles into a matrix solution of gelatin and mannitol, it is possible to provide a rapidly disintegrating solid oral dosage form which does not rely on the use of sweeteners and flavoring agents (although such agents may optionally be present) to mask the taste of the drug.

Other classes of therapeutic agents which may be used are antacids, analgesics, anti-anginals, anti-anniety, anti-arrhythmics, anti-bacterials, anti-diarrhoeals, anti-depressants, anti-epileptics, anti-fungals, anti-histamines, anti-hypertensives, anti-inflammatory agents, anti-virals, cardiac agents, contraceptives, cough suppressants, cytotoxics, decongestants, diuretics, drugs for genito-urinary disorders, drugs for use in parkinsonism and related disorders, drugs for use in rheumatic disorders, hypnotics, minerals and vitamins, lipid lowering drugs and sex hormones. Veterinary drugs may also be processed according to the present invention.

Claim 1 of 23 Claims

1. A process for preparing an oral solid rapidly disintegrating dosage form of a pharmaceutically active substance, comprising the steps of:

forming a suspension in a continuous phase of coarse particles of a pharmaceutically active substance in a carrier material, said carrier material being selected from the group consisting of water-soluble and water-dispersible carrier materials;

reducing the temperature of the suspension to form a cooled suspension of increased viscosity;

forming discrete units of said cooled suspension; and

removing the continuous phase to leave said rapidly disintegrating form in said carrier material.

____________________________________________
If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.