Title:  Process for making a particulate support matrix for making a rapidly dissolving dosage form

United States Patent:  6,207,199

Assignee:  The Board of Regents of the University of Oklahoma (Norman, OK)

Filed:  July 6, 1998

A particulate support matrix, and a dosage form made therefrom, and processes for making such support matrices and dosage forms, which disintegrate or dissolve in a matter of just a few seconds once placed into an aqueous environment. First, a porous particulate powder matrix comprising at least two polymeric components which will serve as the dosage form matrix is produced. The polymeric components have different solubilities. In a second step, a pharmaceutical compound, for example an antihistamine, decongestant, or antibiotic is combined with the powder. Other additives may also be added to the mixture. In a third step the mixture is formed into a dosage form. Finally, in a fourth step, a coating may be formed upon the outer surface of the dosage form to enhance the intactness and durability of the dosage form.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention comprises a particulate support matrix, a dosage form made therefrom which disintegrates or dissolves in a matter of just a few seconds once placed into the oral cavity, or other aqueous environment and methods for making such support matrix and dosage form. This rapidly dissolving tablet or other dosage form made from the matrix described herein has many of the characteristics of a regular tablet up to the point of administration, i.e., convenient size, stable, easy to dispense, easily transportable, easy to alter the dose and easy to administer. Upon placing this dosage form in the mouth, the saliva will serve to rapidly dissolve the dosage form and the patient in effect will swallow the medication in a liquid form. The rapid-dissolving tablets of the present invention will eliminate many of the problems inherent in the other forms of orally-dissolving tablets described above since the matrix and active drug powders are blended and formed into tablets in the same way as regular tablets, except that a very light compression pressure is used in forming the tablets of the present invention.

Where used herein the term "dosage form" is meant to include any dosage form which is intended to be dissolved in any aqueous medium including water, saliva or other aqueous biological fluids or suspensions, and may include tablets, capsules, caplets, boluses, powders cachets, pills and granules.

If a drug entity has little or no taste, the dosage form will generally be prepared to be almost tasteless. If a drug product does have a characteristic, undesirable taste, the taste will preferably either be altered by different mechanisms such as flavorings to make it acceptable, or the drug will be micro- or nano-encapsulated with a coating that dissolves at an acidic pH and incorporated into the tablet. This rapid dissolving tablet will not only provide the geriatric, pediatric and incarcerated populations with an easy to use tablet, but may also result in long-term benefits such as enhanced patient compliance, fewer hospital admissions due to poor compliance, and enhanced health and quality of life.

Furthermore, the application of this dosage form is not limited to oral delivery as it is also applicable for use as a fast dissolving tablet when administered to other moist areas of orifices of the body, such as the rectum.

Generally, the method of the present invention comprises up to four steps. First, a porous particulate powder which will serve as the tablet support matrix is produced. In the second step, the pharmaceutical, for example an antihistamine, decongestant, or antibiotic is combined with the powder. Other additives may also be added to the mixture. In the third step the mixture is formed into a tablet or other dosage form. Finally, in the fourth step, a coating may be applied to the outer surface of the tablet or other dosage form or the dosage form may be otherwise treated to enhance the intactness and durability of the tablet or other dosage form.

More particularly, the invention comprises a particulate support matrix for use in forming a pharmaceutical dosage form and a process for producing it. The process comprises the steps of providing an aqueous composition which further comprises (1) an aqueous medium, (2) a support agent comprising a first polymeric component having a predetermined net charge, a second polymeric component having a predetermined net charge of the same sign as the first polymeric component, and a bulking agent and wherein the second polymeric component has a solubility in aqueous solution greater than that of the first polymeric component, and (3) a volatilizing agent for enhancing the rate of vaporization of the aqueous medium and for enhancing volume and porosity of the support agent during drying.

The particulate support matrix may optionally contain an acidifying or alkalizing agent for setting the predetermined net charge of the components of the support agent. The first polymeric component and second polymeric component of the support matrix may be provided in solution or may be provided in solid form and dissolved within the aqueous medium to form the aqueous composition along with the bulking agent. The aqueous composition is introduced as droplets into a drying chamber heated to a temperature sufficient to evaporate substantially all of the aqueous medium and volatilizing agent from the droplets. This yields the support agent as a dried and expanded particulate form comprising the particulate support matrix.

As contemplated herein, the support matrix, and the dosage form produced therefrom, may comprise more than two polymeric support components. In such a case, the more than two polymeric support components are of the same sign, and have a range of solubilities wherein one polymeric support component is less soluble than the others and another component is more soluble than the others. The most soluble polymeric component is therefore the primary polymeric solubilizing component of the present invention. It will be understood however that the other polymeric components may also contribute to the solubility of the support matrix in an aqueous environment.

The first polymeric component and the second polymeric component may have net charges which are closer to a neutral pH than is preferable for optimal rapid dissolution. For example, when the first polymeric component is an acidic gelatin, and the second polymeric component is an acidic gelatin hydrolysate, the isoelectric points may be higher than the preferred pH, which is below 5.5. In such a case, it is desired to reduce the pH of the solution to a preferred pH by the addition of an acidifying agent, such as citric acid or acetic acid. This will shift the isoelectric points of the gelatin to pH levels within the preferred range and will maintain them at such pH during the drying process.

However, when the first polymeric component and the second polymeric component have isoelectric pHs in their native form which are within the preferred pH range of about 3.5 to 5.5, it may be unnecessary to add an acidifying agent to the aqueous composition. For example, if the first and second polymeric components are polypeptides comprising a preponderance of acidic amino acids, the polypeptides may have isoelectric points which are sufficiently low. Similarly, if the polypeptides comprise a preponderance of basic amino acids, the polypeptides may have isoelectric points sufficiently basic to eliminate the need for an alkalizing agent to raise the pH of the aqueous composition.

After the net charges of the first and second polymeric components are altered (when necessary) either by an acidifying agent or by an alkalizing agent, the altered net charges will be maintained by the polymeric components due to their natural buffering capacity,

The completed particulate support matrix comprises (1) a first polymeric component having a net charge when in solution, (2) a second polymeric component having a net charge when in solution of the same sign as the net charge of the first polymeric component, and (3) a bulking agent. The second polymeric component has a solubility in aqueous solution greater than that of the first polymeric component for enhancing dissolution of the particulate support matrix upon exposure to an aqueous environment. When the support matrix is introduced into an aqueous environment it is substantially completely disintegrable within less than about 20 seconds. The support matrix may be substantially completely disintegrable within less than about 10 seconds, or more preferably within from about 1 second to about 6 seconds. The particulate support matrix preferably has a bulk density within a range of about 0.03 g/ml to about 0.15 g/ml. The particulate support matrix may have a bulk density within a range of from 0.03 g/ml to about 0.3 g/ml.

The first polymeric component may comprise a first polypeptide and the second polymeric component may comprise a second polypeptide. More preferably, the first polypeptide may be a non-hydrolyzed gelatin and the second polypeptide may be a hydrolyzed gelatin. Both the first polypeptide and the second polypeptide may have a net positive charge. Alternatively, the first polypeptide and the second polypeptide may have a net negative charge. The particulate support matrix may further comprise an agent for maintaining the net charge of the first polymeric component and the second polymeric component when it is desired to maintain the net charges at pHs different from those of the pH of the native first and second components in solution.

The invention further comprises a rapidly dissolving solid pharmaceutical dosage form, which is made from an active ingredient such as a pharmaceutical product which is mixed and dispersed throughout the particulate support matrix described herein and then formed into a tablet. When this dosage form is introduced into an aqueous environment the support matrix is substantially completely disintegrable within less than about 20 seconds so as to release the pharmaceutical ingredient to the aqueous environment. The support matrix may be substantially completely disintegrable within less than about 10 seconds, or more preferably in from about 1 second to about 6 seconds. The dosage form may also contain a small amount of an effervescing agent (generally from 0 to 5% of weight and preferably less than about 3%) for aiding in the initial phase of disintegration of the dosage form, a binding agent, and a flavoring agent. Further, the dosage form may have a sintered or polymeric coating on the external surface for enhancing the intactness of the dosage form. The density of the dosage form is generally within a range of about 0.05 g/ml to about 0.4 g/ml, and is more preferably within the range of from 0.1 g/ml to about 0.2 g/ml.

Preparation of the Particulate Support Matrix

The particulate support matrix, in the preferred embodiment, is produced using standard spray-drying techniques, well known to persons of ordinary skill in the art. The components of the composition which is used to produce the matrix include a support agent which comprises in one version a non-hydrolyzed gelatin and a hydrolyzed gelatin and additionally a bulking agent for increasing the bulk and solubility of the support matrix and tablet formed therefrom. Another component is a volatilizing agent, having a volatility which exceeds that of water, such as an alcohol, preferably ethanol. Another optional component is an acidifying or alkalizing agent which functions to cause the components of the support agent to be maintained with a net charge, either positive (when the preferred pH of the composition is below neutral) or negative (when the preferred pH is above neutral). In a preferred version the support matrix is maintained with a net positive charge by an acidic agent such as citric acid. The composition further comprises an aqueous medium such as water.

Critical physical factors in the spray drying process have to do with net charge and solubility of the support agent (for example, of proteins) and the evaporation characteristics of the volatilizing agent (for example, ethanol). In the preferred embodiment, the support agent is comprised of a first polymeric component and a second (solubilizing) polymeric component and a bulking agent. The second polymeric component (solubilizing component) contributes to the support function of the support matrix when in the dried particulate but also serves to enhance the rate of dissolution of the support matrix once the tablet is introduced into an aqueous environment such as the salivary environment of the oral cavity. In one example of the preferred embodiment, the first and second components of the support agent comprise two different forms of gelatin, an unmodified gelatin (the first polymeric component), and a hydrolyzed gelatin (the second polymeric component), and act together to form a support matrix in the dried particles. Both of these forms of gelatin are commercially available. The hydrolyzed gelatin assists the unmodified gelatin as a structural component of the matrix but it also functions to increase the solubility of the matrix. In an experiment where the particulate matrix was formed only from the unmodified gelatin, water and alcohol, the powder dissolved in approximately 25 seconds. When hydrolyzed gelatin was added to the same formula, the powder produced therefrom dissolved in about 15 seconds.

In the preferred version of the invention, the solution of the protein and protein hydrolysate is made acidic, preferably in the pH range of about 3.5 to 5.5, and more preferably from about 4.0 to about 5.0. This acidity causes the protein components of the composition to have a net positive charge at a pH which enhances repulsion of the protein components. Together with or in lieu of gelatins, the first polymeric support component and/or second polymeric component may be comprised of other polymers which can maintain a net charge, including proteins, glycoproteins, acacia, alginic acid, pectin, tragacanth, and xanthan gum and which function in accordance with the present invention.

The following are examples of pairs of first polymeric support and second polymeric (solubilizing) components (respectively) (1) acacia and pectin, 2:1; and (2) tragacanth and xanthan gum, 1:3. The above ratios are approximate.

In a preferred embodiment of the invention both the first polymeric component and the second polymeric component may comprise gelatin which has been hydrolyzed wherein the first component has a molecular weight greater than that of the second component and wherein the second component has an aqueous solubility greater than that of the first component. Hydrolyzed gelatins have molecular weights ranging from 1,000 to 12,000 daltons. Furthermore, the dosage form may comprise one or more intermediate polymeric components having solubilities and molecular weights intermediate between the first polymeric component and second polymeric component contemplated herein.

The effect of the net positive charge of the protein (or polymer) molecules is to cause individual protein (or polymer) molecules to be repellent to each other when in solution thereby reducing the tendency for the protein (or polymer) molecules to "cling" to each other. As a result, the protein (or polymer) molecules tend to remain repelled in the solution and during the spray drying process while the droplets of the composition are drying into particles. As a result, the powder formed will be of relatively low bulk density, generally in the range of from about 0.03 g/ml to about 0.3 g/ml. The bulking agent contributes to the bulk and stability of the support matrix and further increases the rate at which the support matrix will dissolve. Examples of bulking agents are carbohydrates such as mannitol, sorbitol, sucrose, lactose, xylitol, and acacia. Mannitol and sorbitol are preferred bulking agents.

The incorporation of the ethanol (or another volatilizing agent) into the solvent system functions to decrease the vaporization temperature of the solvent and contributes to the production of a more porous particle having a lesser bulk density and thus a greater bulk volume. It has been discovered that if water alone is used as the aqueous solvent, when the composition is introduced as droplets into the spray drying chamber, the droplets will have a tendency to contract in size thus increasing in density, as they traverse from the spray nozzle, through the drying chamber, to the collecting chamber of the spray-drier unit. By incorporating a volatilizing agent such as ethanol into the solvent, numerous pores and channels are formed within the structure of the droplet as the solvent mixture volatilizes from the droplet during the drying process. The particle formed from the droplet retains a higher porosity and low density and even experiences expansion resulting in a powder having a larger bulk volume.

In one experiment, a control comprising a quantity of a formula excluding ethanol produced a dried particulate support matrix powder having a bulk density of 0.077 g/ml (specific bulk volume was about 13 ml/g) and a bulk volume of 180 ml. The treatment comprised a comparable initial quantity of the formula with ethanol added produced a dried particulate support matrix powder having a bulk density of 0.049 g/ml (specific bulk volume was about 20.4 ml/g) and a bulk volume of 450 ml. The formula comprised, mannitol (10 g), sorbitol (5 g), citric acid (0.4 g), sucrose (0.15 g), Explotab.RTM. (0.15 g), gelatin G8-275 (1 g), gelatin hydrolysate (1 g), and a quantity of water sufficient to produce a volume of 500 ml. The amount of ethanol added to the treatment was 150 ml.

The term "bulk volume", as used herein, is defined as the actual volume of a quantity of particulate support matrix material. The term "true volume" as used herein is defined as the volume of a quantity of particulate support matrix material after that quantity has been compacted to eliminate the void space of the quantity. The term "bulk density" as used herein is defined as the mass of a quantity of the particulate support material divided by the bulk volume of that quantity. The term "specific bulk volume" is defined as the bulk volume of a quantity of particulate support material divided by the mass of that quantity. 

This result of a product having a greater bulk volume when ethanol is added is apparently obtained by the lowering of the vaporization temperature of the solvent thus increasing the rate at which the solvent is vaporized. The retention of the porous nature of the particle is critical to the speed with which a tablet constructed of the material dissolves. The porosity enhances the capillary movement of saliva into the interior of the tablet thereby increasing the dissolution rate of the support matrix of the tablet.

The acidifying or alkalizing agent, when present in the composition serves to maintain the net charge of the molecules of the support matrix. For example, in one preferred embodiment, the predetermined net positive charge of the protein components is set by an acidifying agent such as citric acid. When the support matrix makes contact with an aqueous solution the proteins comprising the support matrix will have a positive charge and immediately repel each other as soon as they dissolve, thus causing the particles of the tablet to repel each other, enhancing the rapidness of disintegration of the tablet. A similar phenomenon may be effected by using an alkalizing agent such as sodium bicarbonate as an alkalizing agent (causing the polymeric components of the support matrix to be negatively charged).

In the present invention, the first polymeric and second polymeric components of the support matrix together generally comprise from 2-35% of the dry components of the aqueous composition (percentage by weight, when the composition comprises the first polymeric and second polymeric components, the bulking agent and, optionally, the buffering agent) used to form the particulate support matrix. More preferably, the range is from 5-25% and more preferably is from 10-20%. Most preferably the first polymeric and second polymeric components of the support matrix together comprise from 12-16% of dry portion of the aqueous composition. Generally, the first polymeric component and the second polymeric components are present in the formulation in a range of first polymeric component:second polymeric component ratios of from about 20:1 to about 1:100 by weight, or in a range of from about 5:1 to about 1:40, or more preferably in a range of from about 2:1 to about 1:25, or still more preferably in a range of from about 1:2 to about 1:10.

In addition, the bulking agent of the support matrix generally comprises from 45-97% of the dry components of the aqueous composition (percentage by weight) used to form the particulate support matrix. More preferably, the range is from 70-92% and more preferably is from 75-90%. Most preferably the bulking agent of the support matrix comprises from 80-85% of the dry portion of the aqueous composition. In addition, the acidifying or alkalizing agent of the support matrix generally comprises from 0-30% of the dry components of the aqueous composition (percentage by weight) used to form the particulate support matrix. More preferably, the range is from 1-16% and more preferably is from 1-6%. Most preferably, when present, the acidifying or alkalizing agent of the support matrix comprises from 1-3% of the dry portion of the aqueous composition. As noted below, the matrix may further comprise a flavoring agent preferably added during the formation of the matrix. The flavoring agent may comprise from 0% to 10% of the aqueous composition in a preferred version and more preferably from 0.001% to 0.05%.

Formation of the Tablet

Before forming the particulate support matrix into a tablet, a quantity of the drug, medication, or pharmaceutical and any desired flavoring agent is added to a quantity of the particulate support matrix. The optional addition of a small amount of effervescent material serves to assist in the initial stage of the disintegration of the particles of the tablet. The tablet may be formed by methods known to those of ordinary skill in the art. For example, the tablet may be formed by direct compression. Or, it may be formed by first adding a moistening agent such as alcohol, then compressing or molding the composition. Or, it may be formed by first adding a binding agent such as polyvinylpyrrolidone, then compressing or molding the composition into a tablet. The dosage form described herein may include one or more adjuvants which can be chosen from those known in the art including flavors, diluents, colors, binders, fillers, compaction vehicles, effervescent agents, and non-effervescent disintegrants, such as those disclosed in U.S. Pat. No. 5,178,878, issued to Wheling et al. on Jan. 12, 1993, and in U.S. Pat. No. 5,215,756, issued to Gole et al., on Jun. 1, 1993, the specifications of which are hereby incorporated herein by reference. More specifically, the tablets may be composed of, but not limited to, the following: gelatin (commercially available Pharmagel.RTM. A and B, Type A, 275 Bloom, and Type B, 100 Bloom), hydrolyzed gelatin, sugars (mannitol, sucrose), organic acids (citric acid, succinic acid), sodium bicarbonate, ethyl alcohol, disintegrants such as Explotab.RTM. (sodium starch glycollate) and AcDiSol.RTM. (modified cellulose gum), starch, polyvinylpyrrolidone polymers, alginic acid, bulking and electrical charge agents such as acacia, and polyethylene glycol polymers.

Following the formation of the mixture into a tablet, it may be desired to form a coating on or to apply a very thin coating to the external surface of the tablet. The function of the coating, when applied, is to enhance the intactness of the tablet. Due to the porous nature of the tablet, the tablet tends to be rather fragile and breakable and generally benefits from the added protection afforded by the coating. The coating may comprise a polymer, such a polyvinyl alcohol or a polyvinylpyrrolidone, which, when applied forms a polymeric "net" over and into the tablet. This "net" maintains the tablet intact but does not inhibit the capillary uptake by the tablet once placed in the aqueous environment of the oral cavity although dissolution time may be slightly increased when a coating is applied to the tablet (see Example 17).

Alternatively, a coating may be formed on the surface of the tablet or dosage form by a sintering process. Methods of sintering pharmaceutical dosage forms are well known to those of ordinary skill in the art, and one is directed to pages 87-101 in the "Encyclopedia of Pharmaceutical Technology, Vol. 14, 1996, (which is hereby incorporated herein by reference) for a review of this technology.

In a preferred version of the sintering technique used in the present invention, one or more PEGs preferably having MWs of 3000-6000, for example, PEG 3350, are pulverized to a fine powder. A quantity of this PEG powder (which may include one or more types of PEG) is mixed with the drug/support matrix mixture defined elsewhere herein. A loose tablet or dosage form is formed and heated briefly, for example at 90^oC. for about 10 minutes. The PEG within the mixture melts, forming a thin coating on the tablet. No organic solvents are necessary in this sintering process. Examples of the sintering method are shown in Examples 36 and 37. One of ordinary skill in the art will be aware of other methods of forming tablet coatings.

In preparation for forming the tablets, a tablet blend is produced by combining a quantity of the particulate support matrix with a quantity of the pharmaceutical or drug and optionally with a quantity of an effervescent blend, a binding solution and/or a flavoring (or the flavoring may be added during the formation of the matrix to produce a flavored matrix).

The pharmaceutical composition can be added at several different stages of the formulation of the dosage form depending on the circumstances. The pharmaceutical can be added directly to the liquid composition before or during the spray drying process at the inlet nozzle. The resulting product can then be incorporated into the tablets. Alternatively, the pharmaceutical, in untreated or encapsulated form, is mixed with the particulate support matrix (after the spray drying process, before or after adding the binder, if a binder is added) and then formed into tablets. Alternatively, the pharmaceutical could be added by direct application to the preformed tablet by spray coating or drop coating.

As noted, the addition of the effervescent blend, the binding solution (also referred to herein as the binding agent) and the flavoring are optional. In one embodiment, the binding solution and the effervescent blend may be added to the support matrix powder in a ratio of about 20:10:1 (support matrix:binding solution: effervescent blend). The binding agent in one embodiment comprises from 0% to about 20% of the dry components of the aqueous composition and from 0% to 5% of the aqueous composition. The effervescent blend preferably consists of an approximately stoichiometric ratio of citric/tartaric acids with sodium bicarbonate in a powder form. In various versions, the effervescent blend may comprise the following ratios of components:

(1) citric acid:sodium bicarbonate, 1:1.2

(2) tartaric acid:sodium bicarbonate, 2:2.24

(3) citric acid:tartaric acid:sodium bicarbonate, 1:2:3.4

The blend is slightly acidic so there will be a slight tartness in the mouth upon dissolution of the product. As is indicated above, the amount of effervescent blend present is minimal (from 0 to 5% of total weight) such that its fizzing properties are almost non-detectable in the mouth. Its presence enhances the separation of the porous particles and enhances capillarity during dissolution of the tablet within the oral cavity thereby decreasing dissolution time of the tablet (see Example 15). The effervescent blend also enhances salivation in the oral cavity.

The binding solution in one version of the invention consists of 1% PVP-40 in ethanol (e.g., see Example 14). Other binding solutions may consist of mixtures of PEG 1000 and PEG 4000 in alcohol, or PEG 1000 and PVP 1000 in alcohol. Acetone may be substituted for ethanol or other alcohols in these formulations. The binding solution may further comprise a quantity of a surface active agent such as sodium lauryl sulfate for further increasing the dissolution rate of the dosage form. The binding solution, when used is generally incorporated by slowly mixing the solution with the spray dried powder, then drying at about 40-50^oC.

In one method used for forming the tablets, a quantity of the tablet blend is lightly compressed. The tablets thus produced may be coated with a very thin coating of an organic solution of a polymer, which rapidly evaporates leaving a polymeric "net" on the surface of the tablet. This thin external "net" aids in keeping the tablets intact during handling. Polymers may include, but are not limited to PVP and PVA. The coating may be applied by passing the tablet into a chamber having a saturated atmosphere of the coating material. Alternatively, the coating may be applied by lightly spraying the coating material onto the surface of the tablet.

In another method for forming the tablets, a quantity of the tablet blend is moistened with ethanol then passed through a #40 mesh screen and immediately compressed into tablets and dried overnight at about 50^oC. The tablets thus produced may be then coated with a very thin coating of an organic solution of a polymer, which rapidly evaporates leaving a "net" on the surface of the tablet. Alternatively, as discussed elsewhere herein, the coating may be formed by sintering the tablet.

The present invention contemplates a tablet which is much lighter (for example 50 mg) than a comparable typical commercially available tablet (for example 400-500 mg).

The present invention further contemplates a tablet which will disintegrate within the oral cavity in less than about 20 seconds. More preferably, the tablet will disintegrate within less than about 10 seconds. More preferably, the tablet will disintegrate within the oral cavity in less than about 6 seconds. Still more preferably, the tablet will disintegrate in from about 1 second to about 4 seconds. The bulk density of the formed tablet is preferably in a range of from about 0.1 g/ml to about 0.2 g/ml, but may be either less or greater than the bounds of this range, for example, 0.05 g/ml to 0.4 g/ml. Porosity may be in a range of from about 50 to 75% in a preferred embodiment.

Claim 1 of 32 Claims

What is claimed is:

1. A process for producing a particulate support matrix for use in forming a pharmaceutical dosage form, comprising:

providing an aqueous composition comprising:

an aqueous medium,

a support agent comprising an amount of a first polypeptide component having a predetermined net charge, an amount of a second polypeptide component having a predetermined net charge of the same sign as the first polypeptide component and a bulking agent and wherein the first polypeptide component and the second polypeptide component together comprise about 2% to 35% by weight of the particulate support matrix and wherein the bulking agent comprises about 45% to 97% by weight of the particulate support matrix, and wherein the second polypeptide component has a solubility in aqueous solution greater than that of the first polypeptide component, and

a volatilizing agent; and

introducing the aqueous composition as droplets into a drying chamber heated to a temperature sufficient to evaporate substantially all of the aqueous medium and volatilizing agent from the droplets leaving the support agent in a dried particulate form comprising the particulate support matrix and wherein the particulate support matrix is substantially completely disintegrable within less than about 20 seconds when introduced into an aqueous environment.

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